Indian Patents. 235051:"A QUINAZOLINE DERIVATIVES AND A PROCESS FOR PREPARING THE SAME THEREOF"

Title of Invention	"A QUINAZOLINE DERIVATIVES AND A PROCESS FOR PREPARING THE SAME THEREOF"
Abstract	A quinazoline derivative of the Formula (I): wherein the substituents are as defined in the text for use in the production of an anti proliferative effect which effect is produced alone or in part by inhibiting erbB2 receptor tyrosine kinase in a warm-blooded animal such as man.

Full Text	FIELD OF THE INVENTION he invention concerns certain novel quinazoline compounds, or pharmaceutically acceptable salts 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. BACKGROUND OF THE INVENTION 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 BioK 1999,3,459-465). It 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 of a variety of human cells. These mutated and over-expressed forms of the kinase are present in a large proportion of human tumours (reviewed in Kolibaba et al, Biochimica et Biophysica 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 mis 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 et a/, Oncoeene. 2000,12,5548-5557). 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 the cell. It is known that the erbB family of receptor tyrosine kinases, which include EGFR, erbB2, erbB3 and erbB4, are frequently involved in driving the proliferation and survival of tumour cells (reviewed in Olayioye etal.. 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.. 2000,21» 25) such as breast cancer (Sainsbury et al., Brit. J. Cancer. 1988,58,458; Guerin ej a]., Oncogene Res.. 1988,3, 21; Slamon etal.. Science. 1989,244.707; Kh"jn et aL, Breast Cancer Res. Treat.. 1994,2j>, 73 and reviewed in Salomon et al., Grit Rev. Oncol. Hematol. 1995,19,183), non-small cell lung cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J. Cancer. 1986, 54, 265; Reubi etal, Int. J. Cancer. 1990,45, 269; Rusch et al., Cancer Research, 1993, 53, 2379; Brabender etal. Clin. Cancer Res.. 2001, 7,1850) as well as other cancers of the lung (Hendler et al., Cancer Cells. 1989,7, 347; Ohsaki et al.. Oncol. Rep.. 2000, 7,603), bladder cancer (Neal et al., Lancet, 1985, 366; Chow et al.. Clin. Cancer Res.. 2001,7,1957, Zhau et al., Mol 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.. 1987,1,149; Kapitanovic etal.. Gastroenterologv. 2000,112,1103; Ross etal.. Cancer Invest.. 2001,19,554), cancer of the prostate (Visakorpi et al., Histochem. J.. 1992,24,481; Kumar et ai.. 2000,3^, 73; Scheretal.. J. Natl. Cancer Inst.. 2000, 92,1866), leukaemia (Konaka etal.. Cell. 1984, 3J, 1035, Martin-Subero et al.. Cancer Genet Cvtogenet.. 2001, 127.174), ovarian (Hellstrom etal.. Cancer Res.. 2001,61,2420), head and neck (Shiga et 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 (in particular erbB2), it is widely believed that many tumours become clinically more aggressive and so correlate with a poorer prognosis for the patient (Brabender et al, Clin. Cancer Res.. 2001,7, 1850; Ross etal. Cancer Investigation. 2001,19,554, Yu etal.. Bioessavs. 2000,22.7.673). In addition to these clinical findings, a wealth of pre-clinical 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 etal.. 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 et al 2000, Oncogene. 19,5690-5701; Mendelsohn et al, 2000, Oncogene. 19,6550-6565). In addition to this pre-clinical data, findings using inhibitory antibodies against EGFR and erbB2 (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 die ErbB type 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. Pharm. Des.. 2000,6,933; Elder el ah, Science, 1989,243.811), benign prostatic hyperplasia (BPH) (Kumar eUl., Lit Urol. Nephroi.. 2000,32_,73), atherosclerosis and restenosis (Bokemeyer eta!.. Kidnev Int.. 2000, 58,549). It is therefore expected that inhibitors of erbB type receptor tyrosine kinases will be useful in the treatment of these and other non-malignant disorders of excessive cellular proliferation. International Patent Applications WO 96709294, WO 96/15118, WO 96/16960, WO 96/30347, WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/03069, WO 97/13771, WO 97/30034, WO 97/30035, WO 97/38983, WO 98/02437, WO 98/02434, WO 98/02438, WO 98/13354, WO 99/35132, WO 99/35146, WO 01/215%, WO 01/55141 and WO 02/18372 disclose that certain quinazoline derivatives which bear an anilino substituent at the 4-position possess receptor tyrosine kinase inhibitory activity. International Patent Applications WO 97/22596 and WO 98/13354 disclose that certain 4-anilinoqumazoline derivatives that are substituted at the 7-position are inhibitors VEQF or mixed VEOF/EGF receptor tyrosine kinase inhibitors. The anilino group in these applications is substituted with small groups such as halogeno or (l-3C)alkyl. International Patent Application WO 01/94341 discloses that certain quinazoline derivatives which are substituted at the 5-position are inhibitors of the Src family of non-receptor tyrosine kinases, such as c-Src, c-Yes and c-Fyn. There are no disclosures in WO 01/94341 of 4-anilinoquinazolines wherein the aniline group is substituted in the para position by a substituent containing an aryl or a heteroaryl group. International Patent applications WO 03/040108 and WO 03/040109 disclose that certain 5-substitued quinazoline derivatives are inhibitors of the erbB family of tyrosine kinase inhibitors, particularly EGFR and erb-B2 receptor tyrosine kinases. All the compounds in these applications carry a ring containing substituent at the 5-position on the quinazoline ring. Mone of the prior art discloses 4-anilinoquinazolines that are substituted at the 5- position by an \|bylaminoethoxy group and which carry an aryl or heteroaryl containing substituent at the para-position on the aniline ring. STATEMENT OF THE INVENTION A quinazoline derivative of the formula I: (Formula Removed) wherein: m is 0, 1 or 2 ; each R', which may be the same or different, is selected from hydroxy, (1-6C) alkoxy. (3-7C) cycloalkyl-oxy and (3-7C) cycloalkyl- (1-6C) alkoxy, and wherein any CH2 or CH? group within a R1 substituent optionally bears on each said CH2 or CM- group one or more halogeno or (1-6C) alky! substituents. or a substituent selected from hydroxy and (1-6C) alkoxy. R2 is hydrogen or (1-4C) alkyl; nisO, 1,2, 3 or 4 ; each R\ which may be the same or different, is selected from cyano, halogeno,'(l- 4C) alkyl. trifluoromethyl, (1-4C) alkoxy, (2-4C) alkenyl and (2-4C) alkynyl; X1 is selected from O, S, SO, S02, N(R7), CH(OR7), CON(R7), N(R7) CO, S02N(R7), N(R7) S02, OC (R7)2, C(R7)20, SC(R7)2, C(R7)2S, CO, C(R7)2N(R7) and N(R7)C(R7)2. wherein each R7, which may be the same or different, is hydrogen or (1-6C) alkyl; Q1 is aryl, or heteroaryl, and wherein Q' optionally bears one or more substituents, which may be the same or different. selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl. formyl. mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy. (2-6C) alkenyloxy, (2- 6C)alkynyioxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl. (1-6C) alkylamino. di-\|(l- 6C) alkyl]amino, (1-6C) alkoxycarbonvl. N- (I-6C) alkvlcarbamovi. N. N-di-[(l-6C)alk\l) carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)aIkynoyl. (2-6C)alkanoyloxy. (2-6C) (pkanoylamino, N-(1-6C) alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3- 6C)alkenoylamino. (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(I-6C) alkylsulfamoyl, N. N-di-[(l-6C) alkyl] sulfamoyl, (l-6C)alkanesulfonylamino. N-(1-6C) alkyl-(l-6C) alkanesulfonvlamino. and a group of the formula: -X2-R8 wherein X2 is a direct bond or is selected from O, CO and N (R9), wherein Ry is hydrogen or (I-6C) alkyl, and R8 is halogeno- (1-6C) alkyl, hydroxy- (1-6C) alkyl. carboxy-(l- 6C) alkyl. (1-6C) alkoxv-(I-6C) alkyl, cyano- (1-6C) alkyl, amino- (I-6C) alkyl. N- (1-6C) alkylamino- (1-6C) alkyl. N. N-di-[(1-6C) alkyl] amino- (1-6C) alkyl, (2-6C) alkanoylamino- (I-6C) alkyl, N- (I-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-[(l-6C) alkyl] carbamoyl- (1-6C) alkyl. (I- 6C) alkylthio- (1-6C) alkyl, (1-6C) alkylsulfinyl- (1-6C) alkyl, (1-6C) alkylsulfonyl- (1-6C) alkyl sulfamoyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl (I-6C) alkyl, N, N- di- (1-6C) alkylsulfamoyl (1-6C) alkyl, (2-6C) alkanoyl- (1-6C) alkyl, (2-6C) alkanoyloxy- (1- 6C) alkyl or (1-6C) alkoxycarbonyl- (1-6C) alkyl, and wherein any CH2 or CH5 group within-X'-Q1 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. (1-4C) alkoxy, (I-4C) alkylamino and di- [ (1-4C) alkylamino]; R4 R4a,R5 and R5a, which may be the same or different, are selected from hydrogen and (1-6C) alkyl. or R4 and R4a together with the carbon atom to which they are attached form a (3- 7C) cycloalkyl ring, or R3 and R5a together with the carbon atom to which they are attached form a (3- 7C) cycloalkyl ring. and wherein any CH2 or CH3 group within any of R1, R4'1. R3 and R';1 optionally bears on each said CH2 or CH, group one or more halogeno substituents or a substituent selected from hydroxy, cyano. (I-6C) alkoxy, amino, (2-6C) alkanoyl, (1-6C) alkylamino and di-[(l- 6C) alkylamino]; R6 is selected from hydrogen, (1-6C) alkyl, (2-6C) alkenyl. (2-6C) alkynyl, (3- 7C) cycloalkyl. (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl, (3-7C) cycloalkenyl- (1- 6C) alkyl, heterocyclyl and heterocyclyl-( 1 -6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, 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-[(l-6C) alkyl] amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O, CO, S02 and N (RM). wherein R" is hydrogen or of 4C) aikyl, and R10 is halogeno- (1-4C) alkyl, hydroxy- (1-4C) aikyl, (1-4C) alkoxy- (I-4C) alkyl. cyano- (1-4C) alkyl, amino- (1-4C) alkyl, N- (1-4C) alkylamino- (1-4C) alkyl and N. N-di- [ (I-4C) alkyl] amino- (1-4C) alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 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. (I-6C) alkylsulfonyl, (I-6C) alkylamino, di- f (1-6C) alkyl] amino, N- (1-6C) alkylcarbamoyl. N. N-di- \| (I-6C) alkyl] carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino. N- (I-6C) alkyl- (2-6C) alkanoylamino, N- (1-6C) alkylsulfamoyl. N, N-di- [ (1-6C) alkyl] sulfamoyl. (I-6C) alkanesulfonylamino and N- (1-6C) alkyl- (1-6C) alkanesulfonylamino ; A is selected from hydrogen, a group of the formula Z-(CRl2R13)p-and R14, wherein p is 1,2, 3, or 4. each R12 andR13 which may be the same or different, is selected from hydrogen, (1- 6C) alkyl. (2-6C) alkenyl and (2-6C) alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C) cycloalkyl or (3-7C) cycloalkenyl ring, and wherein any CH2 or CH-, group within any of Ru and R13, optionally bears on each said CH2 or CH3 group one or more halogeno or (I-6C) alkyl substituents or a substituent selected from hydroxy, cyano, (1-6C) alkyl, (1-6C) alkoxy, amino, (2-6C) alkanoyl. (I- 6C) alkylamino and di- [ (1-6C) alkyl] amino, Z is selected from hydrogen, OR15, NR,6R17, (l-6C)alkylsulfonyl, (I-6C) alkanesulfonyl amino and N-(1-6C) alkyl- (1-6C) alkanesulfonylamino, wherein each of R15, R16 and R1', which may be the same or different, is selected from hydrogen, (1-6C) alkyl, (2-6C) alkenyl. (2-6C) alkynyl and (I-6C) alkoxycarbonyl, or Z is a group of the formula: Q2-X4- wherein Bis selected from O, N(R18), S02 and S02N (R18). wherein RIS is hydrogen or (1-6C) alkyl. and Q2 is (3-7C) cycloalkyl, (3-7C) cycloalkenyl or heterocyclyl, R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1- 6C) alkyl. (2-6C) alkenyl and (2-6C) alkynyl, and wherein R16 and RI7 are as defined above, or R14 is a group of the formula: Q3-X5- wherein X5 is selected from O and N (R20), wherein R20 is hydrogen or (1-6C) alkyl, and Q3 is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heterocyclyl and heterocyclyl- (1-6C) alkyl, or R'4 is Q4 wherein Q4 is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl. (3-7C) cycloalkenyl. (3- C) cycloalkenyl- (1-6C) alkyl, heterocyclyl or heterocyclyl-( I - 6C) alkyl. and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O. S, SO. SO:, N (R2'). CO,-C=C-and-CsC-, wherein R2' is hydrogen or (1-6C) alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more substituents, 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) alkynyi. (1-6C) alkoxy. (1-6C) alkylthio, (1-6C) alkylsulfinyl, (I-6C) alkylsulfonyl, (1-6C) alkylamino. di-[(l-6C) alkylj amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and from a group of the formula: -Xf,-R22 wherein X6 is a direct bond or is selected from O, CO, S02 and N (R23), wherein R2, is hydrogen or (1-4C) alkyl, and R22 is halogeno- (1-4C) alkyl. hydroxy- (I-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl. cyano- (I-4C) alkyl, amino- (1-4C) alkyl, N- (1-4C) alkylamino- (1-4C) alkyl and N. N-di- [ (1-4C) alkyl] amino-(1-4C) alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears I or 2 oxo or thioxo substituents. and wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 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) alkynyi, (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, (I-6C) alkanesulfonylamino and N- (1-6C) alkyl- (1-6C) alkanesulfonylamino; or a pharmaceutical!} acceptable salt thereof. SUMMARY OF THE INVENTION We have now found that surprisingly certain quinazoline derivatives substituted at the 5-position with a substituent containing an acylaminoethoxy group possess potent anti-tumour activity. 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 EGFR and/or erbB2 receptor tyrosine kinases. Generally the compounds of the present invention possess potent inhibitory activity against the erbB receptor tyrosine kinase family, for example by inhibition of EGFR and/or erbB2 and/or erbB4 receptor tyrosine kinases, whilst possessing less potent inhibitory activity against other kinases. Furthermore, generally the compounds of the present invention possess substantially better potency against the erbB2 over that of the EGFR tyrosine kinase, thus potentially providing effective treatment for erbB2 driven tumours. Accordingly, it may be possible to administer a compound according to the present invention at a dose that is sufficient to inhibit erbB2 tyrosine kinase whilst having no significant effect upon EGFR (or other) tyrosine kinases. The selective inhibition provided by the compounds according to the present invention may provide treatments for conditions mediated by erbB2 tyrosine kinase, whilst reducing undesirable side effects that may be associated with the inhibition of other tyrosine kinases. Generally the compounds according to the invention also exhibit favourable DMPK properties, for example high bioavailability, and favourable physical properties such as solubility. Furthermore, many of the compounds according to the present invention are inactive or only weakly active in a hERG assay. DETAILED DESCRIPTION According to a first aspect of the invention there is provided a quinazoline derivative of the formula I: wherein: m is 0,1 or 2; each R1, which may be the same or different, is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7)cycloalkyl-(l-6C)alkoxy and wherein any CH2or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy, R2 is hydrogen or (l-4C)alkyl; n is 0,1,2,3 or 4; each R3, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alfeenyl and (2-4C)alkynyl; X1 is selected from O, S, SO, SO2 N(R7), CH(OR7), CON(R7), N(R7)CO, SOzN(R7), N(R7)S02, OC(R7)2, C(R7)2O SCCR7)2, COR-V, CO, C(R7)2N(R7) and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl; Q1 is aryl, or heteroaryl, and wherein Ql optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, fonnyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6G)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, H-(l6C)alkylcarbamoyl, N,N-di-(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyl.(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulfanioyl)N,N-di-[(l-6C)alky1]sulfamoyl, (l-6C)alkanesulfonylamino, N-(l-6C)alkyMl-6C)alkanesulfonylamino, and a group of the formula: -X2-R8 wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-(l-6C)alkylamino-(l-6C)alkyl,N>N-di-[(l-6C)aIkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, N-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl,carbamoyl-(l-6C)alkyl, N-(l-6C)alkylcarbamoyl(l-6C)alkyl,N,N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkyl,(l- 6C)alkylthio-(l-6C)allcylXl-6C)alkylsulfinyl and wherein any CHfe or CHa group within -X^Q1 optionally bears on each said GHz or CHs group one or more (for example 1,2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino]; R4, R4, R5 and R5, which may be the same or different, are selected from hydrogen and(l-6C)alkyl,or R4 and R4a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, or R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, and wherein any CH2 or CHa group within any of R4, R4, R5 and R5a optionally bears on each said CHa or CHa group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino]; R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, fonnyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]arnino, (2-6C)alkanoyl, (2-6C)aJkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O, CO, SOz and N(Rn), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)aIkyl and N^-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and wherein any CHfe or CHa group within a R6 substituent, other than a CHa group within a heterocyclyl group, optionally bears on each said. 2 or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6Qalkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6Qalkylthio, (l-6Qalkylsulfinyl, (l-6C)alkykulfonyl, (l-6C)alkylamino, di-[(l-6C)allcyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)aDcanoylamino, H-(l-6C)alkylsulfamoyl, JLH-di-[Cl-6C)aIkyl]sulfamoyl, (l-6C)alkanesulfonylamino and M-(l-6C)alkyl-(l-6C)alkanesulfonylamino; A is selected from hydrogen, a group of the formula Z-(CR12R13)p- and R14, wherein p is 1,2,3, or 4, each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyl ring, and wherein any CH2 or CHfe group within any of R12 and R13 optionally bears on each said CH2 or CHs group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, Z is selected from hydrogen, OR15, NR16R17, (l-6C)alkylsu!fonyl, (l-6C)alkanesulfonyIamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)aUcenyl, (2-6C)alkynyl and(l-6C)alkoxycarbonyl, or Z is a group of the formula: Q2-X4- wherein X4is selected from O, N(R18), SO2 and SO2N(R18), wherein R18 is hydrogen or (l-6C)alkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl, R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above, or R14 is a group of the formula: Q3-X5- wherein X5 is selected from O and NCR20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyI, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl~(l-6C)aIkyl, or RM is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyHl-6C)alkyl, (3-7C)cycioalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R21), CO, -C=C- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent 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, ammo, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)a!kylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula; -X"-R22 wherein X6 is a direct bond or is selected from O, CO, SOa and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N (l^C)alkylamino-(l-4C)alkyl andH,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 1 oxo or thioxo substituents, and wherein any CH2or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)a!kylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyllamino, N-(l-6C)alkylcarbaraoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)aIkanoyloxy, (2-6C)alkanoylamino, N;-(i-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulfamoyl, N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and H-(l-6G)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof. According to a second aspect of the invention there is provided a quinazoline derivative of the formula I, wherein: m is 0,1 or 2; each R1, which may be the same or different, is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycIoalkyl-oxy and (3-7C)cycloalkyl-(l-6C)alkoxy, and wherein any CH2 or CEb group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy, R2 is hydrogen or (l-4C)alkyl; n is 0,1,2,3 or 4; each R3, which may be the same or different, is selected from halogeno, (l-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl; X1 is selected from O, S, SO, SO* N(R7), CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)S02, OC(R7)2, CCR7)2O, SC(R7)a, C(R7)2S, CO, CCR^CR7) and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl; Q1 is aryl, or heteroaryl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, catbamoyl, sulfamoyl, formyl, mercapto, (l-6C)alkyl, (2-8Qalkenyl, (2-8C)alkynyl, (l-6G)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsutfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, M-(l-6C)alkylcarbamoyl, £LN-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-U -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-( 1 -6C)a]kyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulfamoyl,N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylammo, N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, and a group of the formula: -X2-R8 wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)a!kyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-(l-6C)alkylaaiino-(l-6C)alkyl,N,N-di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, N-(l-6C)aIky-(2-6C)alkanoylamino-(l-6C)alkyl, (l-6X^)alkoxycaibonylaniino-(l-6C)alkyl,carbamoyl-(l-6C)alkyl, N(1-6C)alkylcarbamoyl-(l-6C)allcyl,N,N-di-[(l-6C)alkyl]carbamoyKl-6C)alkyl,(l-6C)alkylthio-(l-6C)alkyl, (l-6C)alkylsulfinyl(l-6C)alkyl, (l-6Qalkylsulfonyl-(l-6C)alkyl sulfamoyl(l-6C)alkyl, N-(l-6C)alkylsulfamoyl(l-6C)alkyl, &N-di-(l-6C)alkylsulfamoyl(l-6C)alkyl, (2-6C)alkanoyHl-6C)alkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6Oalkoxycarbonyl-(l-6C)alkyl, and wherein any CH2 or CHs group within -Xl-Q! optionally bears on each said CK-z or CHb group one or more (for example 1,2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino]; R4, R4, R5 and R5a, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, or R4 and R4 together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, or R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, and wherein any CH2 or CHs group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino]; R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyK (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3-R"° wherein X3 is a direct bond or is selected from O, CO, SOa and NOR.11), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amiiio-(l-4C)alkyl, H-(l-4C)allcylamino-(l-4C)alkyl and H^^-[(l-4C^kyl]ainino-(l-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and wherein any CHj or CHs group within a R6 substituent, other than a CHj group within a heterocyclyl group, optionally bears on each said CHj or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, EN^(l-6C)alkyl3carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, H-(l-6C)alkylsulfamoyl, &£^-[(l^C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l -6C)alkyl-(l-6C)alkanesulfonylamino; A is selected from hydrogen, a group of the formula Z-(CR12R13)p- and R14, wherein p is 1,2,3, or 4, each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloaIkenyl ring, and wherein any CH2 or CHs group within any of R12 and R13 optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (i-6C)alkylamino and di-[(l-6C)alkyllamino, Z is selected from hydrogen, OR15, NR16R17, (l-6C)alkylsulfonyl, (l-6C)alkanesulfonylamino andN-(l-6C)aIkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or Z is a group of the formula: Q"-X4- wherein X4is selected from O, N(R18), SC>2 and S02N(R18), wherein R18 is hydrogen or (l-6C)alkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl, R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 arc as defined above, or R14 is a group of the formula: Q3-X5- wherein X5 is selected from O and NCR20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloalkyKl-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocycIyl-(l-6C)alkyl, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO, N(R21), CO, -C=C- and -C=C-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)aIkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -XO-R22 wherein Xs is a direct bond or is selected from O, CO, SO2 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)aIkyl, M-(l-4C)alkylamino-(l-4C)alkyl and M,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH3 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CHaor CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N^i-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, M-(l-6C)alkylsulfamoyl, H,H-di-[(l-6Qalkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof. According to a third aspect of the invention there is provided a quinazoline derivative of the formula I, wherein: misO, 1 or 2; each R1, which may be the same or different, is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(l-6C)alkoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy, R2 is hydrogen or (l-4C)alkyl; n is 0,1,2,3 or 4; each R3, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl; X1 is selected from O, S, SO, SO N(R7), CH(OR7), CON(R7), N(R7)CO, S02N(R7), N(R7)S02, OC(R7)2\| CCR^O, SC(R7)2, CQL\S, CO, C(R7>2N(R7) and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl; Q1 is aryl, or heteroaryl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, fonnyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, 43" (l-6C)a1kylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N~(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l -6C)alkylsulfamoyl, N,N-di-[( 1 -6C)alkyl]sulf amoyl, (1 -6C)alkanesulfonylamino, N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, and a group of the formula: -X2-R8 wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, andR8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-(l-6C)alkylamino-(l -6C)alkyl, N,M-di-l(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, M-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, [l-6C)alkoxycarrx)nylaniinc-(l-6C)alkyl,cart)arnoyl-(l-6C)alkyl, S-(l-6C)alkylcarbamoyHl-6C)ancyl, H,H-di-[(l-6C)alkyl]carbamoyHl-6C)alkyi, (1-6C)alkylthio-(l-6C)allcyl, (l-6C)alkylsulfinyHl-6C)alkyl, (!-6C)aIkylsulfonyHl-6C)alkyl sulfamoyKl-eQalkyl, M-(l-6Qalkylsulfamoyl(l-6X^alkyl» M^i-di-(l-6Oalkylsulfamoyl(l-6C)alkylt (2-6C)alkanoyl-(l-6C)alkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)alkoxycarbonyl-(l-6Qalkyl, and wherein any CHa or CHs group within -X^Q1 optionally bears on each said CHj or CHs group one or more (for example 1,2, or 3) halogeno or (l-6C)alkyl substitaents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino]; R4, R4, R5 and R5a, which may be the same or different, are selected from hydrogen and(l-6C)alkyl, and wherein any CEk or CH3 group within any of R, R4, R5 and R5a optionally bears on each said CKfe or CEfo group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino]; R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, ( 6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and firom a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O, CO, SO2 and N(RU), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)aUeyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and HJi-di-[(l-4C)alkyl]aniino-(l-4C)allcyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and wherein any CHj or CH3 group within a R6 substituent, other than a CKfe group within a heterocyclyl group, optionally bears on each said CHj or CKb group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfcmyl, (l-6C)alkylamino, di-[(l-6C)alkyl]ainino, H-(l-6C)alkylcarbamoyI, && A is selected from hydrogen, a group of the formula Z-(CR12R13)P- and R14, wherein p is 1,2,3, or 4, each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyl ring, and wherein any CHz or CHs group within any of R12 and R13 optionally bears on each said CHj or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6Qalkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkylamino anddi-[(l-6C)alkyl]amino, Z is selected from hydrogen, OR15, NRI6R17, (l-6C)alkylsulfonyl, (l-6C)alkanesulfonylamino andN-(l-6C)alkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and Rn, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl, or Z is a group of the formula: Q2-X4- wherein X4 is selected from O, N(R18), SO2 and SO^R18), wherein R18 is hydrogen or (l-6C)alkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl, R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above, or R14 is a group of the formula: Q3-X5- wherein X5 is selected from O and NCR20), wherein R20 is hydrogen or (l-6C)alkyl, andQ3 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycioalkenyl, (3-7C)cycloalkenyHl-6Qalkyl, heterocyclyl and heterocyclyl-(l-6C)aDcyl, or R14 is Q4 wherem Q4 is (3-7C)cycloalkyl, (3-7C)cycbalkyl-(l-6C)alkyl$ (3-7C)cycIoalkeiiyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyHl-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SCb, N(R21), CO, -C=C- and -CsC-, wherem R21 is hydrogen or (l-6C)alkyl, and wherem any heterocyclyl group within a Z or R14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-^C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X^-R22 wherein X6 is a direct bond or is selected from O, CO, SOa and NCR23), wherem R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)^llcoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, . N-(l-4C)alkylamino-(l-4C)alkyl and H.N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a Z or Ru substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH2or CH3 group within a Z or R14 group, other than a CH-z group within a heterocyclyl ring, optionally bears on each said CHa or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, ammo, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)allcyl]amino, £Hl-6C)alkylcarbamoyl, H»N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulfarnoyl, N^[-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesuIfonylamino and £i-(l-6C)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof. In this specification the generic term "alky!" includes bom straight-chain and branched-chain alkyl groups such as propyl, isopropyl and text-butyl. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms, for example (l-6C)alkoxy includes methoxy, ethoxy and isopropoxy, (l-6C)alkylamino includes methylamino, ethylamino and isopropylamino and di-[(l-6C)alkyI]amino includes dimethylamino, diethylamino and Ji-isopropyl-Ji-niethylamino, It 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£) denotes any scalemic or racemic mixture while (R) and (5) denote the enantiomers. In the absence of (/?,5), (R) or (S) 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 S 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 substituents herein (for example Q1) when it is aryl or for the aryl group within a "Q" group is, for example, phenyl or naphthyl, preferably phenyl. A suitable value for any one of the substituents herein when it is (3-7C)cycloalkyl or for a (3-7C)cycloalkyl group defined herein within, for example a "Q" group or Rl substituent is, for example, cyclopropyl, cyclobutyi, cyclopentyl, cyclohexyU cycloheptyl or bicyclo[2.2. l)heptyl. A suitable value for any one of the substituents herein, when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a substituent is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. A suitable value for any one of the substituents herein when it is heteroaryl or for the heteroaryl group within a "Q" group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulfur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 13,5-triazenyl, 13-benzodioxolyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cirmolinyl or naphthyridinyl. Particular heteroaryl groups include, for example, pyridyl, pyrimidyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl (more particularly pyridyl, pyrazinyl, thiazolyl and isoxazolyl). A suitable value for any one of the substituents when it is heterocyclyl or for the heterocyclyl group within a substituent 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 sulfur, which, unless specified otherwise, may be carbon or nitrogen linked, for example oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, decahydroisoquinolinyl or decahydroquinolinyl, particularly tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,4-oxazepanyI, thiamorpholinyl, l,l-dioxotetrahydro-4H-l,4-tWazinyl, piperidinyl or piperazinyl, more particularly tetrahydrofuran-2-yl, 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, pipcridin-3-yl, piperidin-2-yI or piperazin-1-yl. A nitrogen or sulfur 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-dioxoimidazolidmyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups include, for example, non-aromatic saturated or partially saturated 3 to 7 membered monocydic heterocyclyl rings with 1 ring nitrogen or sulfur heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of such rings include azetidtnyl, oxazepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidmyU tetrahydrothienyl, tetrahydrothiopyranyl or thiomorpholinyl. Other particular heterocyclyl groups include, for example, 4, 5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl rings containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur such as oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl or tetrahydrothiopyranyl, Further particular heterocyclyl groups include, for example 4,5,6 or 7 membered saturated or partially saturated monocyclic heterocyclyl rings containing 1 nitrogen atom and optionally 1 heteroatom selected from nitrogen, oxygen and sulfur such as piperazinyl, pyrrolidinyl, piperidinyl, particularly pyrrolidin-l-yl, pyrrolidin-2-yl, piperazin-1-yl, piperidino or morphohno. Other heterocyclyl groups include, for example, non-aromatic saturated or partially saturated 4, 5, 6 or 7 membered monocyclic heterocyclyl rings containing 1 or 2 oxygen atoms such as tetrahydrofuranyl, 1,3-dioxolanyl and tetrahydiopyranyl (for example tetrahydrofuran-2-yl and tetrahydropyran-4-yl). A suitable value for a substituent herein when it is heterocyclyl-(l-6C)alkyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. The invention comprises corresponding suitable values for other substituents when, for example, rather than a heterocyclyl-(l-6C)alkyl group, an (3-7C)cycloalkyl-(l-6C)alkyl or (3-7C)cycloalkenyl-(l-6C)alkyl is present. Suitable values for any of the substituents herein, for example the "R" groups (R1 to R23) or for various groups within a Q1, X1 or A group include:- w hen in this specification reference is made to a (l-4C)alkyl group it is to be understood that such groups refer to alkyl groups containing up to 4 carbon atoms. A skilled person will realise that representative examples of such groups are those listed above under (l-6C)alkyl that contain up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. Similarly, reference to a (l-3C)alkyl group refers to alkyl groups containing up to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl. A similar convention is adopted for the other groups listed above such as (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl and (2-4C)alkanoyl. When, as defined hereinbefore, in the group of the formula -X"-Q1, and X1 is, for example, a OC(R7)2 linking group, it is the oxygen atom, not the carbon atom, of the OC(R )2 linking group which is attached to the phenyl ring in the formula I and the carbon atom is attached to the Q1 group. Similarly when X1 is a N(R7)C(R7>2 linking group the nitrogen atom of the N(R7)C(R7)2 group is attached to the phenyl ring in formula I and the carbon atom is attached to the Q1 group. A similar convention is applied to other linking groups used herein, for example when A is a group of the formula Z-(CR12R13)p- and Z is Q2-X- and X4 is SOiNXR18), the SO2 group is attached to Q2 and the nitrogen atom is attached to X4 in formula I. It is to be understood that references herein to adjacent carbon atoms in any (2-6C)alkylene chain within a group may be optionally separated by the insertion into the chain of a group such as O or OC refer to insertion of the specified group between two carbon atoms in an alkylene chain. For example, when A is R14 and R14 is a 2-pyrrolidin-l-ylethoxy group insertion of a CsC group into the ethylene chain gives rise to a 4-pyrrolidin-l-ylbut-2-ynyloxy group. When reference is made herein to a CH2or CH3 group optionally bearing on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-6C)alkyl substituents present on each said CHa group and there are suitably 1, 2 or 3 such substituents present on each said CHa group. Where reference is made herein to any CHa or CHa group optionally bearing on each said CHa or CHa group a substituent as defined herein, suitable substituents so formed include, for example, hydroxy-substituted heterocyclyl-(l-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy, hydroxy-substituted heterocyclyl-(l-6C)alkylammo groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino> and hydroxy-substituted (2-6)alkanoyl groups such as hydroxyacetyl, 2-hydroxypropionyl and 2-hydroxybutyryl. Where reference is made herein to, for example, R4 and R4a together with the carbon atom to which they are attached forming a (3-7C)cycloalkyl ring herein, the ring so formed is a (3-7C)cycloalkylidene group, for example a cyclopropylidene group of the formula: wherein * represent the bonds from the cyclopropylidene group. It is to be understood that the quinazoline in formula I is unsubstituted at the 2-position on the quinazoline ring. It is to be understood that certain compounds of the formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase. It is also to be understood that certain compounds of the formula I may exhibit polymorphism, and that the invention encompasses all such forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase. It is also to be understood that the invention relates to all tautomeric forms of the compounds of the formula I forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase. A suitable pharmaceutically acceptable salt of a compound of the formula I is, for example, an acid-addition salt of a compound of the formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the formula I which is sufficiently acidic, 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. Particular novel compounds of the invention include, for example, quinazoline derivatives of the formula I, or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of R\ R2, R3, R4, R4a, R5, R5a, X1, Q1, m, n and A has any of the meanings defined hereinbefore or in paragraphs (a) to (yyyyyy) hereinafter :- (a) m is 0 or 1 and R1, when present, is located at the 7-position on the quinazoline ring in formula I; (b) R1 is selected from hydroxy, (l-6C)alkoxy, hydroxy(l-6C)alkoxy, (l-6C)alkoxy-(l- 6C)aikoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(l-6C)alkoxy, and wherein any CHior CHb group within a R1 substituent optionally bears on each said CHa or CHs group one or more substituents selected from fluorb and chloro; (c) m is 0 or 1 and R1, when present, is located at the 7-position on the quinazoline ring and is selected from (l-6C)alkoxy, cyclopropyl-(l-4C)alkoxy, cyclobutyl-(l-4C)alkoxy, cyclopentyl-(l-4C)alkoxy and cyclohexyl-(l-6C)alkoxy, and wherein any CKi or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro substituents, or a substituent selected from hydroxy, methoxy and ethoxy; (d) m is 1 and R1 is located at the 7-position on the quinazoline ring and is (l-4Qalkoxy, for example methoxy or ethoxy, and wherein any CH2 or CHa group within a R1 substituent optionally bears on each said CH2 or CHa group one or more fluoro or chloro substituents, or a substituent selected from hydroxy, methoxy and ethoxy; (e) m is 1 and R1 is located at the 7-position on the quinazoline ring and is selected from methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, trifluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy; (f) m is 1 and R1 is located at the 7-position on the quinazoline ring and is methoxy; (g) misO; (h) R2 is hydrogen or methyl; (i) R2 is hydrogen; (j) n is 0,1 or 2 and, when present, at least one R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I; (k) n is 0, 1 or 2 and, when present, at least one R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from halogeno, (l-4C)alkyl, (l-4C)alkoxy and (2-4C)alkynyl; (1) n is 0,1 or 2 and, when present, at least one R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from halogeno and (l-4C)alkyl; (m) n is 0 or 1 and, when present, R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from halogeno (particularly fluoro or chloro) and (l-4C)alkyl; (n) n is 0 or 1 and, when present, R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from cyano, fluoro, chloro, methyl, methoxy and ethynyl (particularly fluoro, chloro, methyl, methoxy and ethynyl); (o) n is 1 and R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from halogeno (particulariy fluoro or chloro) and(l-4C)aIkyl; (p) n is 1 and R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from cyano, fluoro, chloro, methyl, methoxy and ethynyl (particularly fluoro, chloro, methyl, methoxy and ethynyl); (q) n is 1 and R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from chloro and methyl; (r) n is 1, R3 chloro and wheren R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I; (s) n is 1, R3 is methyl and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I; (t) X1 is selected from O, S, OC(R7)2, SC(R7)2, SO, SO2, N(R7), CO and N(R7)C(R7)2 wherein each R7, which may be the same or different, is selected from hydrogen or (l-6C)alkyl; (u) X1 is selected from O, S and OC(R7)2 wherein each R7 is, independently, hydrogen or (l-4C)alkyl; (v) X1 is selected from S and OC(R7)2 wherein each R7 is, independently, hydrogen or (l-4C)alkyl; (w) X1 is selected from O and OC(R7)a wherein each R7 is, independently, hydrogen or (l-4C)alkyl (particularly hydrogen or (l-2C)alkyl); (x) X1 is selected from O, S, OCH2 and OC(CH3)2; (y) X1 is selected from O, OCH2 and OC(CH3)2; (z) X1 is selected from O, S and OCH2; (aa) X1 is O; (bb) X1 is S; (cc) X"isOCH2; (dd) X1 is OaCHbk (ee) X1 is selected from O, OCH2 and OCCCHa^, n is 0 or 1 and, when present, R3 is selected from halogeno (particularly chloro) and (l-4C)alkyl (particularly methyl); (ff) X1 is OCHa, n is 0 or 1 and, when present, R3 is halogeno, particularly chloro; (gg) X1 is OCH2> n is 1, R3 is selected from fluoro, chloro and methyl (particularly chloro and methyl), and wherein R3is in a meta-position (3-position) relative to the nitrogen of the aniline group in formula I; (hh) X1 is O, n is 1, R3 is selected from fluoro, chloro and methyl (particularly chloro and methyl), and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I; (ii) X1 is O, n is 1, R3 is methyl, and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I; (jj) X1 is OC(CH3)2, n is 1, R3 is selected from fluoro, chloro and methyl (particularly chloro and methyl), and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I; (kk) X1 is OCXCHs^, n is 1, R3 is chloro, and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I; (11) Q1 is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylaniino> (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, K-(l-6C)alkyl-(3-6C)alkynoylamino, ]N-(l-6Qalkyl8ulfamoyl, N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino, N-(l-6C)alkyl-(l-6C)alkanesulfonylainino, and a group of the formula: -X2-R8 wherein X2 is a direct bond or is selected from O, CO and NCR9), wherein R9 is hydrogen or (l-6C)alkyl, andR8 is halogeno-(l-6Qalkyl, hydroxy-(l-6C)alkyl, catboxy-(l-6C)alkyl, (l-o^alkoxy-a-eQalkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N- (2-6C)alkanoylamino-(l-6C)alk:yl, N^l-6C)aUcyH2-^Qalkanoylamino-(l-6C)alkyl, M-(l-6C)alkylcarbamoyl-(l-6C)alkyl> N^[-di-[(l-6C)alkyl3carbamoyHl-6C)alkyl, (1-6C)alkylthio-(l-6C)alkyl, (l-oOalkylsulfinyHl-eCJalkyl, (l-6C)alkylsulfonyHl-6C)alkyl sulfamoyl(l-6X:)alkyl, S-(l-6C)alkylsulfamoyl(l-6C)alkyl, EH-di-(l-6C)alkylsulfamoyl(l-6C)alkyl, (2-6C)alkanoyl-(l-6C)aIkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)alkoxycarbonyl-(l-6C)alkyl, and wherein any CEb or CHs group within -Xl-Q* optionally bears on each said CHa or CHb group one or more (for example 1, 2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino]; (mm) Ql is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1 nitrogen heteroatom and optionally 1 additional heteroatom selected from oxygen, nitrogen and sulfur, and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, as hereinbefore defined in (11), (nn) Q1 is phenyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (oo) Q1 is a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1 nitrogen heteroatom and optionally 1 additional heteroatom selected from oxygen, nitrogen and sulfur, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (PP) Q1 is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl, IH-imidazolyl, 1H-pyrazolyl, 1,3-oxazolyl and isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (qq) Q1 is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl and isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (rr) Q1 is selected from pyridyl, pyrazinyl, 13-thiazolyl and isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (ss) Q1 is selected from phenyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 1,3-thiazol-4-yl, l,3-thiazol-5-yl, 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (tt) Q1 is selected from 2-, 3- or 4-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl, l,3-thiazol-5-yl, 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (uu) Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazoi-2-yl, 1,3-tniazol-4-yl and 3-isoxazolyl, and wherein Q1 optionally bears one or more oubstitucnts (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (vv) Ql is selected from 2-pyridyI, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 1,3-thiazol-4-yl and 3-isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (ww) Q1 is selected from 2-pyridyl, 2-pyrazinyl, l,3-thiazol-4-yl, l,3-thiazol-5-yl and 3-isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (xx) Q1 is pyrazinyl (particularly 2-pyrazinyl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (yy) Q1 is isoxazolyl (particularly isoxazol-3-yl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in 00; (zz) Q1 is pyridyl (particularly 2-pyridyl or 3-pyridyl, more particularly 2-pyridyl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in Ql); (aaa) Q1 is 13-thiazolyl (particularly l,3-thiazok4-yl or 13-thiazolyl-2-yI), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11); (bbb) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, hydroxy, cyano, carboxy, nitro, amino, (l-4Qalkyl, (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)a!kylthio, (1-4C)alkylsulfmyl, (l^C)alkylsulfonyl, (2-4C)alkanoyl, N-(l-4C)alkylamino, & M-di-[(l-4C)alkyl]amino, (l-4C)alkoxycarbonyl, carbamoyl, £Hl-4C)alkylcarbamoyl, Mi M-di-[(l-4C)alkyI]carbamoyl, (2-4C)alkanoyloxy, (2-4C)alkanoylamino, M-(l-4Qalkyl-(2-4C)alkanoylamino, halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, carboxy-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and IiN-di-[(l-4C)alkyl]amino-(l-4C)alkyl; (ccc) Q1 is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1 nitrogen heteroatom and optionally 1 additional heteroatom selected from oxygen, nitrogen and sulfur, and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different as hereinbefore defined in (bbb), (ddd) Q1 is phenyl, and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (eee) Q1 is selected from pyridyl, pyrazinyl, 1,3-tiiiazolyl and isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (fff) Q1 is selected from phenyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 13-thiazol-4-yl, l,3-thiazol-5-yl, 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (ggg) Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, 13-thiazol-2-yl, 1,3-thiazol-4-yl and 3-isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (hhh) Q1 is selected from 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl and 3-isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (iii) Q1 is pyrazinyl (particularly 2-pyrazinyl), which optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (ijj) Q1 is isoxazolyl (particularly isoxazol-3-yl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (kkk) Q1 is pyridyl (particularly 2-pyridyl or 3-pyridyl, more particularly 2-pyridyl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (111) Q1 is 1,3-thiazoIyl (particularly l,3-thiazol-4-yl or l,3-thiazolyl-2-yl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb); (mmm) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from fluoro, chloro, bromo, hydroxy, carboxy, cyano, nitro, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 2-propynyl, methylthio, methylsulfinyl, methylsulfonyl, acetyl, propionyl, methylamino, ethylamino, N,N-diinethylamino, N,N-diethylamino, N-methyl-N-ethylamino methoxycarbonyl, etboxycalbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetoxy, acetamido, fluoromethyl, 2-fluoroethyl, chloromethyl, 2-chloroethyl, hydroxymethyl, 2-hydroxyethyl, methoxyrnethyl, 2-methoxyethyl, cyanomethyl, 2-cyanoethyl, carboxymethyl, 2-carboxymethyl, aminomethyl, methylaminomethyl, ethylaminomethyl, NJN-dimethylaminoniethyl, N,N-diethylaminomethyl, N-methyl-N-emylaminomethyl, 2-aminoethyl, 2-(methylamino)ethyl, 2-(emylamino)ethyl, 2-(N,N-dimeraylamino)ethyl, 2-(NJNf-diethylamino)ethyl, 2-(N-methyl-N-ethylamino)ethyl, carbamoylmethyl, N-methylcarbamoylmethyl and N J«J-dimethylcarbamoylroethyl; (nnn) Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 1,3-thiazol-4-yl and isoxazol-3-yl, and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, as hereinbefore defined in (mmm); (ooo) Q1 is selected from phenyl, 2-pyridyl, 2-pyrazinyl, l,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl, and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, as hereinbefore defined in (mmm); (PPP) Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl and isoxazol-3-yl, and wherein Q2 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (1-4C)alkoxy; (qqq) Q1 is selected from phenyl, 2-pyridyl, 2-pyrazinyl, l,3-thiazol-4-yl, l,3-thiazol-5-yl and isoxazol-3-yl, and wherein Q2 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (1-4C)alkoxy; (rrr) Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 13-thiazol-4-yl and isoxazol-3-yl (particularly phenyl, 2-pyridyl, 3-pyridyl and isoxazol-3-yl), and wherein Q2 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro) and (l-4C)alkyl (for example methyl); (sss) Q1 is phenyl which bears 1 or 2 substituents, which may be the same or different, selected from halogeno (particularly fluoro and chloro, more particularly fluoro); (ttt) Q1 is selected from 2-fluorophenyl and 3-fluorophenyl; (uuu) Q1 is 3-fluorophenyl; (vvv) Q1 is 2-fluorophenyl; (www)Q1 is pyridyl (for example 2-pyridyl or 3-pyridyl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (l-4C)alkoxy (particularly (l-4C)alkyl, for example methyl); (xxx) Q1 is 2-pyridyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (l-4C)alkyl and (l-4C)alkoxy; (yyy) Q1 is selected from 2-pyridyl, 6-methyl-pyrid-2-yl and 6-methyl-pyrid-3-yl; (zzz) Q1 is 2-pyridyl; (aaaa) Q1 is 6-methyl-pyrid-2-yl; (bbbb) Q1 is 6-methyl-pyrid-3-yl; (cccc) Q1 is 1,3-thiazolyl (for example 1,3-thiazol-2-yl Or l,3-thiazol-4-yl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (l-4C)alkyl and (l-4C)alkoxy; (dddd) Q1 is l,3-thiazol-2-yI; (eeee) Q1 is l,3-thiazol-4-yl; (ffff) Q1 is pyrazinyl (for example 2-pyrazinyl) which optionally bears 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, hydroxy, (l-4C)alkyl and (l-4C)alkoxy; (gggg) Q1 is 2-pyrazinyl; (hhhh) Q1 is isoxazolyl (for example 3-isoxazolyl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (l-4C)alkyl and (l-4C)alkoxy (particularly (l-4C)alkyl, for example methyl); (iiii) Q1 is 5-methyl-isoxazol-3-yl; Gift) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl (particularly pyridyl, more particularly 2-pyridyl), and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, cyano, nitro, amino, (l-4C)alkyl, (1-4C)alkoxy, N-(l-4C)alkylamino and &M-di-[(l-4C)alkyl]ainino, X1 is selected from OCH2,0(CH3>2 and O, and n is 0 or 1, R3, when present, is located at the meta-position (3-position) relative to the nitrogen in the anilino group, wherein R3 has any of the values defined above (for example R3 is selected from fluoro, chloro and (l-3C)alkyl (such as methyl)); (kkkk) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl (particularly pyridyl, more particularly 2-pyridyl), and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, cyano, nitro, amino, (l-4C)alkyl, (1-4C)alkoxy, H-(l-4C)alkylamino and &N-di-[(l-4C)alkyl]amino, X1 is O(CH3)2, and 3 n is 0 or 1, R , when present, is located at the meta-position (3-position) relative to the nitrogen in the anilino group, wherein R3 has any of the values defined above (for example R3 is selected fromfluoro, chloro and (l-SC)alkyl (such as methyl)); (1111) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl (particularly pyridyl, more particularly 2-pyridyl), and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, cyano, nitro, amino, (l-4C)alkyl, (1-4C)alkoxy, H-(l-4C)aUcylamino and N» N-di-[(l-4C)alkyl]amino, X1 is OCH2, and n is 0 or 1, R3, when present, is located at the meta-position (3-position) relative to the 1 ^ nitrogen in the anilino group, wherein R has any of the values defined above (for example R is selected from fluoro, chloro and (l-3C)alkyl (such a methyl)); (rnmmm) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl, and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, cyano, nitro, amino, (l-4Qalkyl, (1-4C)alkoxy, £J-(l-4C)alkylamino and £L N-di-[(l-4C)alkyl]ainino, X1 is O, and n is 0 or 1, R3,when present, is located at the meta-position (3-position) relative to the nitrogen in the anilino group, wherein R3 has any of the values defined above (for example R3 is selected from fluoro, chloro and (l-3C)alkyl (such as methyl)); (nnnn) R4, R4a, R5 and R5, which may be the same or different, are selected from hydrogen and (l-3C)alkyl (particularly methyl); (oooo) R4, R4a, R.5 and R5at which may be the same or different, are selected from hydrogen and (l-3C)alkyl (particularly methyl), wherein at least one of R4, R4, R5 and R5" is (1-3C)alkyl (particularly methyl); (pppp) R4, R4* and R5 are all hydrogen and R5a is (l-3C)alkyl (particularly methyl); (qqqq) R4, R5 and R5a are all hydrogen and R4a is (l-3C)alkyl (particularly methyl); (nrr) R4 and R4a are both hydrogen and R5 and R5a are both (l-3C)alkyl (particularly methyl); (ssss) R4a and R5a are both hydrogen; (tttt) R4a, R5a and R4 are hydrogen and R5 is (l-6C)alkyl, or R4, R5a and R5 are hydrogen and R4 is (l-6C)alkyl, and wherein any CH2 or CH3 group within any of R4 and R5 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (uuuu) R4and R4Aare hydrogen, and R5 and R5a are both (l-6C)alkyl, or R5 and R5a are hydrogen, and R4 and R4 are both (l-6C)alkyl, and wherein any CH2 or CHa group within any of R4, R4, R5 and R5a optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)a!koxy; (ww) R5 and R5a are hydrogen, and R4 and R4 together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and wherein any CH2 or CHa group within any of R4 and R4* optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (wwww) R4 and R4* are hydrogen, and R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and wherein any CH2 or CHa group within any of R5 and R5a optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (xxxx) R4, R4a, R5 and R5a are all hydrogen; GW) R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)aikynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkylJamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3~R10 wherein X3 is a direct bond or is selected from O and N(RU), wherein RM is hydrogen or (l-4C)a!kyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl( and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents; and wherein any CH2 or CHs group within a R6 substituent, other than a CHi group within a heterocyclyl group, optionally bears on each said CH2 or CHb group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6Qalkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (zzzz) R6 is selected from hydrogen, (l-6C)alkyl, hydroxy-(2-6C)alkyl, (l-6C)alkoxy-(2-6C)alkyl, halogeno-(2-6C)alkyl, amino-(2-6C)alkyl, H-(l-6C)alkylamino-(l-6C)alkyl, N^I-di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyI, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O and N(Rn), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents; (aaaaa) R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)aIkenyl, (2-6C)alkynyl, (3-TQcycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl andheterocyclyl-(l-6C)alkyl, wherein any heterocyclyl group within R6 is a 4, 5,6 or 7 membered raonocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinylt (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]anrino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O and N(Rn), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyi, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, HKl-4C)alkylamino-(l-4C)alkyl andN,N-di-[(l-4Qalkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents; and wherein any CHb or CEfe group within a R6 substituent, other than a CHfe group within a heterocyclyl group, optionally bears on each said CHa or CSLj group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (bbbbb) R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycIoalkyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, wherein any heterocyclyl group within R6 is a 4,5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclyl group is linked to the group to which it is attached by a ring carbon atom, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto; (li6C)alkyl, (2-6G)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O and N(R11), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyU (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, M-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)aJkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents; and wherein any CH2 or CHs group within a R6 substituent, other than a CHa group within a heterocyclyl group, optionally bears on each said CH2 or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (ccccc) R6 is selected from hydrogen, (l-3C)a!kyl, (2-3C)alkenyl, (2-3C)alkynyl, (3-SQcycloalkyl, (3-5C)cycloalkyl-(l-3C)alkyl, heterocyclyl and heterocyclyl-(l-3C)alkyl, wherein any heterocyclyl group within R6 is a 4,5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclyl group is linked to the group to which it is attached by a ring carbon atom, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifiuoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)aIkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyi, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O and N(R1!), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-(l-4C)alkylamino-(l-4C)alkyl and N,H-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein, any heterocyclyi group within an R* substituent optionally bears 1 or 2 oxo substituents; and wherein any CHa or CR3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CHa or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl] amino; (ddddd) R6 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, isopropenyl, allyl, but-2-enyl, ethynyl, 2-propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridmyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropybncthyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, azetidinylmethyl, pyrrolinylmethyl, pyrrolidinylmethyl, morpholinylmethyl, piperidinylmethyl, homoptperidmylxnethyl, piperazinylmethyl, homopiperazinylmethyU dihydropyridinylmethyl, tetrahydropyridmylmeihyl, dihydropyrimidinylmethyl, tetrahydropyrimidinyhnethyl, tetrahydrothienylrnethyl, tetrahydrothiopyranylmethyl, thiomorpholinylmethyl, tetrahydrofuranyhnethyl, tetrahydropyranylmethyl, 2-(azetidinyl)ethyl, 2-(pyrrolinyl)ethyl, 2-(pyrrolidinyl)ethyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl, 2-(homopiperidinyl)ethyl, 2-(piperazinyl)cthyl, 2-(homopiperazinyl)ethyl, 2-(dihydropyridinyl)ethyl, 2-(tetrahydropyridinyl)ethyl, 2-(dihydropyrimidinyl)ethyl, 2- and wherein any GHz or CH3 group within a R6 substituent, other than a CEfe group •within a heterocyclyl group, optionally bears on each said CH2 or CHs group one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, methyl, ethyl, propyl and isopropyl, or a substituent selected from hydroxy, amino, methoxy, ethoxy, rnethylamino, ethylamino, di-methylamino, di-emylamino andH-methyl-H-ethylamino, and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tlifluoromethyl, vinyl, isopropenyl, I allyl, but-2-enyl, ethynyl, 2-propynyl, butynyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, acetyl, propionyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-- • hydroxyethyl, 2-methoxyethyl and 2-ethoxyethyl; (eeeee) R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyL 2-methoxyethyl, propyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-methoxypropyl, 2-methoxypropyl, isopropyl, vinyl, isopropenyl, allyl, but-2-enyl, ethynyl, 2-propynyI, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, homopiperidinylmethyl, tetrahydrothiopyranylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, 2-(azetidinyl)ethyl, 2-(pyrrolidinyl)ethyl, 2-(piperidinyl)ethyl, 2-(homopiperidinyl)ethyl, 2-(tetrahydrothienyl)ethyl, 2-(tetrahydrothiopyranyl)ethyl, 2-(thiomorpholinyl)ethyl, 2-(tetrahydrofuranyl)ethyl and 2-(tetrahydropyranyl)ethyl, and wherein any CH2 group within a cycloalkyl group within R6 optionally bears on each CHz group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy, and wherein any CEfe or CH3 group within a R6 substituent, other than a GHz group within a heterocyclyl group, optionally beats on each said CH2 or CHb group one or more fluoro substituents, and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy; (fffff) R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-methoxypropyl, 2-methoxypropyl, isopropyl, allyl, but-2-enyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, tetrahydrofuranyknethyl, tetrahydropyranylmethyl, 2-(azetidinyl)ethyl, 2-(pyrrolidinyl)ethyl, 2-(piperidinyl)ethyl, 2-(tetrahydrofuranyl)ethyl and 2-(tetrahydropyranyl)ethyl, ( ,.,. and wherein any CHa group within a cycloalkyl group within R6 optionally bears on each CH2 group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy, and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy; (ggggg) R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl and cyclopropylmethyl, and wherein any CHfe group within a cycloalkyl group within R6 optionally bears on each CH2 group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy, and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy; (hhhhh) R6 is selected from hydrogen and (l-3Qalkyl (for example R6 is hydrogen or methyl); R6 is hydrogen; R6 is (l-3C)alkyl (for example methyl); (kWdkk) R6is(l-3C)alkyl, and wherein any CHa or CHfe group within aR6 substituent, other than a CHfe group within a heterocyclyl ring, optionally bears on each said CHa or CH3 group one or more substituents selected from hydroxy and (l-6C)alkoxy (for example methoxy); (11111) R6 is (2-6C)alkenyl (for example allyl); (rnrnmmm) R6 is (2-6C)alkynyl (for example 2-propynyl); (nnnnn) R6 is selected from (3-7C)cycloalkyl and (3-7C)cycloalkyl-(l-6C)alkyl (for example R6 is selected from cyclopropyl, cyclobutyl, cyclopropyl-methyl and cyclobutyl-methyl); (ooooo) R6 is heterocyclyl (for example R6 is selected from piperidinyl and tetrahydropyranyl); (PPPPP) A is selected from a group of the formula Z-(CR12R13)P- and Rw, wherein pis 1,2,3-,or4y • .-•?•;-.•/,•• K « each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloaJkyl or (3-7C)cycIoalkenyl ring, and wherein any CEb or CHs group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, Z is selected from hydrogen, OR15, NRI6R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl, R14 is selected from OR19 and NR16R17, wherein R19 is selected from (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16and R17 are as defined above, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7Ocycloalkenyl, (3-7C)cycloalkenyI-(l-6Qalkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)aIkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a groap selected from O, S, SO, SO2, N(R21), CO, -OC- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a Z orR14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkyIamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyIoxy and from a group of the formula: _X6_R22 wherein X6 is a direct bond or is selected from O, CO, SO* and N(R23), wherein R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyllamino-(l-4C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CHfe or CHj group within a Z or R14 group, other than a GH2 group within a heterocyclyl ring, optionally bears on each said CHa or CHj group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)aIkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)a!kylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyI, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulfamoyl, N,N-cii-[(l-6C)alkyl]sulfaraoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino; (qqqqq) A is selected from a group of the formula Z-(CR12R13)p- and R14, wherein p is 1,2 or 3, each R12 and R13, which may be the same or different, is selected-from hydrogen and (l-6C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring, and wherein any CEfe or CH3 group within any of R12 and R13 optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl and (l-6C)alkoxy, Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6Qalkyl and (l-6C)alkoxycarbonyl, R14 is selected from OR19 and NR16R17, wherein Rw is selected from (l-6C)alkyl and wherein R16 and R17 are as defined above, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SOa, N(R21), CO, -C=C- and -DC-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent 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, forrayl, mercapto, (l-6C)aIkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amrao, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: wherein X6 is a direct bond or is selected from O, CO, SO2 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkylaTidNIN-di-[(l-4C)alkyl]ainino-(l-4C)alkyl( and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CKb or CH3 group within a Z or R14 group, other than a CHz group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, M-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)aIk;anoyloxy, (2-6C)alkanoylamino, M-(l-6Qalkyl-(2-6C)alkanoylamino, M-(l-6C)alkylsulfamoyl, &&Kti-[(l-6Qalkyl]sulfamoyl, (l-6C)alkanesulfonylamino and H-(l-6C)alkyl-(l-6C)aIkanesulfonylaimno; (rmr) A is selected from a group of the formula Z-(CR12RI3V and RM» wherein p is 1,2 or 3 (particularly 1 or 2), each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, and wherein any CHa or CHs group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)aBcoxy (particularly hydroxy), Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (l-6C)alkoxycarbonyl, R14 is selected from OR19 and NR16R17, wherein R19 is selected from (l-6C)alkyl and wherein R16 and R17 are as defined above, or R14 is Q4 wherein Q4 is (S-TQcycloalkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, trifluorximethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy, and wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy; (sssss) A is selected from a group of the formula Z-(CR12R13)P- and R14, wherein p is 1,2 or 3 (particularly 1 or 2), each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, and wherein any CHa or CHs group within any of R12 and R13 optionally bears on each said CHi or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy (particularly hydroxy), Z is selected from hydrogen, OR15, NRl R14 is selected from OR19 and NR16R17, wherein R19 is selected from (l-6C)a!kyl and wherein R16 and R17 are as defined above, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, heterocyclyl or heterocyclyl-(l-6C)alkylt and wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, hydroxy, (l-6C)alkyl and (l-6C)alkoxy (particularly (l-6C)alkyi), and wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CHi or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy (particularly a substituent selected from halogeno and hydroxy); (ttttt) A is selected from a group of the formula Z-(CR12RI3)p- and R14, wherein p is 1,2,3, or 4, each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyl ring, and wherein any CKfe or GHj group within any of R12 andR13 optionally bears on each said CHj or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)a!koxy, amino, (2-6C)alkanoyl, (l-6C)alkylamino and di-[(l-6C)alkylamino], and wherein Z is selected from hydrogen, OR15, NR16R17, wherein each of R1S, Ri6 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R14 is Q4 wherein Q4 is heterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SOa, N(R21), CO, -C=C- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a Rw substituent 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, fonnyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l~6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino,dK(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: wherein X6 is a direct bond or is selected from O, CO, SOj and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is nalogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-d-4C)aIkylamino-( l-4G)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within an R14 substituent optionally bears 1 or 2 oxo substituents, and wherein any CEb or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CHa or CHg group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6Qalkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (I-6C)alkylthio, (l-6<: di- n- n h and a is selected from group of the formula z- ru> wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring, and wherein any CH2 or CHs group within any of R12 and R13 optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy, and wherein Z is selected from hydrogen, OR15, NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6G)alkynyl, and wherein R14 is Q4 wherein Q4 is a 4,5,6 or 7 membered saturated or partially saturated monocyclic heterocyclyl ring containing i nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, and wherein Q4 optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, trifluoromcthyl, cyano, nitro, hydroxy, amino, mercapto, (l-6Qalkyl, (2-6C)alkenyI, (2-6C)alkynyl, (l-6C)alfcoxy, (l-6C)alkylthio, (l-6C)alkyIsulfinyl, (l-6C)alkylsulfonyl, (l-6C)aIkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)aDcanoyloxy and from a group of the formula: -X"-R22 wherein X6 is a direct bond or is selected from O and NOR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)aIleyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, E-(l-4C)aIkylamino-(l-4C)alkyl and H,M-di-Kl-4C)alkyl]amino-(l-4C)alkyl, and wherein Q4 optionally bears 1 or 2 oxo substituents, and wherein any CH2 or CHa group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said Clfc or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (wwv) A is selected from a group of the formula Z-(CR12R13)p- and R14, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring, and wherein any CH2 or CH3 group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy, and wherein Z is selected from hydrogen, OR15, NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R14 is Q4 wherein Q4 is a 4, 5,6 or 7 membered saturated or partially saturated monocyclic heterocyclyl ring containing 1 nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, which ring is linked to the carbonyl group in formula I by a ring carbon atom, and wherein Q4 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, mercapto, (l-6C)aIkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6X3)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X6-R22 wherein X6 is a direct bond or is selected from O and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-(l-4C)alkylamino-(l-4C)alkyl and H,H-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein Q4 optionally bears 1 or 2 oxo substituents, and wherein any CEfe or GHj group within a Z or R14 group, other than a CHfe group within a heterocyclyl ring, optionally bears on each said CHa or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (wwwww) A is a group of the formula Z-(CR12R13)P-, wherein p is 1 or 2, each R12 andR13, which may be the same or different, is selected from hydrogen and U-6C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring, and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (l-6C)alkoxycarbonyl, and wherein any CEfeor CHs group within any of R12, R13 and Z, optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (xxxxx) A is a group of the formula Z-(CR12R13)p-, wherein pis 1 or2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)aIkyl and (l-6C)aIkoxycarbonyl, and wherein any CH2 or CH3 group within any of R12, R13 and Z, optionally bears on each said CH2 or CHs group one or more (for example 1,2 or 3) halogeno, (l-6C)alkyl or hydroxy substituents; (yyyyy) A is a group of the formula Z-(CR12R13V, wherein pis lor 2, each R12 and R13, which may be the same or different; is selected from hydrogen and (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom, form a (3-7C)cycloalkyl ring, and wherein Z is selected from hydrogen, OR15, NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein any CH2 or CKfe group within any of R12, R13 and Z, optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (zzzzz) A is a group of the formula Z-(CR12RI3)P-, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)aIkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein Z is selected from hydrogen and OR15, wherein R15 is selected from hydrogen and (l-6C)alkyl, and wherein any CH2 or CH3 group within any of R12, R13 and Z, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy; (aaaaaa) A is a group of the formula Z-(CR12R13)P-, wherein p is 1 or 2, each R12 andR13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3~6C)cycloalkyl ring, and wherein any CHz or CHs group within any of R12 and R13 optionally bears on each said CH2 or CHs group one or more (for example 1,2 or 3) halogeno or (l-4Qalkyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy, and wherein Z is hydroxy; (bbbbbb) A is a group of the formula Z-(CR12R13)p-. wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring, and wherein Z is NR16R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein any CH2 or CHs group within any of R12, R13 and Z, optionally bears on each said CHa or CHs group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl suostituente or a substuuent selected from hydroxy and (l-6C)a!koxy; (cccccc) A is a group of the formula Z-(CR12Rl3)p-, wherein p is 1 or 2, .; .,(4,eachR^and RJ3, v^hich may be the same or different,^ selected from hydrpgertand (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, provided (i) that at least one of the R12 or R13 groups is (l-4C)alkyl, or (ii) that an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyU and wherein any CH2 or CHs group within any of R12, R13 and Z, optionally bears on each said CHz or CEfe group one or more (for example 1, 2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (dddddd) A is a group of the formula ZKCR^R1 V wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloaIkyl ring, provided (i) that at least one of the R12 or R13 groups is (l-4C)alkyl, or (ii) that an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein Z is selected from hydrogen, OR13, NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)a!kyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein any GHz or CHa group within any of R12, R13 and Z, optionally bears on each said CHz or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6Qalkoxy; (eeeeee) A is Ru, wherein R14 is selected from OR19 and NR16R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl, and wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6G)alkyV and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R 4 group are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(Rai), CO, -C=C- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a R14 group 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, formyU mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)a!kylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: _X6.R22 wherein X6 is a direct bond or is selected from O, CO, SCfe and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-Cl^Qalkyl, H-(l-4C)alkylamino-(l-4C)alkyl and H,S-di-l(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a R14 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CEfe or CHs group within a R14 group, other than a CHj group within a heterocyclyl ring, optionally bears on each said CHa or CHs group one or more halogeno or (l-6C)alkyl substituents or a subsdtuent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, M-(l-6C)alkylcarbamoyl, M,M-di-[(l-6C)alkyl]carbainoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyl-(2-6C)alkanoylamino, M-(l-6C)alkylsulfamoyl, M,M-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino; (ffffff) A is R14, wherein R14 is selected from OR19 and NR16R17, wherein each of R16 and Rn, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (1-6C)alkoxycarbonyl, and wherein R19 is selected from (l-6C)alkyl, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyi, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within a R14 group 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a R14 group optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH2 or CHs group within a R14 group, other than a CHj group within a heterocyclyl ring, optionally bears on each said CHz or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (gggggg) A is Ru, wherein R14 is OR19, wherein R19 is (l-6C)alkyl (particularly (l-3C)alkyl, such as methyl); (hhhhhh) A is R14, wherein R14 is NR16R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (l-6C)alkoxycarbonyl, and wherein any CEfe or CH3 group within a R16 or a R17 group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6Qalkyl substituents or a substituent selected from hydroxy and (l-6G)alkoxy, (iiiiii) A is R14, wherein R14 is Q4 wherein Q4 is (3-7Qcycloalkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within a R14 group 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, formyl, mercapto, (l-6Qalkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy, and wherein any heterocyclyl group within a R1* group optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH2 or Cfife group within a R14 group, odier than a CH2 group within a heterocyclyl ring, optionally bears on each said CHfeor CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (jjjjjj) A is Q4 wherein Q4 is a 4,5,6 or 7 membered saturated or partially saturated monocyclic heterocyclyl ring containing 1 nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, and wherein Q4 optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, ammo* (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6G)alkoxyi (l-6C)alkylthioy (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula-. -X6-R22 wherein X6 is a direct bond or is selected from O and N(R23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein Q4 optionally bears 1 or 2 oxo substituents; (kkkkkk) A is Q4 wherein Q4 is a 5 or 6 membered saturated or partially saturated monocyclic heterocyclyl ring containing 1 nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, and wherein Q4 optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy, and wherein Q4 optionally bears 1 or 2 oxo substituents; (111111) A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dmydropyrirnidinyl, tetrahydropyrimidinyl, tetrahydrofuranyl and tetrahydropyranyl, and wherein A optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, trifluoromethyl, vinyl, isopropenyl, allyl, but-2-enyl, ethynyl, 2-propynyl, butynyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, acetyl, propionyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-hydroxyethyl, 2-methoxyethyl and 2-ethoxyethyl; (mmmmmm) A is selected from cyclopropyl, pyrrolidinyl, piperazinyl, morpholinyl and tetrahydrofuranyl, and wherein A optionally bears one or more substituents, which may be the same or different, selected from methyl, ethyl, propyl, butyl, isopropyl and isobutyl (particularly methyl); (nnnnnn) A is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, tetrahydrofuranyl and tetrahydropyranyl, and wherein A optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, 2-propynyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy and acetyl; (oooooo) A is selected from methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl, 1,3-dihydroxypropyl, 2-(hydroxymethyl)prop-2-yl, 2-hydroxy-2-methylpropyl, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 3-methoxypropyl, 1-methoxypropyl, 2-methoxypropyl, 2-methoxyprop-2-yl, 2-(methoxymethyl)prop-2-yl, 2-methoxy-2-methylpropyl, ethoxymethyl, 2-ethoxyethyl, 1-ethoxyethyl, l-hydroxy-3-bromopropyl, (methylsulfonyl)methyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl, 2-aminopropyl, 2-aminoprop-2-yl, 2-(aminomethyl)prop-2-yl, 2-amino-2-methylpropyl, N-methylaminomethyl, 2-(N-methylamino)ethyl, 1-QJ-methylamino)eti\yl, 3-(N-methyIammo)propyl, l-(M-nielhylainino)propyl> 2-(N-methylamino)pn^)yl, 2-(H-methylamino)prop-2-yl, 2-(\|i-melhylaniinomethyl)prop-2-yl> [(N-methyl)^-^-butoxycarboi>yl)aniino]mettiyl, 2-Qi-melhylaiiiino)-2-methylpropyl, dimethylaminoinethyl, 2-QiH-diniethylamino)ethyl, l-^LK- (PPPPPP) A is selected from methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl, 2-(hydroxymethyl)prop-2-yl, 2-hydroxy-2-methylpropyl, methoxynjethyl, 2-methoxyethyl, 1-methoxyeihyl, 3-methoxypropyl, 1-methoxypropyl, 2-methoxypropyl, 2-methoxyprop-2-yl, 2-(methoxymethyl)prop-2-yl, 2-methoxy-2-methylpropyl, ethoxymethyl, 2-ethoxyethyl, 1-ethoxyethyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-arainopropyl, 2-aminopropyl, 2-aminoprop-2-yl, 2-(aminomethyl)prop-2-yl, 2-amino-2-methylpropyl, N-methylaminomethyl, 2-(N-methylamino)ethyl, l-(N-methylamino)emyU 3-(N-methylamino)propyl, l-(N-methylamino)propyl, 2-(N-methylamino)propyl, 2-(N-raethylamino)prop-2-yl, 2-(N-methylaminomethyl)prop-2-yl, 2-(N-methylamino)-2-methylpropyl, H,N-dimethylaminomethyl, 2-(NJN-dimethylamino)ethyl, 1-(£LN-dimethylamino)ethyl, 3-(N,N-dimetoylamino)propyl, l-(NJi-dimethylamino)propyl, 2-(N[,N-dimethylamino)propyl, 2-(N,N-dimemylanimo)prop-2-yl, 2-(N,N-dimethylaminomethyl)prop-2-yl, 2-(M,N-dunemylamino>2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl."cyclohexyl, 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, 1-hydroxymethylcyclopropyl, 1-hydroxymethylcyclobutyl, l-hydroxymethylcyclopentyl, 1-hydroxymethylcyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azen"din-2-yl, azetidin-3-yl, l-methylazetidin-2-yl, l-melhylazetidin-3-yl, pyrrolidin-2-yl, pyrrolidm-3-yI, l-methylpynolidin-2-yl, 1-methyl pyrroUdin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, l-memylpiperidin-2-yl, l-methylpiperidin-3-yl and l-methylpiperidin-4-yl; (qqqqqq) A is selected from methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl, 1,3-dihydroxypropyl, 2-(hydroxymethyl)prop-2-yl, 2-hydroxy-2-methylpropyl, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 3-methoxypropyl, 1-methoxypropyl, 2-methoxypropyl, 2-methoxyprop-2-yl, l-hydroxy-3-bromopropyl, (methylsulfonyl)methyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl, 2-aminopropyl, 2-aminoprop-2-yl, 2-(aminomethyl)prop-2-yl, 2-amino-2-methylpropyl, N-methylaminomethyl, 2-(N-methylamino)ethyl, l-(N-methylamino)ethyl, [(N-memyl)-(N-^-butoxycarbonyl)amino]methyl, HJ^-dmiethylaminomethyl, 2-QJ.N-dimethylamino)ethyl, l-(N,N-dimefoylamino)ethyl, methylamino, dimethylamino, ethylamino, diethylamino, (2-chloroethyl)amino, methoxy, ethoxy, cyclopropyl, cyclobutyl, 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxymethylcyclopropyl, 1-hydroxymethylcyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yLtettabydrjDpyran-4-yl; pyrrolidin-2-yl, pyrrolidin-3-ylv l^ ^"^kv>fe ->" "" methylpyrrolidin-2-yl, l-methyIpyrrolidin-3-yl, pyrrolidin-1-ylmethyl, morpholin-4-yl, morpholin-4-ylmethyl, l-methylpiperazin-4-ylmethyl; (rrrrrr) A is selected from methyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3- hydroxypropyl, 1,3-dihydroxypropyl, 2-(hydioxymethyl)prop-2-yl, methoxymethyl, 1- methoxyethyl, l-hydroxy-3-bromopropyl, (methylsulfonyl)methyl, aminomethyl, N- methylaminomethyl, [(N-methyl)-(N-tert-butoxycarbonyl)ainino]methyl, methylamino, (2- chloroethyl)amino, methoxy, 1-hydroxycyclopropyl, tetrahydrofuran-2-yl, 1- methylpyrroIidin-2-yl, pyrrolidm-1-ylmethyl, morpholin-4-ylmethyl, l-methylpiperazin-4- ylmethyl; (ssssss) A is selected from hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3- hydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl, 2- (hydroxymemyl)prop-2-yl and 2-hydroxy-2-methylpropyl; (tttttt) A is selected from methyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyeth.yl and 2-hydroxyprop-2-yl; (uuuuuu) A is selected from methyl and hydroxymethyl; (www) A is hydroxymethyl; (wwwwww) A is a group of the formula Z-(CR!2R13)p-, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-3C)alkyl, and wherein Z is a group of the formula NRI6R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, and wherein any CHj or CHs group within any of R12, R13 and Z, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents, and wherein any CH2 or CHa group within any of Ru, R13 and Z which is not attached to a nitrogen atom optionally bears on each said CEfe or CH3 group a substituent selected from hydroxy and (l-6C)alkoxy; (xxxxxx) A is selected from aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl, 2-aminopropyl, 2-aminoprop-2-yl, 2-(aminomethyl)prop-2-yl, 2-amino-2-methylpropyl,M-methylaminomethyl, 2-Q5-methylamino)ethyl, l-(H-methylamino)ethyl, 3-(N-methylamino)propyl, l-(JJ-methylamino)propyl, 2-Qi-methylamino)propyl, 2-(H-methylamino)prop^2-yl, 2-QS-methylaminomethyl)prop2-yl, 2-(tJ-methylamino)-2-methylpropyl, £J,M-oMnethylaminomethyl, 2-(N^f-dimethylamino)ethyl, 1-QI^J-dimethylamino)ethyl, 3-(HJS-dunethylamino)propyl, l-(H,N-dimethylamino)propyl, 2-Qi^i- dimethylamino)propyl, 2-(N,N-dimethylamino)prop-2-yl, 2-(N,N- dimethylaminomethyl)prop-2-yl, 2-(N,N-dimethylamino)-2-methylpropyl and [(N-methyl)- (N-tert-butoxycarbonyl)amino]methyl;and (yyyyyy) A is selected from aminomethyl, 2-arainoethyl, N-methylaminomethyl, 2-(N- methylamino)ethyl, N,N-dirnethylaminomethyl, 2-(N,N-dimethylamino)ethyl and [(N- memyl)-(N-tejt-butoxycarbonyl)ainino]methyl (particularly A is N,N-dimethylarainomethyl). A particular embodiment of the present invention is a quinazoline derivative of the formula I of the formula la: m is 0,1 or 2; each R1, which may be the same or different, is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyHl-6C)alkoxy, and wherein any Ofo or CHs group within a R1 substituent optionally bears on each said CHjor CHa group one or more halogeno or (l-6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy, R3" is selected from cyano, halogeno, (l-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl; n is 0,1 or 2; each R3b, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl (particularly halogeno and (l-4C)alkyl); X1 is selected from O, S, SO, SO2, N(R7), CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(Rt)S02, OC(R7)2, C(R7)20, SC(R7>2, C(R7)2S, CO, C(R7>2N(R7) and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl; Ql is aryl, or heteroaryl, and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, fonnyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyI, (l-6C)alkylamino, di-Kl-eQalkylJamino, (l^C)alkoxycarbonyl, N-(l-6Qalkylcarbamoyl, N^-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyIoxy, (2-6C)alkanoylamino, H-(l-6C)alkyl-(2-6C)alkanoylamino, (S^Qalkenoylamino, 6C)alkenoylarnino, (3-6C)alkynoylamino, H-(l-6C)alkylsulfamoyl, HJS^-Kl^)^yl]sulfamoyl, (l-6C)alkanesulfonylamino, M-(l-6C)alkyl-(l-6C)aIkane8ulfonylanrino, and a group of the formula: -X2-R8 wherein X2 is a direct bond or is selected from O, CO and NCR9), wherein R9 is hydrogen or (l-6C)alkyl, andR8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)aIkyi, N-(l-6C)alkylamino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, (l-6X^alkoxycarbonylarnino-(l-6C)alkyl, carbamoyl-(l-6C)alkyl, H-(l-6C)alkylcarbamoyl-(l-6C)alkyl, Mii-di--[(l-6QaIkyl]carbainoyl-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl, (l-6C)alkylsulfinyHl-6C)alkyl, (l-6Qalkylsulfonyl-(l-6C)alkyl di-(l-6C)alkylsulfamoyl(l-6C)alkyl, (2-6C)alkanoyl-(l-6Qalkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)alkoxycarbonyl-(l-6C)alkyl, and wherein any CH2 or CH$ group within -O^-Q1 optionally bears on each said CHj or CHa group one or more (for example 1, 2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino]; R4, R4i, R5 and R5, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, or R4 and R4a together with the carbon atom to which they are attached form a (3- • 7C)cycloalkyl ring, or R5 and R5a together with the carbon atom to which they are attached form a (3- 7C)cycloalkyl ring, and wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino]; R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyU (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsuffinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl)ainino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O, CO, SOa and N(Rn), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, ammo-(l-4C)alkyl, M-(l-4C)alkylamino-(l-4C)alkyl and N,H-di-[(l-4C)alkyl]ainino-(l-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and wherein any CHa or CHa group within a R6 substituent, other than a CHa group within a heterocyclyl group, optionally bears on each said CHj or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, H-(l-6C)alkylcarbamoyl, M^i-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N ,1 -6C)alkylsulfamoyl, N^J-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and H-(l-6C)alkyHl-6C)alkanesulfonylamino; v , . .,, A is selected from hydrogen, a group of the formula Z-(CR12R13)p- and R14, wherein p is 1, 2, 3, or 4, each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyI ring, and wherein any CH2 or CHa group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl» (l-6C)alkoxy, amino, (2-6C)aIkanoyl, (l-6Qalkylamino and di-[(l-6C)alkyl]amino, Z is selected from hydrogen, OR15, NRi6R17, (l-6C)alkylsulfonyl, (l-6C)aIkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl, or Z is a group of the formula: Q2-4- wheiein X is selected from O, N(R18), SO2 and SO^NCR1), wherein R18 is hydrogen or (l-6Qalkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl, R14 is selected from hydrogen, OR19 and NR16R17, wherein Rw is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)aIkynyl, and wherein R16 and R17 ate as defined above, or R14 is a group of the formula: Q3-X5- wherein X5 is selected from O and NOR20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloaikyHl-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyHl-6C)alkyl, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyKl-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyHl-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R21), CO, -C=C- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylammo, di-[(l~6C)aDcyl]amino, (2-6C)allcanoyl, (2-6C)alkanoyloxy and from a group of the formula: _X6_R22 wherein X6 is a direct bond or is selected from O, CO, SO2 andN(R23), wherein R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l-4C)alkyl, hydroxy-(MC)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and JiN-di-[(l-4C)alkyl]ainino-(l-4C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH2 or CHs group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sutfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]aminot M-(l-6Qalkylcarbamoyl, Ji^i-di-[(l-6C)alkyl]caibamoyl, (2-6Qalkanoyl» (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6Qalkyl-(2-6C)aIkanoylamino, H-(l-6C)alkylsulfamoyl, N,H-di-[(l-6C)aIkyl]8ulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamhio; or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention is a quinazoline derivative of the formula la, wherein: misOorl; R1 is selected from (l-4C)alkoxy (for example methoxy or ethoxy), and wherein any CBfe or CHs group within a R1 substituent optionally bears on each said CH2 or CHs group one or more fluoro or chloro substituents, or a substituent selected from hydroxy and (l-3C)alkoxy; R3 is selected from hydrogen, halogeno, trirluoromethyl, (l-4C)alkyl, (l-4C)a!koxy, (2-4C)alkenyl and (2-4C)alkynyl; nisO, lor2; each R3b, which may be the same or different, is selected from halogeno and (1- 4C)alkyl; " X1 is selected from O, S and OC(R7)2) wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl; Q1 is aryl, or heteroaryl, and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, ammo, carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6G)aIkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino,di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, M-d-6C)alkylcarbamoyl, N^}-di-[(l-6C)aIkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, H-(l-6Qalkyl-(3-6C)alkenoylamino, (3-6C)alkynoylainino, M-(l-6C)alkyl-(3-6C)alkynoylamino, H-(l-6C)alkylsulfamoyl, H^i-di-Kl-fiQalkyllsulfamoyl, (l-6C)alkanesulfonylamino, HKl-^C)alkyl-(l-6C)alkanesulfonylainino, and a group of the formula: -X2-R8 wherein X2 is a direct bond or is selected from O, CO and NOR9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6Qalkyl, amino-(l-6C)alkyl, £J- (2-6C)alkanoylamino-(l-6C)alkyl, N-{l-6C)alkyl-(2-6C)alkanoylamino-(l^C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl, carbamoyl-(l -6C)alkyl, H-(l-6C)alkylcarbamoyl-(l-6C)alkyl, HOi-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkyl, (1- sulfamoyl(l-6C)alkyI, H-(l-6C)alkylsulfamoyl(l-6C)alkyl, di-(l-6C)alkylsulfamoyl(l-6€)alkyl, (2-6C)alkanoyKl-6C)alkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)alkoxycarbonyl-(l-6C)alkyl, and wherein any CHa or CHs group within -X"-Q1 optionally bears on each said CHj or CHa group one or more (for example 1, 2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino]; R4, R4", R5 and R5, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, or R4 and R4a together with the carbon atom to which they are attached form a (3- 7C)cycloalkyl ring, or R5 and RSa together with the carbon atom to which they are attached form a (3- 7C)cycloalkyl ring, and wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino]; R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)aflcenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)aUcylsulfonyl, (l-6X:)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O, CO, SCh and N(Rn), wherein R11 is hydrogen or (l-4QalkyU and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and M,N-di-[(l-4C)alkyl]amino-(l^C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and wherein any CHa or CHa group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (i-6C)alkylsulfonyl, (l-6Qalkylamino, di-t(l-6C)alkyl]amino, H-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylanuno,H-(l-6C)alkyl-(2-6C)alkanoylaimno, H-(l-6C)alkylsulfamoyl, N,H-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and H-(l-6C)alkyl-(l-6C)alkanesulfonylamino; A is selected from a group of the formula Z-(CR12R13)P- and R14, wherein pis 1,2 or 3, each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyi ring, and wherein any CHj or CHa group within any of R12 and R13 optionally bears on each said CH2 or CHs group one or more (for example 1, 2 or 3) halogeno or (l-6C)aBeyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkyl amino and di-[(l-6C)alkylamino], Z is selected from hydrogen, OR15, NR16R17 and R14 wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, R14 is a 4, 5, 6 or 7 membered saturated or partially saturated monocyclic heterocyclyl ring containing 1 nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, and wherein any heterocyclyl group within a R14 substituent 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, formyl, mercapto, (l-6C)aLkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-C)alkylthio, (l-6Qalkylsulfinyl, (l~6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: wherein X6 is a direct bond or is selected from O, CO, SO7 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyI, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and U^J-di-[(l-4C)a]kyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH2 or CHs group within a Z group optionally bears on each said CHa or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy^ earbamoyl, sulf amoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, ^-(l-6C)alkyl-(2-6C)alkanoylamino,N-(l-6C)alkylsulfamoyl) N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof. In an embodiment, in the compound of formula la m is 0 or m is 1 and R1 is (1-3C)alkoxy, for example methoxy. Particularly m is 0. In another embodiment, in the compound of formula la, n is 0 and R3a is selected from halogeno, trifluoromethyl, (l-4C)alkyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl. Particularly R3a is selected from halogeno and (l-3C)alkyl, more particularly R3a is selected from chloro and methyl, still more particularly R3a is chloro. In this embodiment n is suitably 0 or 1. Particularly n is 0. In another embodiment, in the compound of formula la, X1 is selected from O, S and OC(R7)2, wherein R7 is hydrogen or (l-3C)alkyl, more particularly X1 is selected from O and OC(R\, for example X1 is selected from O, OCH2 and OC(CH3)2. In another embodiment, in the compound of formula la, X1 is selected from S and OC(R7)2, wherein R7 is hydrogen or (l-3C)alkyl, more particularly X1 is QC(R\, for example X1 is OCH2. In another embodiment, in the compound of formula la, Q1 is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1 nitrogen heteroatom and optionally 1 additional heteroatom selected from oxygen, nitrogen and sulfur, and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different selected from halogeno, hydroxy, cyano, carboxy, nitro, amino, (l-4C)alkyl, (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkylthio, (1-4C)alkylsulfinyl, (l-4Qalkylsulfonyl, (2-4C)al3canoyl, N-(l-4C)alkylamino, ^N-di-Ul-4C)aDcyl]amino, (l-4C)alkoxycarbonyl, carbamoyl, N-(l-4C)alkylcarbamoyl, N» £f-di-[(l-4C)alkyl]carbamoyl, (2-4C)alkanoyloxy, (2-4C)alkanoylamino, H-(l-4C)alkyl-(2-4C)alkanoylamino, halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, carboxy-U^Qalkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N, M-di-[(l-4C)alkyl]amino-(l-4C)alkyl In another embodiment, in the compound of formula la, Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl, optionally substituted by 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (l-4C)alkoxy. For example Q1 is selected from phenyl optionally substituted with 1 or 2 substituents selected from fluoro and chloro or Q1 is selected from 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl, 1,3-thiazol-5-yI and isoxazol-3-yl (particularly 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl and isoxazol-3-yl), and wherein any heterocyclic group in Q1 optionally bears 1, 2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (l-4C)alkoxy. In another embodiment, in the compound of formula la, Q1 is pyridyl (for example 2-pyridyl or 3-pyridyl, particularly 2-pyridyl), which optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (l-4C)alkoxy. For example, Q1 is particularly pyridyl, optionally substituted by 1 or 2 (l-4C)alkyl substituents (for example by 1 or 2 methyl substituents). In another embodiment, in the compound of formula la, R4, R4, R5 and R5a are selected from hydrogen and (l-3Qalkyl, for example R4, R4, R5 and RSa are selected from hydrogen and methyl. In another embodiment, in the compound of formula la, R4, R4, R5 and R51 are all hydrogen. In another embodiment, in the compound of formula la, R4", R5 and R5a are hydrogen and R4 is (l-3C)alkyl, for example methyl. In another embodiment, in the compound of formula la, R4, R4 and R5a are hydrogen and R5 is (l-3C)alkyl, for example methyl. In another embodiment, in the compound of formula la, R4 and R4* are both hydrogen and R3 and R5* are both (l-3C)alkyl, for example methyl. In another embodiment, in the compound of formula la, R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, wherein any heterocyclyl group within R6 is a 4,5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno,trifluoromethyl, hydroxy, amino, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O and N(Rn), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and M,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents. In another embodiment, in the compound of formula la, R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-4C)alkyl, heterocyclyl and heterocyclyl-(l-4C)alkyl, wherein any heterocyclyl group within R6 is a 4, 5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bronto, hydroxy, (l-4C)alkyl, (2-4Qalkenyl, (2-4C)alkynyl and (l-4C)alkoxy, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 oxo substituent, and wherein any CH2 or CHa group within a R6 substituent, other than a CHa group within a heterocyclyl ring, optionally bears on each said CHfe or CHs group one or more substituents selected from fluoro and chloro, or a substituent selected from hydroxy and (l-4C)alkoxy, (l-6C)alkylamino anddi-[(l-6C)alkyl]amino. In another embodiment, in the compound of formula la, R6 is selected from hydrogen and (l-4C)alkyl. For example R6 is (l-3C)alkyl such as methyl. In another embodiment, in the compound of formula la, R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl and cyclopropylmethyl, and wherein any CHj group within a cycloalkyl group within R6 optionally bears on each CHa group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy, and wherein any hetetocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chioro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy. In another embodiment, in the compound of formula la, A is a group of the formula Z- (CR12R"V wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)a!kyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein any CHa or CEfe group within any of R12 and R13, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyl substituents or a substituent selected from hydroxy and (l-4Qalkoxy," and wherein Z is selected from hydrogen, OR15, NR16Rn and (l-6C)alkylsulfonyl( wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-4Qalkyl and (l-4C)aIkoxycarbonyl. For example, in an embodiment, Z is selected from hydrogen, hydroxy, methoxy, N-methylamino, N,N-dimethylamino, (N-methyl)-(N-tert-butoxycarbonyl)amino and methylsulfonyl (particularly Z is hydroxy). In another embodiment, in the compound of formula la, A is a group of the formula Z- (CR12R13y, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein any CH2 or CHa group within any of R12 and R13, optionally bears on each said CHz or CKb group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyI substituents or a substituent selected from hydroxy and (l-4C)alkoxy, and wherein Z is selected from hydrogen, hydroxy and (l-3C)alkoxy. For example Z is hydrogen or hydroxy, particularly Z is hydroxy. In another embodiment, in the compound of formula la, A is selected from methyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 2-hydroxyprop-2-yl. Particularly A is hydroxymethyl. In another embodiment, in the compound of formula la: misO; R3a is selected from fluoro, chloro and (l-3C)alkyl (for example R3a is chloro or methyl, particularly R3a is chloro); n is 0; X1 is selected from O and OCH2 (for example X1 is OCH2); R4, R4a, R5 and R5a are selected from hydrogen and (l-3C)alkyl, for example R4, R1, R5 and R5" are selected from hydrogen and methyl (for example R4 and R5a are hydrogen and one of R4 and R5 is methyl and the other of R4 and R5 is hydrogen or R4 and R4* are both hydrogen and R5 and R5* are both methyl); or R4 and R4* togemer with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring, or R5 and R5a together with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring; R6 is hydrogen or (l-3C)alkyl, for example R6 is hydrogen or methyl (a particular value for R6 is methyl); A is a group of the formula Z-(CR12Rl3)p-, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-3C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein Z is selected from hydrogen, hydroxy and (l-3C)alkoxy (for example Z is hydrogen or hydroxy, particularly Z is hydroxy). In another embodiment, in the compound of formula la: misO;R is selected from fluoro, chloro and (l-3C)alkyl (for example R3a is chloro or methyl, particularly R3a is chloro); n is 0; X1 is selected from O, OCH2 and OC(CH3)2 (for example X1 is OCH2); R4, R4a, R5 and R5a are selected from hydrogen and (l-3C)alkyl, for example R4, R48, R5 and R5a are selected from hydrogen and methyl (for example R4, R4, R5 and R5a are all hydrogen, or R4 and R5a are both hydrogen and one of R4 and R5 is methyl and the other of R4 and R5 is hydrogen, or R4 and R49 are both hydrogen and R5 and R5a are both methyl); R6 is selected from hydrogen, (l-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (3-5C)cycloalkyl, (3-5C)cycloalkyl-(l-3C)alkyl and heterocyclyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more (l-6C)alkyl substituents (for example R6 is hydrogen or methyl (a particular value for R6 is methyl)); A is selected from a group of the formula Z-(CR12R13)p- and R14, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, and wherein any CHa or CHa group within any of R12 and R13, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy (particularly hydroxy), Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (l-6C)alkoxycarbonyl, R14 is selected from OR19 and NR16R17, wherein R19 is selected from (l-6C)alkyl and wherein R16 and R17 are as defined above, orR14 is Q4 wherein Q4 is (3-7C)cycloalkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, hydroxy, (l-6C)alkyl and (l-6C)alkoxy (particularly (l-6C)a!kyl), and wherein any CHa or CHb group within a Z or R14 group, other than a Cfife group within a heterocyclyl ring, optionally bears on each said CHfe or CHa group one or morehalogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy (particularly a substituent selected from halogeno and hydroxy). Another particular embodiment of the present invention is a quinazoline derivative of the formula I of the formula Ib: J Ib wherein: R3" is selected from cyano, halogeno, (l-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl; Q1 is aryl, or heteroaryl, and wherein Q! optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, cd-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, M-(l-6C)alkylcarbamoyl, &H^-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)aIkenoylamino, H-d-6C)alfcyl-(3-6C)alkenoylamino, C3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l^C)alkylsulfamoyl,EN^-[(l-6C)allcyl]sulfamoyl,(l-6C)alkanesulfonylarnino, H-(l-6C)aikyl-(l-6C)alkanesulfonylamino, and a group of the formula: -X2-R8 wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyi, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (1 -6C)allcoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-(r-6C)alkylarnino-(l-6C)alkyl,H,H-di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, N-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl, carbamoyl-(l-6C)alkyl, N-0-6C)alkylcarbamoyl-(l-6C)alkyl, N^-di-[(l-6C)alkyl]carbamoy]-( l-6C)alkyl, (1-6C)alkylthio-(l-6C)alkyl,(l-6C)alkylsuJfinyl-(l-6C)alkyl, (l-6C)alky]sulfonyl-(l-6C)alkyl sulfamoyl(l-6C)aIkyl, N-(l-6C)aIkylsulfamoyl(l-6C)alkyl, N.N- di-(l-6C)alkylsulfamoyl(l-6C)aIkyl, (2-6C)alkanoyl-(l-6C)alkyl,(2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)aIkoxycarbonyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within -X"-Q1 optionally bears on each said CH2 or CHa group one or more (for example 1,2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)aIkylamino and di-[(l-4Qalkylamino]; R4, R4, R5 and R3a, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, and wherein any CHfe or CHs group within any of R4, R4, R5 and R5a optionally bears on each said CHfe or CHs group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)atkanoyl, (1-6C)alkylamino anddi-[(l-6C)alkylamino]; R6 is selected from hydrogen, (l-6C)alkylt (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl andheterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, m"tro, hydroxy, amino, fonnyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O, CO, SOa and N(Rn), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l^C)alkyl, (l-4C)alkoxy-(l-4C)aIkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-(l-4C)alkylamino-(l-4C)alkyl and H,H-di-[(l-4C)alkyl]amino-(l-4C)aUcyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy> carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyI, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N^-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyI-(2-6C)alkanoylamino, N-(l-6C)alkylsulfamoyl, N^i-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonyIamino; A is selected from hydrogen, a group of the formula Z-(CR12Rl3)p- and R14, wherein p is 1, 2,3, or 4, each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7Qcycloalkyl or (3-7C)cycloaIkenyl ring, and wherein any CH2 or CH3 group within any of Ru and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkyIamino and di-((l-6C)alkyl]amino> Z is selected from hydrogen, OR15, NR16R17, (l-6C)alkylsulfonyl, (l-6G)alkanesulfonylamino andN-(l-6C)alkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl, or Z is a group of the formula: Q"-X4- wherein X4 is selected from O, N(R18), SOa and SO2N(R18), wherein R18 is hydrogen or (1 -6C)alkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl, R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-SQalkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above, or R14 is a group of the formula: Q3-X5- wherein Xs is selected from O and N(R20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl--(l-6C)alkyl, or R14 is Q4 wherein Q4 is (3-7Qcycloalkyl, (3-7Qcycloalkyl-(l-6C)alkyl, (3-7Ocycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6Qalkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO* N(R21), CO, -C=C- and -GC-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl> (2-6C)alkanoyloxy and from a group of the formula: -X"-R22 wherein X6 is a direct bond or is selected from O, CO, SO2 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l~4C)alkyl, hydroxy-(l^C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, M-(l-4C)alkylamino-(l-4C)alkyl and H,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CEfeor CHa group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CHa or CEfe group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N^-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-£C)alkanoyloxy, (2-6C)alkanoylamino, HKl^Qal^H2-6C)alkanoylamino, N-(l-6C)alkylsulfamoyl, N,,M-di-[(l-6C)alkyl]sulfamoyl, (l-6QaIkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof. Another particular embodiment of the present invention is a quinazoline derivative of the formula I of the formula lb, wherein: R3a is selected from hydrogen, fluoro, chloro, trifluoromethyl, (l-3C)alk;yl, (1-3C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl; Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl, optionally substituted by 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (l-4C)alkoxy; R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (I~3C)alkyl, and wherein any CH2 or CH3 group within any of R4, R4, R5 and R5 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-3C)alkoxy; R6 is selected from hydrogen and (l-4C)alkyl; A is a group of the formula Z-(CR12R13)P- , wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4Qalkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein any CHa or CEb group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, and (l-3C)alkoxy, Z is selected from hydrogen, OR15 and NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, and wherein any CH2or CH3 group within a Z group optionally bears on each said CHa or CH3 group one or more fluoro or chloro substituents or a substituent selected from hydroxy, (2-4C)alkenyl, (2-4C)alkynyl and (l-4C)a!koxy; or a pharmaceutically acceptable salt thereof. In an embodiment, in the compound of formula Ib, R3a is selected from hydrogen, chloro and (l-3C)alkyl, particularly R3a is chloro or (l-3C)alkyl (such as methyl), more particularly R3a is chloro. In another embodiment, in the compound of formula Ib, Q1 is selected from phenyl optionally substituted with 1 or 2 substituents selected from fluoro and chloro, or Ql is selected from 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl, 1,3-tniazol-5-yl and isoxazol-3-yl (particularly 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 1,3-thiazol-4-yl and isoxazol-3-yl), and wherein Ql optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (1-4C)alkoxy. In another embodiment, in the compound of formula Ib, Q1 is pyridyl (for example 2-pyridyl or 3-pyridyl, particularly 2-pyridyl). In another embodiment, in the compound of formula Ib, R4, R4", R5 and R5" are selected from hydrogen and (l-3C)alkyl, for example R4, R4, Rs and R5a are selected from hydrogen and methyl. In another embodiment, in the compound of formula Ib, R4, R4, R5 and R5* are all hydrogen. In another embodiment, in the compound of formula Ib, R4, R5 and R5 are hydrogen and R4 is (l-3C)alkyl, for example methyl. In another embodiment, in the compound of formula Ib, R4, R4* and R5a are hydrogen and R5 is (l-3C)alkyl, for example methyl. In another embodiment, in the compound of formula Ib, R4 and R4* are both hydrogen and R5 and R5a are both (l-3C)alkyl, for example methyl. In another embodiment, in the compound of formula Ib, R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl and cyclopropylmethyl, and wherein any CHa group within a cycloalkyl group within R6 optionally bears on each CH2 group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy, and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy. In another embodiment, in the compound of formula Ib, A is a group of the formula Z- (CR12R1V, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (MC)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein any CH2 or CH3 group within any of R12 and R13, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy, and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-4C)alkyl and (l-4C)alkoxycarbonyl. For example, in an embodiment, Z is selected from hydrogen, hydroxy, merhoxy, N-methylamino, N^-dimethylamino, (N-memylHN-Jert-butoxycarbonyI)amino and methylsulfonyl (particularly Z is hydroxy). In another embodiment, in the compound of formula Ib, A is a group of the formula Z-(CR12R13)p-, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein any CH2 or CHa group within any of R12 and R13, optionally bears on each said CBfe or CHa group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy, and wherein Z is selected from hydrogen, hydroxy and (l-3C)alkoxy. For example Z is hydrogen or hydroxy, particularly Z is hydroxy. In another embodiment, in the compound of formula Ib, A is selected from methyl and hydroxymethyl. Particularly A is hydroxymethyl. In another embodiment, in the compound of formula Ib, A is a group of the formula Z- (CR12R13V, wherein p is 1 or 2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring, and wherein Z is NR16R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen and (l-4C)alkyl (for example Z is selected from amino, H-methylamino and N^J-dimethylamino, particularly Z is N^J-dimethylamino). In another embodiment, in the compound of formula Ib: Q1 is pyridyl (for example 2-pyridyl); R3* is selected from chloro and methyl (particularly R3* is chloro); R4, R4, R5 and R5, which may be the same or different, are selected from hydrogen and methyl; and A is a group of the formula ZKCR^R13),-» wherein pis 1 or2, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-3Qalkyl (for example R12 and R13 are selected from hydrogen and methyl), and Z is selected from hydrogen, and hydroxy (particularly Z is hydroxy). A particular embodiment of the present invention is a quinazoline derivative of the formula I of the formula Ic: (Figure Removed)herein: R3a is selected from cyano, halogeno, (l-4C)alkyl, triflupromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl; n is 0,1 or 2; each R3b, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl; R3a is selected from halogeno and (l-4C)alkyl; R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, or R4 and R4a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, or R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, and wherein any CH2 or CH3 group within any of R4, R4, R5 and R5 optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino]; R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloaIkenyl, (3-7Qcycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: wherein X3 is a direct bond or is selected from 0, CO, SOa and N(R11), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, M-(l-4C)alkylamino-(l-4C)al]cyl and H^-di-[(l-4C)alkyl]amino-(l-4C)alkyi, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and wherein any CHj or CHj group within a R6 substituent, other than a CEfe group within a heterocyclyl group, optionally bears on each said CHa or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, v crboxy, jarbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alleylsu]fonyI, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, £Hl-6C)aIkylcarbamoyl, N£-di-[(l-6C)alkyl]cart>amoyl, (2-6C)alkanoyl, (2-6C)a]kanoyIoxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, H-(l-6C)alkyisuIfamoyl, N^{-di-[(l-6C)alkyl]sulfamoyl( (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesuIfonyIamino; A is selected from hydrogen, a group of the formula Z-(CRl2R13)p- and R14, wherein p is 1,2, 3, or 4, each Ri2 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyI ring, and wherein any CHa or CHa group within any of R12 and R13, optionally bears on each said CH2 or CEfe group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, ammo, (2-6C)alkanoyI, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, Z is selected from hydrogen, OR15, NRI6R17, (l-6C)alkylsulfonyl, (l-oX^alkanesulfonylamino andN-(l-6XH)alkyKl-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyI, (2-6C)alkynyl and (l-6C)alkoxycarbonyI, or Z is a group of the formula: Q2-X- wherein Xis selected from O, N(R18), SOz and SOzNfR18), wherein R18 is hydrogen or (l-6C)a!kyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl orhetetocyclyl, R14 ia selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above, or R14 is a group of the formula: Q3-X5- wherein X5 is selected from O andN(R20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloaIkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl,(3-7C)cycloalkyHl-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituenl are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R21), CO, -C=C- and -C=C-, wherein R21 is hydrogen or (l-6C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent 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, ammo, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6Qalkylamino, di-tCl-eQalkyllamino, (2-6C)alkanoyl, (2-6C)alkanoyIoxy and from a group of the formula: -X"-R22 wherein X6 is a direct bond or is selected from O, CO, SO2 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4Qalkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-(l-4C)alkylaniino-(l-4Qalky] and H^-di-[(l-4C)a!kyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and wherein any CH2 or CHb group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsuIfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyI, &N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylainino, Ji-(l-6C)alkyl-(2-6C)alkanoylamino, JS-(l-6Qalkylsulfamoyl, H.N-di-[(l-6C)alkyl]suIfamoyl, (l-6C)alkanesulfonylamino and £J-(l-6C)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof. In another embodiment, in the compound of formula Ic, n is 0 and R3a is selected from halogeno, trifluoromethyl, (l-4C)alkyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl. Particularly R3a is selected from halogeno and (l-3C)alkyl, more particularly R3a is selected from chloro and methyl, still more particularly R3a is chloro. In this embodiment n is suitably 0 or !>.• Particularly .-Q: is Q. .1 , In another embodiment, in the compound of formula Ic, R3c is (l-4C)alkyl, particularly methyl. In another embodiment, in the compound of formula Ic, R4, R4a, R5 and R5a are selected from hydrogen and (l-3C)alkyI, for example R4, R4, R5 and RSa are selected from hydrogen and methyl. In another embodiment, in the compound of formula Ic, R4, R4a, R5 and R5a are all hydrogen. In another embodiment, in the compound of formula Ic, R4a, R5 and R5a are hydrogen and R4 is (l-3C)alkyl, for example methyl. In another embodiment, in the compound of formula Ic, R4, R4 and R5a are hydrogen and R5 is (l-SC)alkyl, for example methyl. In another embodiment, in the compound of formula Ic, R4 and R48 are both hydrogen and R5 and R5" are both (l-3C)alkyl, for example methyl. In another embodiment, in the compound of formula Ic, Rti is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyHl-6€)alkyl, heterocyclyl and heterocyclyHl-6C)alkyl, wherein any heterocyclyl group within R6 is a 4, S, 6 or 7 numbered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, and from a group of the formula: -X3-R10 wherein X3 is a direct bond or is selected from O and N(RU), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and H^-^-[(l-4C)alkyl]amincKl-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents. In another embodiment, in the compound of formula Ic, R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyI, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-4C)alkyl, heterocyclyl and heterocyclyl-(l-4C)alkyl,wherein any heterocyclyl group within R6 is a 4, 5, 6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and wherein any heterocyclyl group within an R6 substiruent optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, hydroxy, (MQalkyl, (2-4C)alkenyl, (2-4C)alkynyl and (l-4C)alkoxy, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 oxo substituent, and wherein any CHa or CH3 group within a R6 substituent, other than a CHj group within a heterocyclyl group, optionally bears on each said CHa or CBb group one or more substituents selected from fluoro and chloro, or a substituent selected from hydroxy and (l-4C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]arnino. In another embodiment, in the compound of formula Ic, R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl and cyclopropylmethyl, and wherein any CH2 group within a cycloalkyl group within R6 optionally bears on each CHa group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy, and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy. In another embodiment, in the compound of formula Ic, A is a group of the formula Z- (CR12R13)P-, wherein p is 1 or 2, each R12 andR13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl, or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyI ring, and wherein any CHa or CH? group within any of R12 and R13, optionally bears on each said.CHa or CHa group one or more (for example 1,2 or 3) halogeno or (l-4C)allfyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy, and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-4C)a!kyl and (l-4Qalkoxycarbonyl. For example, in an embodiment, Z is selected from hydrogen, hydroxy, methoxy, N-methylamino, N,N-dimethylamino, (N-methyl)-(N-tert-butoxycarbonyl)amino and methylsulfonyl (particularly Z is hydroxy). A particular compound of the invention is, for example, one or more quinazoline derivatives of the formula I selected from: AT-{2-[(4-{3-chloro^Kpyridin-2-ylmemoxy)aiiiUno}qiiinazolin-5-yl)oxy]ethyl}-2-methoxy-N-methylacetamide; N-{2-[(4-{3 N-{(2J?>2-[(4-{3^hloro-4^yridin-2-ymiethoxy)anilino}quinazomi-5-yl)oxy]prop }~2-meffloxy-tf-inethylacetamide); 2-hydroxy-N-n»myl-^-{2-[(4-{3-methyl^(pyrazin-2-ylmemoxy)anilirH)}quinazolin-5-yl)oxy]ethyl} acetamide; 2-hydroxy-W-mernyl-#-{2-[(4-{3-mernyl-4Kl,3^ yl)oxy]ethyl} acetamide; 2-hydroxy-iV-methyl-JV-(2-{[4-(3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]anilino)quinazolin-5-yl]oxy}ethyl)acetamide; JV-{(2^)-2-[(4-{3^hloix)^(pyiidin-2-ylinfimoxy)anilmo}qiiinazolm-5-yl)oxy]piopyl}-^^ methoxyacetamide; ^K2-{[4-(3-chloro^[(6-memylpyridin-2-yl)methoxy]animio)quma2olm-5-yl]oxy}emyl)-2- hydroxy-JV-methylacetamide; ^-((2^)-2-{[4-(3 ynoxyJpropylH-hydroxy-W"-methylacetamide-, ^^2-{[4-(3-chloro^[(6^memylpvridin-2-yl)memoxy]anilmo)qumazo^ methylacetamide; N-(2-{[4^3^hloro-4-[(2-fluorobenzyl)oxy]amlmo)quinazolm-5-yl]oxy}ethyl>^ methylacetamide; N-(2-{[4 methylacetamide; /V-{2-[(4-{3-chIoro-4-(l,3-thiazol-4-ylmethoxy)anilino}quinazo)in-5-yl)oxy]ethyl}-N- rnethylacetamide; /y_{ 2-[(4- { 3-chloro-4-(pyrazin-2-ylmethoxy)anilino }quinazolin-5-yl)oxy]ethyl }-N- methylacetamide; N- { (27?)-2-[(4- { 3-chIoro-4-(pyridin-2-ylmethoxy)anilino } quinazolin-5-yl)oxy]propyl } -2- hydroxyacetamide; ^-{2-[(4-{3-chIoro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-]V- methylacetamide; 2-hydroxy-Ar-methyl-A^-{2-[(4-{3-methyl-4-(pyridin-2-yltnethoxy)anilmo}quinazoHn-5- yl)oxy]ethyl}acetamide; ^-{(l/?)-2-[(4-{3-chloro-4-(pyridiii-2-ylmethoxy)aralino}qiunazolin-5-yl)oxy]-l- methylethyl}acetamide; methylethyl }-2-hydroxyacetamide; W-{2-[(4-{3^hloro^(pyridin-2-yln»oxy) methylacetamide; N-(2-{[4-(3-cWc«)^-[(3-fluorobenzyl)oxy]aniUno)qidriazolin-5-yl]oxy}e1hyl>2-hydK)xy-^^ methylacetamide; N-{2-[(4-{3^Wcm>^(13-thiazol-4-yImethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-^V-methylacetamide; JV-{2-[(4-{3-cMoro^-(pynizin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-N-methylacetamide; N-{2-[(4-{3-chlon>-4-(pyridin-2-ylmethoxy)anilmo}quinazolm-5-yl)oxy]ethyl}acetamide; N-{(2^)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilmo}quinazolin-5-ylX>xy]propyl}acetamide; JV-{(2jR)-2-[(4-{3-chloro-4-(pyridm-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-N-methylacetamide; N- { (2/?>2-[(4- { 3-chloro-4-(pyra2in-2-ylmethoxy)anilino } quinazolin-5 -yl)oxy]propyl } -2-hydroxy-]V-methylacetamide; N-((2/?)-2-{[4-(3-chloro-4-[(3-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}propyl)-2-hydroxy-N-methylacetamide; AT-{(2R)-2-((4-{3-chloro-4-(l,3-thiazol-4-ylmethoxy)anilino}qumazolm-5-yl)oxy]propyl}-2-hydroxy-N-methylacetamide; N- {(2R}-2- [(4- {3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl} -N- raethylacetamide; N- {2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino} quinazolin-5-yl)oxy]ethyl} -N- ethylacetamide; AT-{2-[(4-{[3K;hlQro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoUn-5-yl)oxy]ethyl}-A^ ethyl-2-hydroxyacetamide; ^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5--yl)oxy]ethyl}-^- propylacetamide; N-{2-[(4-{[3-chloro-4^yridin-2-ylmethoxy)ph^ hydroxy-^V-propylacetainide; ^-(2-[(4-{ [3^hloro^pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl }-JV- isopropylacetamide; N-{2-[(4-{[3^hloro^-(pyridn-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyI}-2- hydroxy-^V-isopropylacetamide; N-allyl-^-{2-[(4-{[3-cWoro^(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5- yl)oxy]ethyl} acetamide; 7/-allyl-N-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl} -2-hydroxyacetamide; ^-{2-[(4-{[3K;Woro^ cyclopropylacelamide; //-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-^V- cyclopropyl-2-hydroxyacetamide; N-{2-[(4-{[3-chloro^-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-^^ (cyclopropylmethyl)acetamide; jV-{2-[(4-{[3-chloit>4-(pyridin-2-ylinethoxy)phenyl]ainino}quinazolin-5-yl)oxy]ethyl}-^- (cyclopropylmethyl>2-hydroxyacetamide; N- {2-[(4-{ [3-chloro-4-(pyridin-2-ylmelhoxy)phenyl3amino }quinazolin-5-yl)oxy]ethyl }-N- cyclobutylacetamide; N~{2-[(4-{ [3-chloro^-(pyridin-2-ylmethoxy)phenyllamino }quinazolin-5-yl)oxy]ethyl }-N- cyclobutyl-2-hydroxyacetamide; ^.{2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-AL(l- methylpiperidin-4-yl)acetamide; jV-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIin-5-yl)oxy]ethyl}-N- (tetrahydro-2H-pyran-4-yl)acetamide; ^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]ainino}quina2olin-5-yl)oxy]ethyl}-2- hydroxy-N-(tetrahydro-2H-pyran-4-yl)acetamide; N- {2-1(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -N-(2- hydroxyethyl)acetamide; A/r-{2-[(4-{[3-cWoro^(pyridin-2-ylmethoxy)phenyllamino}quinazolm-5-yl)oxy]ethyl}-2- hydroxy-N-(2-hydroxyethyl)acetamide; Wr-{2-[(4-{[3-chloro^(pyridin-2-ylmethoxy)phenyl]anrino}quinazolin-5-yl)oxy]ethyl}-N-(2- methoxyethyl)acetamide; N-( 2-[(4- {[3^hl hydroxy-N-(2-methoxyethyl)acetaniide; AT-{2-[(4-{[3^hloro^-(pyridiii-2-yImethoxy)phenyl]aiiuno}quinazolin-5-yl)oxy]ethyl}-N- prop-2-yn-l-ylacetamide; N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino }quinazolin-5-yl)oxy]ethyl} -2- hydroxy-JV-prop-2-yn-l-ylacetamide; N-{ 2-[(4-{ [3-chIoro-4-(pyridin-2-ylinethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl}-2- hydroxy-N-methylpropanamide; AT-{2-[(4-{[3^hloro^(pyridin-2-ylmelhoxy)phenyl]arnino}quinazo!in-5-yl)oxy]ethyl}-N- methyl-tetrahydrofuranyl-2-carboxamide; A/"-{2-[(4-{[3K;hIoro^(pyridin-2-ylmethoxy)phenyl]aniino}qiunazolin-5-yl)oxy]ethyl}-N,l- dimethylprolinamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-Ar,2-dimethylpropanamide; 7^-{2-[(4-{[3^hlor(>4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-l- bydroxy-Ar-methylcyclopropanecarboxamide; Nl-{ 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl }- N1 jV2-dimethylglycmamide; AM 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -3- hydroxy-M2,2-triraethylpropanamide; N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-ylX)xy]ethyl} -3- hydroxy-N-methylpropanamide; N-{(25)-2-[(4-{[3-chloro-4-(pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl} acetamide; N-{ (2S)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phcnyl]amino }quinazolin-5- yl)oxy]propyl}-2-hydroxyacetaniide; Nl-{ (2S)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phwiyl]amino}quinazolin-5- yl)oxy]propyl} -JV2 J^-dimethylgiycinamide; N-{ (25)-2-[(4-{ [3-chl«x>-4-(pyriclin-2-ylinethoxy)phenyl]ainino}quinazolin-5- yl)oxy]propyl} -2-methoxyacetamide; N-{ (25>2-[(4-{ [3^hlc>ro-4^pyridin-2-ylinethoxy)phenyl]ainino}quinazolin-5- yl)oxy]ptopyl} -2-(methylsulfonyl)acetamide; ^-{2-[(4-{[3^hl(m>-4^yri(tin-2-ylinrthoxy)phenyl]aiiriiK)}qomazoUn-^ hydroxyacetamide; AT1-{2-[(4-{[3^Waro^pyridin-2-yktiethoxy)phenyl]aniiiK>}qira A^^-dimethylglycinainide; ^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phCTyl]amino}quinazoUn-5-yl)oxy]ethyl}^ methoxyacetaraide; AT-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]aimno}quinazoUn-5-yl)oxy]e^ (methylsulfcmyl)acetamide; A/^-{(25)-2-[(4-{[3K;hloix)^(pyridin-2-yImethoxy)phenyl]amino}qumazolin-5- yl)oxy]propyl}-JV-metihylacetamide; ^-{(25)-2-[(4-{[3^hloK>4^yridin-2-ylniethoxy)phenyl]ainino}quinazolm-5- yl)oxy]propyl}-2-hydroxy-JV-methylacetamide; JV1-{(2^2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]aniino}quinazolm-5- yl)oxy]propyl}-Nl^JV2-trimethylglycinainide; A^{(2^2-[(4-{[3-cWoro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- ylX>xy]propyl} -2-methoxy-N-methylacetamide; N- {(25>2-[(4- {[3-chloro-4-(pyridin-2-ylmcthoxy)phenyl]amino }quinazolin-5- yl)oxy]propyl}-JV-methyl-2-(methylsulfonyl)acetaniide; N-{ (2K)-2-[(4- { [3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]propyl } -W-methylacetamide; /\r-{(2/?)-2-[(4-{[3-chIoro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl } -AT-methylacetamide; N-((2R)-2-{ [4-( {3-chloro-4-[(3-fluorobenzyl)oxy]phenyl } amino)quinazolin-5- yl]oxy } propyl)-W-methyl acetamide; ^-((2/?)-2-{[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}aniino)quinazolin-5- yl]oxy } propyl)-A^-methylacetamide; N-{(l/?)-2-l(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]anuno}quinazolin-5-yl)oxy]-l- methylethyl}-2-hydroxy-?/-methylacetamide; A^{(l/?)-2-[(4-{[3-chloro^pyridin-2-ylrnetlioxy)phenyl]amino}quinazolin-5-yl)oxy]-l- methylethyt}-N-methylacetamide; AT-{(l,S)-2-[(4-{[3-chloro-^pyridin-2-ylmethoxy)phenyl]ainino}quinazolin-5-yl)oxy]-l- methylethyl}-2-hydroxy-N-methylacetamide; ^-{(15^2-[(4-{[3^hlon>-4^yridin-2-ylmethoxy)phenyl]aiiiino}quina2olin-5-yI)oxyl-l- methylethyl }-JV-methylacetamide; N-{(lS)-2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l- methylethyI}-2-methoxy-N-methylacetamide; N-{(15)-2-[(4-{[3-chlon>^pyridin-2-ylinethoxy)phenyl]aniino}quinazolin-5-yl)oxy]-l- methylethyl}-2-hydroxyacetamide; ^-{(15)-2-[(4-{E3-chlon)^(pyridin-2-ylinethoxy)ph«iyl]aniino}quinazoIin-5-yl)oxy]-l- methylethyl } acetamide; methylethylJ-^^-dimethylglycinamide1, JV1-{(2^>2-[(4-{[3^hloro-4-(pyridm-2-ylmethoxy)phenyl]ainino}quina2olin-5- yl)oxy]propyl } -N2 ^-dimethylglycinamide; (2S)-AT-{2-[(4-{[3 2,4-dihydroxybutanamide; (2R)-N-{ 2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl}- 2,4-dihydroxybutanamide; (2/?)-AH(2/?)-2-[(4-{[3^fopro-4-(pyrid yl)oxy]propyl}-2,4-dihydroxybutanamide; (2S)-N-{ (2tf )-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5- yl)oxy]propyl} -2,4-dihydroxybutanamide; (2/?)-A^{(25r)-2-[(4-{[3-ch1oro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl} -2,4-dihydroxybutanamide; (2S)-N- {(25>2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino }quinazolin-5- yl)oxy\|propyl} -2,4-dihydroxybutanamide; (25)-JV-{(l/?)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]arnino}quinazo]in-5-yl)oxy)- 1-methylethyl }-2,4-dihydroxybutanamide; (2R)-^{(l/0-2-[(4-{[3-chlon>4-(pyridm^ 1-methylethyl }-2,4-dihydroxybutanamide; (2/0-#-{2-[(4-{[3-cMoro-4-(l,3-tm"azol-4-ylm^ ylX>xy]ethyl} -2,4-dihydroxybutanamide; (2S)-N- {2-[(4- {[3-chloro-4-(13-thiazol-4-ylmethoxy)phenyl]amiiio }quinazoIin-5- yl)oxy]ethyl}-2,4-dihydroxybutanamide; (2J?)-^-{(l/?)-2-[(4-{[3-cWoro-4^13-^^ol-4-ymiethoxy)pb^ayl]ainino}qi^ yl)oxy]-l-memylemyl}:2t4-dihydhx)xybiitanainide; (2S)-N-{(lR)-2-[(4-{ [3HJhloro-4K13-miazol-4-ylmeajoxy)phenyl]amino} quinazolin-S- yl)oxy]-l-methylethyl}-2,4-dihydroxybutanamide; yV-memyl-N-{2-[(4-{[3-memyl-4-^yridin-2-ylmethoxy)phenyl]anrino}quinazolin-5- yl)oxy]ethyi} acetamide; JV-methyl-A^-{2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazoKn-5- yl)oxy]ethyl }acetamide; quinazolin-5-yl]oxy}ethyl)acetamide; 2-hydroxy-N-rnethyl-JV-{2-[(4-{[3-methyl-4-(l,3-thia2ol-2-yImethoxy)phenyl] amino} quinazolin-S-yl)oxy]ethyl} acetamide; 2-hydroxy-N- {2-[(4-{ [3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolm-5- yl)oxy]ethyl} acetamide; 2-hydroxy-A^{2-[(4-{[3-memyl^(l,3~thiazol^ylmemoxy)phenyl]amino}quinazolin-5- ylX>xy]ethyl} acetamide; ^-{2-[{4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]aniino}quinazolm-5-y^ dimethylethyl} -2-hydroxyacetamide; 2-hydroxy-A^-{(2/?)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}qoina2olm-5- yl)oxy]propyl} acetamide; 2-hydroxy-/V-{(2/?)-2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin- 5-yl)oxy]propyl} acetamide; N-((2/?)-2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)quiiiazolin-5- yljoxy }propyl)-2-hydroxyacetamide; 2-hydroxy-N-{(2^)-2-[(4-{[3-methyl-4-(l,3-thiazol-2-ylmethoxy)phenyl]amino}quinazoIin- 5-yl)oxy]propyl} acetamide; AT-{(2/?)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- y l)oxy]ptopyl} acetamide; N- {(2K)-2-[(4-{ [3-methyl-4-(l ,3-thiazol-4-ylmethoxy)phenyl]ainino }quinazolin-5- yl)oxy]propyl} acetamide; N-((2R)-2- ([4-( {4-[(3-fluorobenzyl)oxy]-3-methylphenyl} amino)quinazolin-5- yl]oxy }propyl)acetamide; N- {(2/?)-2- [(4- {[3-methyl-4-(l 3-thiazol-2-ylmethoxy)phenyl]amino }quinazolin-5- yl)oxy]propy 1} acetamide; 2-hydroxy-AT-niethyl-N-{(2R>2-[(4-{[3-methyl-4-(pyridin-2--ylmethoxy)phenyl] amino}quinazolin-5-ylX>xy]prq)yl}acetamide; 2-hydroxy-AT-methyl-^-{(2R)-2-[(4-{[3-methyl-4.(U-thiazol-4- ylmethoxy)phenyl]amino}qumazolin-5-yl)oxy]propyl}acetamide; 2-hydroxy-#-methyl-jV-((2/0-2-{ [4-({ 3-methyl-4-[(5-methylisoxazol-3- yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; A^methyl-//-{(l/?)-l-methyl-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl] ammo }quinazolin-5-yl)oxy]ethyl} acetamide; N-mefoyl-N- {(IK)- l-methyl-2-[(4- {[3-methyl-4-(l ,3-thiazol-4- ylmethoxy)phenyl]amino}quinazotin-5-yl)oxy]ethyl}acetamide; JV-{(l/?)-2-[(4-{[3-chloro^(13-tWazol-4-ylmethoxy)phenyl]amino}quina2olin-5-yl)oxy]-l- methylethyl} -2-hydroxy-AT-methylacetamide; 2-hydroxy-A^-methyl-AT-{ (l/?)-l-metbyl-2-[(4-{ [3-methyl-4-(pyridin-2- ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl }acetamide; ylmethoxy)phenyl]amino}qumazolm-5-yl)oxy]ethyl}acetamide; N- { (2K)-2-[(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- ylX>xy]propyl}-l-hydroxy-N-methylcyclopropanecarboxamide; (25)-N-{(2/?)-2-[(4-{[3-chloro-4-(pyridin-2-y]methoxy)phenyl]an)ino}quinazolin-5- yl)oxy]propyl } -2-hydroxy-N-methylpropanamide; ^-{(2J?)-2-[(4-{[3-chloro-4-(pyridin-2-ylrnethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl } -2-hydroxy-JV,2-dimethylpropanamide; (2R)-N~ { (lR)-2-[(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino }quinazolin-5- yl)oxy]propyl } -2-hydroxy-JV-methylpropanamide; (2/?)-Ar-{(2l?)-2-[(4-{[3^hloro-^(pyridin-2-ylmethoxy)phenyI]ainino}quina2olin-5- yl)oxy]propyl } -2-methoxy-JV-metfiylpropanamide; 2-hydroxy-Ar-methyl-7V-((2/?)-2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ajnino)quinazolin-5-yl]oxy}propyl)acetainidc; N-mett\y\-N-((2R)-2-{ [4-({ 3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl } amino)quinazolin- 5-yl]oxy}propyl)acetamide; yl)oxy]phenyl}amino)quinazolin-5-y]]oxy}propyl)glycinamide; M-methyl-M-((2l?)-2-{[4-({3-rr»thyl^[(6-methylpyridin-3-yl)oxy]phenyl}amino)q^^ 5-yl]oxy}propyl)-2-pyrrolidin-l-ylacetamide; 5-yl]oxy}propyl)-2-moiphoKn-4-ylacetaniide; JV-me%l-/H(2/?)-2-{[4-({3-meAyl^ 5-yl]oxy}ptopyl)-2-(4-methylpiperazin-l-yl)acetamide; 2-hydroxy-Ar-methyl-^-((25)-2-{[4-({3-methyl-4-[(6-tnethylpyridin-3- yl)oxy]phenyl } amino)quinazolin-5-yl]oxy }propyl)acetamide; A>r-methyl-A/-((2S)-2-{[4-({3-ira^^ 5-yl]oxy}propyl)acetamide; ^-methyl-A^((25)-2-{[4-({3-methyl^[(6-methylpyridin-3-yl)oxy]phenyl}anuno^ 5-yl]oxy}propyl>2-pyrrolidin-l-ylacetamide; (25)-2,4-dihydroxy-^V-((2/?)-2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl } amino)quinazolin-5-yl]oxy}propyl)butanainide; (25)-4-bromo-2-hydroxy^-((2/?)-2-{[4-({3-tnethyl-4-E(6-methylpyridin-3- yl)oxy]phenyl } amino)quinazolin-5-yl]oxy }propyl)butanamide; ,V-(2-chloroethyl)-^V-((2^)-2-{[4-({3-raethyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}arnino)quinazolin-5-yl]oxy}propyl)urea; 2-hydroxy-A^-methyl-//-((l^)-l-methyl-2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl} amino)quinazolm-5-yl]oxy }ethyl)acetamjde; TV-methyl-W-K!/?)-! -raethyl-2- {[4-({ 3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl} amino)quinazoHn-5-yl]oxy }ethyl)acetamide; 2-hydroxy-//-methyl-^-((15)-l-methyl-2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl} ainino)quinazolin-5-yl]oxy }ethyl)acetamide; 7V-methyl-Ar-((15)-l-methyl-2-{[4-({3-niethyl-4-[(6-methylpyridin-3- yl)oxy]phenyl} atnino)qumazolin-5-yl]oxy }ethyl)acetamide; methyl-{2-[(4-{[3K;hloro^-(pyridin-2-ylniethoxy)phenyl]ainino}quina2olin-5- yl)oxy]ethyl }methylcarbamate; N-{ 2-[(4- {[3-chloro^(pyridin-2-ylme(hoxy)phejiyl]amino}quinazolin-5-yl)oxy]ethyl} - dimethylurea; ^^2^hloroethyl>-^-{2-[(4-{[3^hl(»o-4^yridin-2-ylmethoxy)phenyl]aniino}qm^ yl)oxy]cthyl }-#-methylurea; N-{ (2R)-2-[(4-{ [3-chloro-4-(pyridin-2-ylinethoxy)phenyl]ainino }quinazo!in-5- yl)oxy]propyl} -JV-methylurea; [((/?)-2-{4-f3^hloro-4^yridin-2-ylmethoxy)phenylaniino]quinazolm-5- yloxy}propylcarbamoyl)methyl]mcthylcarbamic acid Jraj-butyl ester, Nl- {(2R)-2-[(4- {[3-chlofo-4-(pyridin-2-yImethoxy)phenyl]amino }quina2»lin-5- yl)oxy]propyl J-^-methylgJycinamide; 2-hydroxy-JV-methyl-A^-(2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl} amino)quinazolm-5-yl]oxy }ethyl)acetamide; Ar-niethyl-JV-(2-{ [4-( {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl} amino)quinazoIin-5- yl]oxy}ethyl)acetamide; and ^V-{2-[(4-{[3-chloro-4-(l-methyl-l-pyridin-2-ylethoxy)phenyI]amino}quinazolin-5- yl)oxy]ethyl} -JV-methylacetamide; or a pharmaceutically acceptable salt thereof. A particular compound of the invention is, for example, one or more quinazoline derivatives of the formula la selected from: A^-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-methoxy- A/-methylacetamide; //-{2-[(4-{3-chloro-4-(pyridin-2-ylinethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2- (dimethylamino)-JV-methylacetamide; JV-{(2J?)-2-[(4-{3^hloit)^(pyridin-2-ylm^hoxy)anilino}quinazolin-5-yl)oxy]propyl)-2- roethoxy-JV-methylacetamide); 2-hydroxy-A/r-methyl-/V-{2-[(4-{3-raetty^ yl)oxy]ethyl } acetamide; 2-hydroxy-AT-nwlhyl-yV-{2-[(4-{3-methyl^(13-thiazol^ylniethoxy)anilino}qumazolin-5- yl)oxy]ethyl } acetamide; 2-hydroxy-AT-metfiyl-^-(2-{[4-(3-metfiyl-4-[(5-methylisoxazol-3- yl)methoxy]anilino)quinazoUn-S-yl]oxy}ethyl)acetaniide; ^-{(2J?)-2-[(4-{3^hloro^pyridin-2-ylmeihoxy)aniHno}quina2oIiii-5-yl)o^ methoxyacetamide; ^-(2-{[4^3n;hl hydroxy-JV-methylacetamide; ylloxyJpropyl^-hydroxy-N-metbylacetamidc; ^-(2-{[4^3^hloro^[(6-methylpyridin-2-yl)methoxy]aiulino)quinazoUn-5-yi]o^^ metiiylacetamide; N-(2-{ [4^3K;hlon)^-[(2-fluorobenzyl)oxy]anilino)quinazoliii-5-yl]oxy }ethyl)-N- methylacetamide; ^(2-{[4-(3^Woro^[(3-fluorobenzyl)oxy]aiiilino)quina2olin-5-yl]oxy}ethyl)-N- methylacetamide; //-{2-[(4-{3^hloro^(l,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-JV- methylacetamide; methylacetamide; A^-{(2/?)-2-[(4-{3^hloro^(pyridin-2-ylmethoxy)aniUno}quinazoUn-5-yl)oxy]propyl}-2^ hydroxyacetamide; A^{2-[(4-{3^Woro-4-(pyridin-2-ylroethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-^ methylacetamide; 2-hydroxy-N-methyl-N-{2-[(4-{3-methyl-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5- yl)oxy]ethyl} acetamide; N-{ (l/?>2-[(4-{ 3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l- methylethyl} acetamide; N-{(l/?)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l- methylethyl}-2-hydroxyacetamide; N- {2-[(4-{ 3-chloro-4-(pyridin-2-ylraethoxy)anilino }quinazolin-5-yl)oxy]ethyl} -2-hydroxy-W-methylacetamide; N-(2- {[4- ^-{2-[(4-{3^Woro^-(13-thiazol-4-ylmethoxy)anUmo}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-AT-methylacetamide; N-{2-[(4-{ 3-chlwro-4-(pyrazin-2-yhnethoxy)anilmo }quinazolin-5-yl)oxy]ethyl }-2-hydroxy-A^-methylacetamide; ^-{2-[(4-{3 N-{ (2R)-2-[(4-{ 3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl} acetamide; JV-{(2/f)-2-[(4-{3^hloio^(pyridiiv2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-^V-methylacetamide; j/V-{(21?)-2-[(4-{3KJhloro^(pyrazin-2-ylinethoxy)anilino}quinazolm-5-yl)oxy]propyl}-2-hydroxy-JV-methylacetamide; ^(21?)-2-{[4 ^V-{(2/?)-2-[(4-{3-chloro-4-(l,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxy]piopyl}-2-hydroxy-A^-methylacetamide; JV-{(2^)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl}-^-methylacetamide; W-{2-[(4~{[3-chloro-4-(pyridin 2-ylmethoxy)phenyl]aimno}quuiazolin-5-yl)oxy]ethyl}-A/r-ethylacetamide; -{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-A"r-ethyl-2-hydroxyacetamide; A/r-{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]araino}quinazolin-5-yl)oxy]ethyl}-Ar-propylacetamide; Ar-{2-[(4-{[3-chloro-4-(pyridin-2-ylroethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-W-propylacetamide; ^-{2-[(4-{[3 isopropylacetamide; ^-{2-[(4-{[3^;hloro^-(pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-AMsopropylacetamide; N-ally\-N~{ 2-[(4- {[3-chloro-4-^>yridin-2-ylmetfioxy)phenyl]amino }quinazolin-5- yl)oxy]ethyl}acetamide; yV-allyl-JV-{2-[(4-{[3-chloit)^(jpyridin-2-ylniethoxy)phenyl]amino}quina2olin-5- yl)oxy]ethyl} -2-hydroxyacetamide; JV-{2-[(4-{ [3 cyclopropylacetamide; ^-{2-[(4-{[3^hloro^-(pyridin-2-ylmethoxy)phenyl]anMno}quinazoUn-5-yl)oxy]ethyl}-A^ cyclopropyl-2-hydroxyacetamide; ^-{2-[(4-{[3^hloro^-(pyridin-2-ylinettioxy)phenyl]ainino}quinazolin-5-yl)oxy]ethyl}-A/- (cyclopropylmethyl)acetamide; N-{2-[(4-{ [3^hloKMl.-(pyridiiH2-ylineftoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl }-A/- (cyclopropylmethyl>2-hydroxyacetanride; A^-{2-[(4-{[3-chlorc>^-(pyridin-2-ylniethoxy)phenyl]amino}quinazoIin-5-y^ cyclobutylacetamide; ^{2-[(4-{[3^hloro-4-(pyridin-2-ylniethoxy)phenyl]amino}quinazolin-5-yl)oxy]e^ cyclobutyl-2-hydroxyacetamide; //-{2-[(4-{[3-4-(pyridin-2-ylme^ methylpiperidin-4-yl)acetamide; 7V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N- (tetrahydro-2H-pyran-4-yl)acetamide; /^{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino}quinazolin--5-yl)oxy]ethyl}-2- hydroxy-^-(tetrahydro-2H-pyran-4-yl)acetamide; W-{2-[(4-{[3 chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl}-A/-(2- hydroxyethyl)acetamide; jV_{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]atnino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-/V-(2-hydroxyethyl)acetamide; Af-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-AT-(2- methoxyethyl)acetamide; A^-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino}quinazolin-5-yl>)xy]ethyl}-2- hydroxy-Af-(2-methoxyethyl)acetamide; N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -N- prop-2-yn-1 -ylacetamide; N-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-N-prop-2-yn-l-ylacetamide; N-{2-[(4-{[3^hloro^(pyridin-2-ylmcthoxy)phenyl]anjino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-^-methylpropanamide; ^-{2-[(4-{[3-chloro-4^pyridin-2-ylraethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N- methyl-tetrahydrofuranyl-2-carboxamide; ^-{2-[(4-{[3^hloro^-(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl}-^V,l- dimethylprolinamide; jV-{2-[(4-{[3 hydroxy-//,2-dimethylpropananiide; ^-{2-[(4-{[3 hydroxy-N-methylcyclopropanecaiboxamide; jV1-{2-[(4-{[3-chloro^-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}- Nl ^-dimethylglycinamide; A^-{2-[(4-{[3-chloro^-(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl}-3- hydroxy-JV,2,2-trimethylpropanamide; N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]aniino} quinazolin-5-yl)oxy]ethyl} -3- hydroxy-^V-methylpropanamide; N- {(2S)-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5- >l)oxy]propyl} acetamide; A^{(25)-2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phcnyl]anuno}quina2ofIrn-5- yl)oxy]propyl }-2-hydroxyacetamide; )-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]propyl } -W2^2-dimethylglycinamide; Af-{ (25>2-[(4~ { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]propyl } -2-methoxyacetamide; N- { (2S>2-[(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]aniino }quinazoKn-5-yl)oxy]propyl } -2-(methy Isulfonyl)acetamide; JV-{2-[(4-{[3^hloro-4-(pyridin-2-yImethoxy)phenyl]ainino}qumazolin-5-yl)oxy]ethyl}-2-hydroxyacetamide; ^-{2-[(4-{[3^hloro^pyTidin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-^^-dimethylglycinamide; A^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]anuno}quinazoIin-5-yl)oxy]ethyl}-2-mcthoxyacetamide; #-{2-[(4-{ [3-chloro-4-(pyridin-2-yhnetfioxy)phenyl]aTnino }qirinazolin-5-yl)oxy]ethyl}-2-(methylsulfonyl)acetamide; ^-{(25>2-[(4-{[3^hIoro^^yridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]propyl} -N-m^hylacetamide; yIX>xy]prc^)yl } -2-hydroxy-^V-methylacetamide; f?-{ (2S)-2-[(4-{ [3^hloro-4~^yridin-2-ylmethoxy)phenyl]aimno}quinazolin-5- yl)oxy]propyl } -N1 JV^-trintethylgtytinamide; ^-{(2^2-[(4-{[3-chlon>4-(pyridin-2-yli]Mthoxy)phenyl]ainino}quina2o]in-5- yl)oxylpropyl } -2-methoxy-^V-methylacetanride; AT-{(25)-2-[(4-{[3-chlon)-4-(pyridin-2-ylmethoxy)pheny]]ainino}quina2olin-5- yl)oxy]propyl } -JV-methyl-2-(methylsulf onyl)acetamide; ^-{(21?>-2-[(4-{[3^hloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]ptopyl}-N-mcthylacetamide; Ar-{(2/?)-2-[(4-{[3-cMoro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl }-JV-methylacetamide; N-((2R)-2-{ [4-({ 3-chloro-4- [(3-fluorobenzyl)oxy]phcnyl} amino)quinazoKn-5- yl]oxy }propyl)-JV-methylacetamide; N-((2K)-2- { [4-( { 3-chloro-4-[(2-fluorobenzyl)oxy]phenyl } amino)quinazolin«5- yl]oxy }propyl)-/V-methylacetamide;-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]-l-methylethyl} -2-hydroxy-N-methylacetarnide; jV-{(l/?)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl>oxy]-l-methylethyl} -W-methylacetamide; yV-{(15)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l-methylethyl} -2-hydroxy-N-methylaeetamide; ^-{(15)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l-methylethyl}-]V-methylacetainide; N- {(lS)-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]-l-methylethyl}-2-methoxy-N-methylacetamide; N-{(lS)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]-1-methylethyl}-2-hydroxyacetamide; A^{(15>2-[(4-{[3^hloro^(pyridin-2-ylinethoxy)phenyl]aniino}qumazolin-5-yl)oxy]-l-methylethyl} acelamide; 7V1-{(15>2-[(4-{[3^Mon>^(pyridin-2-ylmethoxy)phenyl]aimiK»}quinazolin-5-yl)oxy]-l-methylethyll-A^JS^-dimelhylglycinaraidc; ^1-{(2/?>2-[(4-{[3^hloro^-(pyridin-2-ylmethoxy)phenyl]ainino}qiiinazolin-5-yl)oxy]propyl} -N2 ^-dimethyl glycinamide; (25>^-{2-[(4-{[3^hloKh4-(pyiidin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy^^ 2,4-dihydroxybutanamide; (2R)-N-{ 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl }-2,4-dihydroxybutanamide; (2J?)-^-{(2^)-2-[(4-{[3-chloro-4-(pyridiiv2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI}-2,4-dihydroxybutanamide; (2S>-^-{(2/?)-2-[(4-{[3 (2^)-AT-{(2^-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl}-2,4-dihydroxybutanamide; (25)-^V-{(25)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy3propyl}-2,4-dihydroxybutanamide; (2S)WVr{(l/?)-2-[(4«{[3-cMoro^-(pyiidin-2-ylmethoxy)phenyI]amino}quinazdin^ l-methylethyl}-2,4-dihydroxybutanamide; (2/?)-A^-{(l/?)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]araino}quinazolin-5-yl)oxy]- i-methylethyl}-2,4-dihydroxybutananude; (2/?)-A^-{2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylraethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl}-2,4-dihydroxybutanamide; (25)-^V-{2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]ainino}quinazolin-5- yl)oxy]ethyl } -2,4-dihydroxybutanamide; (2/?)-AT-{(lJ?)-2-[(4-{[3-chloro^(I,3^iazol^ylmethoxy)phenyl]amino}quinazolin-5- ylX>xy]-l-methylethyl}-2,4-dihydroxybutanamide; (2S)-A^-{(l/?)-2-[(4-{[3^hloro^l,3-thiazol^ylmethoxy)phcnyl]amino}quinazolin-5- yl)oxy] -1-methylethyl } -2,4-dihydroxybutanamide; ^-methyl-^-{2-[(4-{[3-methyl-^(pyridin-2-ylmethoxy)phenyl]amino}quinazolm-5- yl)oxy]ethyl } acetamide; #-methyl-#-{2-[(4-{[3-methyl^(13^azol^y yl)oxy]ethyl } acetamide; A^methyl-^-(2-{[4-({3-methyl^[(5-methylisoxazol-3-yl)meAoxy]phOT quinazolin-5-yl]oxy}ethyl)acctamidc; 2-hydioxy-^methyl-Ap-{2-[(4-{[3-inethyl-^(13-thiazol-2-ylinethoxy)phenyl] atnino}quinazolin-5-ylX>xy]ethyl } acetamide; 2-hydroxy-^-{2-[(4-{[3-n»thyI^(pyridin-2-ylmethoxy)phenyl]anriiio}quinazoUn^ yl)oxy]ethyl}acetamide; 2-hydroxy-^-{2-[(4-{ [3-methyl-4-(l^-thiazol-4-ylmethoxy)phenyl]amino } quinazolin-5- yl)oxy}ethyl}acetaniide; ^-{2-[(4-{[3^pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l,l- dimethylethyl } -2-hydroxyacetamide; 2-hydroxy-tf-{ (2R ^>-2-[(4-{ [3-methyl^(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5- yl)oxy]propyl } acetamide; 2-hydroxy-^{(2J?)-2-t(4-{[3-methyl^(13-thiazol^ylmethoxy)phenyl]aniino}quinaro 5-yl)oxy]propyl}acetamide; /K(2/?)-2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}ainino)quinazolin-5- yl]oxy}propyl)-2-hydroxyacetamide; 5-yl)oxy]propyl } acetamide; V-{(2/?)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl )ox y ]propy 1} acetamide; N-{(2/?)-2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylrnethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl} acetamide; N-((2/?)-2-{[4-({4-[(3-nuorobenzyl)oxy]-3-methylphenyl}amino)quinazolin-5- yl]oxy} propyl)acetamide; N- {(2K)-2-[(4- {[3-methyl-4-(l ,3-thiazol-2-ylmethoxy)phenyl] amino} quinazolin-5- yl)oxy]propyl} acetamide; 2-hydroxy-/^-methyl-//-{(2/?)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl] amino} qumazolin-5-yl)oxy]propyl} acetamide; 2-hydroxy-^-methyl-^-{(2^>2-[(4-{[3-methyl-4-(l,3-thia2ol-4- ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]propyl} acetamide; 2-hydroxy-JV-methyl-AT-((2/?)-2-{[4-({3-methyl-4-[(5-methylisoxazol-3- yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; AT-methyl-^-{(l/?)-l-methyl-2-[(4-{[3-methyl-4-(pyridin-2-ylinethoxy)phenyl] amino }quinazolin-5-yl)oxy]ethyl }acetamide; Ar-methyl-Ar-{(l/?>l-methyl-2-[(4-{[3-methyl-4-(l,3-thiazol-4- ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetamide; JV-{(17?)-2-[(4-{[3^Woro^(13-thJazol^ylmethoxy)phenyl]aniino}qmnazolin-5-yl)oxy]-l- methylethyl}-2-hydroxy-N^-methylacetamide; 2-hydroxy-//-methyl-JV-{(l/?>l-melhyl-2-[(4-{[3-methyl-4-(pyridin-2- ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetainide; 2-hydroxy-A^-methy]-^-{(l^>-l-methyl-2-[(4-{[3-methyl-4-(l,3-thiazol-4- ylmethoxy)phenyl]ainino}quinazolin-5-yl)oxy]ethyl}acetamide; Af-{(2^>2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl}-l-hydroxy-N-methylcyclopropanecarboxamide; (25)-AT-{(2^)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino}quinazolin-5- yl)oxy]propyl} -2-hydroxy-JV-methylpropanamide; N- {(2/?)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5- yP )xy]propyl}-2-hydroxy-JV,2-dimethylpropanamide; yi;u-y]propyl}-2-hydroxy-N-methylpropanamide; (2R)-N- {(2tf)-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5- yl)oxy]propyl}-2-methoxy-#-methylpropanamide; methyl-{ 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amiiio }quinazolin-5- yl)oxy]ethyl }methylcarbamate; N-{ 2-[(4- {[3-ch]oro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} - dimethyJurea; AT-(2-chloroethyl)-#- {2-[(4-{ [3-chloro-4-(pyridin-2-yimethoxy)phenyl]aniino }quinazolin-5- yl)oxy]ethyl }-W-methylurea; A^{(2/?)-2-[(4-{[3-cWoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl }-yV-methylurea; [((/?>2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]quinazolin-5- yloxy}propylcarbamoyl)roethyl]methylcarbaniic acid teg-butyl ester; ^-{(2/?)-2-[(4-{[3K;hIoix)-4^yridin-2-ylineAoxy)phenyl]amino}quinazolin-5- ylX>xy]propyl}-AT2-methylglycinamide; and N-{ 2-[(4-{ [3^hlwt)^l-methyl-l-pyiidin-2-yletlioxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl }-7V-methylacetamide; or a pharmaceutically acceptable salt thereof. A particular compound of the invention is, for example, one or more quinazoline derivatives of the formula Ib selected from: JV-{2-[(4-{3-chloro^-(pyridin-2-yliM^ A^-methylacetamide; N- {2-[(4- {3-chloro-4-(pyridin-2-yhnethoxy)anilino }quinazolin-5-yl)oxy]ethyl} -2-(dimethylamino)-yV-methylacetamide; A^{(21?>2-[(4-{3^Woro^(pyridin-2-yhnethoxy)amlino}quinazolin-5-yl)oxy]propyl}-2- mcthoxy-A^-methylacetamide); 2-hydroxy-AT-methyl-Ar- {2-[(4- {3-methyl-4-(pyrazin-2-ylmethoxy)anilino}quinazoUn-5- yl)oxy]ethyl} acetamide; 2-hydroxy-^methyl-AT-{2-[(4-{3-methyl-^(13-tWazol-^ylmethoxy)anilino}quina2olin-5- yl)oxy]ethyl} acetamide; 2-hydroxy-A^-methyl-Ar-(2-U4~(3-memyl-^[(5-methylisoxazol-3- •UitW yl)methoxy]anilino)quinazolin-5-yl]oxy}ethyl)acetamide; N- { (2/?)-2-[(4- { 3-chloro-4-(pyridin-2-ylmethoxy)anilino } quinazolin-5-yl)oxy]propyl } -2- methoxyacetamide; JV-(2-{[4-(3-chloro-4-[(6-raethylpyridin-2-yl)methoxy]anilino)quinazolin-5-yl]oxy}ethyl)-2- hydroxy-Af-methylacetamide; AT-((2/?>2-{[4-(3-chloro-4-[(6-methylpyridin-2-yl)methoxy]anilino)quinazolin-5- yl]oxy}propyl)-2-hydroxy-A/r-methylacetamide; AT methylacetamide; ^.(2-{[4-(3K;hloro-4-[(2-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}ethyl)-//- methylacetamide; methylacetamide; ^.{2-[(4-{3^hloro^(l,3-thiazd^ylmethoxy)anilino}quinazolin-5-ylX>xy]ethyl}-JV- methylacetamide; ^-{2-[(4-{3^hloro-4^yrazin-2-ylinethoxy)anilino}qirinazolin-5-yl)oxy]eAyU methylacetamide; JV"-{(2/Z)-2-[(4-{3^hloro^(pyridin-2-ylmethoxy)amlmo}quinazoUn-5-yl)oxy]piopyl}-2- hydroxyacetamide; ^-{2-[(4-{3-4^yridin-2-ylmethoxy)aniUno}quinazolin-5-yl)oxy]ethyl}-N- methylacetamide; 2-hydroxy-JV^methyl-^r-{2-[(4-{3-methyl^(pyridin-2-ylmethoxy)anilino}quinazolin--5- yl)oxy]ethyl } acetamide; N-{(l/?)-2-[(4-{3-chloro-4-(pyridin-2-ylmeflioxy)anilino}quinazolin-5-yl)oxy]-l- raethylethyl } acetamide; Ar-{(ll?)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l-methylethyl }-2-hydroxyacetamide; A-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-W-methylacetamide; ^-(2-{[4-(3-chloro-4-[(3-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}ethyl>2-hydroxy-JV-methylacetamide; N-{ 2-[(4-{ 3-chloro-4-(l ,3-thiazol-4-ylmethoxy)anilino } quinazolin-5-yl)oxy]ethyl } -2- h j drox y-JV-methyl acetamide; A/-{2-[(4-{3-chloro-4-(pyrazin-2-ylinethoxy)anilino}quinazolin-5-yl)oxylethyl}-2-hydroxy-TV-methylacetamide; N- {2-[(4- {3-chloro-4-(pyridin-2-ylmethoxy)anilino} quinazolin-5-yl)oxy]ethyl} acetamide; N- {(2R)-2-[(4~ {3-chloro-4-(pyridin-2-yImethoxy)anilino }quinazolm-5-yl)oxy]propyl} acetamide; N- {(2/?)-2-[(4- {3-chloro-4-(pyridin-2-ylinethoxy)aralino} quinazolin-5-yl)oxy]propyl} -2-hydroxy-^V-methylacetaniide; N-{(2/f)-2-[(4-{3^hloro^Kpyrazin-2-yhnethoxy)anilino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-A^-methylacetainide; N-((2R)-2-{ [4-(3^hloro^[(3-fhicm)benzyl)oxy]anilino)quinazolin-S-yl]oxy }propyl)-2-hydroxy-M-naethylacetamide; hydroxy-A^-methylacetaniide; ^-{(2/?>2-[(4-{3^Woro^(pyridin-2-ylmethoxy)aniUno}qiuna2oUn-5-yl)oxy3propyl}-^^ methylacetamide; JV-{2-[(4-{[3K;hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quitiazolin-5-yl)oxy3ethyl}-A/f-ethylacetamide; N-{2-[(4-{[3^hloit>^(pyridin-2-ylnwthoxy)phenyl]amino}quinazoUn-5-yl)oxy] ethyl-2-hydroxyacetamide; ^-{2-[(4-{[3^hlorcHt-(pyridin-2-ylinethoxy)phenyl]aimno}quinazoUn-5-yl)oxy]ethyl}-N-propylacetamide; ^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]ainino}quina2olin-5-yl)oxy]ethyl}-2-hydroxy-N-propylacetamide; ^-{2-[(4-{[3^hIoro^(pyridin-2-ylmethoxy)phenyl]amino}qiMnazolra-5-yl)oxy]ethyl}-^^ isopropylacetamide; AT-{2-[(4-{[3^hloi^4-(pyridin-2-ylme1hoxy)phenyl]amino}quinaz»lin-5-yl)oxy]ethyl}-^^ hydroxy-JV-isopropylacetamide; Ar-allyl-Ar-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} acetamide; I ^-aIIyl-A^{2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quina2olin-5-yl)oxy]ethyl} -2-hydroxyacetamide; ^-{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl3amino}quinazolin-5-yl)oxy]ethyl}-A/- cyclopropylacetamide; A^-{2-[(4-{[3-chloro-4-(pyridin-2-yimethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-A":- cyclopropyI-2-hydroxyacetamide; Af-{2-[(4-{[3-chloro-4-(pyridin-2-ylrnethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N- (cyclopropylmethyl)acetamide; ^V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl}-N- (cyclopropyImethyl)-2-hydroxyacetamide; /V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-//- cyclobutylacetainide; AT-{2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy3ethyl}-JV- cyclobutyl-2-hydroxyacetamide; N- {2-[(4-{ [3-chloro-4-(pyridin-2-ylniethoxy)phenyl]aniino }quinazolin-5-yl)oxy]ethy]} -N-(l - methy]piperidin-4-yI)acetamide; ^-{2-[(4-{[3^hloro^pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5-yl)oxy]etiiyl}-JV- (tetrahydro-Z&-pyran-4-yl)acetamide; Y-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]aniiiio}quina2olin-5-yl)oxy]ethyl}-2- tiydroxy-^tetrahydro-^-pyran^-yOacetamide; V-{ 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)pheTiyl]amino }quinazolin-5-yl)oxy]ethyl} -#-(2- liydroxyethyl)acetaniide; V-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl}-2- tiydroxy-^^-hydroxyethyOacetamide; iV-{2-[(4-{[3xy]ethyl}-W-(2- methoxyethyl)acetamide; ^{2-[(4-{[3^Woro^(pyridin-2-ylmethoxy)phenyI]amino}qiiinazolin-5-yl)oxy]ethyl}-2- tiydroxy-^-(2-methoxyethyl)acetamide; IV- {2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -W- prop-2-yn-l-ylacetamide; V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl}-2- (iydroxy-AT-prop-2-yn-l-ylacetamide; V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmelhoxy)phenyl]amino}quinazolra-5-yl)oxy]ethyl}-2- nydroxy-A?-methylpropanamide; -chloro-4-(pyridin-2-ylniethoxy)pheaiyl]amino}quinazolin-5-yl)oxy]ethyI }-N-methyl-tetrahydrofuranyl-2-carboxainide; N-(2-[(4-{ [3-chloio-4-(pyridin-2-ylinethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl } -AU-dimethylprolinamide; A^-{2-[(4-{[3n;hIoro-4-(pyridin-2-ylinethoxy)phenyl]anjino}quinazoMn-5-yl)oxy]e^yl}-2-hydroxy-^,2-dimethylprc^>anamide; AM2-[(4-{[3^hlon>-4^yridiii-2-ylinedioxy^^^ hydroxy-A^-methylcyclc^rqpanecaiboxainide; Nl ^-diinethylglycinamide; N- { 2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yI)oxy]ethyl } -3- hydroxy-/V^,2-tnmetfaylpiopanamide; N-{2-[(4-{ [3-chloro-4-(pyridin-2-yhnethoxy)phenyl]amino }quinazoKn-5-yl)oxy]ethyl }-3- hydroxy-JV-methylpropanamide; tf-{(25>-2-[(4~{[3^:hloro-4^yricfo^ yl)oxy]propyl}acetamide; A^- { (25>2-[(4-{ [3-chIoro-4-(pyridin-2-ylmethoxy)phenyriamino }quinazolin-5- y!X>xy]propyl}-2-bydroxyacetarmde; yl)oxy]piopyl } -A^ ^-dimrthylglycinamide; Ar-{(25>2-[(4-{[3- yl)oxy]propyl }-2-methoxyacetamide; N- { (25)-2-[(4- { [3-chloro-4-(pyridin-2-ylmeAoxy)ph«iyI]amino }quinazolia-5- yl)oxy]ptopyl } -2-(methylsulf onyl)acetamide; A/-{2-[(4-{[3^hlon)^(pyridin-2-ylinethoxy)phenyl]ainino}quinazolin^ hydroxyacetamide; A^1-{2-[(4-{[3^(pyridin-2-ylmethoxy)phenyl]ainiiM)}quinazoUn-5-yl)^^ A^^-dimethylglycmaniide; A^{2-[(4-{[3^hloro^(pyri(tii^2-ylinethoxy)phenyl]aniino}quitiazolin-5-y methoxyacetamide; A^-{2-[(4-{[3K:Moro-4^yridin-2-yln»thoxy)phenyl3amino}quinazolin-5^ (mcthylsulfonyl)acetamide; N-{ (25>2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino}quina2olin-5- ylX>xy]propyl}-N-methylacetanaide; N- { (25)-2-t(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino } quinazolin-5- yI)oxy]propyl}-2-hydroxy-A/-methylacetamide; Nl-{(25)-2-[(4-{[3^hlofo^p>ddin-2-yln^oxy)phenyl]amino}quinazolin-5- yl)oxy]propyl }-Nl ^^-trimethylglycinamide; N-{(25)-2-[(4-{[3^Uoix>^pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5- yl)oxy]propyl}-2-niethoxy-N-methylacetamide; N-{ (25)-2-[(4-{ [3^h)oro^pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5- yl)oxy]propyl}-^-raethyl-2Knjethylsulfonyl)acetamide; N-{(2/?>2-[(4-{[3^Woro^(pyrazin-2-ylineAoxy)phenyllainino}quinazoliii-5- yl)oxy]propyl}-N-methylacetamide; yl)oxy]ptopyl}-JV-methylacetainide; // yl]oxy}propyl)-N-methylacetamide; N-((2K)-2-{ [4-{{3-chloro-4-[(2-flucMX>ben2yl)oxy]phenyl } amino)quinazolin-5- yl]oxy}propyl)-JV-inettiylacetainide; ^-{(!J?)-2-[(4-{[3^hloro-4^yridin-2-ylmethoxy)phenyl]anuno}quina2oUn-^ methylethyi}-2-hydroxy-JV-methylacetamide; ^-{(lU)-2-[(4-{ [3-chloro-4-Q)yridin-2-yImethoxy)phenyl]ainino }quinazolin-5-yl)oxyH- methylethyl}-N-methykcetamide; ^-{(lS)-2-[(4-{[3 methylethyl}-2-hydroxy-^V-niethylacetamide; N-{(15>2-[(4-{[3^WorcMKpyridin-2-yln»thoxy)phenyl]amino}quinazolin-5-yl)oxy]-l- methylethyl}-N-methylacetamide; methylethyl } ^-methoxy-AT-methylacetamide; A/"-{(lS>2-[(4-{[3^Woro^-(pyridin-2-y^ methylethyl }-2-hydroxyacetamide; /^{(^^^^^-{p^jilpro^Xpyrictin^TylniethoxyJphenyllai^^ methylethyl } acetamide; ridm-2-y^ methylethyl }-N* J^-dimethylglycinainide; yl)oxy]propyl }- (2S)-/V-{2-[(4-{[3-chIoro-4-(pyridin-2-yline^ 2,4-dihydroxybutanamide; (2JQ-AH2-[(4-{[3- 2,4-dihydroxybutanamide; (2K)-tf-{(2ff)-2-[(4-{ [3^hloro^(pyridin-2-ylmethoxy)phenyl]anuiio}quina2olin-5- yl)oxy]propyl}-2,4-dihydroxybutananride; (25)-A^-{(2J?)-2-[(4-{[3^hloro-4^>ddin-2-ylmethoxy)phenyl]arnino}quinazolin-5- yl)oxy]propyl }-2,4-dihydroxybutanamide; (2J?>AT-{(25>2-[(4-{[3^hloro-4^yridin-2-ylmethoxy)phenyl]aniino}quuiazolin-5- yl)oxy]propyl}-2,4-dihydroxybutanamide; (2S>JV-{(2S)-2-[(4-{[3^hlo!ro-4^yridiii-2-ylnieflioxy)phCT yl)oxy]propyl}-2,4-dihydroxybiitanainide; (25>-^{(l/?>2-[(4-{[3^hlon>4^yridin-2-yhnethoxy)phenyl]an^ 1-methylethyl }-2,4-dihydroxybutanamide; (2R)-^-{(lJ?)-2-[(4-{P4^yridin-2-ylmettioxy)phenyl]ainino}qiim 1 -methylethyl } -2,4-dihydroxybutanamide; (2^)-AT-{2-[(4-{[3-chloro-4-(l,3-tfiiazol-4-ylmethoxy)phenyl]aniino}quinazolin-5- yl)oxy]ethyl } -2,4-dihydroxybutanamide; (25^-^{2-[(4-{[3-cMoro-4-(l,3-tfuazol-4-ymiethoxy)phenyl]ainiiK)}qm yl)oxy]ethyl }-2,4-dihydroxybutanamide; (2fl)-JH(ll?)-2-[(4-{[3-cUoro-^^ yl)oxy]-l-methylethyl}-2,4-dihydroxybutanamide; (25)-^-{(l/?)-2-[(4-{ [3-chloio-4- yl)oxy]-l-methyletfiyl}-2,4-dihydroxybutanaimde; ^-methyl-^{2-[(4-{[3-mcthyl-4-^yridii^2-yhnethoxy)phenyl]anuno}quinazol^^ ylX>xy]ethyl }acetamide; A^methyl-7V-{2-[(4-{[3-ine^yl-4-(13-thiazol-4-yhiiethoxy)phenyy yl)oxy]ethyl Jacetamide; -methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl Jamino) quinazolin~5-yl]oxy } ethyl)acetamide; 2-hydroxy-Ar-methyl-N-{2-[(4-{[3-inefliyl-4-(l,3-thiazol-2-ylmethoxy)phenyl] amino } quinazolin-5-yl)oxy]ethyl } acetamide; 2-hydioxy-N- { 2-[(4-{ [3-methyl-4-(pyridin-2-yhnethoxy)phenyl]ainino } quinazolin-5- yl)oxy]ethyl}acetamide; 2^ydroxy-^-{2-[(4-{[3-methyW-(13-thiazol^ylmethoxy)pbenyl]ainino}quinazoU yl)oxy]ethyl} acetamide; //-{2-[(4-{[3^hlon>-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l,l- dimethylethyl}-2-hydroxyacetamidc; 2-hydroxy-JV-{(2^)-2-[(4-{ [3-metfiyl-4-(pyridin-2-ylinethoxy)phenyl]amino} quinazolin-5- yl)oxy]propyl } acetamide; 2-hydroxy-AH (2R)-2-[(4-{ [3-methyl-4-(l ,3-thiazol-4-ylmethoxy)phenyl]ammo } quinazolin- 5-yl)oxy]propyl}acetamide; JV^(2J?)-2-{[4^{4-[(3-fluorobenzyl)oxy]-3-meAyiphenyl}aimno)qi^ yl]oxy }propyl>2-hydroxyacetamide; 2-hydroxy-^-{ (2J?)-2-[(4-{ [S-methyl-^Cl^-tiiiazol^-ylmethoxy^henyllamino} quinazolin- S-yl)oxy]propyl}acetamide; ^-{(2R)-2-[(4-{[3-methyl^(pyridin-2-ylinethoxy)phenyl]ainino}quina^ yl)oxy]propyl} acetamide; yl)oxy]propyl}acetamide; N-((2J?)-2-{[4K{4-[(3-fluon^nzyl)oxy]-3-methylphenyl}anuno)quinazolin-5- yl]oxy}propyl)acetainide; ^-{(2/J)-2-[(4-{[3-methyl^(13-thiazoI-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl}acetainide; 2-hydroxy-JV-methyl-/V-{ (2/?>-2-[(4-{ [3-methyl-4-(pyridin-2-ylmethoxy)phenyl] amino }qumazolin-5-yl)oxy]propyl}acetainide; 2-hydroxy-JV-methyl-Ar-{(2/Z)-2-[(4-{[3-methyl-4-(13-thiazol-4- ylmethoxy)phenyl]amino }quinazolm-5-yl)oxy]propyl }acetamide; ^-hydroxy^methyl^((2R)-2-{[4K{3-methyl^£(5^nw%lisa»^ . yl)methoxy]phenyl}amino)quina2olin-5-yl]oxy}propyl)acetamide; l-#-{ (l/?)-l-methyl-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl] amino}quinazolin-5-yl)oxy]ethyl}acetamide; N-methyl-AM (I* H-methyl-2-[(4-{ [3-methyl-4-(l,3-thiazol-4-ylmethoxy)phcnyl]aniino}quinazo]in-S-yl)oxy]ethyl}acetamide; A^-{(l/?)-2-[(4-{[3^hloro^l,3-thiazol^ylmethoxy)phenyl]amino}quinazolm-5-yl)oxy]-l-methylethyl}-2-hydroxy-N-methylacetamide; 24iydroxy-JV-methyl-^-{ (lK)-l-methyl-2-[(4-{ [3-methyl-4-(pyridin-2-ylmethoxy)phenyl]anrino}quinazolin-5-ylX»xy]ethyl}acetamide; y!inethoxy)phenyl]ainino}quinazoUn-5-yl)oxy]ethyl}acetamide; N-{ (2K)-2-[(4-{ [3^hloro-4- yl)oxy]propyl}-l-hydroxy-JV-methylcyclopropanecarboxaniide; yl)oxy]propyl }-2-hydroxy-/^-methy)propanamidc; #-{(2/?>2-[(4-{[34^pyri yl)oxy]propyl }-2-hydroxy-^,2-dimethylpropanamide; (2/0-^-{(2/?>2-[(4-{[3-2-ylmethoxy)phenyl]ainii» ylJoxyipropylJ^-hydroxy-^-methylpropananufc; (2R)-N-{ (2R)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5- yl)oxylpropyl}-2-methoxy-]V-methylpropanamide; methyl-{2-[(4-{[3-^^oro^(pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl }methylcarbamate; JV-{2-[(4-{[3^Woro^^pyridin-2-yliiMthoxy)phenyl]ainino}quinazolin-5-yl)oxy]eA dimethylurea; -( 2-[(4-{ [3-chloro-4-(pyridiii-2-ylmethoxy^ienyl]ainino }quinazolin-5-}-A^-methylurea; N-{ (2iR)-2-[(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl }-W-methylurea; [((JO-2-{4-[3 yloxy}propylcarbamoyl)methyl]methylcaibamic acidtgtt-butyl ester; and A^-{(2R)-2-[(4-{[3-chloro4-(^yriditt-2-ylmethoxy)phenyl]am^ " yl)oxy]propyl}-^-methylglyeinaniide; or a pharmaceutically acceptable salt thereof. A particular compound of the invention is, for example, one or more quinazoline derivatives of the formula Ic selected from: 2-hyroxy-N-methyl-N-((2R)-2-{[4K{3-methyl-4-[(6-methylpyridin-3-yl)oxy3phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; A^nMrnyl-AK(2fl)-2-{ [4K{3-methy 5-yl]oxy}propyl)acetamide; yl)oxy]phenyl}aniino)quinazolin-5-yl]oxy}propyl)glycinainide; ^inefoyl-AK(2/0-2-{[4^{3-merayl^[^ 5-yl]oxy}propyl)-2-pvrrolidin-l-ylacetamide; tf-inemyl-#K(2/0-2-{[4 5-yl]oxy}propyl>2-morpholin-4-ylacetamide; M-inemyl-M{(2#)-2-{[4^{3-inemyl^ 5-yl]oxy}propyl)-2-(4-methylpiperazin-l-yl)acetamide; yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ptopyl)acetamide; N-methyl-^V-((25)-2-{ [4-({3-methyl-4-[(6-methyipyndin-3-yl)oxy}phenyl} amino)quinazolin- 5-yl]oxy}piopyl)acetamide; ^-methyl-N-((25)-2-{[4^{3-methyl^[(6-methylpvridin-3-yl)oxy]phenyl}aniino)qumazolin- 5-yl]oxy}propyl>2-pyrrolidin-l-ylacetamide; (25)-2,4Ktihydroxy-A^((2«)-2-{[4 y!X>xy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide; yl)oxy]phenyl}amino)quinazolin-S-yl]oxy}propyl)butanamide; ^^^hloKKJthyl^KC^^tL^iS-incmyW-Ke-mcTOylpyridi yl)oxy]phenyl } amino)quinazolin-5-yl]oxy }propyl)urea; ^ yl)oxy]phenyl } amino)quinazolin-5-yl]oxy }ethyl)acetamide; yl)oxy]phenyl} amino)quinazolin-5-yl]oxy }ethyl)acetamide; yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide; N-methyl-N-((1S)-l-methyl-2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy}phenyl} amino)quinazoJin-5-yl]oxy} dhyl)acetaniide; 2-hydroxy-N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetarnide; and N-meftyl-N-(2-{[4-({3-methy1-4-[(6^methylpyridin-3-yl)oxy]phenyl}aniirK))quinazolin-5- yl]oxy}ethyl)acetamide; or a pharmaceutically acceptable salt thereof. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Suitable processes include, for example, those illustrated in International Patent Applications WO 96/15118, WO 01/94341, WO 03/040108 and WO 03/040109. Such processes, when used to prepare a quinazoline derivative of the formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, R1, R2, R3, R4, R4, R5, R5, R6, X1, Q1, A, m, and n have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. Process fa) the coupling, conveniently in the presence of a suitable base, of a quinazoline of the formula II: (Figure Removed)wherein R1, R2, R3, R4, R4", R3, R5t, R6, X1, Q1, m, and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a carboxylic acid of the formula HI, or a reactive derivative thereof: A-COOH III wherein A has any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (b) for the preparation of those compounds of the formula I wherein X1 is OC(R7)2, SC(R7)2or N(R7)C(R7)2, the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula IV: IV wherein Xu is O, S or N(R7) and R1, R2, R3, R4, R4, R5, R5a, R6, R7, A, m, and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the formula V or a salt thereof: wherein L1 is a suitable displaceable group and Q1 and R7 have any of the meanings defined hereinbefore except mat any functional group is protected if necessary; Process fc) for the preparation of those compounds of the formula I wherein A is R14 and R14 is NHR17 or Q3-X5- (wherein R17 and Q3 have any of the meanings defined hereinbefore and X5 is NH), the coupling of a quinazoline of the formula II as defined above with an isocyanate of the formula EHa: A-NCO ma wherein A is R14 as previously defined in this section except that any functional group is protected if necessary, Recess (d) the reaction of a quinazoline of the formula II wherein R6 is hydrogen: (Figure Removed)n wherein R1, R2, R3, R4, R4A, R5, R5A, X1, Q1, m, and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with o-hydroxy-Y-butyrolactone (for example (S)-(-)-α-hydroxy-γ-butyrolactone or (RH+)-«r hydroxy-Y-butyrolactone) wherein any functional group is protected if necessary; or Process (e) the coupling of a quinazoline of the formula VI: herein R1, R4, R4a, R5, R5a, R6, A and m have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the formula wherein R2, R3, X1, Ql and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary; Process (ft for the preparation of those compounds of the formula I wherein X1 is O and Q1 is 2-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl or 3-pyridazinyl, the reaction, conveniently in the presence of a suitable base and a suitable catalyst, of a qumazolme of the formula VII: (Figure Removed)wherein R1, R2, R3, R4, R4A, R5, R5A, R6, A, m and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with 2-bromopyridine, 4-bromopyridine, 2-chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or 3-chloropyridazine; or Process (g) for the preparation of those compounds of the formula I wherein A is Z-(CR12R13)P-, wherein Z is NR16Rn, the reaction, conveniently in the presence of a suitable base, of a quinazolhie of the formula VIII: wherein L1 is a suitable displaceable group and R1, R2, R3, R, R4,R5, R5, R6, Ru, R13, X1, Q1, m, n and p have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the formula IXa, or a reactive derivative thereof: H-NR16R17 IXa wherein R16 and R17 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; and thereafter, if necessary: (i) converting a quinazoline derivative of the formula I into another quinazoline derivative of the formula I; (ii) removing any protecting group that is present by conventional means; (Hi) forming a pharmaceutically acceptable salt Specific conditions for the above reactions are as follows: Process fa) The coupling reaction is conveniently carried out in the presence of a suitable coupling agent, such as a carbodiimide, or a suitable peptide coupling agent, for example O-(7- a2abenzolriazol-l-yl)-NJN[N"-tetramemyluronium hexafluoro-phosphate (HATU) or a carbodiimide such as dicyclohexvlcaibodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pvrrolidinopyridine. The coupling reaction is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylethylamine, M-methyhnorpholine or diazabicyclo[5.4.0]vmdec-7-ene, or, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate,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 methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as HJirnethylformamide, NJimethylacetamide, Ji-mettiylpvrroUdin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from 0 to 120°C, conveniently at or near ambient temperature. By the term "reactive derivative" of the carboxylic acid of the formula HI is meant a carboxylic acid derivative mat will react with the qvrinazoline of formula n to give the corresponding amide. A suitable reactive derivative of a carboxylic acid of the formula HI is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by tile reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as methanol, ethanol, isopropanol, butanol or JJ-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or an acetoxyacetylchloride. The reaction of such reactive derivatives of carboxylic acid with amines (such as a compound of the formula II) is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and hi a suitable solvent, such as those described above. The reaction may conveniently be performed at a temperature as described above. Preparation of Starting Materials for Process (a) Compounds of formula ID (and reactive derivatives thereof) are commercially available compounds or they are known in the literature, or they can be prepared by standard processes known in the art. The quinazoline of the formula II may be obtained by conventional procedures. For example, as illustrated in Reaction Scheme 1: wherein L2 and L3 are suitable displaceable groups, provided that L3 is more labile than L2, and R1, R2, R3, R. R4, R5, R5, R6, X1, Q1, m, and have any of the meanings defined hereinbefore except that any functional group is protected if necessary during the reaction set out above, which protecting groupCs) are removed if necessary at an appropriate stage in Reaction Scheme 1. For example, instead of using the compound of formula lid in step (ii) of Reaction Scheme I, the compound nd" (including a protecting group) could be used: followed by removal of the protecting group, by an appropriate method known to a person skilled in the art. A suitable displaceable group L2 is for example haiogeno or a sulfonyloxy group, for example fluoro, chloro, methylsulfonyloxy or toluene-4-sulfonyloxy group, particularly fluoro. A suitable displaceable group L3 is, for example, haiogeno (such as fluoro or chloro) or an alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfmyl, alkylsulfonyl, arylsulfonyl, alkylsulfonyloxy or arylsulfonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methylthio, methanesulfonyl, methanesulfonyloxy or toluene-4-sulfonyloxy group. Preferably L2 and L3 are bom haiogeno, for example L2 is fluoro and L3 is chloro. 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 inert solvent such as diethyl ether or dioxane) or hydrochloric acid. Alternatively the quinazoline derivative of the formula Ha, wherein L3 is haiogeno (for example chloro), may be reacted with the compound of the formula lib in the absence of an acid or a base. In this reaction displacement of the haiogeno leaving group L3 results in the formation of the acid HL3 in-situ and the autocatalysis of the reaction. Alternatively, the reaction of the quinazoline derivative of formula Ila with the compound of formula lib may be carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,64utidhie, collidine, 4-dimethylaminopYridine, triethylamine, di-isopropylethylamine, N-methylmorpholine or diazabicyclo[S.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or, for example, an alkali metal hydride, for example sodium hydride. The above reactions are 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 methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as tolviene, or a dipolar aprotic solvent such as N-dimethylformamide, H,H-diniethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The above reactions are conveniently carried out at a temperature in the range, for example, 0 to 250°C, conveniently in the range 40 to 80°C or, preferably, at or near the reflux temperature of the solvent when used. Step (u) The reaction a quinazoline of the formula lie and the alcohol of the formula Ud is suitably carried out in the presence of a suitable base, for example a strong non-nucleophilic base such as an alkali metal hydride, for example sodium hydride, or an alkali metal amide, for example lithium di-isopropylamide (IDA). The reaction of the quinazoline of the formula Die and the alcohol of the formula Hd is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, 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 M-dimethylibnnamide, fimemyiaeetamide, N-methylpyrrolidin-2-one or dimemylsulfoxide. The reaction is conveniently carried out at a temperature in the range of, for example, 10 to 250°C, preferably in the range 40 to 150°C. Conveniently, mis reaction may also be performed by heating the reactants in a sealed vessel using a suitable heating apparatus such as a microwave heater. Conveniently, the reaction a quinazoline of the formula He and the alcohol of the formula nd is performed in the presence of a suitable catalyst, for example a crown ether such as lS-crown-5. Starting Materials for Reaction Scheme 1 The quinazoline of formula Ha may be obtained using conventional methods, for example, when m is 0, L2 is fluoro and L3 is halogeno (for example chloro), 5-fluoro- 3,4-dihydroquinazolin-4-one may be reacted with a suitable halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine. The S-fluoro-3,4-dihydroquinazoline starting material is commercially available or can be prepared using conventional methods, for example as described in J. Org. Chem., 1952,17,164-176. Compounds of the formula Ob are commercially available compounds or they are known in the literature, or they can be can be prepared by standard processes known in the art For example, the compound of the formula lib in which R2 is hydrogen and wherein X1 is O, S, SO, SOi, N(R7), OC(R7)2, SC(R7)2 or N(R7)C(R7)2 may be prepared in accordance with HX1Q1 reduction Reaction Scheme 2 wherein L4 is a suitable displaceablc group as hereinbefore defined (for example halogeno such as chloro) and Q1, X1, R3 and n are as hereinbefore defined, except any functional group is protected if necessary, and any protecting group that is present in Reaction Scheme 2 is removed if necessary at an appropriate stage of Reaction Scheme 2 by conventional means. Notes for Reaction Scheme 2 Step (i): The compounds of the formula HJ^Q1 are commercially available, or they are known in the literature, or can be prepared using well known processes in the art For example compounds of the formula QCHaOH may be prepared using known methods, for example by reduction of the corresponding ester of die formula Q"COOR, wherein R is, for example (l-6C)alkyl, or benzyl, with a suitable reducing agent, for example sodium borohydride, followed by ester hydrolysis. The reaction in step (i) is conveniently carried out in the presence of a suitable base and in the presence of a suitable inert diluent or solvent Suitable reaction conditions, solvents and bases for use in step (i) are analogous to those used in Process (b) described below. Step (ii): The reduction of the nitro group in step (ii) may be carried out under standard conditions, for example by catalytic hydrogenation over a platinum/carbon, palladium/carbon or nickel catalyst, treatment with a metal such as iron, titanium chloride, tin n chloride or indium, or treatment with another suitable reducing agent such as sodium dithionite. Compounds;6f therformulalib wherein X1 is C)C(R7)2, SC2 ot N(R7)CCR7 for example, be prepared in accordance with Reaction Scheme 3: (0 Reaction Scheme 3 wherein L1 is a suitable leaving group as defined hereinafter in relation to Process (b), X1 is as hereinbefore defined in Process (b), and R3, R7, Ql, X1 and n are as hereinbefore 5 defined except any functional group is protected if necessary, and any protecting group that is present in Reaction Scheme 3 is removed if necessary at an appropriate stage of Reaction Scheme 3 by conventional means. Notes for Reaction Scheme 3 Step (i): Analogous conditions to those used in Process (b) 10 Step (ii): Analogous conditions to those used in Reaction Scheme 2. Other suitable methods for preparing compounds of the formula lib are disclosed in for example WO 03/040108 and as illustrated by the examples herein. Compounds of the formula lib wherein X1 is OC(R7)2 may also be prepared by coupling the appropriate starting nitro phenol in Reaction Scheme 3 (XlkH is OH) with a IS compound of the formula QC(R7)2OH, conveniently hi die presence of a suitable dehydrating agent A suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or H3-diinethy]ammopropyl3-«mylcarbodiimide or a mixture of an azo compound such as diethyl or cti-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine. The reaction is conveniently carried out in the presence of a suitable 20 inert solvent or diluent, for example a haiogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 0 to iSO°C, preferably at or near ambient temperature. The alcohols of the formula Od used in Reaction Scheme 1 are commercially available compounds or they are known in the literature, or they can be can be prepared by standard 25 processes known in the art For example, alcohols of the formula nd may be prepared in accordance with Reaction Scheme 4: catalyst R48 deprotect lid1 Reaction Scheme 4 wherein Pg is a suitable amine protecting group such as allyl, and R4, R4, R5 R5 and R6 arc as hereinbefore defined. 5 Notes for Reaction Scheme 4 Step f i): The coupling and ring opening reaction is conveniently earned out in the presence of a suitable metal catalyst such as ytterbium(ni) trifluoromethanesulfonate. The reaction is suitably earned out in the presence of an inert solvent or diluent such as dioxane. The reaction is preferably carried out at an elevated temperature, for example from SO to about 10 150°C. Step (ii): The protecting group Pg may be removed using conventional methods, for example when Pg is an allyl group by metal catalysed cleavage. A suitable catalyst is, for example, chlorotris(triphenylphosphirie)rhodium (I). As previously discussed, in embodiments, the alcohol of the formula lid" in Reaction 15 Scheme 4 may be used directly in Process (a) (or in the preparation of the intermediates used in Process (b) described below), m mis embodiment the amine protecting group, Pg, may be removed at a convenient stage in the process prior to coupling the acid of the formula HI. The quinazoline of the formula H may alternatively be obtained a conventional procedure, for example as illustrated in Reaction Scheme la: wherein L1 and L2 are suitable displaceable groups and R1, R2, R3, R4, R4, R5, R5i, R6, X1, Q1, m and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary during the reaction set out above, which protecting group(8) are removed if necessary at an appropriate stage in Reaction Scheme la. A suitable displaceable group L2 is for example a halogeno or a sulfonyloxy group, for example a fluoro, chloro, tnethylsulfonyloxy or toluene-4-sulfonyloxy group, particularly fluoro. Preferably L2 is halogeno, for example L2 is fluoro. A suitable displaceable group L1 in die compound of the formula DC" is for example a halogeno or a sulfonyloxy group, for example a fluoro, chloro, methylsulfonyloxy or toluene- 4-sulfonyloxy group. A particular group L1 is fluoro, chloro or methylsulf onyloxy, particularly chloro. Notes for Reaction Scheme la: Step frt: Analogous conditions to those used in step (ii) of Reaction Scheme 2. Step fit): Conducted using a suitable conversion reaction. For example when L1 is chloro, step (ii) is conducted using an appropriate chlorinating agent, for example thionyl chloride. Step (iiiV. The reaction of the compound of formula lie with the amine of formula Ilf may conveniently be carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylethylamine, N-memylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or an alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or an alkali metal hydride such as sodium hydride. Alternatively, the reaction may use an excess of the amine of formula Ilf in place of the aforementioned suitable base. If necessary, the reaction may conveniently be carried out in the presence of a suitable catalyst, for example tetrabutylammonium iodide. The reaction of the compound of the formula and the amine of the formula is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as tLK-dimethylformamide, N,fc[-dimethylacetamide, M-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range of, for example, from 25 to 150°C, conveniently at about 100°C. Starting Materials for Reaction Scheme Iq Compounds of formula He may be prepared using conventional procedures, for example as discussed above in relation to Reaction Scheme 1. Compounds of formulae lie and are commercially available compounds or they are known in the literature, or they can be prepared by standard processes known in the art. Process (b) A suitable displaceable group L1 in the compound of the formula V is for example a halogeno or a sulfonyloxy group, for example a fluoro, chloro, methylsulfonyloxy or toluene- 4-sulfonyloxy group. A particular group L1 is fluoro, chloro or methylsulfonyloxy. The reaction of the quinazoline of formula IV with the compound of formula V is conveniently carried out in the presence of a suitable base. Suitable bases include, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylethylamine, N-mernylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or, for example, an alkali metal hydride, for example sodium hydride. A particular base is an alkali or alkaline earth metal carbonate, for example potassium carbonate. The reaction of the quinazoline of the formula IV and the compound of the formula V is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a dipolar aptotic solvent such as H-dimethylformamide, dimeraylacetamide, K-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range of, for example, from 25 to 100°C, conveniently at or near ambient temperature. The reaction of the quinazoline of the formula IV and the compound of the formula V is conveniently carried out hi the presence of a suitable catalyst, for example a crown ether such as 18-crown-6. Preparation of Starting Materials for Process (b) Compounds of the formula V are commercially available compounds or they ate known in the literature, or they can be can be prepared by standard processes known in the art The quinazoline of the formula IV may be prepared using conventional methods, for example, when Xu is O, in accordance with Reaction Scheme 5: in Reaction Scheme 5 or as a reactive derivative of the compound of formula HI. Suitable reactive derivatives of the compound of formula HI are described in relation to Process (a) above. Preparation of Starting. Compounds of formulae Ha and lid may be obtained by conventional procedures, as discussed above. Anilines of the formula IVa are commercially available compounds or they are known in the literature, or they can be can be prepared by standard processes known in the art Process The reaction of a compound of the formula H with an isocyanate of the formula ma 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 methylene chloride, chloroform or carbon tetrachloridc, an ether such as tetrahydroforan or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aptotic solvent such as H£~dimemylf ormamide, &N-dimethylacetamidc, Ji-methylpyrrohdin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from 0 to 50°C Preparation, of Starting Materials for Process (c) The quinazolme of formula H may be obtained by conventional procedures, as discussed above. The compounds of formula IHa are commercially available compounds or they are known in the literature, or they can be can be prepared by standard processes known in the art Process (dt The reaction of the compound of formula U and Orhydroxy-Y-butyrolactone is conveniently carried out in the presence of a suitable inert solvent or diluent, for example xylene, toluene or dichlorobenzene (particularly xylene). The reaction is conveniently carried out at a temperature in the range, for example, 100 to 180°C. Prearation of Startin Materials forProcess The quinazolme of formula II may be obtained by conventional procedures, as discussed above. The a-hydroxy-Y-butyrolactones are commercially available compounds or they are known in the literature, or they can be can be prepared by standard processes known in the art. Process (e) The reaction of the compounds of formula VI and of formula lib is conveniently carried out using analogous conditions to those described above for Step (i) of Reaction Sdierne 1. The quinazoline of formula VI may be obtained by conventional procedures, as discussed above. The compounds of formula lib may be obtained by conventional procedures, as discussed above. Process (f) A suitable catalyst for the reaction of a quinazoline of the formula VII and 2- chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or 3-chloropyridazinc is for example a crown ether such as 18-crown-6. A suitable catalyst for the reaction of a quinazoline of the formula VII and 2- bromopyridine or 4-bromopyridine is a palladium catalyst, for example a catalyst formed in situ by the reaction of bis(dibenzylideneacetone)palladium and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene. The reaction is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate. The reaction is conveniently performed in a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane, or a dipolar aprotic solvent such as acetonitrile. Suitably the reaction is carried out at a temperature of, for example 0 to 180°C, particularly 20°C to the reflux temperature of the solvent/diluent Conveniently the reaction may also be carried out by heating the reactants in a sealed vessel using a suitable heating apparatus such as a microwave heater. Preparation of Starting Materials for Process (f) The quinazoline of formula VII may be obtained by conventional procedures, as discussed above. The 2-bromopyridine, 4-bromopyridine, 2-chloropyrimidine, 4-chloropyrimidine, 2- chloropyraztne and 3-chloropyridazine reagents are commercially available compounds or they are known in the literature, or they can be can be prepared by standard processes known in the art. Rocess The reaction of the compound of formula VHI and the arnine of formula IXa is conveniently carried out using analogous conditions to those used in step (iii) in Reaction Scheme la. Preparation of Starting Materials for Process (g) The quinazoline of formula VIQ may be obtained by conventional procedures, as discussed above. The amines of formula IXa are commercially available compounds or they are known in the literature, or they can be can be prepared by standard processes known in the art The quinazoline derivative of the formula I may be obtained from the above processes in the form of the tree base or alternatively it may be obtained in the form of a salt, such as an acid addition salt. When it is desired to obtain the free base from a salt of the compound of formula I, the salt may be treated with a suitable base, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium, carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or by treatment with ammonia for example using a methanolic ammonia solution such as 7N ammonia in methanol. The protecting groups used in the processes above may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in , question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1 to 4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention. A carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1 to 20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (l-12C)aIkyl groups (for example isopropyl, and tort-butyl): lower alkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl andpivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-cthoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobcnzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyi groups (for example trimethylsilvl and j^-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (for example trimethylsilylcthyl); and (2-6C)alkenyl groups (for example allyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example, acid-, base-, metal- or enzymically-catalysed cleavage. Examples of hydroxy protecting groups include lower alkyl groups (for example tejl-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxvcarbonvlV. lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and lerj-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups. Examples of ammo protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); lower alkenyl groups (for example allyl) di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); lower alkanoyloxyalkyl groups (for example pivaloyloxymethyl); trialkylsilyl (for example trimethylsilyl and igt-butyldimethylsilyl); alkyh"dene (for example methylidene) and benzylidene and substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl and allyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl. For example a tertbutoxycarbonyl protecting group may be removed from an amino group by an acid catalysed hydrolysis using trifluoroacetic acid. The reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2"1 Edition, by T. Green et aL, also published by John Wiley & Son, for general guidance on protecting groups. It will be appreciated 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 prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group, When a pharmaceutically acceptable salt of a quinazoline derivative of the formula I is required, for example an acid-addition salt, it may be obtained by, for example, reaction of said quinazoline derivative with a suitable acid using a conventional procedure. As mentioned hereinbefore some of the compounds according to the present invention may contain one or more chiral centers and may therefore exist as stereoisomers (for example when R4 is alkyl and R4 is hydrogen). Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated by separation of a racemate for example by fractional crystallisation, resolution or HPLC. The diastereoisomers may be isolated by separation by virtue of the different physical properties of the diastereoisomers, for example, by fractional crystallisation, HPLC or flash chromatography. Alternatively particular stereoisomers may be made by chiral synthesis from chiral starting materials under conditions which will not cause racetnisation or epimerisation, or by derivatisation, with a chiral reagent When a specific stereoisomer is isolated it is suitably isolated substantially free of other stereoisomers, for example containing less than 20%, particularly less than 10% and more particularly less than 5% by weight of other stereoisomers. In the section above relating to the preparation of the quinazoline derivative of formula I, the expression "inert solvent" refers to a solvent which does not react with the starting materials, reagents, intennediates or products in a manner which adversely affects the yield of the desired product. Persons skilled hi the art will appreciate that, in order to obtain compounds of the invention in an alternative and hi some occasions, more convenient manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. chemical transformations may be performed upon different intennediates to those associated hereinbefore with a particular reaction). Certain intennediates used in the processes described above are novel and form a further feature of the present invention. Accordingly there is provided a compound of the Formula IV as hereinbefore defined, or a salt thereof. The intermediate may be in the form of a salt of the intermediate. Such salts need not be a pharmaceutically acceptable salt. For example it may be useful to prepare an intermediate in the form of a pharmaceutically nonacceptable salt if, for example, such salts are useful in the manufacture of a compound of Biological Assays The inhibitory activities of compounds were assessed in non-cell based protein tyrosine kinase assays as well as in cell based proliferation assays before their in vivo activity was assessed in Xenograft studies. a) Protein Tyrosine Kinase phosphorylation Assays This test measures the ability of a test compound to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by an erb receptor tyrosine kinase enzyme. Recombinant intracellular fragments of EGFR, erbB2 and erbB4 (accession numbers X00588, X03363 and L07868 respectively) were cloned and expressed in the baculovirus/SGl system. Lysates were prepared from these cells by treatment with ice-cold lysis buffer (20mM N^-hydroxyethylpipcrizine-N"-cdianesulfonic acid (HEPES) pH7.5, ISQmM NaCl, 10% glycerol, 1% Triton X-100, LSrnM MgCl2, ImM ethylene glycol-bis(j}-aminoethyl ether) N"T.N""-letraacetic acid (EOTA), plus protease inhibitors and then cleared by centrifugation. Constitutive kinase activity of these recombinant proteins was determined by their ability to phosphorylate a synthetic peptide (made up of a random co-polymer of Ghitamic Acid, Alanine and Tyrosine in the ratio of 6:3:1). Specifically, Maxisorb™ 96-well immunoplates were coated with synthetic peptide (0.2\|ig of peptide in a 200\|d phosphate buffered saline (PBS) solution and incubated at 4°C overnight). Plates were washed in SOmM HEPES pH 7.4 at room temperature to remove any excess unbound synthetic peptide. EGFR or erbB2 activities were assessed by incubation in peptide coated plates for 20 minutes at room temperature in lOOmM HEPES pH 7.4 at room temperature, adenosine trisphosphate (ATP) at Km concentration for the respective enzyme, 10mM MnCl2O.lmM Na3VO4, 0.2mMDL-dithiothreitol (DTT), 0.1% Triton X-100 with test compound in DMSO (final concentration of 2.5%). Reactions were terminated by the removal of the liquid components of the assay followed by washing of the plates with PBS-T (phosphate buffered saline with 0.5% Tween 20). The immobilised phospho-peptide product of the reaction was detected by immunological methods. Firstly, plates were incubated for 90 minutes at room temperature with anti-phosphotyrosine primary antibodies that were raised in the mouse (4O10 from Upstate Biotechnology). Following extensive washing, plates were treated with Horseradish Peroxidase (HRP) conjugated sheep anti-mouse secondary antibody (NXA931 from Amersham) for 60 minutes at room temperature. After further washing, HRP activity in each well of the plate was measured colorimetrically using 22"-Azino-di-[3-ethylbenzthiazoline sulfonate (6)] diammonium salt crystals (ABTS™ from Roche) as a substrate. Quantification of colour development and thus enzyme activity was achieved by the measurement of absorbance at 405nm on a Molecular Devices ThennoMax microplate reader. Kinase inhibition for a given compound was expressed as an IC50 value. This was determined by calculation of the concentration of compound mat was required to give 50% inhibition of phosphorylation in this assay. The range of phosphorylation was calculated from the positive (vehicle plus ATP) and negative (vehicle minus ATP) control values. b) EGFR driven KB cell proliferation assay This assay measures the ability of a test compound to inhibit the proliferation of KB cells (human naso-pharangeal carcinoma obtained from the American Type Culture Collection (ATCQ). KB cells were cultured in Dulbecco"s modified Eagle"s medium (DMEM) containing 10% foetal calf serum, 2 mM glutamine and non-essential amino acids at 37°C in a 7.5% CO? air incubator. Cells were harvested from the stock flasks using Trypsin/emylarmnediaminetetraacetic acid (EDTA). Cell density was measured using a haemocytometer and viability was calculated using trypan blue solution before being seeded at a density of 1.25xl03 cells per well of a 96 well plate in DMEM containing 2.5% charcoal stripped serum, ImM glutamine and non-essential amino acids at 37°C in 15% CCh and allowed to settle for 4 hours. Following adhesion to the plate, the cells are treated with or without EGF (final concentration of Ing/ml) and with or without compound at a range of concentrations in dimethylsulfoxide (DMSO) (0.1% final) before incubation for 4 days. Following the incubation period, cell numbers were determined by addition of SOjil of 3-(4,5- Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (stock Smg/ml) for 2 hours. MTT solution was then tipped off, the plate gently tapped dry and the cells dissolved upon the ^dition of lOOuJ of DMSQ, Absorbance of the solubilised cells was read at 540nm using a Molecular Devices ThermoMax microplate reader. Inhibition of proliferation was expressed as an ICso value. This was determined by calculation of the concentration of compound that was required to give 50% inhibition of proliferation. The range of proliferation was calculated from the positive (vehicle plus EOF) and negative (vehicle minus EOF) control values, c) Cellular EGFR phosphorylation assay This assay measures the ability of a test compound to inhibit the phosphorylation of EGFR in KB cells (human naso-pharangeal carcinoma obtained from the American Type Culture Collection (ATCC). KB cells were cultured in Dulbecco"s modified Eagle"s medium (DMEM) containing 10% foetal calf serum, 2 rnM glutamine and non-essential amino acids at 37°C in a 7.5% CO air incubator. Cells were harvested from the stock flasks using Trypsin/ethylaminediaminetetraacetic acid (EOTA). Cell density was measured using a haemocytometer and viability was calculated using trypan blue solution before being seeded at a density of 2X105 cells per well of a 6 well plate in DMEM containing 2,5% charcoal stripped serum, 2mM glutamine and non-essential ammo acids at 37°C in 7.5% CO and allowed to settle for 72 hours. Following the 72 hour incubation period, the stripped serum containing media was then replaced with serum-free media (DMEM containing 2mM glutamine and non-essential amino acids) and incubated at 37°C in 7.5% CQ for 72 hours. Following this incubation period, the cells were treated with or without compound at a range of concentrations in dimethylsulfoxide (DMSO) (0.1% final) in serum free DMEM. Following incubation forl.5 hours at 37°C in 7.5% CO the cells were treated with EOF (final concentration of lu,g/ml) and incubated at 37°C in 7.5% CO for 3 minutes. The media was then removed and the cells washed twice hi ice cold Phosphate Buffered Saline before lysis of the cells with 1ml of ice cold lysis buffer containing 120mM NaCl2,25mM HEPES, pH 7.6,5mM BGlycerophosphate, 2.5mM MgCfc, ImM EGTA, 0.2mM EDTA, ImM Na3VO4,1% Triton X- 100, lOOmM NaF, ImM DTT, IraMPMSF, 10g/ml Leupeptin and lOu.g/ml Benzamidine. The lysates were centrifuged in a microfuge at 13000 rpm for 15 minutes and the supematants taken before analysis by sandwich Elisa, Nunc Maxisorb F96 Immunoplates were coated with EGFR capture antibody (sc-120, Santa Cruz Biotechnology, Inc.) by incubation at a concentration of 0.16jig/ml in lOOul of 50mM carbonate/bicarbonate buffer, pH 9.6. The plates were incubated at 4°C overnight with a gentle shaking action. Following overnight incubation, the plates were washed extensively with PBS containing 0.05% Tween before blocking with Superblock (Pierce). 100,1 of lysate was then added to each well and incubated overnight at 4°C before extensive washing with PBS containing 0.05% Tween. The immobilised EGFR was then probed with an anti-phosphotyrosine HRP conjugated antibody (4G10, Upstate Biotechnology Inc.) at a dilution of 1 in 800 in PBS containing 0.05% Tween plus 0.5% Bovine Serum Albumen. After further washing, HRP activity hi each well of the plate was measured colorimetrically using Tetra Methyl Benzidine (TMB) from Bushranger (Roche Applied Sciences) in phosphate-citrate-perborate buffer containing 10% DMSO as a substrate. This reaction was stopped by the addition of lOOul of 1M HzSQ after 12 minutes and quantified by measurement of the absorbance at 450nm using a Molecular Devices ThermoMax microplate reader. Inhibition of EGFR phosphorylation for a given compound was expressed as an ICso value. This was determined by calculation of the concentration of compound that was required to give 50% inhibition of phosphorylation hi this assay. The range of phosphorylation was calculated from the positive (vehicle plus EOF) and negative (vehicle minus EOF) control values. d) Clone 24 phospho-erbB2 cell assay This unmunofluorescence end point assay measures the ability of a test compound to inhibit the phosphorylation of erbB2 in a MCF7 (breast carcinoma) derived cell tine which was generated by transfecting MCF7 cells with the full length erbB2 gene using standard methods to give a cell line that overexpresses full length wild type erbB2 protein (hereinafter "Clone 24* cells). Clone 24 cells were cultured in Growth Medium (phenol red free Dulbecco"s modified Eagle"s medium (DMEM) containing 10% foetal bovine serum, 2 mM glutamine and 1.2mg/ml G418) in a 7.5% CQz air incubator at 37°C. Cells were harvested from T75 stock flasks by washing once in PBS (phosphate buffered saline, pH7.4, Gibco No. 10010- 015) and harvested using 2mls of Trypsin (1.25mg/mlethylaminediaminetetraacetic acid (EDTA) (0.8mg/ml) solution. The cells were resuspended in Growth Medium. Cell density was measured using a haemocytometer and viability was calculated using Trypan Blue solution before being further diluted in Growth Medium and seeded at a density of IxlO4 cells perwell(in lOOul) into clear bottomed 96 well platek (Packard, No. 6005182). 3 days later, Growth Medium was removed from the wells and replaced with lOOul Assay Medium (phenol red free DMEM, 2mM glutamine, 1.2mg/ml G418) either with or without erbB inhibitor compound. Plates were returned to the incubator for 4hours and then 20ul of 20% formaldehyde solution in PBS was added to each well and the plate was left at room temperature for 30 minutes. This fixative solution was removed with a multichannel pipette, lOOjil of PBS was added to each well and then removed with a multichannel pipette and then 50ul PBS was added to each well Plates were then sealed and stored for up to 2 weeks at 4°C. Immunostaining was performed at room temperature. Wells were washed once with 200^1 PBS / Tween 20 (made by adding 1 sachet of PBS / Tween dry powder (Sigma, No. P3563) to 1L of double distilled HjO) using a plate washer then 200ul Blocking Solution (5% Marvel dried skimmed milk (Nestle) in PBS Tween 20) was added and incubated for 10 minutes. Blocking Solution was removed using a plate washer and 200^1 of 0.5% Triton X- 100 / PBS was added to permeabalise the cells. After 10 minutes, the plate was washed with 200\|il PBS / Tween 20 and men 200\|il Blocking Solution was added once again and incubated for 15 minutes. Following removal of the Blocking Solution with a plate washer, 30ul of rabbit polyclonal anti-phospho ErbB2 IgO antibody (epitope phospho-Tyr 1248, SantaCruz, No. SC-12352-R), diluted 1:250 in Blocking Solution, was added to each well and incubated for 2 hours. Then mis primary antibody solution was removed from the wells using a plate washer followed by two 200ul PBS / Tween 20 washes using a plate washer. Then 30ul of Alexa-Fluor 488 goat anti-rabbit IgO secondary antibody (Molecular Probes, No. A-11008), diluted 1:750 in Blocking Solution, was added to each well. From now onwards, wherever possible, plates were protected from light exposure, at this stage by sealing with black backing tape. The plates were incubated for 45 minutes and then the secondary antibody solution was removed from the wells followed by two 200ul PBS / Tween 20 washes using a plate washer. Then PBS was added to each plate, incubated for 10 minutes and then removed using a plate washer. Then a further lOOul PBS was added to each plate and then, without prolonged incubation, removed using a plate washer. Then SOuJ of PBS was added to each well and plates were resealed with black backing tape and stored for up to 2 days at 4°C before analysis. The Fluorescence^ signal is each well was measured using an Acumen Explorer, , Instrument (Acumen Bioscience Ltd.), a plate reader that can be used to rapidly quantitate features of images generated by laser-scanning. The instrument was set to measure the number of fluorescent objects above a pre-set threshold value and this provided a measure of the phosphorylation status of erbB2 protein. Fluorescence dose response data obtained with each compound was exported into a suitable software package (such as Origin) to perform curve fitting analysis. Inhibition of erbB2 phosphorylation was expressed as an ICso value. This was determined by calculation of the concentration of compound that was required to give 50% inhibition of erbB2 phosphorylation signal. e) In vivo BT-474 Xeno graft assay This assay measures the ability of a test compound to inhibit the growth of a BT-474 tumour cell xenograft (human mammary carcinoma obtained from Dr Baselga, Laboratorio Recerca Oncologica, Paseo Vail DHebron 119-129, Barcelona 08035, Spain) in Female Swiss athymic mice (Alderley Park, nu/nu genotype) (Baselga, J. et al (1998) Cancer Research, 58,2825-2831). Female Swiss athymic (nu/nu genotype) mice were bred and maintained in Alderley Park in negative pressure Isolators (PFI Systems Ltd.). Mice were housed in a barrier facility with 12hr light/dark cycles and provided with sterilised food and water ad libitum. All procedures were performed on mice of at least 8 weeks of age. BT-474 tumour cell xenografts were established in the hind flank of donor mice by sub-cutaneous injections of IxlO7 freshly cultured cells in lOOul of serum free media with 50% Matrigel per animal. On day 14 post-implant, mice were randomised into groups of 10 prior to the treatment with compound or vehicle control that was administered once daily at O.lml/lOg body weight Tumour volume was assessed twice weekly by bilateral Vernier calliper measurement, using the formula (length x width) x V(Iength x width) x (fl/6), where length was the longest diameter across the tumour, and width was the corresponding perpendicular. Growth inhibition from start of treatment was calculated by comparison of the mean changes in tumour volume for the control and treated groups, and statistical significance between the two groups was evaluated using a Students t test. f) hERG-encoded Potassium Channel Inhibition Assay This assay determines the ability of a test compound to inhibit the tail current flowing through the human ether-a-go-go-related-gene (Herg)encoded potassium channel. Human embryonic kidney (HEK) cells expressing the hERG-encoded channel were grown in Mimhium Essential Medium Eagle (EMEM; Sigma-Aldrich catalogue number M2279), supplemented with 10% Foetal Calf Serum (Labtech International; product number 4-101-500), 10% Ml serum-free supplement (Egg Technologies; product number 70916) and 0.4 mg/ml Geneticin 0418 (Sigma-Aldrich; catalogue number G7034). One or two days before each experiment, the cells were detached from the tissue culture flasks with Accutase (TCS Biologicals) using standard tissue culture methods. They were then put onto glass coverslips resting hi wells of a 12 well plate and covered with 2 ml of the growing media. For each cell recorded, a glass coverslip containing the cells was placed at the bottom of a Perspex chamber containing bath solution (see below) at room temperature (~20 °C). This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately after placing the coverslip in the chamber, bath solution was perfused into the chamber from a gravity-fed reservoir for 2 minutes at a rate of ~ 2 ml/min. After this time, perfusion was ) stopped. A patch pipette made from borosilicate glass tubing (GC120F, Harvard Apparatus) using a P-97 micropipette puller (Sutter Instrument Co.) was filled with pipette solution (see hereinafter). The pipette was connected to the headstage of the patch clamp amplifier (Axopatch 200B, Axon Instruments) via a silver/silver chloride wire. The headstage ground was connected to the earth electrode. This consisted of a silver/silver chloride wire embedded in 3% agar made up with 0.85% sodium chloride. The cell was recorded in the whole cell configuration of Hie patch clamp technique. Following "break-in", which was done at a holding potential of -80 mV (set by the amplifier), and appropriate adjustment of series resistance and capacitance controls, electtophysiology software (CUunpex, Axon Instruments) was used to set a holding potential (-80 mV) and to deliver a voltage protocol. This protocol was applied every 15 seconds and consisted of a 1 s step to 440 mV followed by a 1 s step to -50 mV. The current response to each imposed voltage protocol was low pass filtered by the amplifier at 1 kHz. The filtered signal was men acquired, on line, by digitising this analogue signal from the amplifier with an analogue to digital converter. The digitised signal was then captured on a computer running Clampex software (Axon Instruments). During the holding potential and the step to + 40 mV the current was sampled at 1 kHz. The sampling rate was men set to 5 kHz for the remainder of the voltage protocol. The compositions, pH and osmolarity of the bath and pipette solution are tabulated below. 0.4 ing/ml Geneticin 0418 (Sigma-Aldrich; catalogue number G7034). One or two days before each experiment, the cells were detached from the tissue culture flasks with Accutase (TCS Biologicals) using standard tissue culture methods. They were then put onto glass coverslips resting in wells of a 12 well plate and covered with 2 ml of the growing media. For each cell recorded, a glass coverslip containing the cells was placed at the bottom of a Perspex chamber containing bath solution (see below) at room temperature (-20 °C). This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately after placing the coverslip in the chamber, bam solution was perfused into the chamber from a gravity-fed reservoir for 2 minutes at a rate of ~ 2 ml/mm. After mis time, perfusion was stopped. A patch pipette made from borosilicate glass tubing (GC120F, Harvard Apparatus) using a P-97 micropipette puller (Sutler Instrument Co.) was filled with pipette solution (see hereinafter). The pipette was connected to the beadstage of the patch clamp amplifier (Axopatch 200B, Axon Instruments) via a silver/silver chloride wire. The headstage ground was connected to the earth electrode. This consisted of a silver/silver chloride wire embedded in 3% agar made up with 0.85% sodium chloride. The cell was recorded in the whole cell configuration of the patch clamp technique. Following "break-in, which was done at a holding potential of -80 mV (set by the amplifier), and appropriate adjustment of series resistance and capacitance controls, electrophysiology software (Clampex, Axon Instruments) was used to set a holding potential (-80 mV) and to deliver a voltage protocol. This protocol was applied every IS seconds and consisted of a 1 s step to 440 mV followed by a 1 s step to -50 mV. The current response to each imposed voltage protocol was low pass filtered by the amplifier at 1 kHz. The filtered signal was then acquired, on line, by digitising mis analogue signal from the amplifier with an analogue to digital converter. The digitised signal was then captured on a computer running Clampex software (Axon Instruments). During the holding potential and the step to + 40 mV the current was sampled at 1 kHz. The sampling rate was then set to 5 kHz for the remainder of the voltage protocol. The compositions, pH and osmolarity of the bath and pipette solution are tabulated below. Salt NaCl Kd MgCl2 Cad2 HEPES glucose Na2ATP EGTA Pipette (raM) Parameter pH pH adjustment with Osmolarity (mOsm) Pipette 7.18-7.22 1MKOH 275-285 Bath 7.40 IMNaOH 285-295 The amplitude of the hERG-encoded potassium channel tail current following the step from +40 mV to -50 mV was recorded oo-tine by Clampex software (Axon Instruments). Following stabilisation of the tail current amplitude, bath solution containing the vehicle for the test substance was applied to the cell. Providing the vehicle application had no significant effect on tail current amplitude, a cumulative concentration effect curve to the compound was then constructed. The effect of each concentration of test compound was quantified by expressing the tail current amplitude hi the presence of a given concentration of test compound as a percentage of that in the presence of vehicle. Test compound potency (ICso) was determined by fitting the percentage inhibition values making up the concentration-effect to a four parameter Hill equation using a standard data-fitting package. If the level of inhibition seen at the highest test concentration did not exceed 50%, no potency value was produced and a percentage inhibition value at mat concentration was quoted. Although the pharmacological properties of the compounds of the formula 1 vary with structural change as expected, in general activity possessed by compounds of the formula I, may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d) Test (a):- ICso in the range, for example, 0.001 - 5 Test (b):- ICso in the range, for example, 0.001 - 5 µM; Test (c):- ICso in the range, for example, 0.001 - 5 µM; Test (c):- ICso in the range, for example, 0.001 - S µM; Test (d):- activity in the range, for example, 1-200 mg/kg/day; No physiologically unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested of the present invention. Accordingly no untoward toxicological effects are expected when a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter. By way of example, Table A illustrates the activity of representative compounds according to the invention. Column 2 of Table A shows ICso data from Test (a) for the inhibition of EGFR tyrosine kinase protein phosphorylation; column 3 shows ICso data from Test (a) for the inhibition of erbB2 tyrosine kinase protein phosphorylation; and column 4 shows ICso data for inhibition of phosphorylation of erbB2 in a MCF7 derived cell line in Test (d) described above: According to a further aspect of the invention mere is provided a pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically (Table Removed) acceptable 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, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. The amount of active ingredient mat 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, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from O.S to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. The size of the dose for therapeutic or prophylactic purposes of a quinazoline derivative of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In using a quinazoline derivative of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similariy, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration is however preferred, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention. We have found that the compounds of the present invention possess anti-proliferative properties such as anti-cancer properties that are believed to arise from their erb-B, particularly EOFR and more particularly erbB2 receptor tyrosine kinase inhibitory activity. Furthermore, certain of the compounds according to vie present invention possess substantially better potency against the erbB2 receptor tyrosine kinase, than against other tyrosine kinases enzymes, such as EGFR tyrosine kinase. Such compounds possess sufficient potency against the erbB2 receptor tyrosine kinase mat they may be used in an amount sufficient to inhibit erbB2 receptor tyrosine kinase whilst demonstrating little, or significantly lower, activity against other tyrosine kinases such as EGFR. Such compounds are likely to be useful for the selective inhibition of erbB2 receptor tyrosine kinase and are likely to be useful for the effective treatment of, for example etbB2 driven tumours. Accordingly, the compounds of the present invention are expected to be useful m the treatment of diseases or medical conditions mediated alone or in part by and erb-B, particularly erbB2 receptor tyrosine kinases, i.e. the compounds may be used to produce a erb-B, particularly an erbB2, receptor tyrosine kinase inhibitory effect in a warm-blooded anirnalm need of such treatment Thus the compounds of the present invention provide a for the treatment of maHgnant cells characterised by inhibition of the erb-B, particularly erbB2 receptor tyrosine kinase. Particularly die compounds of the invention may be used to produce an anti-proliferative and/or pro-apoptotic and/or anti-invasive effect mediated alone or in part by the inhibition of erb-B, particularly ertB2, receptor tyrosine kinases. Particularly, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours that are sensitive to inhibition of an erb-B, particularly the erbB2, receptor tyrosine kinase that are involved in the signal transduction steps which drive proliferation and survival of these tumour cells. Accordingly the compounds of the present invention are expected to be useful in the treatment and/or prevention of a number of hyperprolif erative disorders by providing an anti-proliferative effect These disorders include, for example psoriasis, benign prostatic hyperplasia (BPH), atherosclerosis and restenosis and, in particular, erb-B, more particularly erb-B2, receptor tyrosine kinase driven tumours. Such benign or maHgnant tumours may affect any tissue and include non-solid tumours such as leukaemia, multiple myeloma or lyrnphpma, and also solid tumours, for example bile duct, bone, bladder, brain/CNS, breast, colorcctal, cervical, endometrial, gastric, head and neck, hepatic, lung, muscle, neuronal, oesophageal, ovarian, pancreatic, pleural/peritoneal membranes, prostate, renal, skin, testicular, thyroid, uterine and vulval tumours. According to this aspect of the invention there is provided a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament. 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 thereof, as defined hereinbefore 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 mere is provided 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 phannaceutically acceptable salt thereof, as hereinbefore defined. According to a further aspect of the invention there is provided a quinazoline derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in the production of an anti-proliferative effect 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 thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-proliferative effect which effect is produced alone or m part by inhibiting erbB2 receptor tyrosine kinase in a warm-blooded animal such as man. According to a further feature of this aspect of the invention mere is provided a method for producing an anti-proliferative effect which effect is produced alone or hi part by inhibiting erbB2 receptor tyrosine kinase 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 phannaceutically acceptable salt thereof, as hereinbefore defined. According to a further aspect of the invention there is provided a quinazoline derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in the production of an anti-proliferative effect which effect is produced alone or in part by inhibiting erbB2 receptor tyrosine kinase in a warm-blooded animal such as man. According to a further aspect of the present invention mere is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore: in the manufacture of a medicament for use in the treatment of a disease or medical condition (for example a cancer as mentioned herein) mediated alone or in part by erb-B, particularly erbB2, receptor tyrosine kinase. According to a further feature of this aspect of the invention there is provided a method for treating a disease or medical condition (for example a cancer as mentioned herein) mediated alone or in part by erb-B, particularly erbB2, receptor tyrosine kinase 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 pharmaccuticaliy acceptable salt thereof, as defined hereinbefore. According to a further aspect of the invention mere is provided a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical condition (for example a cancer as mentioned herein) mediated alone or hi part by erb-B, particularly erbB2, receptor tyrosine kinase. According to a former aspect of the invention mere is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof , as defined hereunbef ore in the manufacture of a inediwiment for use in the prevention or treatment of those tumours which are sensitive to inhibition of erbB2 receptor tyrosine kinase that is involved in the signal transduction steps which lead to the proliferation of tumour cells. According to a further feature of mis aspect of me invention there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of erbB2 receptor tyrosine kinase, that is involved in the signal transduction steps which lead to the proliferation and/or survival of tumour cells 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 thereof, as defined hereinbefore. According to a further aspect of the invention there is provided a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of those tumours which are sensitive to inhibition of the erbB2 receptor tyrosine kinase, mat is involved hi the signal transduction steps which lead to the proliferation and/or survival of tumour cells. According to a further aspect of the invention mere is provided tile use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a erbB2 receptor tyrosine kinase inhibitory effect According to a further feature of this aspect of the invention there is provided a method for providing an erbB2 receptor tyrosine kinase inhibitory 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 phannaceutically acceptable salt thereof, as defined hereinbefore. According to a further aspect of the invention there is provided a quinazoline derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in providing an erbB2 receptor tyrosine kinase inhibitory effect According to a further aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a phannaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use m providing a selective erbB2 kinase inhibitory effect According to a further feature of this aspect of the invention there is provided a method for providing a selective erbB2 kinase inhibitory 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 phannaceutically acceptable salt thereof, as defined hereinbefore. According to a further aspect of the invention mere is provided a quinazoline derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in providing a selective erbB2 kinase inhibitory effect. By "a selective exbB2 kinase inhibitory effect" is meant that the quinazoline derivative of Formula I is more potent against erbB2 receptor tyrosine kinase than it is against other kinases. In particular some of the compounds according to the invention are more potent against erbB2 receptor kinase than it is against other tyrosine kinases such as other erb-B receptor tyrosine kinases, particularly EGFR tyrosine kinase. For example a selective erb-B2 kinase inhibitor according to the invention is at least 5 times, preferably at least 10 times, more preferably at least 100 times more potent against erbB2 receptor tyrosine kinase than it is against EGFR tyrosine kinase, as determined from the relative ICso values in suitable assays (for example the by comparing the ICso value from the Clone 24 phospho-erbB2 cell assay (assay d) described above which measure the inhibition of erb~B2 phosphorylation hi cells) with the ICso from the KB cellular EOFR phosphorylation assay (assay c) described above which measures the inhibition of EGFR phosphorylation in cells) for a given test compound as described above). According to a further aspect of the present invention mere is provided the use of a quinazoHne derivative of the formula I, or a phannaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of acancer, for example a cancer selected fiom leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, cervical, endometrial, gastric, head and neck, hepatic, lung, muscle, neuronal, oesophageal, ovarian, pancreatic, pleural/peritoneal membranes, prostate, renal, skin, testicular, thyroid, uterine and vulval cancer. According to a further feature of mis aspect of the invention mere is provided a method for treating a cancer, for example a cancer selected fiom selected from leukaemia, multiple myeloma, lymphoma, bfle duct, bone, bladder, brain/CNS, breast, colorectal, cervical, endometrial, gastric, head and neck, hepatic, lung, muscle, neuronal, oesophageal, ovarian, pancreatic, pleural/peritoneal membranes, prostate, renal, skin, testicular, thyroid, uterine and vulval 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 quinazohne derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore. According to a further aspect of the invention there is provided a quinazoline derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in the treatment of a cancer, for example a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, cervical, endometrial, gastric, head and neck, hepatic, lung, muscle, neuronal, oesophageal, ovarian, pancreatic, pleural/peritoneal membranes, prostate, renal, skin, testicular, thyroid, uterine and vulval cancer. The anti-proliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, hi addition to the quinazoline derivative of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents: As mentioned above the size of the dose required for the therapeutic or prophlyactic treatment of a particular disease will necessarily be varied depending upon, amongst other things, the host treated, the route of administration and the severity of the illness being treated. The anti-proliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinazoline derivative of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) antiproUferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as aflcylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoeide and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycLn, bfeomytin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mimramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomcrase inhibitors (for example epipodophyllotoxins tike etoposide and teniposide, amsacrinc, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goseretin, Icuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of So-reductase such as fmasteride; (hi) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™] and the anti-erbBl antibody cetuximab [C22S]), famesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example other inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinoptopoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-methynylienyl)-6,7- bis(2rinelhoxyedK)xy)quinazoliii-4-amiiie (erlotinib, OSI-774) and 6-acrylamido- -(3-cWoio- 4-fluoroph«iyl)-7-{3-morpholinopropoxy)qmnazolin-4-amine (CI 1033)X for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family; (v) antiangiogenic agents such as those which inhibit die effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integral ovfte function and angiostatin); (vi) vascular damaging agents such as CombietastatinA4 and 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)antigens therapies, for example those which redirected to the targets listed above, such as ISIS 2503, an anti-rasantisense; (viii) gene therapy approaches, inchiding for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, inchiding for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytoldnes such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell energy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. According to this aspect of the invention there is provided a pharmaceutical product comprising a quinazoline derivative of the formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer. Although the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of the erbB receptor tyrosine protein kinases. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. The invention will now be illustrated by the following non limiting examples in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, mat is, at a temperature in the range of 18-25°C; (ii) organic solutions were dried over anhydrous magnesium surf ate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mmHg) with a bath temperature of up to 80°C; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; (iv) in general, the course of reactions was followed by TLC and / or analytical LC-MS, and reaction times are given for illustration only; (v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data; (vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulfoxide (DMSO-de) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, muMplet; b, broad; (viii) chemical symbols have their usual meanings imits and symtols arc used; (ix) solvent ratios are given in volume:volume (v/v) terms; and (x) mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (El), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (MH)+ which refers to the protonated mass ion; reference to M1" is to the mass ion generated by loss of an electron; and reference to M-H is to the mass ion generated by loss of a proton; (xi) unless stated otherwise compounds containing an asymmetrically substituted carbon and/or sulfur atom have not been resolved; (xii) where a synthesis is described as being analogous to that described in a previous example the amounts used are the mUlimolar ratio equivalents to those used in the previous example; (xiii) all microwave reactions were carried out in a CEM Discover™ microwave synthesis or CEM Mam microwave synthesiser, (xiv) preparative high performance fiqmd chromatography (HPLQ was performed on a Otlson instrument using the following conditions: Column: 21 mm x 10 cm Hichrom RPB Solvent A: Water0.1% trifluoroacetic acid. Solvent B: Acetonitrile 4- 0.1% trifluoroacetic acid Flow rate: 18ml/min Run time: 15 minutes with a 10 minute gradient from 5-95% B Wavelength: 254 nm, bandwidth 10 nm Injection volume 2.0-4.0 ml; (xv) the following abbreviations have been used: HATU OX7-Azabe«zotriazol- Hexafluoro-Phosphate; and THF tetrahydrofuran; DMF tyN-dimethylformamide; DMA MAWirnethylacetamide; DCM dichloromethane; DIPEA N,N-diisopropylethylamine; DMSO dimethylsulfoxide; DPA Isopropyl alcohol; and ether diethyl ether. Example 1 ntethyteeeiainide A mixture of HATU (197 mg), diisopropylcthylamine (90 pi), acetic acid (22 ul) and AK3hlcfO-4din-2-ymiethoxy)pleny (150 mg) in DCM (20 ml) was stirred for 2 hours. The solution was washed with water, then brine and concentrated in vacua. The residue was purified by chromatography using DCM- 5% methanol as eluent to give the title compound as a white solid (114 mg. 69%Y NMR ffiecjoffi (DMSO-d6) 1.95 (&, 3H), 3.00 (ft, 3H), 3.89 (t, 2H), 4.48 (m, 2H), 5.29 (s, 2HX 7.18 (d, 1H), 7.24 (d. 1H), 735 (m, 2H), 7 59 (m, 2H), 7.72 (dd, ttiQ, 7.85 (dt, 1H), 7.96 (d, 1H), 8.46 (ft, 1H), 858 (m, 1H), 9.70 (bs, 1H); Mass spectrum MH 478.5. The N-[3:hloTO-4^yridm-2-yhnethoxy)phenyl]-5-[2- (me%lainiiK))ethoxy]qumazoliiHl-amine used as starting material was prepared as follows: DMF (0.2 ml) was added to a suspenaon of 5-fluoro-3,4-dihydro-3flr-quinazolin-4-one (1.64 g) in thionyl chloride (10 ml) and the mixture was stirred and heated at 80°C for 6 hours. Volatile material was removed by evaporation and the residue was azeotroped with toluene (20 ml). The resulting solid was added portion wise to a vigorously stirred mixture of saturated sodium bicarbonate (50 ml), crushed ice 50 g) and DCM (50 ml) such that the temperature was kept below 5°C. The organic phase was separated, dried and concentrated to give 4-cMoro-5-fluoroquinazoline (1.82 g, 99%) as a solid which was used without purification; NMR spectrum (CDC) 7.35 - 7.45 (rn, 1H), 7.85 - 7.95 (m, 2H), 9.0 (s, 1H). 4-Chloro-5-fluoroquinazoline (6.75 g) was added to a stirred solution of 3-chloro-4-(2- pyridylmethoxy)aniline (9.27 g, obtained as described in Example 15-21 (note u) of WO 96/15118) in IP A (200 ml), and the solution was stirred and heated at reflux for 8 hours. The solution was allowed to cool to ambient temperature overnight and the precipitated solid was filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol (400 ml) and the mixture was heated on a steam bath until the entire so d had dissolved. The solution was basified by careful addition of aqueous ammonia (0.880), and the mixture was concentrated to remove methanol. Water (300 ml) was added and the mixture was extracted with DCM (600 ml). The extract was washed with water, and brine, and dried. The solvent was removed by evaporation to give a solid, which was re-precipitated from a mixture of ethyl acetate, tetrahydrofuran and isohexane to give A^-[3-chloro-4-(pyridin-2- ylmethoxy)phenyl]-5-fluoroquma2Xtoamine as a beige solid (6.75 g, 48%); NMR spectrum (DMSO-d6) 5.3 (s, 2H), 7.2 - 7.3 (d, IH), 7.35 - 7.5 (m, 2H), 7.5 - 7.65 (m, 3H), 7.8 - 7.95 (m, 3H), 8.55 (s, IH), 8.55 - 8.6 (d, IH), 9.1 - 9.2 (bs, IH); Mass spectrum MH+ 381. Sodium hydride (60% dispersion in mineral oil, 0.63 g) was added to 2- (methylainino)ethanol (055 ml), 15-crown-5 (100 ul) and JV-[3-chloro-4-(pyridin-2- ylinedioxy)pnenyl]-5-fluoroquinazolin-4-amine (1,5 g) in DMA (25 ml) and the reaction heated at 100°C for 2 hours. The reaction was cooled, quenched with saturated aqueous ammonium chloride solution to pH 7-8. Addition of a small amount of saturated aqueous sodium hydrogen carbonate solution resulted in the formation of a precipitate, which was filtered, washed with water and dried The sotid was purified by chroniatography using DCM - 5% methanol / 7N ammonia as eluent to give N-l3^Moro^pvridm-2-ylmethoxy)phenyIJ- 5-[2Kmemylamino)eAoxy]qinnazolm-4-ariiine as a yellow solid (0.27 g, 45%); NMR spectrum (DMSO-d6) 2.AQ (s, 3H), 3.02 (t, 2H), 4.35 (t, 2H), 5.28 (s, 2H), 7.12 (d, IH), 7.25 (d, IH), 7.31 (d, IH), 7.37 (m, IH), 7.57 (d, IH), 7.71 (dd, IH), 7.85 (m, 2H), 8.10 (d, IH), 8.51 (s, IH), 8.58 (m, IH), 10.57 (bs, IH): Mass spectrum MET 436.5. Example 2 Using an analogous procedure to mat described in Example 1 the appropriate quinazoline was reacted with the appropriate acid to give the compounds shown in Table I: (Table Removed)mettexy-Aneiliyiacetatttkle. Prepared by reacting methoxyacetic acid and AH3-chkwo-4- (pyridiiH2-ylmethoxy)phenyl}-52-( (prepared as described in Example in 52% yield: NMR spectrum (DMSO-d6) 3.00 (a, 3H), 3.23 (s» 3HX 3.90 (t, 2H), 4.04 (&, 2H), 430 (t, 2H), 5.29 (s, 2H), 7.17 (d, 1H), 7J23 (d, 1H), 735 (m, 2H), 7 .59 (dd, 1H), 7.72 (dd, 1H), 7.85 (dt, 1HX 7.99 (d, 1H), 8.45 (&, 1H), 838 (m, 1H), 9.70 (bs, 1H); Mas SQ85. [2] 2-[(4-{3-Oikro-4yridi2-ytoirtlKxy) (dlmethylainfaioVA-methylftcetaiBide. Prepared by reacting M-dimethylglycine and N-[3- cWoro-4-(pyridin-2-)dirttthoxy)phenji]-5-[2-(methylamino)etb (prepared as described in Example 1, preparation of starting materials) in 13% yield; NMR spectrum (DMSO-d6) 2.68 (s, 6H), 3.05 (s, 3H), 3.97 (m, 2H), 4.05 (s, 2H), 4.53 (m, 2H), 5.29 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H), 7.37 (m, 2H), 7.60 (d, 1H), 7.65 (d, 1H), 7.54 (t, 1H), 7.86 (dt, 1H), 8.02 (d, 1H), 8.50 (s, 1H), 8.58 (m, 1H), 9.70 (bs, im; Mass spectrum MHT 521.6. [3] yl)oxy]propyl}-2-methoxy-N-nieayla«etainide). Prepared by reacting methoxyacetic acid andJV-Ploro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(l/?)-l-methyl-2- (methylamino)ethoxy]quinazolin-4-amine in 31% yield; Mass spectrnrp MH 522.4. The JV-[3- -4-(pyridfo-2-yta (roethylaniino)etiioxy]qmnazdin-4- used as starting material was prepared as follows: (2K2-methyloxirane (13.76 g) was added to a suspension of Amethylprop-2-en-lamine (25 ml) and ytterbium(III) trifle wromethanesulfonate (100 mg) in dioxane (100 ml) and heated to 140°C for 1 hour under microwave irradiation. The solution was concentrated in vacua and the residue partitioned between water (100 ml) and ethyl acetate (200 ml). The organic extract was dried and solvent removed in vacua yielding (2K)~1- [allyl(methyl)amino]propan-2-ol as a yellow oil (8.8 g, 29%); NMR spectrum (CDC13) 1.20 (d, 3H), 2.33 (s, 3H), 2.27-2.46 (m, 2H), 3.05 (m, 1H), 3.23 (m, 1H), 3.88 (m, 1H), 5.19 - 5.29 (m, 2H), 5.90 (m, 1H); Mass spectrum M 129. (2^1-[aUyl(memyl)amino]propan-2-oJ was reacted with -[3-cnloro-4-(pyridin-2- ylmethoxy)ohenyl]-5-fluoroquinazoHn-4-amine using an analogous procedure to mat ylmethoxy)phenyl]-5- [2thylainrno)ethoxy]qirinazolrn4-amine, to give 5--2-[allyl(methyl)amino]-lmethylethoxy}- -2-yIraethoxy in 53% yield; NMR spectrum (DMSO-d6) 1.45 (d, 3H), 2.17 (s, 3H), 292 - 3.07 (m, 2H), 4.93 (m, 1H), 5.00 (d, 1H), 5.10 (d. 1H). 530 (s, 2H), 5.64 (m, 1H), 7J20 - 7.40 (m, 4H), 7.58 (m, 2H), 7.71 (dd, 1H), 7.85 (dd, 1H), 7.98 (m, 1H), 8.47 (s, 1H), 8.58 (d, 1H), 10.32 (bs, 1H). ylrnethoxy)phenyllquinazolin-4-amine was heated in acetonitrile/water in the presence of chlorotris(triphenylDhosphine)rhodium (I) using an analogous procedure to mat described below in Example 4-11 (preparation of starting materials) to give N-[3-chloro-4-(pyridin-2- yln»thoxy)pheny]]-5-[(ll-iriethyl-2Kmethylamino)ethyl]quina2olin-4-amine in 15 % yield; Mass spectrum M" 450. [4) methylethyl}&cetamide. Prepared by reacting 5-{ -2-aminopropyl]oxy } --[3-chloro-4- (pyridin-2-ylmemoxy)phenyl]quinazolin-4-amine and acetic acid in 99% yield; NMR spectrum CDMSO-d6) 1.20 (d, 3H), 1.70 (s, 3H), 4.2 - 4.3 (tn, 2H), 4.4 (m, 1H), 5.35 (s, 2H), 7.3 - 7.6 (m, 6H), 7.8 (m, 1H), 7.85 - 8.00 (m, 2H), 8.15 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H); Mass spectrum MH4 478. The 5-{ 2-animopropyl]oxy}-Ar-[3hloro-4-(pyridin-2- ylmethoxy)phenyl]qumazolin-4-amine used as starting material was prepared by reacting (R)- (-)-2-amino-l-prooanol and #-[3Moro-4-(pyridm-2-ytoethoxy)ph - 4-amine using an analogous procedure to that described in Example 1 (for the preparation of to give 5-{[(2)-2-aminopropyl]oxy}-N-[3-cMcro-4-(pyridin-2- ylmethoxy)phenyl}quinazolin-4-amine in 63% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 3.4 (m, 1H), 4.0 (t, 1H), 4.2 (dd, 1H), 5.3 (s, 2H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3 (m, 2H), 7.6 (d, 1H), 7.7 (m, 2H), 7.9 (m, 1H), 8.25 (d, 1H), 8.5 (s, 1H), 8.6 (d, 1H); Mass spectrum MH436. [5] JVK012-[(4K3-aiIoropyr methyleihyl}-2-hydroTyftceianiide. Prepared by reacting glycohc acid and 5-{ [(2/0-2- aminopfopyl]oxy}-N-[3-chlon-4-(pyre in 93% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 3.6 - 3.8 (m, 2H), 4.3 (m, 2H), 4.5 (m, 1H), ) 1.78 (s, 3H), 3.62 (m, 2H), 434 (t, 2H). 5.29 (s, 2H), 7.14 (d, 1HX 7.24 (d, 1H), 735 (m, 2H), 7 J7 (m 2H), 7.72 (t, 1H), 7.87 (t, 1H), 8.01 (d, 1H), 855 (bs, 1H), 8.48 (s, 1H), 8.59 (m, 1H) 9.87 (bs. 1H); Mass spectrum MET 464. amine used as a starting material was prepared by reacting ethanolanrine andAr-[3-chlQro-4- (pyridin-2-ylmethoxy)pbenyl]-5-fluoroquinazolin-4-amine using an analogous procedure to that described in Example 1 for the preparation of -[3-chloro-4-(pyridin-2- ylmethoxy)renyl]-5-[2Kmetaylammo)euioxy]quirtazolin-4-amine to give 5-(2- amiiK)euxy)--[3K:Uon)(pyridin-2-ylniethoxy)phem in 49% yield; NMR spectrum (DMSO-d6) 3.12 (t, 2H), 3.29 (2H obscured under water), 4.28 (t, 2H), 5.28 (s, 2H), 7.12 (d, 1H), 721 (d, 1H), 7.34 (m, 2H), 7.57 (d, 1H), 7.71 (m, 2H), 7.87 (t» 1H), 8.23 (d, 1H), 8.51 (s, 1H), 858 (d, Iffi: Mass spectrum MH 422. [7] tf-{(2tf)-2(4.{3-ChlorcMHpyrMrn-yl yl)oxy]propyl}--methylacetaniide. Prepared by reacting acetic acid with ^-[3-chloro-4- (pyridin-2-ymiethoxy)phenyl]-5--l-methyI-2-(metliylarnmo)ethoxy]qum (prepared as described in Example 2-3) to give the title product in 50% yield; NMR spectrum CDCb)-L47 (d, 3H), 2.00 (s, 3H), 3.00 (s, 3H), 3.45 (m lH) 3.93 (m, 1H) 5.00 (m, 1H), 5.25 (s, 2H), 6.98 (m, 2H), 7.40 (m, 1H), 7.49 (m, 1H), 7.59 (m, 2H), 7.70 (m, 1H), 7.90 (s, 1H), 8.53 (s, 2H), 9.82 (bs, 1H); Mass spectrum MBf 492.5. Examples 2-Hydroxy--methyl-A-{2-[(4-{3-iW5thyM-(pyridin-2-yImethoxy)anilino}quinazolin-5- yl)oxy]ethyl}acetainide 2-Hydroxy--[2{4-[4ydroxy-3-methylanibiK]quinazolin-5-yl}oxy)ethyl]-A/- methYlacetamtde (100 mg), picolyl chloride hydrochloride (60 mg) and potassium carbonate (120 mg) were stirred in DMF (5 ml) to which was added 18-crown-6 (1O mg). The reaction was stirred at room temperature for 2 days. The DMF was removed in vacua, water (5 ml) was added and then the suspension was extracted with DCM (2x5 ml). The DCM fraction was purified by chromatography using 25 - 5 % of 10:1 DCM/methanol containing 0^% ammonia (0.880) as eluent. The appropriate fractions were evaporated, and the residue was precipitated from DCM / diethyl ether to give the titte product as a fight yellow solid (28 m& 23%); NMRspectnim (DMSO-do,100°C) 2J29 (s, 3H), 3.00 (s, 3H), 3.9O (t, 2H), 4.16 (s, 2H), 4 JO (t, 2H), 520 (s, 2H), 7.01 (d, 1H), 7.16 (d, 1H), 734 (d, 2H), 7.51 (m, 2H), 7.55 (d, 1H), 7.79 (t, 1H), 7.83 (td, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.62 (s, 1H); Mass spectrum MH 474. The2-hydroxy-N-[2{4-[4-hydroxy-3-mcthy}anilino}quinazoIin-5-yl}oxy)cthyl]-Nmethylacetamide used as starting material was prepared as follows: 4-Chloro-5-fluoroquinazoline (6.76 g) was dissolved in uro-pxopanol (200 ml) and 4- amino-2-methylphenol (5.00 g) was added. The mixture was heated under reflux for 2 hours, causing a yellow solid to precipitate. The mixture was cooled to ambient temperature and the solid was collected by filtration. The solid was dissolved in a boiling mixture of methanol (500 ml) and water (100 ml) to give a brown solution. With vigorous stirring, the solution was basified with aqueous ammonia (0.880,10 ml), causing a light brown solid to precipitate. The mixture was concentrated in vacua to such a volume that all of the methanol had been removed, leaving the product as a suspension in aqueous solution. The suspension was , cooled; the solid was collected by filtration, triturated with ethyl acetate and dried over P&s in a vacuum oven to give 2-memyl4-[(5-fluoroquinazoHn-4-yl)amino]phenol as a light brown solid (8.18 g, 82%); NMR spectrum (DMSO-d6) 3.30 (s, 3H), 6.78 (d, IH), 7.28 (m, 2H), 7.38 (dd, IH), 7.57 (d, IH), 7.78 (m, IH), 8.43 (s, IH), 8.88 (d, IH), 9.22 (s, IH); Mags spectrum MH 270. A solution of N-mcthylanrinoethanol (0.80 g) in DMA (5 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.43 g) in DMA (20 ml). The reaction was stirred for 30 minutes then 15-crown-5 (50 mg) was added, followed by 2- methl[(5-fliK)roquinazohnyl)ammo]phenol (1.00 g). The reaction was heated at 110°C for 2.5 hours. The reaction was cooled, quenched with saturated ammonium chloride, and concentrated in vacua. Saturated sodium bicarbonate solution was added causing precipitation of a solid which was collected by filtration, washed with water and precipitated from ethyl acetate to give 2nneAyl{5-[2rnetiiylamino)etnoxy)unazolin-4- yl }amino)phenol as a grey solid (0.60 g, 50%); NMR spectrum (DMSO-d6) 2.16 (s. 3H), 238 (s, 3H), 3.01 (t, 2H), 432 (t, 2H), 6.87 (d, IH), 7.07 (d, IH), 7.18 (d, IH), 7.45 (d, IH), 7.65 (dd, IH), 7.66 (t, IH), 8.41 (s, 1HX1036 (s, IH); Mass spectrum M 325. AsotoikmofglYcolk acid(100mg)mDMF(2inl)wM (400 mg) in DMP (4 ml) and die mixture held under sonkatton for 5 minutes, A solution of HATU (519 mg) in DMF (2ml) was then added and the solution was stirred at ambient temperature for 16 houra, and men concentrated in vacua. The residue was treated wim water to precipitate a brown solid that was collected by filtration, and washed with water to give 2-hydroxy--[2-({4-[4- hydroxy-3-niemylaiiih"no]quira as a brown solid (406 mg, 86%); NMR spectrum DMSO-d6) 2.15 (s, 3H), 2.94 (s, 3H), 3.87 (m, 2H), 4.04 (s, 2H), 4.48 (m, 2H), 6.81 (d, IH), 7.20 (dd, IH), 7.25 (d, IH), 7.35 (m, 2H), 7.92 (t, IH), 8.64 (s, IH), 9.46 (s, IH), 10.49 (s, IH); Mass spectrum M 383. Example 4 Using an analogous procedure to mat described in Example 3 the appropriate 4-(4- hydroxyanilino)qumazoline was reacted with the appropriate compound of the formula Ql- CHa-L1 to give the compounds shown in Table 2 below, wherein Q1 is a specified in PMR spectrum (DMSO-d6, 100°C) Z22 (s, 3H), 2.41 (s, 3H), 3.00 (s, 3H). 3.92 (t, 2H), 4.05 (s, 2H), 4.48 (t, 2H), 5.15 (s, 2H), 628 (s, 1H), 7.05 (d, 1H), 7.16 (d, 1H), 7.34 (d, 1H), 7.48 (m, 2H), 7.68 (t, 1H), 8.42 (s, 1H), 9.62 (s, 1H); [4] yl)oxy]pTOpyl}-2-mcfaoxyafcrflniide. Prepared by reacting N-[(22-({4[3-chloro-4- - hyditxyarrilino]quinazoUn-5-yl}oxy)propyl]-2-methoxvacetarm and picolyl chloride hydrochloride in 43% yield; NMR spectrum (DMSO-46) 1.19 (d, 3H), 3.10 (s, 3H), 3.21 (dt, 1H), 3.72 (m, 1H), 3.77 (s, 2H), 4.93 (m, 1H), 5.29 (s, 2H), 7.22 (d, 2H), 7.24 (d, 2H), 7.32 (d, 1H), 736 (dd, 1H), 7.58 (m, 2H), 7.71 (t, 1H), 7.86 (td, 1H), 8.15 (d, 1H), 8.19 (t, 1H), 8.47 (s, 1H), 8.59 (d, 1H), 9.97 (s, 1H) Mass spectrum MH 508. The M-[(22{4-[3hloro-4^ydroxyanUiiio]quinazolin-5-}oxy)propyl]-2- methoxyacetamide used as starting material was prepared as follows: (/O-l-amino-2-propanol was reacted with 2-dilon-4-[(5-flucBX)quinazolin-4- yl)aminojphenol (prepared as described in Example 44, preparation of starting materials) using an analogous process to mat described Example 1 for the preparation of A^-[3-chloro-4- (pyridin-2-ymioxy)phenyl]-5-[2rnethylamino)ethoxy]qdnazoUnamine) to give 4-({5- [2-anu"no-l-rnemylettioxy]quinazolmyl}anuiK)2-Worophenol in 64% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.88 - 3.03 (m, 2H), 3.72 - 3.85 (m, 1H), 6.95 (d, 1H), 7.15 (d, 1H), 7.29 (d, 1H), 7.45 - 7.52 (m, 1H), 7.69, (t, 1H), 8.05 (s, 1H), 8.45 (s, 1H) Mass spectrum MH345. 4K{5^(l/f)-2~Amiiio-l-memylethoxy) was reacted with memoxyacetic acid using an analogous process to mat described in Example 3 (preparation of starting materials) to give A4(2tf)-2-({4-[3-chloro-4- in 83% yield; NMR spectrum (DMSQ-do) 1.4 (d, 3H), 3.1 (s, 3H), 335 - 3.45 (m, 1H), 3.72 - 3.85 (m, 3H), 4.95 - 5.05 (m, 1H), 7JK (d, 1H), 731 (d, 1H), 7.4 (dd, 1H), 7.48 (d, 1H), 7.81 (m, 1H), 7^5 (t, 1H), 8.25 (t, 1H), 8.8 (s, 1H), 1039 (s, 1H), 10.74 (s, 1H) Mass spectrum MET 417. [5] -{2-[(4-{3-aUoro(pyrkiin-2-yhnetlMxy) hydroxy-AT-methylacetamkle. Prepared by reacting picolyl chloride hydrochloride and 66% yield; NMR spectmm (DMSO-d6) 2.96 (s, 3H), 3.91 (t, 2H), 4.04 (d, 2H), 4.26 (t, 1H), 4.40 (t, 2H), 5^8 (s, 2H), 7.14 (d, 1H), 722 (d, 1H), 732 (d, 1H), 735 (m, 1H), 7.57 (m, 2H), 7.70 (m, 1H), 7.86 (m, 1H), 7.95 (s, 1H), 8.42 (s, 1H), 8.58 (d, 1H), 9.73 (bs, 1H); Mass spectrum MH" 494. TheA[2-({4-[(3hloro44iydroxyphenyl)ammo]quinazolm-5-yl}oxy)ethyl]-2- hydroxymediylacetamide used as a starting material was prepared as follows: 4-Chloro-5-fluoroquinazoline was reacted with 4-amino-2-chlorophenol using an analogous process ;to that described in Example 3 for the preparation of " 3- fluoroquinazolin-4-yl)amino]phenol, to give 2-chloro-4-[(5-fluoroquinazolin-4- yl)amino]phenol in 85% yield; NMR spectrum (DMSO-d6) 6.97 (d, 1H), 7.38 (dd, 1H), 7.42 (dd, 1H), 7.59 (d, IH), 7.73 (d, IH), 7.81 (dd, IH), 8.51 (s, 1H), 9.03 (d, IH), 10.07 (bs, 1H); Mass spectrum MH 290. 2-ChlcMx-4-[(5-fluoroquina2olin-4-yl)pheno] was reacted with Nraethylaminoethanol using an analogous process to that described in Example 3 for the preparation of 2-niethyl-4{5-[2hylanMno)ethoxy]quinazolin-4-yl}amino)phenol, to give 2-CWoro{5-[2methylamirK)ethoxy]quinazolinyl}aniino)phenol in 96% yield; NMR spectrum (DMSO-d6) 2,41 (s, 3H), 3.05 (t, 2H), 4.36 (t, 2H), 6.97 (d, IH), 7.12 (d, IH), 731 (d, IH), 7.63 (IH, dd), 7.70 (t, IH), 7.96 (s, IH), 8.47 (s, IH) 10.47 (bs, IH); Mass spectrum MH345. 2Moro-4{5-[2-(inethylanuno)ethoxy]qmM was reacted with glycohc acid using an analogous procedure to that described in Example 3 to give AT-[2- ({4-[3-ChlorcMMiydroxyanih^JqninazoKn-5-yl }oxy)ethyl]-2-4iydroxy--memylacetamide in 58% yield; NMR spectrum (DMSO-d6) 2.96 (s, 3H), 3.90 (t, 2H), 4.05 (m, 3H), 4.41 (t, 2H), 6.97 (d, IH), 7.14 (d, IH), 734 (m, 2H), 7.70 (t, IH), 7.79 (d, IH), 8.40 (s, IH), 9.64 hrdroxyWV-inethyiacclunide. Prepared by reamg3-fhx)rooenzylc the title product in 59% yield: NMR spectrumMSO-d6 at 100°Q 2.91 (s,3H),3.83 (t,2H), 3.99 (bs, 3H), 4.42 (t, 3H), 5.17 (s, 2H), 7.00 - 7.30 (m, 6H), 736 (m, IH), 7.50 (dd, IH), 7.63 (t, IH), 7.89 (d, IH), 838 (s, IH), 9.62 (bs, IH); Mass spectrum MH 511. [7] 2-[(43-Chtorol3-thlazol 2"hydroxyA/r-methylacetainide. Prepared by reacting 4-(chlorometiiyl)-l,3-thiazole hydrochloride and -[2K{43hlcm4-hydioxyaniltao]quinazolin-5-yl}oxy)etfiyl]-2- hydroxy-N-mediylacetamide to give the title product in 54% yield; NMRspecrpi (DMSOd6 at 100°C) 2.99 (s, 3H), 3.91 (t, 2H), 4.07 (bs, 3H), 4.50 (t, 2H), 5.34 (s, 2H), 7.17 (d, IH), 7.30 (d, IH), 7.36 (d, IH), 7.59 (dd, IH), 7.72 (m, 2H), 7.96, (d, IH), 8.46 (s, IH), 9.08 (d, IH), 9.70 (bs, IH); MW PTm MH 500. [8] oxy}etfayl2-hydroxy-2V-mediylacetamide. A mixture of methanesulfonyl chloride (0.034 ml), triethylanrine (0.077 ml) and (6-methylpyridin-2-yl)methanol (44 mg) waa stirred in DCM (10 ml) overnight The solution was concentrated m vacua and DMF (20 ml) was added, followed by the addition of JV-[2-({4-[3-chloro-4-hydroxyanilino]quinazolin-5- rl}oxy)ethyl]-2-hydroxy-N-inethylacctainide (125 rag) and potassium carbonate mgj ana he mixture stiired for 2 days. The solution was concentrated MI vacuo and water (50 ml) was idded and die mixture extracted with DCM (60 ml). The extract was dried and concentrated n vacuo and the residue purified by chromatography using DCM -10% methanol (2M anmonia) to give the title compound as a white solid (99 mg, 54%); NMR spectrum (DMSO- 16 at 100°Q 2.50 (s, 3H obscured by DMSO), 2.99 (s, 3H), 3.92 (t, 2H), 4.06 (bs, 3H), 4.49 [t, 2H), 5.22 (s, 2H), 7.13 - 7.26 (m, 3H), 7.37 (m, 2H), 7.57 (dd, IH), 7.72 (m, 2H), 7.98 (d, IH), 8.46 (s, IH), 9.70 (bs, 1HV. Mass spectrum MH 508. [9] AT.{2-[(43ro-4yraziiH2 hydroxy-tf-methylacetamide. Prepared by reacting pyrazin-2-yhnethyl sulfonate with N-[2- ({4-[(3^htoreHWiydroxyphcyl)airnno methvlacetamide to give the title product in 60% yield: NMR spectrum (DMSO-d6 at 100°Q 2.99 (s, 3H), 3.91 (t, 2HX 4.07 (bs, 3H), 4.49 (t, 2h), 537 (s, 2H), 7.17 (d, IH), 7.29 (d, IH), 736 (d, IH), 7.60 (dd, IH), 7.72 (t, IH), 7.99 (d, IH), 8.46 (s, IH), 8.64 (m, 2H), 8.50 (hydroxyaniuno]q/nnazolm-5-yl}cay)propyl]acetarnide and picolyl chloride hydrochloride in 76% yield; NMR spectrum (DMSO-d6) 1.40 (d, 3H), 1.78 (s, 3H), 3.39 (m, IH), 3.62 (m, IH), 4.87 (m, IH), 5.29 (s, 2H), 7.21 - 7.40 (m, 4H), 7.57 (m, 2H), 7.71 (t, IH), 7.87 (m, IH), 8.12 (d, IH), 8.22 (t, IH), 8.49 (s, IH), 8.58 (d, IH), 10.00 (bs, IH): Mass spectrum MH 478. -2-({4-[3^Mon-44iyaroxyanittno] used as starting material was prepared by reacting 4-({5-[( 2-amino-lmemylethoxy] quinazoUnyl}amino-2-chlorophenol (prepared as described in Example 4-4) with acetic acid using an analogous procedure to that described in Example 3 for the preparation of 2-hydroxy--rnethyl-.JV-{2-[(4-{3-methyl-4-yridin-2- ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}acetarriide, to giveN-[-2-({4-[3-chloro-4- hydroxyanilino]quinazolin-5-yl}oxy)propyl]acetamide in 28% yield; NMR spectrum (DMSOd6) 1.40 (d, 3H), 1.78 (s, IH), 3.40 (m, IH), 3.62 (m, IH), 4.87 (m, IH), 6.99 (d, IH), 7.23 (d, IH), 7.31 (d, IH), 7.41 (dd, IH), 7.71 (t, IH), 7.97 (d, IH), 8.22 (t, IH), 7.49 (s, IH), 9.99 (s, 10;0&fe.itHfcMassspeeijfumMHt387. -2-[(4-{3-ailoropyridin-2-ylmetho yl)oxy]propyl}-2-hydroxy-A-methyIacetamide. Prepared by reacting AT-[(2/J2-({4- chloro-4-hydroxyanilmo]quinazolin-5-yl }oxy)pix)pyl]-2-hydioxy-JV-metiiylacetainide and picolyl chloride hydrochloride in 61% yield; NMR spectrum (DMSO-d6 at 100°C) 1.44 (d, 3H), 2.99 (s, 3H), 3.51 (m, IH), 4.07 (m, 2H), 4.13 (m, IH), 5.12 (m, IH), 5.28 (s, 2H), 7.23 (m, 2H), 7.34 (m, IH), 7.60 (m, 2H), 7.70 (t, IH), 7.85 (t, IH), 8.08 (d, IH), 8.47 (s, IH), 8.58 (bd, IH), 9.87 (bs, IH): Mass spectrum MH 508. TheAH(2£)-2K{4-[3hlorohydroxyar hydroxy-tf-raethviacetamide used as a starting material was prepared as follows: 2Atoro(5-fluoropnazohnyl) phenol (2 g) was added to a stirred solution of (2KH-[aUyl(methyl)arnino]propan-2-ol (2.24 g, prepared as described in Example 2-3) in DMA (100 ml) and sodium hydride (60% dispersion in oil, 692 rag), and the mixture heated to 110°C for 16 hours. The mixture was concentrated in vacua men a saturated solution of sodium bicarbonate C200 ml) was added and extracted with DCM (300 ml). The extract was washed with brine, dried and concentrated mvocuo and the residue purified by cnromatognphy using DCM - 10% memanol / 2N ammonia as ehieat to give 4-[(5-{(lR2- [aDyl(met)ryl) as a yellow solid (1.88 g, 68%); M^ spectrum (DMSO46) 1.43 (d, 3H), 2.17 (s, 3H), 254 (dd, IH), 2.97 (m, 3H), 4.94 (m, IH), 5.00 (dd, IH), 5.10 (dd, 1HX 5.63 (m, IH), 6.98 (d, IH), 7.18 (d, IH), 7.29 (d, IH), 7.42 (dd, IH), 7.69 (t, IH), 7.84 (d, IH), 8.44 (s, IH), 10.01 (bs, IH), 10.26 (s, IH); Mass spectrum MH+ 399. mg) in acetonitrile/water (5:1,4 ml), and the mixture heated to 130°C for 10 minutes by microwave irradiation. The cooled mixture was subjected to ion exchange chromatography and product eluted with methanol / 2M ammonia yielding 2-chloro-4-{ 5-[(lft)-l- (methyianiino)ethoxy]quinazolin-4-yl}amino)phenol as a brown solid (776 mg, 100%); spectrum (DMSO-d6) 1.40 (d, 3H), 2.33 (s, 3H), 2.87 (m, 2H), 3.29 (IH obscured by water), 4.88 (m, IH), 6.97 (d, IH), 7.14 (d, IH), 7.28 (d, IH), 7.55 (dd, IH), 7.68 (t, IH), 7.95 (d, IH), 8.45 (s, IH), 10.51 (bs, IH); Mass spectrum MH359. AK(2/?2K{4-[(3hloro-4ydroxyphCTyl)anti hydroxy-tf-methyiacetamide starting material was prepared by reacting 2-chloro- an analogous procedure to that described in Example 3 for the preparation of 2-hydroxy-JV-[2- ({4-[4-hydroxy-3-meuylam"lmo]quinazo to give 2/2-({4-[3-chloro-4-hydroxyanilino]quinazolin-5-yl}oxy)propyl]-2-hydroxy-Nmethylacetamide in 57% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.91 (m, 1H), 2.97 (s, 3H), 3.39 (dd, 1H), 4.04 (d, 2H), 4.16 (m, IH), 4.39 (m, IH), 5.08 (mt 1H), 6.98 (d, IH), 7.27 (m, 2H), 7.47 (dd, IH), 7.70 (t, IH), 7.97 (d, IH), 8.43 (s, IH), 9.85 (s, IH), 9.99 (bs, IH); Mass spectrum MH 417. [12] N(2R)-2-[(4-{3-Ch-(pyrazin-2-ylinethoxy)anilino}quinazoKn-5- y!)oxy]propyl}-2-hydroxy-A-metbylacetaniide. Prepared by reacting pyrazin-2-ylmethyl sulfonate and JV-[(2R)-2K{4-[3^hloro^hydroxyaniIino)quinazolin-5-yl}oxy)propyl]-2- hydroxy-methylacetamide to give the title product in 20% yield; NMR spectrum (DMSOd6) 1.41 (d, 3H), 2.98 (, 3H), 3.42 (dd, IH), 4.06 (m, 2H), 4.23 (m, IH), 4.41 (m, IH), 5.12 (m, IH), 5.39 (s, 2H), 7.25 - 7.38 (m, 3H), 7.72 (m, 2H), 8.15 (d, IH), 8.48 (s, IH), 8.68 (d, 2H), 8.87 (s, IH), 9.% (s, IH); Mass spectrum MET 509. [13] AK(213-24[431oro[(6-methy Prepared by reacting (6-methyIpyridin-2- hydoroxy-tfHnethylacetanude, using an analogous procedure to that described in Example 4-8 (in-situ formation of (6-methyh-2-yl)methyl memanesulf onate), to give the title product in 48% yield; NMR spectrum (DMSO-46) 1.40 (d, 3H), 2.50 (3H obscured by DMSO), 2.98 (s, 3H), 3.37 (dd, IH), 4.06 (d, IH), 4.22 (m, IH), 4.41 (t, IH), 5.10 (m, IH), 526 (s, 2H), 7.20 - 7.30 (m, 3H), 7.33 (d, IH), 7.37 (d, IH), 7.67 (dd, IH), 7.70 - 7.80 (m, 2H), 8.15 (d, IH), 8.48 (s, IH), 9.95 (s, IH); Mass spectrum MH+ 522. [14] N-((2R)-2[4-(3loro[(3-4hiort yQoxy}propyl)-2-hydroxy-/Vroetibylacetaniide. Prepared by reacting l-(chloromethyl)-3- fluoroDOT2eneandA-[-2-({4-[3hlorohydroxyaniUno]quinazolin-5-yl}oxy)propyll-2- hydroxy-AT-methylacetaniide to give the title product in 61% yield; NMR spectrum (DMSOd6) 1.40 (d, 3H), 2.98 (s, 3H), 3.37 (dd, IH), 4.06 (d, 2H), 4.22 (m, IH), 4.41 (t, IH), 5.1 1 (m, IH), 5.28 (s, 2H), 7.19 (m, IH), 7.22 - 7.38 (m, 5H), 7.47 (m, IH), 7.68 (dd, IH), 7.72 (t, IH), 8.13 (d, IH), 8.48 (s, IH), 9.94 (s, IH); Mass spectrum MH 525. [15] A^-{(2/?)-2-[(4-{3.Chlon(lthiazol ylmethoxy)}quinazolin-5- yl)oxy]propyl}-2-hydroxy-N-mhylacetamide. Prepared by reacting 4-(chloromethyl)-l,3- ydrpchlpride and WX21)-2r({4H[(3WoroT4ydroxyamUno] yl}oxy)propyl]-2-hydroxy-N-methylacetamide to give the title product in 61% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 2.98 (s, 3H), 3.38 (dd, IH), 4.06 (d, 2H), 4.22 (m, IH), 4.42 (t, 1H), 5.11 (m, IH), 5.34 (s, 2HX 7.28 (d, IH), 7.34 (m, 2H), 7.69 (dd, IHX 7.73 (t, IH), 7.82 (s, IH), 8.12 (d, 1H), 8.48 (s, IH), 9.18 (d, IH), 9.95 (s, 1HV. Mass spectrum MH 514. [16] Prepared by reacting (6-methy]pyridin-2-yl)roethanol and -[2-({4-[3-chloro4-hydroxyanilino]quinazoKn-5-yl }oxy)e4hyl]-M-methylacetainide using the procedure described in Example 4-8 (in-situ formation of (6-methylpyridin-2- yl)methyl methanesulfonate), to give the title product in 67% yield; NMR spectrum (DMSOd6) 1.94 (s, 3H), 3.06 (s, 3H), 3.27 (s, 3H), 3.84 - 3.96 (m, 2H), 4.35 - 4.45 (m, 2H), 5.24 (s, 2H), 7.16 (d, IH), 7.20 - 7.27 (m, 2H), 732 - 7.40 (m, 2H), 7.58 (dd, IH), 7.70 - 7.79 (m, 2HX 7.92 (d, IHX 8.45 (s, IH), 9.74 (s, IH); Mass spectrum MH 492. The N-[2K{44(3-chlorc-4-hydroxyairiliiK)lqmnazolin-5-yl}oxy) methylacetamide used as starting nwterial wa» prepvtd ae follows: Acetic acid wat reacted with 2{5-I2pCnelbyiaiKnio)etlio yi}amiiK)phenol (prepared as described in Exampte 4-5, prepaiatk)n of sorting njaterials) using an analogous proceduie to tiiat described in Eumpfe 3 for the preparation of 2- methylacetamide, to give the title product in 56% yield; (EMSO-d6) l.%(s, 3H), 2.48 (B, 3H), 3.84 (m, 2H), 436 (t, 2H), 6.96 (d, IH), 7.14 (d, IH), 732 (m, 2H), 7.70 (m, 2H), 8.40 (s, IH), 9.62 (bs, IH), 10.01 (be, 1HV. Mass spectrum MH 370. [17] JVKM[4-(3-Oiloro[ rnethylacetamide. Prepared by reacting 2-fluorobenzyl chloride with -[2-({4-[(3-chloio-4- hydroxyanilino]quinazolin-5-yl}oxy)ethy}]-N-methylacetamide, to give the title product in 71% yield; NMR spectrum (DMSO-d6) 1.94 (B, 3H), 3.05 (s, 3H), 3.89 (t, 2H), 4.40 (t, 2H), 5.27 (s, 2H), 7.17 (d, IH), 7.22 - 739 (m. 4H), 7.41 - 7.48 (m, IH), 7.56 - 7.65 (m, 2H), 7.73 (dd, IH), 7.90 (d, IH), 8.44 (s, IH), 9.74 (s, KB: Mass spectrum MH 495. [18] Af2-{[4-(3-ChJoro[(3-fliKroben2yl)oxylanmiio)quhiazoli methylacetamide. Prepared by reacting 3-fluorobenzyl chloride and -[2-{4-[3-chloro-4- hydroxyanilino]quinazolin-5-yl}oxy)ethyl]-N-to give the title product in 80% yield; NMR spectrum (DMSO-d6) 1.94 and 1.97 (each s, together 3H), 2.90 and 3.05 (each s, together 3H); 3.89 and 3.91 (each t, together -2H), 4.40 and 4.55 eteh t, t6gemer2H), SMQ&aate 7.14 - 7.27 (m, 3H), 7.29 - 739 (m, 3H), 7.45 - 7.51 (m, IH), 7.53 - 7.60 (m, IH), 7.73 and 7.76 (each t, together 1H), 7.91 and 8.04 (each d, together 1H), 8.45 and 8.50 (each s, together lh), 9.73 and 9.77 (each s, together 1H); Mass spectrum NOT 495. JV-rnethytecetamide. Prepared by reacting 4-(chloromethyl)-13-thiazole and AT-[2-({4~[3- chk)rohydroxyanilino]quinazolin-5-yl}oxy)ethyl]--niediyiacetarnide to give the tide product in 67% yield; NMR spectrum (DMSO-d6) 1.94 and 1.96 (each s, together 3H), 2.90 and 3.05 (each s, together 3H), 3.89 and 3.92 (each t, together 2H), 4.40 and 4.55 (each t, together 2H), 5.35 (s, 2H), 7.16 and 7.24 (each d, together 1H), 7.34 and 7.37 (each d, together 2H), 7.56 and 7.59 (each dd, together 1H), 7.73 and 7.76 (each t, together 1H), 7.83 (s, 1H), 7.90 and 8.02 (each d, together 1H), 8.44 and 8.50 (each s, together 1H), 9.16 (d, 1H), 9.73 and 9.76 (each s, together 1H); Mass spectrum NOT 484. [20] tf[(43loro(pyizin-2-yu naethybcetaraide. Prepared by reacting pyrazm-2-ylinethyl methanesulf onate (prepared as described in Example 4-1, preparation of starting material) and N-[2-({4-[3-cUoro~4- -5- to give the title product in 6X)NMR spectrum (DMSO-dfr 1.94 and 1.96 (each 8, together 3H), 2.90 and 3.05 (each s, together 3H), 3.89 and 332 (each t, together 2H), 4.40 and 4.55 (each t, together 2HX 5.40 (s, 2H), 7.16 and 724 (each d, together 1H), 729 - 7.39 (m, 2H), 7.58 and 7.60 (each dd, together 1H), 7.73 and 7.76 (each t, together 1H), 7.93 and 8.05 (each d, together 1H), 8.44 and 8.51 (each s, together 1H), 8.68 (d, 1H), 8.69 (d, 1H), 8.87 (s, 1H), 9.74 and 9.77 (each s, together 1H); Mass spectrum MH479. [21] tfH(2t)-2-[(4K3-£Iiloro yl)oxy]propyl}-2"hydroxyacetamlde. Prepared by reacting //-[(2K)-2-({4-[3-chIoro-4- hydroxyaniUno]quinazo]m-5-yl}oxy)pTOpyl]-2-hydroxyacetamide and picolyl chloride hydrochloride to give the title product in 61% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 3.45 - 3.47 (m, 1H), 3.70 - 3.83 (m, 3H), 4.86 - 4.99 (m, 1H), 5.29 (s, 2H), 5.48 (t, 1H), 7.20 - 7.27 (m, 2H), 7.28 - 739 (m, 2H), 7.54 - 7.64 (m, 2H), 7.71 (t, 1H), 7.87 (t,lH), 8.11 - 8.21 (m, 2H), 8.48 (s, 1H), 8.59 (d, 1H), 9.98 (s, 1H) Mass spectrum MH" 494. hydroxyacetamide used as starting material was prepared as follows: (prepared as described in Example 4-4, preparation of starting materials) was reacted with glycolic acid using an analogous procedure to that used in Example 1 for the preparation of N{ 2-[(4-{3XCMt(pyridin-2-ylmethoxy)amlino}quinazolin-5-yl)oxy]ethyl} methylacetamide, to give the title product in 61% yield; NMRspertmm (DMSO-d6) 139 (d, 3H), 3.70 - 3.80 (m, 3H), 4.90 - 4.97 (m, 1H), 7.0 (d, 1H), 7.26 - 7.31 (m, 2H), 7.41 (dd, 1H), 7.75 (t, 1H), 7.92 (d, 1H), 8.16 (t, 1H), 8.53 (s, 1H), 10.09 (s, 1H), 10.15 (s, 1H) spectrum MH 403. amine (58 mg) in DCM (3 nl) was treated with acetyl chloride (15 mg) and DIPBA (39 mg) and stined over The solution purified by duromatognphyusingDCMtolO%7N ammonia in methanol in DCM to give after trituration with dtethyl ether N-{2-((4-{[3-chtoro- 4-(pyridtn-2-ylmetfaoxy)phenyl] amino}qiMnazolin-5-yi)oxy]ethyl}-N-ethylacetamide (39 mg, 61%); NMR spectrum (DMSO-d6) 1.12 (t, 3H), 1.98 (s, 3H), 3.37 - 3.42 (m, 2H), 3.87 (t, 2H), 4.39 (t, 2H), 5.31 (s, 2B), 7.16 (d, 1H), 7.22 - 7.28 (m, 1H), 7.33 - 7.39 (m, 2H), 7.55 - 7.61 (m, 2H), 7.71 - 7.75 (m, 1H), 7.87 - 7.91 (m, 1H), 7.94 (d, 1H), 8.45 (s, 1H), 8.61 (d, 1H), 9.80 (s, 1HV. Mass spectrum MIT 492. TheN-[3hloro-(pyridm-2-ylraethoxy)phenyl]-5-[2Kethylaniino)ethoxy] quinazolin-4-amine used as starting material was prepared as follows: Ethylenc glycol (150 ml) was treated with sodium hydride (60% in oil, 3.15 g) and the exotherra controlled to about 10 °C with an ice-bath. A/r-[3-Chloro-4-(pyridin-2- ylmethoxy)phenyl]-5-fluoroquinazobn-^arnine (obtained as described in Example 1, preparation of starting materials, 12 g) was added in small portions and trie mixture heated at ,420 °C for 1 hour. The slurry was, copied, poured chloride.... (1.5 litres) and the solid collected and dried to give 2-[(4-{[3-chloro-4-(pyridin-2- ylmethoxy)phOTyl]ammo}quinazx) -5-yl)oxy]etharK)l (12.6 g, 95%); (DMSO-d6) 3.89 - 3.98 (m, 2H), 4.33 (t, 2H), 5.27 (s, 2H), 5.37 (t, 1H), 7.13 (d, 1H), 7.23 (d, 1H), 7.31 - 7.38 (m, 2H), 7.57 (d, III), 7.68 - 7.75 (m, 2H), 7.83 - 7.90 (m, 1H), 8.26 (d, 1H), 8.54 (s, 1H), 8.58 (d, 1H), 10.41 (s, 11H); Mass spectrum MH 422. To a stirred solution of the 2-[(4-{ [3-chlc-4-(pyridm-2-ylmemoxy)phenyl] amiDo}quinazolin-5-yl)oxy]ethanol (20 g) in DCM (200 ml) and THF (200 ml) was added thionyl chloride (20 ml) at ambient temperature. The solution was men heated under reflux for 2 hours. The solution was cooled and product filtered off to give 5-(2-chloroethoxy)--[3- chloro-4^yridin-2-yhTietrK)xy)rAenyl]quinazolin-4-amine as its hydrochloride salt (25 g, 98%); NMR spectrum (DMSQ-d6) 4.20-4.40 (t, 2H), 4.60-4.80 (t, 2H), 5.40 (s, 2H), 7.20- 7.60 (m, 3H), 7.60-7.80 (m, 3H), 7.90-8.10 (m, 3H), 8.60-8.70 (d, 1H), 8.9 (s, 1H), 10.65- 10.83 (bs, 1H); Mass spectrum MH 441. 5^-Chkmjerhoxy) [3-chloro-4-(pyridm (0.400 g) nd ethyiamine (1.2 g) were heated at 50 °C overnight and then the solution The procedure described in Example 1 was repeated using glycotic acid and AT-[3- chloro-4-(pyridin-2-ymiemoxy)phenyl]-5-[2-(emylamino)ethoxy]quinazoHn-4-an^ (obtained as described in Example 5, preparation of starting materials) to give the title compound in 70% yield; NMR spectrum (DMSO-d6) 1.10 (t, 3H), 3.29-3.45 (m, 2H), 3.80- , 7.30-7.40 (m, 2H), 7.60 (d, 2H), 7.70-7.78 (m, 1H), 7.82-7.92 (M, 1H), 7.95 (s, 1H), 8.43 (s, 1H), 8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH508. 17-t The procedure described in Example 1 was repeated using glycolic acid and JV-[3- chloro-4yridin-2-ylinethoxy)phenyl]-5-[2-propvlam (obtained as described in example 7, preparation of starting materials) to give the title compound in 26% yield; NMR spectrum (DMSO-d6) 0.84 (t, 3H), 1.53 -1.65 (m, 2H), 3.26 (t, 2H), 3.95 (t, 2H), 4.14 (d, 2H), 438 (t, IH), 4.47 (t, 2H), 4.53 - 4.58 (m, IH), 5.36 (s, IH), 117 7.24 (d, 1H), 7.31 (d, 1H), 7.39 - 7.44 (m, 2H), 7.63 - 7.67 (m, 2H), 7.76 - 7.81 (m, 1H), 7.92 - 7.96 (m, 1H), 8.05 (s, 1H), 8.51 (s, 1H), 8.66 (d, 1H), 9.87 (s, 1H); Mass spectrum MH 522. Example 9 isopropylacetamide The procedure described in Example 5 was repeated using -[3-chloro-4-(pyridin-2- 2rand acetyl chloride to rive the title compound in 49% viektNMR gpectrum (DMSO-d6 1.19 (d 6HX 2.07 (s. 3H). 3.77 (t, 2HX 4.06 - 4.14 (m. 1H), 434 (t, 2HX 531 (, 2HX 751 (d, 1H), 77 (d, 1H), 732 - 739 (m, 2H), 7J7 - 7.63 (m, 2H), 79 - 7.75 (m. 1H), 7.86 - 7.91 (m, 1H), 8.01 (d, 1H), 8.46 (s, 1H), 8.60 (d, 1H), 10.00 (s, IIP: MM spectrum MlT 506. The AT-[3-chkiro-4yridnv2-y!methoxy)rAenyl]-5H[2 edioxy]quinazolin-4-amine used as starting material was prepared as described in Example 5 (preparation of starting materials) using 52hloroethoxy)-[3-hloro-4-(pyridin-2- ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 5, preparation of starting materials) and isopropylamine; Mass spectrum MH 464. Example 10 AM2-[(4-{[3-Oiloro(pyridin-2-yniietto hydroxy-AMsopropylacetamide The procedure described in Example 1 was repeated using glycolic acid and JV-[3- chloro-4yridin-2-ylmethoxy)phenyl]-5-[2ylamino)ethoxy]quinazolin (obtained as described in Example 9, preparation of starting materials) to give tne nue compound in 11% yield; NMR spectrum (DMSO-d6) 1.19 (d, 6H), 3.81 (t, 2H), 3.93 - 4.01 (m, 1H), 4.14 - 4.18 (m, 2H), 4.35 - 4.47 (m, 3H), 5.31 (s, 2H), 7.21 - 7.29 (m, 2H), 7.32 - 7.40 (m, 2H), 7.56 - 7.63 (m, 2H), 7.70 - 7.76 (m, 1H), 7.86 - 7.91 (m, 1H), 8.04 (s, 1H), 8.47 (s, 1H), 8.60 (d, 1H), 10.02 (s, 1H); Mass spectrum MH+ 522. Example 11 The procedure described in Example 5 wat repeated u N^3-chloro-4iidiiH2-yliD6thQxy)pheny)]qra and acetyl chloride to give the title compound in 47% viekL NMR spectrum OMtSO-d6 1.95 (t. 3ID. 3.86 (U 2H). 4.02 - 4.06 (m, 2HX 438 (t, 2H), 5.07 - 5.18 (m, 2H), 531 (s, 2H), 5.82 - 552 (m, 1HX 7.14 (d, 1H), 7.25 (d, 1H), 7.32 - 7.40 (m, 2H), 7.55 - 7.61 (m, 2H), 7.70 - 7.75 (m, 1H), 7.86 - 753 (m, 2H), 8.44 (s, 1H), 8.61 (d, 1H), 9.76 (s, IIP: Mass spectrum MH* 504. The 5-[2^aUylaniino)ethoxy]--[3hloro(pyridin-2-ylinethoxy)pbenyl] quinazolin-4-amine used as starting material was prepared as described in Example 5 (preparation of starting materials) using 52-cWoroettioxy--[3-chloro-4-(pyridin-2- ylmethoxy)phenyl]quinazolin-4-aniine (obtained as described in Example 5, preparation of starting materials) and allylamine; MflMWftrum 462. Example 12 y!)oxy]ethyI}-2-hydroxyacetamkie The procedure described in Example 1 was repeated using gjycdic acid and 5-[2- (obtained as described in Example 11, preparation of starting materials) to give the title compound in 24% yield; NMR spectrum (DMSO-d6) 3.79 - 4.19 (m, 6H), 438 - 4.63 (m, 3H), 5.06 - 5.19 (m, 2H). 531 (s, 2H), 5.69 - 5.90 (m, 1HX 7.16 (d, 1H), 7.25 (d, 1H), 733 - 739 (m, 2HX 7.56 - 7.63 (m, 2HX 7.70 - 7.76 (m, 1HX 7.86 - 7.91 (m, 1H), 13% (s, 1H), 8.45 (s, 1H), 8.61 (d, 1H), 9.80 (s, 1HV. Mass spectmm MET 520. Example 13 cydopropylacaniide The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2- yknethoxy)phenyl]-5-[2-(cyclopropylamino)ethoxy]quinazolm-4-amine and acetyl chloride to give the title compound in 38% yield; NMR spectrum (DMSO-d6) 0.76 - 0.82 (m, 4H), 2.06 (s, 3H), 2.76 - 2.83 (m, 1H), 3.87 (t, 2H), 4.42 (t, 2H), 531 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H), 732 - 7.40 (m, 2H), 7.56 - 7.61 (m, 2H), 7.70 - 7.75 (m, 1H), 7.86 - 7.92 (m, 1H), 7.94 - 7.96 (m, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.76 (s, 1H); Mass spectrum MH 504. The (pyridin-2-yhiiethoxy)phenyl]-5-[2-(cyclopropylaniino) ethoxy]quinazolin-4-amine used as starting material was prepared as described in Example 5 (preparation of starting materials) using 5-(2-chloroemoxy)-[3-chloro-4-(pyridin-2- ylmethoxy)phenyl]quinazolin-4-aniine (obtained as described in Example 5, preparation of starting materials) and cyclopropanamtne; Mass spectrum MH 462. Example 14 tf-{2-[(4[3-Chkro-4yridta-2-ybae cydopropyl-2-hydroxyacetandde The proceduie described in Example 1 was repeated using glycolic acid and [3 quinazolin~4-amine (obtained as described in Example 13, pjepmtion of starting materials) to give the title compound in 19% yield; SMRm (DMS(d6) 0.73-0 JO ODB.4HX 2.73 -i80(m, IH), 3.90 (t, 2H), 4.24 (s, 3HX 4.44 (t, 2H), 5.31 (s, 2H), 720 (d, IH), 7.25 (d, IH), 735 (d, IH), 736 - 7.40 (m. IH), 737 - 7.62 OBI, 2H), 7.71 - 7.76 (m, IH), 7.86 - 7.92 (m, IH), 8.01 (d, IH), 8.46 (s, IH), 8.61 (d, IH), 9.80 (s, IH); Mass spectrum MH 520. Example 15 (cydopropylmethyDacetamide The procedure described in Example 5 was repeated using [3-chloro-4-(pyridin-2- ylrnethoxy)phenyl3-5-{2-[(cycloprcylmethyl)ammo]ethoxy}quina2olin^amine and acetyl chloride to give the title compound in 58% yield; FIMR gpretfflm (DMSO-d6) 0.16 - 0.27 (m, 2H), 0.36 - 0.52 (m, 2H), 0.97 -1.06 (m, IH), 2.00 (s, 3H), 324 - 3.29 (m, 2H), 3^3 - 4.02 (m, 2H), 433 - 4.56 (m, 2H), 5.31 (s, 2H), 7.13 - 7.18 (m, IH), 7.21 - 7.29 (m, IH), 731 - 7.40 (m, 2H), 7.54 - 7.62 (m, 2H), 7.69 - 7.79 (m, IH), 7.86 - 7.92 (m, IH), 7.93 - 7.96 (m, IH), 8.44 (s, IH), 8.61 (d, IH), 9.81 (s, IH); Mass spectrum MET 518. The 3Moro-4-(pyridin-2-yme amino]ethoxy}quinazoiin-4-amiiie used as starting material was prepared as described in Example 5 (preparation of starting materials) using 5-(2-chloroethoxy)-W-[3-chloro4- i (pyridin-2-ylmethoxy)phenyl}quinazo)in-4-amine (obtained as described in Example 5, preparation of starting materials) and (cyclopropylmethyl)amine; Mass spectrum MH 476. Example 16 (cydopropylroethyl)-2-hydroxya The procedure descntodm Example 1 was repeated using glycohc acid cUofo-4yricim-2-ylinethoxy)p ethoxy}quinazolin- 4-amine (obtained as described in Example 15, preparation of starting materials) to give the title compound in 23% yield; NMR spectrum (DMSO-d6) -0.04 - 0.04 (m, 2H), 0.13 - 0.29 (m, 2H), 0.74 - 0.83 (m, IH), 2.98 (d, IH), 3.66 - 3.80 (m, 2H), 3.85 - 3.93 (m, 2H), 4.12 - 4.32 (m, 4H), 5.08 (s, 2H), 6.95 (d, IH), 7.02 (d, IH), 7.09 - 7.17 (m, 2H), 7.30 - 7.40 (m, 2H), 7.47 - 7.54 (m, IH), 7.63 - 7.68 (m, IH), 7.73 - 7.82 (m, IH), 8.21 - 8.29 (m, IH), 8.37 (d, IH), 9.62 (s, IH): Mass spectrum MH4^ 534. Example 17 AH2-[(4[3-CWoropyridra-2-ylmetto cyclobutylacetamlde The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2- ylinethoxy)phenyl]-]quma2olinamine and acetyl chloride to give the title compound in 42% yield; NMR spectrum (DMSO-d6) 1.50 - 1.65 (m, 2H), 2.01 (s, 3H), 2.12 - 2.21 (m, 4H), 3.94 (t, 2H), 4.28 - 4.38 (m, 3H), 5.31 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H), 732 - 7.40 (m, 2H), 7.57 - 7.62 (m, 2H), 7.69 - 7.76 (m, 1H), 7.86 - 7.91 (m, 1H), 7.97 (s, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.90 (s, 1H); Mass spectrum MH+ 518. TheN-[3hJoro-4yridin-2-ylmethoxy)phenyl]-5-[2cvclobutylarnino) ethoxyJqumazolin-4-amine used as starting material was prepared as described in Example 5 (preparation of starting materials) using Hhlorocthoxy)-N-[3-chIoro-4-(pyridin-2- ylrnetrK)xy)phenyl)quinazoliii^amine (obtained as described in Example 5, preparation of starting materials) and cyclobutanamine; Mfttf ypectrun MH 476. Example 18 The procedure described in Example 1 was repeated using glycolic acid and cWro-4yridin-2-ylmethoxy) phcjiyl]-52cyclobutyl (obtained as described in Example 17, preparation of starting materials) to give the title compound in 22% yield; NMR spectrum (DMSO-d6) 1.49 1.65 (m, 2H), 2.08 - 2.27 (m, 4H), 3.97 (s, 2H), 4.12 (d, 2H), 4JM) - 4.29 (m, 1H), 432 - 4.43 (m, 3H), 5.31 (s, 2H), 7.21 (d, 1H), 7.26 (d, 1H), 7.33 - 7.40 (m, 2H), 7.57 - 7.63 (m, 2H), 7.71 - 7.76 (m, 1H), 7.86 - 7.92 (m, 1H), 8.02 (s, 1H), 8.47 (s, 1H), 8.60 (d, 1H), 9.92 (s, 1H); Mass spectrum MH534. Example 19 The procedure described in Example 5 was repeated using 2V-[3-chloro-4-(pyridin-2- ylroethoxy)phenyl]-5-{2-[(l-methylpiperidii4-yl)amino]ethoxy} quinazolin-4-amine and acetyl chJoridc to give die tide compound in 41% yield; NMR spectrum (DMSO-d6) 1.62 - 1.90 (m, 4H), 2.09 (s, 3H), 2.15 - 2.43 (m, 4H), 2.79 - 3.13 (m, 3H), 3.76 - 3.83 (m, 2H), 3.86 - 3.92 (m, 1H), 430 - 4.47 (m, 2H), 531 (s, 2H), 7.21 (d, 1H), 7.26 (d, 1H), 732 - 7.40 (m, 2H), 7.57 - 7.61 (m, 2H), 7.69 - 7.75 (m, 1HX 7 J6 - 7.92 (m, 1H), 7.98 - 8.00 (m, 1H), 8.46 (8,1H), 8.61 (4 1IQ, 9.95 (s, 1HV. MMS spectrum MlT 561. The J^3^diloro-4pyndii2-y)metyl)unino)ethoxy}quinazoliiK4-ainine used at starting material was ptepated as deacnbed in Example 5 (preparation of starting using 5-2-diloroeaioxy)-W-[3-chloro-4- (pyridin-2-yIrnethoxyphenyl]quinazoUn-4^Bnine (obtained as described in Euunple 5, preparation of starting materials) and l-mettoylpiperidin-4-amine; Mass spectrum Example 20 The procedure described in Example 5 was repeated using A[3-chloro-4-(pyridin-2- ylnwthoxy)phenyl]-5-[2-(tetrahydK)-2H-pyranylanuno)ethoxy] quinazolin-amine and acetyl chloride to give the tide compound in 68% yield; NMR spectrum (DMSOd6) 1.49 - 1.71 (m, 2H), 1.75 - 1.98 (m, 2H), 2.11 (s, 3H), 3.36 - 3.45 (m, 2H), 3.78 - 3.96 (m, 5H), 4.26 - 4.46 (m, 2H), 5.31 (s, 2H), 7.22 (d, 1H), 7.26 (d, 1H), 7.33 (d, 1H), 7.35 - 7.40 (m, 1H), 7.56 - 7.63 (m, 2H), 7.69 - 7.75 (m, 1H), 7.86 - 7.91 (m, 1H), 7.99 - 8.03 (m, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.98 (s, 1H); Mass spectrum MH~ 548. ylanimo)etboxy]quinazolin-4-amine used as starting material was prepared as described in Example 5 (preparation of starting materials) using 5-(2-chloroethoxyN-[3-chloro-4- (pyridin-2-ylnietiioxy)phenyI]quinazolin-4-amine (obtained as described in Example 5, preparation of starting materials) and tetrahydro-2/f-pyran-4-amine;; The procedure described in Example 1 was repeated using glycolic acid and N-{3- ylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 20, preparation of starting materials) to give the title compound in 12% yield; NMR spectrum (DMSO-d6) 1.53 - 1.69 (m, 2H), 1.77 - 2.07 (m, 2H), 3.34 - 3.42 (m, 2H). 3.73 - 3.92 (m, 5H), 4.14 - 4.25 (m, 2H), 4.31 - 4.54 (m, 3H), 5.31 (s, 2H), 721 - 7.29 (m, 2H), 732 - 7.40 (m, 2H), 7.57 - 7.63 (m, 2H), 7.70 - 7.76 (m, 1H), 7.86 - 7.91 (m, 1H), 8.03 (s, 1H), 8.47 (s, 1H), 8.61 (d, 1H), 9.99 (s, 1H); Mass spectrum MIT 564. IfcS Example 22 (2-hydroxyethyl)acetainkie The procedure described in Example 5 was repeated using 2-({2-[(4-{[3-chloro-4- (pyridin-2-ylmethoxy)phcnyl]ainiiK)}quinazolin-5-yl)oxy]ethyl}amino) ethanol and acetyl chloride to give the title compound hi 21% yield; NMR spectrum (DMSO-d6) 2.00 (s, 3H), 3.43 (t, 2H), 3.54 - 3.59 (m, 2H), 3.88 - 3.97 (m, 2H), 4.41 (t, 2H), 4.85 (t, 1H), 5.31 (s, 2H), 7.16 (d, 1H), 7.25 (d, 1H), 733 (d, 11, 735 - 7.40 (m, 11, 7 J7 - 7.62 (m, 2H), 7.70 - 7.75 (m, 1HX 7.86 - 7.92 (m, 1H), 7.96 (d, 1HX 8.45 (s, 1H), 8.61 (d, 1HX 9.83 (s, 1H); Mass spectrum MH^" 508. The 2K{2-[(4-{[3n;Moro-4Kpyridtn-2-y]raethoxy yl)oxy]ethyl}aniino)ethanol used as starting material was prepared as described in Example 5 (preparation of starting materials) using 5K2^hloroethoxy-Ar-[3-chksro-4-(pyridin-2- ylmethoxy)pbenyI]quinazotin-4-amine (obtained as described in Example 5, preparation of starting materials) and 2-aminoethanol; Mass spectrum MET 466. Example 23 V2-[(4-{[3-CWort-4yridto-2-ylmetb hydroxy-N-(2-hydroxyethyl)acetamkle -ChJoro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5- yl)oxy]ethyl}amino)etfianol (obtained as described in Example 22, preparathrti of starting materials) (0.208 g) in DCM (10 ml) was treated with 2-chloro-2-oxoethyl acetate (0.091 g) and DIPEA (0.173 g) and stirred for 30 minutes. 7N Ammonia in methanol (20 ml) was added and the solution stirred overnight The mixture was evaporated and purified by chromatography using DCM to 8% 7N ammonia in methanol in DCM to give die title compound in 30% yield; NMR spectrum (DMSO-d6) 3.37 (t, 2H), 3.56 (t, 2H), 3.95 (t, 2H), 4.11 - 4.17 (m, 2H), 4.25 (t, IH), 4.44 (t, 2H), 4.91 (t, IH), 531 (s, 2H), 7.17 (d, IH), 7.25 (d, IH), 7.32 - 7.40 (m, 2H), 759 (d, 2H), 7.70 - 7.76 (m, IH), 7.86 - 7.91 (m, IH), 8.00 (d, IH), 8.46 (s, IH), 8.61 (d, IH), 9.85 (s, IH); Mass spectrum MH+ 524. Example 24 (2-methoxyethyl)acetainide The procedure described in Example 5 ytanetiKxy)phenyl]-5-{2-[(2-metha and acetyl chloride to give the title compound in 30% yield; lMK^EKtQflBCDMSO-d6) 1.99(s,3H), 3.24 (», 3H), 3.46 - 3.51 (m, 2H), 3.52 - 3.57 (m, 2H), 3.88 - 3.98 (m, 2H), 437 - 4.43 (m, 2H), 531 (s, 2H), 7.17 (d, IH), 7.26 (d, IH), 734 (d, IH), 7.35 - 7.40 (m, IH), 7.55 - 7.63 (m, 2H), 7.71 - 7.78 (m, IH), 7.86 - 7.92 (m, IH), 7.94 (d, IH), 8.46 (s, IH), 8.61 (d, IH), 9.86 (s, IH); A%g spectrum MH 522. TTie//-[3-cWoro(pyridin-2-ylmethoxy)phenyl]-5-{2-[(2-medioxyethyl) amino]ethoxy }quinazolin-4-amine used as starting material was prepared as described in Example 5 (preparation of starting materials) using 5-(2-chloroettioxyJV-[3-chloro-4- (pyridin-2-ylinethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 5, preparation of starting materials) and rc-methoxyBthyrVamine; MaM spectrum MH480. Example 25 hydroxyWV2Hroethoxyethyl)acetaniide The procedure described in Example 1 was repeated using glycolic acid and N-[3- 4-(pyridin-2-ylmethoxy)phenyl]-5-{ 2-[(2-methoxyethyl)amino]ethoxy} quinazolin-4- amine (obtained as described in Example 24, preparation of starting materials) to give the title compound in 27% yield; NMR spectrum (DM5O-d6) 3.18 (s, 1H), 3.24 (s, 2H), 3.48 (s, 3H), 3.55 - 3.60 (m, lift 3.86 - 3.98 (m, 2H), 4.10 - 4.15 (m, 2H), 432 (t, 1HX 4.43 (t, 1H), 4.51 - 4SI (m, lift, 531 (s, 2HX 7.17 (d, lift 7.25 (d, lift 733 - 7.40 (m, 2HX 757 - 7.63 (m, 2HX 7.71 - 7.76 (m, 1H), 7.86 - 7.91 (m, 1HX 7.99 - 8.05 (m, 1H), 8.46 (s, 1H), 8.60 (d, IB), 9.84 (s, 1H); Mass spectrum MIT 538. The procedure described in Example 5 was repeated using Ar-[3-chloro-4-(pyridin-2- ylmethoxy)phenyl]-5-[2-(rMX^2-yn-l-ylarnmo)ethoxy] and acetyl chloride to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 2.03 (s, 3H), 3.27 (s, 1H), 3.93 - 4.04 (m, 2H), 4.24 - 4.32 (m, 2H), 4.43 (t, 1H), 4.56 - 4.63 (m, 1H), 5.31 (s, 2H), 7.13 (d, 1H), 7.25 (d, 1H), 7.34 (d, 1H), 7.35 - 7.41 (m, 1H), 7.52 - 7.63 (m, 2H), 7.70 - 7.79 (m, 1H), 7.86 - 7.93 (m, 2H), 8.44 (s, 1H), 8.61 (d, 1H), 9.69 (s, liT); Mass spcctrtim " The -[3hlor&4Kpyridin-2-ylinethoxy)enyl)-5-[2-(prop-2-yn-lylamtno) ethoxy]quinazoiin-4-amine used as starting material was prepared as described in Example 5 (preparation of starting materials) using 5-{2-chloroethoxy/-[3-chIoro-4- (pyridin-2-ylmethoxy)phenyl]qiraiazlirHanaine (obtained as described in Example 5, preparation of starting materials) and prop-2-yn-l-amine; Mass spectrum MET 460. Example 27 AK2-[(4[3-Oiloropyridi The procedure described in Example 1 was repeated using grycolic arid an qnmazolin-4- amme (obtained as described in Example 26, pcepratkof starting materials) to give tbe title compound in 26% yield; NMRgpectnm (DMSOd6) 3.98 (s, 2H), 4.16 (s, 2H)t 4.28 (s, 2H), 4.47 (s, 1H), 4 J5 - 4.66 (m, 1H), 531 (s, 2H), 7.12 - 7.21 (m, 1H), 1.25 (d, 1H), 7.32 - 7.40 (m, 2H), 7.59 (d, 2H), 7.70 - 7.78 (m, 1H), 7.86 - 7.92 (m, 1H), 7.97 - 8.06 (m, 1H), 8.43 - 8.51 (m, 1H), 8.61 (d, 1H), 9.76 (s, MB: Masa spectrum MH" 518. Example 28 ftM2~[(4[3-OiIonHl-pyridm hydroxyl-A-methylpropanamide The procedure described in Example 1 was repeated using 2-hydrdxypropahbtc acid " amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 56% yield: NMR spectrum (DMSO-d6) 1.08 (d, 3H), 3.11 (s, 3H), 3.82 - 4.12 (m, 2H), 4.36 - 4.47 (m, 3H), 432-4.72 (m, IH), 5.31 (s, 2H), 7.18 (d, 1H), 7.25 (d, 1H), 7.34 (d, 1H), 735 - 7.40 (m, 1H), 7.52 - 7.62 (m, 2H), 7.70 - 7.76 (m, IH), 7.86 - 7.91 (m, 1H), 7.94 - 7.97 (m, IH), 8.44 (s, 1H), 8.61 (d, 1H), 9.75 (s, 1H); Mass spectrum MH508. Example 29 The procedure described in Example 1 was repeated using tetrahydrofuran-2- carboxytic acid and [3htoro-4-(pyikiiiv-2-ylmcthoxy)pbenyl]-5-[2- (metfaylamiiK)ethoxy]quinazoiin-4-amiiie (obtained as described in Example 1, preparation of starting materials) to give the tide compound in 89% yield: NMR spectrum (DMSO-d6) 1.64 - 1.94 (m, 4H), 3.09 (s, 3H), 3 SI - 3.70 (m, 2H), 3.82 - 3.97 (m, 2H), 4.42 (t, 2HX 4.60 - 4.66 (m, 1H), 5.31 (s, 2H), 7.16 (d, 1H), 7^3 (d, 1H), 7.33 (d, 1H), 735 - 739 (m, 1H), 7 J2 - 7.57 (m, 1H), 7.59 (d, 1H), 7.70 - 7.75 (m, 1H), 7.85 - 7.91 (m, 1H), 7.92 (d, 1H), 8.42 (s, IH), 8.61 (d, IH), 9.70 (s, IH); Mass spectrum Example 30 {2-[(4-{[3-CbJoro(pyim-2-yliMthoxy)phenyl]ajmno}quiiiazolln-5.yI)oxy]ethyl}- V,l-dimethylprolinainide The procedure described in Example 1 was repeated using l-methylproline and -[ cWoro-4yridin-2-ylniethoxy)phenyl]-5-[2-(methylamino)cthoxy] quinazoUnamin (obtained as described in Example 1, preparation of starting materials) to give the title compound in 38% yield; NMR spectrum (DMSO-d6) 1.55 - 1.68 (m, 3H), 1.92 - 2.03 (m, 2H) 2.12 (s, 2H), 329 (s, 6H), 3.87 - 4.03 (m, 2H), 4.40 - 4.61 (m, 2H), 5.31 (s, 2H), 7.17 (d, 1H), 7.22 (d, 1H), 7.33 (d, 1H), 735 - 7.39 (m, 1H), 7.57 - 7.63 (m, 2H), 7.69 - 7.75 (m, 1H), 7.86 - 7.91 (m, 1H), 8.05 (d, 1H), 8.43 (s, 1H), 8.60 (d, 1H), 9.76 (s, 1H); Mass spectrum MIT 547. Example 31 The procedure described in Example 1 was repealed usng 2-hydroxy-2- memyhjffopanoic acid and JH3-clfoco-4- (methylainino)etiKny]quiruaoli]i^Hi(nine (obtained as described in Example 1, preparation of starting materials) to give the tide compound in 39% yield; HMRjsj2e£trj^(DMSO-d6) 1.20 (s, 6H), 3.34 (s, 3H), 3.89 (s, 2H), 4.43 (s, 2H), 5.27 (s, 1H), 531 (s, 2H), 7.18 (d, 1H), 74 (d, 1H), 732 - 7.40 (m, 2H), 7.53 - 7.57 (m, 1H), 7.58 (d, 1H), 7.70 - 7.76 (m, 1H), 7.86 - 7.91 (m, 2H), 8.43 (s, 1H), 8.59 - 8.61 (m, 1H), 9.75 (s, 1H); Mass spectrum MH522. Example 32 AT2-[(4-{[3hloro(pyrldln-2-ylmethoxy)phenyl]ainiiio}quiiiazolinhydroxy-V-methylcyclopropanecarboxamide The procedure described in Example 1 was repeated using 1- hydroxycyclopropanecarboxylic acid and AT-[3-chloro-4-(pyridin-2-ylmethoxy) phenyl]-5-[2- (methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give die title compound in 54% yield; NMR spectrum (DMSO-d6) 0.68 - 0.80 (m, 4H), 3.30 (s, 3H), 3.84 - 3.96 (m, 2H), 4.37 - 4.49 (m, 2H), 5.31 (s, 2H), 6.16 - 6.23 (m, IH), 7.14 - 7.21 (m, IH), 7.24 (d, IH), 7.32 - 7.40 (m, 2H), 7.51 - 7.56 (m, IH), 7.59 (d, IH), 7.71 - 7.76 (m, IH), 7.86 - 7.91 (m, 2H), 8.40 - 8.47 (m, IH), 8.61 (d, IH), 9.68 - 9.75 (m, IH); Mass spectrum MH4" 520. Example 33 The procedure described in Example 1 was repeated using tf-methylgjycine and AT-Pchlcro- 4^yrklm-2-ylinetixy)phenyI]-5 quinazolin-4-amine (obtained at described in Example 1, preparation of starting materials) to give the title compound in 25% yield; NMR spectrum (DMSO-d6) 3.06 (s, 2H), 3.30 (s, 6H) 3.90 (t, 2H), 4.33 - 4.42 (m, 3H), 531 (s, 2H), 7.16 (d, IH), 7.24 (d, IH), 7.34 (d, IH), 7.35 - 7.40 (m, IH), 7.53 - 7.57 (m, IH), 7.60 (d, IH), 7.70 - 7.75 (m, IH), 7.86 - 7.92 (m, IH), 7.93 (d, IH), 8.43 (s, IH), 8.61 (d, IH), 9.74 (s, IH); Ma^g spectrum MR 507. Example 34 A4M(4-{[3-CWoro-4Kpyittin-2-ylmeto hydroxy-JV2-trimethylpropanamide The procedure described in Example 1 was repeated using 3-hydroxy-2,2- dimethylpropanoic acid and N-[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2- (methylamino)ethoxy]quina2olin-4-amjne (obtained as described in Example 1, preparation of starting materials) to give the title compound in 25% yield; NMR spectrum (DMSO-d6) 1.07 (s, 6H), 3.15 (s, 3H), 3.35 (d, 2H), 3.91 (t, 2H), 4.41 - 4.48 (m, 3H), 5.30 (s, 2H), 7.18 (d, IH), 7.24 (d, IH), 7.34 (d, IH), 735 - 739 (m, IH), 7.56 - 7.61 (m, 2H), 7.71 - 7.76 (m, IH), 7.86 - 7.91 (m, IH), 7.98 (d, IH), 8.45 (s, IH), 8.60 (d, IH), 9.81 (8, IH); Mass spectrum MH+ 536. Example 35 hydroxy--methylpropanamide (AZ12240261) The procedure described in Example I was repeated using 3-hydnxypropnoic acid and A[3-chlofo4-(pyridi2-ylin amiiie(obtaiiied a described in Example l,pie compound in 24% yield; NMR spectrum (DMSO-do) 2.13 - 2.26 (m, 2H), 2.65 - 2.79 (m, 2H), 3.30 (s, 3H), 3.87 - 3.97 (m, 2H), 4.13 - 4.25 (m, IH), 434 - 4.61 (m, 2H), 531 (s, 2H), 7.15 (d, IH), 7.25 (d, IH), 7.32 - 739 (m, 2H), 7.53 - 7.57 (m, IH), 7.60 (d, 1HX 7.70 - 7.76 (m, IH), 7.86 - 7.92 (m, 2H), 8.42 (s, IH), 8.61 (d, IH), 9.70 (s, IH); Mass spectrum MH 508. The procedure described in Example 1 was repeated using acetic acid and 5-[(15)-2- aniino-l-methyletnoxy]-[3-chlon-4-(pyridin-2-yljnethoxy)phenyl] quinazolin-4-armne to give the title compound in 60% yield; NMR spectrum (DMSO-d6) 1.40 (d, 3H), 1.80 (s, 3H), 3.40 (m, 1H), 3.62 (m, 1H), 4.85 (m, 1H), 5.30 (s, 2H), 7.23 (m, 2H), 7.30 (d, 1H), 736 (m, 1H), 7.57 (m, 2H), 7.71 (t, 1H), 7.87 (td, 1H), 8.12 (d, 1H), 8.22 (t, 1H), 8.49 (s, 1H), 8.58 (d, 1H)T 10.00 (s, 1H); Mass Spectrum MH 478. The5-[(lS2-aimno-l-inemylethoxy]- pnenyl]qumazoUn-4-amine used as starting material was prepared as follows: The procedure described in Example 1 (preparation of starting materials) was repeated using (SX+H-amino-2-propanol and 5-fluoro-7^-[3-chloro-4-{pyridin-2- ylmethoxy)phenylJquinazolin-4-arnine (obtained as described in Example 1, preparation of "nting materials) to give 5-[(15-2-amino-l-mylemoxy]--[3Woro-4-(pyridin-2- ylmethoxy)phenyl}quinazolin-4-amine in 46% yield; NMR spectrum (DMSCNJ6) 1.39 (d, 3HX Z96 (m, 2H), 4.79 (m, l8 (s, 2H), 7.17 (d, 1H), 71 (d, 1H), 7.29 (d, 1H), 735 (m, IH), 7.56 (d, 1H), 7.64 (dd, 1H), 7.70 (t, 1H), 7.86 (dt, 1H), 8 JO (d, 1H), 8.48 (s, 1HX 8.58 (d, 1H), 10.60 (bt. IHh MM Spectmm NflT 435. Example 37 fl)oxy]propy]}-2-hydroxyacetamide The procedure described in Example 1 was repeated using glycolic acid and 5-[(15)-2- amino- l-methylethoxy]-JV-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl] quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 47% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 3.41 (m, 1H), 3.74 (m, 1H), 3.78 (d, 2H), 4.92 (m, 1H), 5.29 (s, 2H), 5.48 (t, 1H), 7.23 (dd, 2H), 7.31 (d, lH),-7.35 (m, 1H), 7.58 (m, 2H), 7.70 (t, 1H), 7.87 (td, 1H), 8.13 (d, 1H), 8.17 (t, 1H), 8.47 (s, 1H), 8.58 (d, 1H), 9.98 (s, 1H); Mass Spectrum Mlf 494. Example 38 The procedure described in Example 1 was repeated using MJV-dimethylglycine and -inethyleth()xy]-M amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 49% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.07 (s, 6H), 2.80 (s, 2H), 3.41 (m, 1H), 3.73 (m, 1H), 4.93 (rnlH), 5.29 (s, 2H), 7.23 (m, 2H), 730 (d, IB). 735 (t, 1HX7J8 On, 2HX 7.70(1, H),7.86(td, 1H), 8.12 Cm, 211X8.47(5,1H), 8^8 (d, 1H), 9.96 (s, 1HX Mass Spectrum MH521. Example 39 yl)oxy]propyl}-2-metfaoxyarrtamide The procedure described in Example 1 was repeated using memoxyacetic acid and 5- [(lS2-amino-l-methylethoxy]-AT-[3nloix-4yridin-2-ylme(hx)xy)phenyl]quinazolm amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 139 (d, 3H), 3.20 (s, 3H), 3.40 (m, 1H), 3.72 (m, IH), 3.75 (s, 2H), 4.93 (m, 1H), 529 (s, 2H) 7.23 (m, 2K), 7.3t (d, H; T.58 (m, 2H), 7.7O (t, IH), 7.86 (dt, IH), 7.95 (s, IH), 8.12 (d, IH), 8.19 (t, IH), 8.47 (s, IH), (m, IH), 9.97 (s, IH); Mass Spectrum MET 508. Example 40 The procedure described in Example 1 was repeated using methanesulfonylacetic acid and 5-[(lS-2-amiiio-l-inethyletlKxy yhnethoxyhenyl]qomiizolin-4«nine (obtained as described in Example 36, preparation of starting materials) to give the tide compound in 72% yield: NMR spectrum (DMSOdSH 42 (d, 3H), 3.02 (s, 3H). 3.49 (m, ffi). 3 .76 On, 1HX 4.06 (s, 2H), 4.89 (m,ffiX 5.28 (s, 2HX 7.22 (m, 2HX 734 (m, 2H), 76 (d, 2H), 7.72 (t, 1HK 76 (A, 1HK 8.15 (d, 1H), 8.48 fclH), 8.71 (t, Example 41 WM(4[3a)lonHKpjnri hydroxyacetamide The procedure described in Example 1 was repeated using glycolic acid and 5-(2- aininoethoxy)-N-[3hlaro(pyridin-2-ylmethoxy)phenyl]quinazoUn-amine (obtained as described in Example 2.6, preparation of starting materials) to give the title compound in 60% yield; NMR spectrum (DMSO-d6) 3.71 (q, 2H), 3.78 (d, 2H), 4.36 (t, 2H), 5.28 (s, 2H), 5.49 (t. 1H), 7.13 (d, 1H), 7.21 (d, 1H), 7.32 (d, 1H), 7.35 (m, 1H), 7.56 (m, 2H), 7.7JI (tr 1IJ), 7.87 (dt, 1H), 7.98 (d, 1H), 8.18 (t, 1H), 8.45 (s, 1H), 8.58 (d, 1H), 9.82 (s, 1H); Mass Spectrum Example 42 The procedure described in Example 1 was repeated using M-dimethylglycine and 5- as described in Example 2.6, preparation of starting materials) to give the title compound in 31% yield; NMR spectrum (DMSOd6) 2.08 (s, 6H), 2.79 (s, 2H), 3.68 (q, 2H), 4.36 (t, 2H), 5.29 (8, 2HX 7.13 (d, 1HX 7.21 (d 1HX 7.34 On, 2H), 7.55 (m, 2HX 7.70 (t, IH), 7.86 (dt, IH), 7.98 (d, IH), 8.11 (t, IH), 8.45 (t IH), 838 (d, IH), 9.80 (s, 1HV. Mass SpectmrnMET 507. methoxyiicetainicie The procedure described in Example 1 was repeated using methoxyacetic acid and 5- -[3hlorD(pyddm-2-ymiemoxy)phenyQquinazol as described in Example 2.6, preparation of starting materials) to give the tide compound in 50% yield; NMR spectrum (DMSO-d6) 3.20 (s, 3H), 3.68 (m, 2H), 3.73 (s, 2H), 4.38 (t, 2H), 5.29 (s, 2H), 7.14 (d, IH), 7.21 (d, IH), 7.34 (m, 2H), 7J5 (t, IH), 7.71 (t, IH), 7.86 (t, IH), 7.97 (d, IH), 8.17 (m, IH), 8.44 (s, IH), 8.58 (d, IH), 9.81 (s, IH); Mass Spectrum MH494. Example 44 (methykulfonyftecetamide The procedure described in Example 1 was repeated using methanesulfonylacetic acid (obtained as described in Example 2.6, preparation of starting materials) to give the title compound in 51% yield: NMR spectrum (DMSOdfl 2,99 (s, 3HX 3.74 (m, 2H), 4.04 (s, 2H), 434 (t, 2HX 529 (s, 2H), 7.13 (d, IHX 722 (d, IHX 735 (m, 2HX 7.55 (m, 2HX 7.71 (t, IHX 7.87 (dt, IH), 8.03 (d, IHX 8.46(8, IHX 88(d, IHX 876 (t,!H), 9.79 (s,lH); Mass Spectrum MET 542. yl)oxy]propy1}-A^-methy The procedure described in Example 1 was repeated using acetic acid and A-[3- ernoxy)phenyl]-5-[(lSH- quinazolm-4-amine (obtained as described for the R-antipode in Example 23, preparation of starting materials, using (2S2-methyloxirane) to give the title compound in 51% yield; NMI 136(d,3H), 14(s,3H)3.03(s,3H),332(lHobscuredbyH2OX - 4.20 (m, IH), 5.08 (m.lH), 5.30 (s, 2H), 723 (m, 2H), 7.34 (rn, 2H), 7.57 (d, IH), 7.68 (m, 2H), 7.87 (dt, IH), 8.11 (d, IH), 8.46 (s, IH), 8.59 (d, IH), 9.94 (s, IH); JVbss Spectrum MH 492. Example 46 The procedure described in Example 1 was repeated using glycoticatid8ndtf-[3- cbJoro-4-(pyridin-2-ylmethoxy) rtbaxylquinazolin-4-«mine (obtained as described for the R-antipodem Example 23, ptepaiation of starting material^ to pve the titlecoinpouiKlm53% viekkNMRspectrom (DMSO-d6) 1.39 (d, 3H), 296 (s. 3H), 336 (dd, IH), 4.04 (d, 2H), 4.21 (m, IH), 437 (t, IH), 5.09 Cm, IH), 5^9 (s, IH), 7J5 On, 2H), 735 (m, 2H), 737 (d, IH), 7.65 (dd, IH), 7.70 (t, IH), 7.87 (dt, IH), 8.12 (d, IH), 8.46 (s, IH), 8.58 (d, IH), 9.93 (s, IH); Mass Spectrum MH+508. Example 47 ulM The procedure described in Example 1 was repeated using AAW-dimethylglycme and N-[3KW(wo-4pyridin-2-yteicthoxy)phenyl]-5-[(lSV (methylarano)ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 27% yield; StMR spectrum (DMSO-d6) 1.37 (d, 3H), 2.06 (s, 6H), 3.08 (s, 3H), 323 (dd, IH), 3.25 (s, H), 4.26 (dd, IH), 5.10 (m, IH), 5.29 (s, 2H), 7.23 (m, 2H), 7.30 (d, IH), 7.35 (m, IH), 756 ;s, IH), 7.68 (m, 2H), 7.87 (dt, IH), 8.13 (d, IH), 8.44 (s, IH), 8.58 (d, IH), 9.90 (s, IH); Mass Spectrum MfT 535. Example 48 The procedure described in Example 1 was repeated using methoxvacetic acid and Nsthoxylquinazolin- 4-amine (obtained as described for the R-antipode in Example 23, preparation of starting materials) to give die title compound in 39% yield; gpectiniT11 JMSO-d6) 1.38 (d, 3H), 2.99 (s, 3H), 3.16 (s, 3H), 3.27 (IH obscured by H2O), 4.03 (s, 2H), 1.23 (m, IH), 5.1 1 (m, IH), 529 (s, 2H), 724 (m, 2H), 730 (d, IH), 735 (m, IH), 7 .57 (d, IH), 7.65, (dd, IH), 7.71 (t, IH), 7.86 (dt, IH), 8.12 (d, IH), 8.44 (s, IH), 8.58 (d, IH), 9.90 [s, IH); Mass Spectrum MH522. The procedure described in Example 1 was repeated using methanesutfonylacetic acid and tf-[3-ctooro-4yridin-2-ylin (mediylamino)eftoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 23. preparation of stinting material to give the title compound in 61% vickUNMR sjggm 0MSOd6) 138 (d, 3H), 195 (s, 3H), 3.15 (s, 3HX 337 (dd, H),430(in,lH), 4.41 (d, 2HX 5.11 Cm. IH), 5.29 (s, 2H), 724 (m, 2H), 730 (d, IH), 735 (m, IH), 737 (d, IH), 7.64 (dd, IH), 7.70 (t, IH), 7.86 (dt, IH), 8.11 (d, IH), 8.45 (s, IH), 838 (d. IH), 9.88 (s, IHk Mass Spectrum MH 570. oxy]propyI}-N-methylacetaniide The procedure described in Example 4.1 was repeated using JV[(2/0-2-({4-[(3-chloro- 4^ydroxyphenyl)amino]quinazoUn-5-yl}oxy)propyl]--methylacetamide and pyrazin-2- ylmcthyl methanesulfonate to give the title compound in 61% yield; NMR spectrum (DMSOd6) 13 (d,3H), 1.95 (s, 3H), 3.03 (s, 3H),337 (IH obscured by HiO), 4.21/(dd\tlH), 5.08 (m, IH), 537 (s, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 8.11 (d, IH), 8.46 (s, IH), 8.66 (m, 2H), 8.85 (s, IH), 9.94 (s, 1HV. Mass Spectrum MH 493. The A-[(2)-2-({4-[(31oTohydroxyphenyl)arninquiiiazolin-5-yl}oxy) propyl]- JV-metbylacetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 2-chlonv4-({ 5-[( -l-methyl-2-(methylamino) ethoxy]quinazolin-4- yl}ammo)phenol (obtained as described in Example 4.11, preparation of starting materials) to give JV-[(2R)-2-({4-[(3-chloro4-hydroxyphenyl) amino)quinazolin-5-yl }oxy)propyl]-ATmemylacetamide in 45% yield: NMR spectrum 0MSO-d6) 1.37 (d, 3H), 1.94 (s, 3H), 3.03 (s, 3H), 3.31 (dd, 1H), 4.15 (dd, 1H), 5.06 (m, 1H), 6.97 (d, 1H), 7.23 (d, 1H), 7.29 (d, 1H), 7.46 (dd, 1H), 7.69 (m, 1H),7.95 (d, 1H), 8.42 (s, 1H), 9.98 (bs, 1H); Mass Spectrum MET 401. Example 51 The procedure described in Example 3 was repeated using N-[(22-({4-[(3-chloro-4- hydroxypheiiyl)amino]qiiinazolin-5-yl}oxy)rjropyl]-N^nethylacctamide (obtained as described for in Example 50, preparation of starting materials) and 4-(chloromethylthiazole hydrochloride to give the titk compound in 17% yield; NMR spectrum (DMSO-d6) 1.36 (d, 3H), 1.94 (s, 3H), 3.02 (s, 3H), 3.3O (1H obscured by EfeO), 4.21 (dd, 1H), 5.09 (m, 1H), 5.33 (s, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 7.81 (s, 1H), 8.08 (s, 1H), 8.47 (s, 1H), 9.13 (s, 1H), 9.96 (s, IHfc Mass Spectrum MH498. Example 52 The procedure described in Example 3 was repeated using 7-[(2R)-2-({4-[(3-chloro-4- hydroxyphenyl)uBmo]qi)mazoli (obtained as described for in Example 50, preparation of starting niaterials) and 3-fluorobenzyl chloride to give the title compound in 87% yield: NMRspectmm (DMSO-d6) 136 (d, 3H), 153 (a, 3H), 3.04 (t,3HX 3.27 (fflobtconxl by HbO), 4-22 (ddlH), 5.07 (m, 1HX5J25 (2H)7.16 1H), 79 (m, 5H), 7.45 (m, 1HX 75 (dd, 1H), 7.71 (t, IH), 8.09 (d, 1HX 8.46 (1HX 9.93 (s, 1H); yl]oxy}propyl)-inetiiyl The procedure described in Example 3 was repeated using -[(2R2-({4-[(3-chloro-4- hydroxyphenyl)amino]quiiuizolin-5-yl}oxy)prcoyl]-N-riiethylacetami (obtained as described for in Example 50, preparation of starting materials) and 2-fluorobenzyl chloride to give the title compound in 72% yield; flMR spectrum (DMSO-d6) 137 (o\ 3HX 1.94 (s, 3H), 3.04 (s, 3H), 3.30 (1H obscured by HO), 4.20 (dd, 1H), 5.07 (m, 1H), 5.25 (s, 2H), 7.27 (m, 5H), 7.43 (m, 1H), 7.59 (t, 1H), 7.67 (dd, 1H), 7.70 (t, 1H), 8.07 (d, 1H), 8.45 (s, 1H), 9.93 (s, 1H); Mass Spectrum MET 509. Example 54 The procedure described in Example 3 was repeated using picolyl chloride spectnimrDMSOd61.19fd.3H. 2.79 fa.3HL 3.87- 4.26 fm.3Hl4.38- 4.48 fm.2H). 5.11 - 5.22 (m, 1H), 5.29 (s, 2H), 7.18 - 7.25 (m, 2H), 732 - 738 (m, 2H), 7.48 (d, 1HX 7^8 1HX 938 (s, 1H); Mass spectrum MHf 5083. The Ar-[(l)-2-({4-[(3-chloTO^hydroxyphenyl)amiiHlquinazolin-5-yl}oxy)-lmethylethyl)- 2-hydroxy-N-methylacetainide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repealed using (2/0-2-methylainino)propan-l-ol (obtained as described in Becker et al., J. Chem. Soc. 1957, 858) and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) to give 2-chloro-4-[(5-{[(2R2- (methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol in 100% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 2.40 (s, 3H), 3.30 (m, 1H), 4.25 (dd, 1H), 4.35 (dd, 1H), 7.00 (d, 1H), 7.10 (d, 1H), 7.30 (d, 1H), 7.60 (dd, IH), 7.70 (t, 1H), 7.90 (d, 1H), 8.50 (s, 1H); Mass spectrum MH 359.1 The procedure described in Example 3 (preparation of starting materials) was repeated using gjycollc adid and 2-cnloro-4[(5-{ [(2/0-2KiMrnyiarniho yl)amino]phcnol to give JV-[(l/Z)-2-({4-[(3-chloro-4-hydroxyphenyl) amino]quinazolin-5- yl}oxyl-methylethyl]-2-hydroxy-N-methylacetannde in 100% yield; Mass spectrum MH4" 416.9. Example 55 AM(l)-2(4[3-Chloroyridki-2-ylii methyiethyl}-N-methylacetamide The procedure described in Example 3 was repeated using picolyl chloride hydrochtoride tnd/(lK)-2{4-[(3 methyfethyO-AtaiediyUcetra (DMSO-d6) 1.18 (d, 3H), 1.83 (s, 3H), 2,84 (s, 3HX 4.19 - 4.43 (m, 2H), 5.14 - 5.24 (m, IH), 530 (s, 2H), 7.16 - 7 .27 On, 2H), 732 - 738 (m, 2H), 7.45 - 7 JO (m, IH), 7 J8 (d, IH), 7.72 (t, IH), 7.87 (t, 2H), 8.43 (s, IH). 859 (d, IH), 9.53 (s, IH); MH 4923. mediylethyl]-M-methylacetainide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 21oro4-[(5-{[(2/0-2methylamino)propyl]oxy} quinazolin-4- yl)amino]phenol (obtained as described in Example 54, preparation of starting materials) to give M[(l«)-2{4-[(3hloio-4-hydioxyphenyl)amino] quinazolin-5-yl}oxy)-l-methylethyl]- -methylacetamide in 100% yield; Mass spectrum MH" 401. Example 56 methylethyl}-2-hydroxy-/V-incfliylftrrtmtde The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and JV-[(15)-2K{4-[(3hIMt4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)- methylethyl]- 2-hydroxy-^-methylacetainide to give the tide compound in 57 % yield; NMR spectrum (DMSO-d6) 1.20 (dd, 3H), 2.80 (d, 3H), 3.10 (m, 1H), 3.80-4.20 (m, 2H), 4.20-4.50 (m, 2H), 5.15 (m, 1H), 5.30 (s, 2H), 7.20 (m, 2H), 7.30 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H), 7.70 (m, 1H), 7.80-7.95 (m, 2H), 8.40 (d, 1H), 8.60 (d, 1H), 9.60 (s, 1H); Mass spectrum MET 508.2. The (152-({4-[(31oio4-hydroxyphenyl)arnino]qiiinazolin-5-yl }oxy)-lmethylethyi]- 24iydroxy-#-methylacetarnide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using (25)-2-(inethylamino)propan-l-ol (obtained as described in Chacchio et al., Tetrahedron, 1995,51,5689) and 2-chloro-4-[(5-fluoroqurna2olin-4-yI)amino] phenol (obtained as described in Example 4.5, preparation of starting materials) to give 2-chloro-4- [(5-{[(22Kmethylaramo)propyI in 100% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 2.40 (s, 3HX 3.20 (m, 1H), 4.15 (dd, 1H), 4.30 (dd, 1HX 7.00 (d, IB), 7.10 (d, 1H), 730 (d, 1H), 7.60 (dd, 1H), 7.70 (t, 1H), 8.00 (d, 1H), 8.50 (s, 1H); Mflft* Tpecftum MET 359.4. The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 2-chloro-4-[(5-{ [(25)-2-(methylamino)propyl]oxy} quinazolin-4- yl)amino]phenol to give-[(15)-2-({4-r(3-chloro-44iydroxyphenyl) amino]quinazolin-5- yl}oxy)-l-methylethyi]-2-hydroxy-W-methylacetamide in 48% yield; Mass spectrumMH 4173. Examples The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(152{4(3hloro-4ydroxypheiiyl)amino]quinazolin-5-yl}oxy)-lmethyIethyl]- N-methylacetamide to give the title compound in 34 % yield; NMR spectrum (DMSO-d6, 373K) 120 (d, 3H), 1.85 (s, 3H), 2.80 (s, 3H), 3.00 (m, IH), 4.30 (m, IH), 4.40 (m, 1HX 5.30 (s, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.50 (d, IH), 7.60 (d, IH), 7.70 (t, IH), 7.80 (m, IH), 7.90 (d, IH), 8.40 (s, IH), 8.60 (d, IH), 9.6O (s, IH); Mass spectrum MH 492.2. metiiylethyl]-N-methylacetarnide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 2hloro4-[(5-{[(252-(rrieuiylaniin.o)propyl]oxy} quinazolin-4- yl)anuno]phenol (obtained as described in Example 56, preparation of starting materials) to give tf-[(lS)-2{4-[(3-criro-4ydrOT qainazoUn-5-yl}oxy)-l-methylethyl N-methytecetamkte in 27% yield; MaASjejaMB MH 4013. Example 58 The procedure described in Example 3 was repeated using picolyl chloride methylethyl]-2-mcthoxy-methylacetamide to give the title compound in 39% yield; HM& sj£c£uin_(DMSO-d6, 373K) 1.20 (m, 3H), 2.80 (s, 3H), 3. 10 (s, 3H), 3.90 (m, 2H), 4.20 (m, IH), 4.50 (m, IH), 5.10 (m, IH), 530 (s, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.50 (d, IH), 7.60 (d, IH), 7.70 (t, IH), 7.90 (t, IH), 7.95 (s, IH), 8.40 (s, IH), 8.60 (d, IH), 9.60 (s, IH); spectrum MH 522.2. TteJV"-[(lSV2{4-[(3blcco-44iydroxyphenyl)aniino]quinaz rnethylemyl]-2Hiiethoxy-JV^memylacetamide used as staxting material was obtained as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using methoxyacctic acid and 2-chloro-4-[(5-{[(2lS2-(methylamino)propyl] oxyjquinazolin- 4-yl)amino]phenol (obtained as described in Example 56, preparation of starting materials) to give A[(12{4-[(3-cUonydroxyphenyl)ainino] quinazoIin-5-yl }oxy)-l -methylethyl)- 2-methoxyWV-methvIacetaniide in 49% yield; Mass spectrum MH 429.2. Example 59 A4(lS2(4-{[3-toro(pyridin-2-ylro methytethyl}-24tydroxyacetamide The procedure described in Example 3 was repeated using picoiyi chloride vphCTyl)anM methylethyl}-2ydraxyacetauide to give the titteconipoundin57%yield; (DMSO-d6) 1.23 (d, 3H), 3.64 - 3.81 (m, 2H), 4.24 - 436 (m, 2H), 4.45 - 4.59 (m, IH), 5.29 (s, 2H), 5.45 (t, IH), 7.13 - 7.23 (m, 2H), 7.35 (t, 2H), 7.49 - 7.53 (m, IH), 7.56 - 7 39 (m, IH), 7.72 (t, IH), 7.87 (t, IH), 7.99 - 8.02 (m, 2H), 8.46 (s, IH), 8.59 (d, IH), 9.75 (s, IH); Mass spectrum MH493.95. The HKlS)-2K{4-[(3Moiohydroxy methylediyl]-2-hydroxyacetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using (2S)-2-aminopropan-l-ol and 2-chloro-4-[(5-fluoroquinazohn-4-yl) aminojphenol (obtained as described in Example 4.5, preparation of starting materials) to give 4-[(5-{[(25)- 2-aniiiK)propyl]oxy}quinazoIin-4-yl)ammoJ-2-chlorophenol in 54% yield; NMR spectrum (DMSO-d6); 1.30 (d, 3H), 3.30 (bs, 2H), 3.80 (m, IH), 4.40 (m, 2H), 7.00 (d, IH), 7.20 (d, IH), 7.30 (d, IH), 7.50 (dd, IH), 7.70 (t, IH), 8.00 (d, IH), 8.45 (s, IH); Mass spectrum MH 345.1. The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-[(5-{[(25)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2- chlorophenol to give JV-[(lS)-2-({4-[(3-chkwo-4-hydroxyphenyl)amino] quinazolm-5- yl}oxy)-l-!nethylethyl]-2-hydroxyacetamide hi 73% yield: Mass spectrum MH403.0. Example 60 tnetbytetbyDacetamkle The procedure described in Example 3 was repeated using picolyl chloride bydrochloride aodNH(l{44(3-dikoydraxyt 1.21 (s, 3H), 1.73 (s, 3H), 4.12 - 430 (m. 2H), 433 - 4.43 (m, 1B 59 (s, 2, 7.15 - 7.25 (m, 2HX 735 (t, 2HX 7.51 - 7.59 (m, 2 7.72 (t, 1HX 7.87 (t, 1HX 7.99 (s. 1HX 8.14 (d, 1H), 8.48 (, 1H), 8.59 (d, 1H), 9.80 (s, 1H); MSSStBHB MlT 478.0. methylethyl]acetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 4-[(5-{[(22-anopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol (obtained as described in Example 59, preparation of starting materials) to give N-[(152-({4- K3-chloco-4-hydroxyphenyl)amino] qumazoUn-5-yl}oxy)-l-rnethylethyl]acetainidein 100% yield: Mass spectrum MET 387.0. Example 6 N1-{(152-[(4-{[3-Chk)ro-4-(pvridin-ylirictlxy)phenyIlair methylethylJ-NV-dimethylglydnamide The procedure described in Example 1 was repeated using JVWV-dimethylglycine and 5- {[(2S)-2-ainiiiopixpyl)oxy}--[3-cW to give the title compound in 42% yield; NMR spectrum (DMSCM6) 1.21 (d, 3H), 2.05 (s, 6H), 2.60-2.80 (m, 2H), 4.20-4.40 (m, 2H), 4.40-4.60 (m, IH), 5.30 (s, 2H), 7.15 (m, IH), 722 (m, IH), 735 (m, 2H), 7.54 (m, 2H), 7.70 (t, IH), 7.90 (t, IH), 7.98 (m, 2H), 8.48 (s, IH), 8.59 (d, IH), 9.76 (s, IH): Mass spectrum MH 521.4. The 5-{[(252-aminop!ropyl]oxy}TAH3-Woro-(pyrklin-2- ylmethoxy)phcnyl]quinazolin-4-amine used as starting material was prepared as follows: The procedure described in Example 2.4 (preparation of starting materials) was repeated using (25)-2-aminopropan-l-ol and H;3-chloro-4-yridin-2-yhnethoxy)phenyl]-5- fluoroquinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give 5-{[(25-2-aminopnyl]oxy}-[3-chloro-4-(pyridin-2- The procedure described hi Example 3 was repeated using JVl-[(2ft)-2-({4-[(3-chloro- 4^ydroxyphenyl)arrdno]quina2oUn-5-yl}oxy)propyl]-A-diinethylglycinamide and picolyl chloride hydrochloride to give the title compound in 59% yield; NMR spectrum (CDCM 1.47 (d, 3H), 2.11 (s, 6H), 2.88 (s, 2H), 3.50-3.63 (m, IH), 3.64-3.78 (m, IH), 4.76-4.90 (m, IH), 523 (s, 2H), 6.92-7.00 (m, 2H), 7.13-7.19 (m, IH), 736-7.49 (m, 2H), 7.52-7.72 (m, 4H), 7.90 (d, IH), 8.55 (m, 2H), 9.82 (s, IH): Mass spectrum MH 521.0. imethylglycinamide amide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using 4-({5-[(12-amino-l-methylemoxy]quina2to-4-yl}amino)-2-chlorophenol (obtained as described in Example 4.4, preparation of starting materials) and AJV-dimethylglycine to give A-[(2R2-({4-[(3-chloro-4-hydroxyphenyl)amino] quinazolin-5-yl}oxy)propyl]-WaVachmethylglycinamide amide in 11% yield; NMR spectrum (CDC13) 1.46 (d, 3H), 2.09 (s, 6H), 2.84 (d, 2H), 3.52-3.75 (m, 2H), 4.77-4.89 (m, IH), 6.89-6.99 (m, 2H), 7.27 (dd, IH), 7.40 (dd, IH), 7.51-7.61 (m, 2H), 7.80 (d, IH), 8.52 (s, IH), 9.76 (s, IH); Mass spectrum Example 63 (obtained as described in Example 2.6, preparation of Parting materials, 0.5 g 1.19 imnol) was heated to 130°C in xylene (20 ml) until it had dissolved (S(-a-hyd«oxy-YbutyroUctone (0.10 ml, 131 mmo!)was added and the mixture was stirred at 13CPC for 3 hows. Mote (SX-)ydroxy-Y4Myrolacone (0.05 ml, 0.66 msnol) was added and the mixture was heated for a further 2 hours. The resultant precipitate was fUtered off white the mixture was hot, washed with diethyl ether (3 x 10 ml) and dried to give the title compound as a solid (430 mg, 69%); NMR spectrum (DMSO-d6) 138-1.55 (m, IH), 1.69-1.85 (m, IH), 337-3.50 (m, 2H), 3.61-3.77 (m, 2H), 3.89-4.00 (m, IH), 4.28-4.45 (m, 3H), 59 (s, 2H), 5.51 (d, IH), 7.13 (d, IH), 7.22 (d, IH), 7.28-7.41 (m, 2H), 7.49-7.62 (m, 2H), 7.71 (t, IH), 8.01 (d, IH), 8.14-8.25 (m, IH), 8.45 (s, IH), 8.59 (d, IH), 9.82 (s, im: Mass spectrum MH 523.9. Example 64 (2JJN-{2-[( yl)oxylethyl)-2,4-dlhydro7cybutaiiaiiilde The procedure described in Example 63 was repeated using 5-{2-aniinoethoxy)-N-[3- chkMO-4yridin-2-ylmexy)pheiiyl]qiiinazolin-4-arijine (obtained as described in Example 2.6, preparation of starting materials) and (RH+^hydroxy-y-butyrolactone to give the title compound in 55% yield; NMR spectrum (DMSO-d6) 1.38-1.55 (m, 1H), 1.69-1.85 (rn, 1H), 3.37-3.50 (m, 2H), 3.61-3.77 (m, 2H), 3.89-4.00 (m, 1H), 4.28-4.45 (m, 3H), 5.29 (s, 2H), 5.51 (d, 1H), 7.13 (d, 1H), 7.22 (d, 1H), 7.28-7.41 (m, 2H), 7.49-7.62 (m, 2H), 7.71 (t, 1H), 8.01 (d, 1H), 8.14-8.25 (m, 1H), 8.45 (s, 1H), 8.59 (d, 1H), 9.82 (s, 1H); Mass spectrum 523.9. Example 65 (2)(2Jt)-24(4[3-Chloro4 yl)oxy3prpyl}-2y4-dihydroxybnhiiuimid The procedure described mExanir& 63 was repeated niethylethoxy][3-chloio-4-(pyiidb2-yh and CRH+)- o-hydroxy-y-butyrolactone to give the title compound in 54% yield; NMR spectrum CPMSOd6) 139 (d, 3H), 1.43-1 SJ (m, 3H), 1.71-1.86 (m, 1H), 333-3.53 (m, 3H), 3.65-3.79 (m, 1H), 3.88-4.00 (m, 1H), 4.36 (t, 1H), 4.85-4.96 (m, 1H), 5.29 (s, 2H), 5.45 (d,lH), 7.24 (d, 2H), 728-7.41 (m, 2H), 7.59 (t, 2H), 7.71 (t, 1H), 7.87 (t, 1H), 8.10-821 (m, 2H), 8.48 (s, 1H), 8.59 (d, 1H), 9.99 (s, 1H); Mass spectrum MIT 537.9. The5-[)-2-ainino-l-methylemoxy]-[3-cWoio-4-(pyridin-2-ylmethoxy) phenyl]quinazolin-4-amine used as starting material was prepared as follows: Benzaldehyde (1.46 ml, 14.3 mmol) was added to a solution of 4-({5-[()-2-aminol- methylethoxy]quinazolin-4-yl}amino2-chlorophenol (obtained as described in Example 4.4, preparation of starting materials, 4.5 g, 13.08 mmol) in DMF (50 ml) and the mixture was stirred for 20 minutes. Potassium carbonate (723 g, 52.32 mmol), picolyl chloride hydrochloride (2.57 g, 15.70 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (18~crown-6 catalytic amount) were added and the reaction mixture was stirred vigorously for 16 hours. The reaction mixture was concentrated, the residue was stirred in water (250 ml) and the precipitated solid was filtered off. The solid was dissolved in 1M HC1 (150 ml) and the butyrolactone to give the title compound in 62% yield; NMR spectrum (DMSO-d6) 1.31-1.47 (m, 4H), 1.64-1.77 (m, IH), 333-3.50 (m, 3H), 3.71-3.84 (m, IH), 3.90-4.00 (m, IH), 4.32 (t, IH), 4.87-4.98 (m, IH), 5.29 (s, 2H), 5.48 (d, IH), 7.18-7.27 (m, 2H), 7.28-7.40 (m, 2H), 7.54-7.64 (m, 2H), 7.87 (dt, IH), 8.10-8.21 (m, 2H), 8.47 (s, IH), 8.59 (d, IH), 9.95 (s, IH); Mass spectrum MH 537.9. Example 61 The procedure described in Example 63 was repeated using 5-[(lS)-2-ainroo ylethcy)-fl43-chk»ro-4-{p (obtaaed as described in Example 36, preparation of starting Materials) and (S xydaaiyfbutyiDiactone to give the title compound in 60% yield; 3H), 1.43-1.57 (m, 3H), 1.71-1.86 (m, 1HX 333-3.53 (m, 3H), 3.65-3.79 (m, 1HX 3.88-4.00 (m, IH), 436 (t, IH), 4.85-4.96 (m, IH), 5.29 (s, 2H), 5.45 (d,lH), 7.24 (d, 2H), 7.28-7.41 (m, 2H), 7.59 (t, 2H), 7.71 (t, IH), 7.87 (t, IH), 8.10-8.21 (m, 2H), 8.48 (s, IH), 8.59 (d, IH), 9.99 (s, IH): Mass spectrum MH* 537.9. Example 69 (257V-{(l)-2-[(4-{[3-aikro-4-(pvrklin-2-yliTeUioxy)phenyI]aniiM ytxyl-l-methylethyll-lAdihydroxybutanamide The procedure described in Example 63 was repeated using 5-{ [(2K)-2- y}-JV-[3-chloKHHpyridin-2 as described in Example 2.4, preparation of starting materials) and (S(-)-a-hydroxy-Ybntyrolactone to give the title compound in 79% yield; NMR spectrum (DMSO-d6 400MHz) 1.24 (d, 3H), 1.30-1.41 (m, IH), 1.63-1.74 (m, IH), 3.32-3.46 (m, 2H), 3.91-3.98 (m, IH), 4.24 (dd, IH), 4.31 (t, IH), 438 (t, IH), 4.47-4.57 (m, IH), 5.30 (s, 2H), 5.43 (d, IH), 7.16 (d, IH), 7.23 (d, IH), 7.31-7.41 (m, 2H), 7.56 (dd, IH), 7.60 (d, IH), 7.73 (t, IH), 7.89 (dt, IH), 755 (d, IH), 8.06 (d, IH), 8.48 (s, IH), 8.61 (d, IH) 9.79 (s, IH): Mass spectrum MH* 538.0. Example 70 yl)oxy]-l-ineaylethy2,4-dihydroxybutaiiamkk The procedure described in Example 63 was repeated using 5-{ [(2/0-2-aminopropyl] (obtained as described in Example 2,4, preparation of starting materials) and (RH+)-butyrolactooe to IH), 1.72-1.86 (m, IH), 338-3.51 (m, 2H), 3.83-3.93 (m, IH). 4.20-4.40 (m, 3H), 4.42-4.55 (m, 1HX 5.29 (s, 2H), 539 (d, IH), 7.14 (d, IH), 7.21 (d, IH), 730-7.40 (m, 2H), 7.47-7.55 (m, IH), 7.58 (d, IH), 7.72 (t, IH), 7.87 (t, IH), 757 (d, IH), 8.01 (s, IH), 8.46 (s, IH), 8.59 (d, IH), 9.74 (s, IH): Mass spectrum MH 538.0. Example 71 yl)oxy]ethyl2Adihydroxybutanamide The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)- V-[3- chloro(13-thiazol-4-ylmethoxy)phenyl]quinazolm-4-amine and (RH+hydroxyjybutyrolactone to give the title compound in 69% yield; NMR spectrum (DMSO-d6 400MH2) 1.44-1.55 (m, IH), 1.73-1.85 (m, 1H), 3.41-3.52 (m, 2H), 3.65-3.77 (2ll)," 3.93-4.02 (hX IH), 431-4.48 (m, 3H). 538 (s, 2H), 5.50 (d, IH), 7.17 (d, IH), 7.33 (t, 2H), (7-60 (dd, IH), 1.24 (d, 3H), 1.30-1.41 (m, IH), 1.63-1.74 (m, IH), 3.32-3.46 (m, 2H) 4.24 (dd, IH), 4.31 (t, IH), 4.38 (t, IH), 4.47-4.57 (m, IH), 5.30 (s, 2H IH), 7.23 (d, IH), 7.31-7.41 (m, 2H), 7.56 (dd, 1H),7.60 (d, IH), 7.73 7.95 (d, IH), 8.06 (d, IH), 8.48 (s, IH), 8.61 (d, IH) 9.79 (s, IH); M§s_ Example 70 (2V.{(l)-2-[(4-{[3-Chkro-4.(pyrklin-2-ytmetboxy)phenyl]amL yl)oxy]-l-methylethyl}-2,4-dihydroxylatanainide The procedtm described in 63 was repeated uabg 5- OKy}-3-di]o(o-4- in Example 2.4, preparation of starting materials) and (RM+)-tt-hydrcr ^ the title compound in 77% viekthMRgpec IH), 1.72-1.86 (BO, IH), 338-3.51 (m, 2HX 3.83-3.93 (m, IH), 4.20-4. (m, IHX 5.29 (s, 2H), 539 (d, IH), 7.14 (d, IHX 7.21 (d, IH), 730-7.~ (m, IH), 7.58 (d, IH), 7.72 (t, IH), 7.87 (t, IH), 757 (d, IH), 8.01 (s, (d, IH), 9.74 (s, IH); MafffRPWhim MH 538.0. Examine 71 (2{2-[(4-{[3-ChIor(4-(13-thiazol-4-yhnethoxy)phenynaminc yl)oxy]ethyl}2vt-dihydroxybutanainide The procedure described in Example 63 was repeated using 5— chloro4-(13-thiazol-4-yhT»thoxy)phenyl]quinazolin-4-arnine and (EL butyrolactone to give the title compound in 69% yield; NMRspectrur 1.44-1.55 (m, IH), 1.73-1.85 (m, 1 H), 3.41-3.52 (m, 2H), 3.65-3.77 C IH), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, IH), 7.17 (d, IH), 7.33 1.24 (d, 3H), 1.30-1.41 (m, 1H), 1.63-1.74 (m, 1H), 3.32-3.46 (m, 2H), 3.91-3.98 (m, 1H), 4.24 (dd, 1H), 4.31 (t, 1H), 4.38 (t, 1H), 4.47-4.57 (m, 1H), 5.30 (s, 2H), 5.43 (d, 1H), 7.16 (d, 1H), 7.23 (d, 1H), 7.31-7.41 (m, 2H), 7.56 (dd, 1H), 7.60 (d, 1H), 7.73 (t, 1H), 7.89 (dt, 1H), 7.95 (d, 1H), 8.06 (d, 1H), 8.48 (s, 1H), 8.61 (d, 1H) 9.79 (s, 1H); Mass spectrum MH 538.0. Example 70 (pyridin-2-yImetboxy)phenyI]amino}quinazolin-5- yl)oxy]-l-nietbykthyl}-2,4dlhydroxybutananiide The procedure described in Example 63 was repeated using 5-{ [(22-ainmopropyl] oxy)-tf-(3-cfaloiD-4-pyiklfo-2-yh (obtained as described in Example 2.4, preparation of starting materials) and butyiolacone to give ttetrttecompotmdm 77% vidd:NMR spectrum 1H), 1.72-1.86 (m, 1H), 338-3.51 (m, 2S& 3.83-3.93 (m» 1H), 4JO-.40 (m, 3HX 4.42-45 (m, 1HX 5.29 (s, 2H), 539 (d, 1H), 7.14 (d, 1HX 7^1 (d, 1H), 73O-7.40 (m, 2H), 7.47-735 (m, 1H), 7 J8 (d, 1H), 7.72 (t, 1H), 7.87 (t, 1H), 7.97 (d, 1H), 8.01 (s> 1H), 8.46 (s, 1H), 8.59 (d, 1H), 9.74 (s, 1H); Mass spectrum MlT 538.0. Example 71 (2fi)-Ar.{2.[(44[3-Chloro(lthiazol-4-ylmethoxy)phenyl]amino}qumazolln.5- yl)oxy]ethyl}-2,4-dihydnxybutananiide The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-N-[3- chloro4-(13-thiazol^ylmethoxy)phenyl]quinazolm-4-amine and (RX+)-oc-hydroxy-Ybutyrolactone to give the title compound in 69% yield; NMR spectrum (DMSO-d6 400MHz) 1.44-1.55 (m, 1H), 1.73-1.85 (m, 1H), 3.41-3.52 (m, 2H), 3.65-3.77 (m, 2H), 3.93-4.02 (m, 1H), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, 1H), 7.17 (d, 1H), 7.33 (t, 2H), (7.60 (dd, 1H), 7.74 (t, 1H), 7.83 (s, 1H), 8.02 (s, 1H), 8.20 (t, 1H), 8.48 (s, 1H), 9.17 (s, 1H), 9.85 (s, 1H); Mass spectrum MH529.9. The 5-(2-aminoethoxy)-jiV-[3-chloro-4-(l ,3-thiazol-4-ylmethoxy)phenyl] quinazoIin-4- amine used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) and ethanolamine to give 4-{ [5-(2- aminoethoxy)quinazolin-4-yl]amino}-2-chlorophenol in 84% yield NMR spectrum (DMSOd6) 3.12 (t, 2H), 4.27 (t, 2H), 6.96 (d, 1H), 7.11 (d, 1H), 7.31 (d, 1H), 7.53 (dd, 1H), 8.08 (d, 1H), 8.47 (s, 1H); Mass spectrum MH 331.0. The procedure described in Example 65 (preparation of starting materials) was repeated using 4-{[52-arnmcthoxy)quinazolin-4-yl]amino}-2-chlorophenol and 4- (chloromethyl)-13-thiazok; hydrochloridc to give 5-(2-aminoenV)xy)-N-[3-ch]oro-4-(l,3- Wazol^ylmethoxy)ptKMyl)quiiiazolin-4-amiDe in 91% yield; NMR spectrum (DMSO-d6 400MHz) 3.02-3.19 (bs, 2H), 4.22-436 (m, 2H), 533 (s. 2H), 7.14 (d, 1H), 7J7-7.40 (m, 2H), 7.67-7.86 (m, 3H), 8.23 (s, 1H), 8J2 (&, 1H), 9.15 (s, 1H) (3 exchangeaWes); Mass MH 427.9. Example 72 , (25Ar-{2-[(4-{[3-Clilon-4K13-thiazol-4-ylmetboxy)phenyl]arniiM}quinflzo yl)oxy]ethyl}-2,4-dihydroxybutanamide The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-AT-[3- chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 71, preparation of starting materials) and (SH-)-a-hydroxy-Y-butyrolactone to give the title compound in 66% yield; NMR spectrum (DMSO-d6 400MHz) 1.44-1.55 (m, 1H), 1.73-1.85 (m, IH), 3.41-3.52 (m, 2H), 3.65-3.77 (m, 2H), 3.93-4.02 (m, 1H), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, 1H), 7.17 (d, 1H), 7.33 (t, 2H), (7.60 (dd, 1H), 7.74 (t, 1H), 7:83 (s, 1H), 8.02 (s, 1H), 8.20 (t, 1H), 8.48 (s, 1H), 9.17 (s, 1H), 9.85 (s, 1H); Mass spectrum MET 529.9. Example 73 (2K)-AM(l)-2-l(4-{[3-Coro yDoxyl-l-methylethylj-dibydroxybutanamide The procedure described in Example 63 was repeated using 5-{[(2R}-2- }-N-[3-chloro-4-(13~tra"azol (R)-(+) a-hydroxy-Y-butyrolactoDe to give the title compound in 73% yield; NMR spectrum (DMSO-d6) 1.22 (d, 3H), 1.46-1.61 (m, 1H), 1.72-1.87 (m, 1H), 3.40-3 .54 (m, 2H), 3.84-3.97 (m, 1H), 4.19-4.41 (m, 3H), 4.42-4.58 (m, 1H), 535 (s, 2H), 5.40 (d, 1H), 7.14 (d, 1H), 7.25- 738 (m, 2H), 753 (dd, 1H), 7.72 (t, 1H) 70 (d, 1HX 7.92-8.05 (m, 2H), 8.47 (s, 1H), 9.14 (d, 1H), 9.75 (s, 1H); Massspcctmm MH 543. phenyl](yHnazofin-4-aTnine used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using 2-Koro[(5-fluoroquinazolin-4-yi)arnino phenol (obtained as described in Example 4.5, preparation of starting materials) and (2R2-aminopropan-l-ol to give 4-[(5-{ [(22- arninopropy]]oxy}quinazolin-4-yl)amino]-2-chlorophenol in 100% yield; NMR spectrum (DMSO-d6) 1.16 (d, 3H), 3.29-3.44 (m, 1H), 3.98 (dd, 1H), 4.22 (dd, 1H), 6.96 (d, 1H), 7.09 (d, 1H), 7.30 (d, 1H), 7.58 (dd, 1H), 7.69 (t, 1H), 8.10 (d, 1H), 8.47 (s, 1H) (4 exchangeables); Mass spectrum MH" 344.9. The procedure described in Example 65 (preparation of starting materials) was repeated using 4-[(5-{[(2)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol and 4-(cMoromethylH,3-thiazole hydrochloride give 5-{[(2 2-aminopropyl]oxy}-JV-[3-chlon- 4-(l,3-tWazol-4-ylmemoxy)phenyl]qumazolin-4-amine in 65% yield; NMR spectrum (DMSO-d6) 1.17 (d, 3H), 3.33-3.45 (m, 1H), 4.00 (dd, 1H)), 4.24 (dd, 1H), 5.32 (s, 2H), 7.11 (d, 1H), 7.30 (d, 1H), 733 (d, 1H), 7.67-7.82 (m, 3H), 8.23 (d, 1H), 8.51 (s, 1H), 9.14 (d, 1H); Mass spectrum MH 441.9. Example 74 (25)-V-{(l)-2-[(4-{[3-Chloro-4-(llhiazol-4-ylmethoxy)phenyl]amino}quinazoHn-5- yl)oxy]-l-inetbylethyl}-2,4ihydroxybutanamide The procedure described in Example 63 was repeated using 5-{[(2)-2- (obtained as described in Example 73, preparation of starting materials) and (S)-(-)-ahydroxy- Y-butyrolactone to give the title compound in 58% yield; NMR spectrum (DMSOd6) 1.23 (d, 3H), 1.27-1.40 (m, 1H), 1.60-1.62 (m, 1H), 3.33-3.46 (m, 2H), 3.87-3.97 (m, 1H), 4.19-4.41 (m, 3H), 4.42-4.58 (m, 1H), 5.35 (s, 2H), 5.40 (d, 1H), 7.14 (d, 1H), 7.25-738 (m, 2H), 7.53 (dd, 1H), 7.72 (t, 1H), 7.80 (d, 1H), 7.92-8.05 (m, 2H), 8.47 (s, 1H), 9.14 (d, 1H), 9.75 (s, 1H); Mf TTO MR 543. Example 75 N-Methylyl) oxy]ethyl}acetamlde The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine andM[2-({4-[(4-hydnxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]- methylacetamide to give the title compound as a white solid in 11% yield; NMR spectrum (DMSO-d6 373K) 1.94 (s, 3H), 2.28 (s, 3H), 3.00 (s, 3H), 3.88 (t, 2H), 4.46 (m, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.16 (d, 1H), 7.34 (m, 2H), 7.51 (m, 2H), 7.55 (d, 1H), 7.68 (t, 1H), 7.83 (td, 1H), 8.41 (s, 1H), 8.58 (d, 1H), 9.63 (s, 1H); Mass spectrum MH 458. TheW-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyI]-7V1- methylacetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 2-rneAyl-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol (obtained as described in Example 3, preparation of starting materials) to give JV-[2-({4-[(4- hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy) ethyl]-methylacetamide as alight brown solid in 100% yield; NMR spectrum (DMSO-d6) 1.90 (s, 3H), 2.16 (s, 3H), 3.02 (s, 3H), 3.85 (t, 2H), 4.45 (t, 2H), 6.82 (d, 1H), 7.18 (dd, 1H), 7.25 (d, 1H), 7.34 (m, 2H), 7.92 (t, 1H), 8.65 (s, 1H), 9.45 (s, 1H), 10.52 (s, 1H); Mass spectrum Mlf 367. Example 76 tf-Methyl-N2-[(4-{[3-meroyl ethyl acetwnld The procedure described in Example 3 was repeated using 4-{cMorornethyl)-13- thiazole and AT-[2K{4(4ydroxy-3-rnethylrjhenyl)MnirK)]quiMZoUn-5ethyQ-tfmethylacetamide (obtained as described in Example 75, preparation of starting materials) to give the title compound as an off-white solid in 5% yield; NMR spectrum (DMSO-d6 373K) 1.94 (s, 3H), 2.24 (s, 3H), 2.99 (s, 3H), 3.87 (t, 2H), 4.46 (m, 2H), 5.25 (s, 2H), 7.08 (d, 1H), 7.17 (d, 1H), 7.35 (d, 1H), 7.47 (d, 1H), 7.54 (dd, 1H), 7.70 (m, 2H), 8.41 (s, 1H), 9.07 (d, 1H), 9.63 (s, 1H); Mass spectrum MH 464. Example 77 N-Mcthyl-NK2-{l4-({3-methylw4.[(5-rn€thylisoxazol-3-yl)roethoxy]phenyl}arnirio) quinazolin-5-yl]oxy}ethyl)acetaniide The procedure described in Example 3 was repeated using 3-(chloromethyl5- methylisoxazole and N-[2{4-[(4-hydroxy-3-memylphenyl)arnino]quinazolin-5- yl}oxy)ethyi]-W-methylacetamide (obtained as described in Example 75, preparation of starting materials) to give the title compound as a white solid in 14% yield; NMR spectrum (DMSO-d6 373K) L95 (s, 3H), 2.23 (s, 3H), 2.43 (s, 3H), 3.57 (s, 3H), 3.88 (t, 2H), 4.47 (m, 2H), 5.15 (s, 2H), 6.29 (s, IH), 7.05 (d, IH), 7.15 (d, IH), 7.34 (d, IH), 7.48 (d, IH), 7.54 (dd, IH), 7.69 (t, IH), 8.42 (s, IH), 9.64 (s, IH); Mass spectrum MH+ 462. Example 78 2-Hydroxy--methyl-Af-{2-[(4-{[3-roethyl-4-(l,3-thiazoI-2-ylmetboxy)phenyl] amino}quina2oUn-5-yl)oxy]ethyl}acetam}de The procedure described in Example 3 was repeated using 2-(chloroinethyl)-13- yl }oxy)ediyl]-Amemytacetamide (obtained as described in Example 3, preparation of starting materials) to give the title compound as a wbite solid in 38% yield; NMR spectrum (DMSOd6 373K) 2.27 (s, 3H), 2.98 (s, 3H), 3.91 (t, 2H), 4.07 (s, 2H), 4.47 (t, 2H), 5.44 (s, 2H), 7.09 (d, IH), 7.16 (d, IH), 734 (d, IH), 7.54 (m, 2H), 7.67 (t, IH), 7.70 (d, IH), 7.83 (d, IH), 8.41 (s, IH), 9.63 (s, IH); Mass spectrum MfiT 480. Example 79 2-Hydnxy-A-{2-[(4-{[3-methyl(pyridm-2-ylmethoxy)phenyl]andno}quinazoliri-5- yl)oxy]ethyl}acetamide The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and 2-hydroxy-JV-[2-({4-[(4-hydroxy-3-methylphenyl)ainino] quinazolin-5- yl}oxy)ethyl]acetamide to give the title compound as a yellow solid in 27% yield; HMfi spectrum (DMSO-d6) 2.27 (s, 3H), 3.71 (q, 2H), 3.77 (d, 2H), 4.38 (t, 2H), 5.20 (s, 2H), 5.49 (t, 1H), 6.98 (d, 1H), 7.14 (d, 1H), 7.31 (d, 1H), 7.35 (dd, 1H), 7.45 (d, 1H), 7.56 (m, 2H), 7.68 (t, 1H), 7.85 (td, 1H), 8.17 (t, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.75 (s, 1H); Mass spectrum MH 460. The2-hydroxy-JV-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5- yl }oxy)ethyl]acetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using ethanolamine and 4-[(5-fluoroquinazolin-4-yl)amino]-2-rnethylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-{ [5-(2- aminoethoxy)qiimazolin-4-yl]arnrno}-2--methylphenol as a grey solid in 23% yield; NMR spectrum (DMSO16) 2.14 (s, 3H), 3.09 (d, 2H), 3.28 (s, 2H), 4.25 (t, 2H), 6.77 (d, 1H), 7.08 (d, 1H), 7.28 (d, 1H), 7.46 (dd, 1H), 7.55 (d, IH), 7.66 (t, 1H), 8.40 (s, 1H), 10.31 (s, 1H); Mass spectrum MH 311. The pnxxlureedm Example 3 (pnjar using glycolic acid and 4-{ [S42-umiioetixxxy)qum to give 2vdroxy-2{4-[(4ydroxy-3-n«thylphenyl)amino] quinazolin-5- yl}oxy)ethyl]acetamide as m light brown sobdm 58% yield; NMR^ecmffin(DMSO-d6) 2.16 (s, 3H), 3.69 (q, 2H), 3.76 (d, 2H), 4.43 (t, 2H), 6.82 (d, 1H), 730 (m, 4H), 750 (t, 1H), 8^0 (t, 1H), 8.66 (s, 1H), 9.42 (s, 1H), 10.55 (s, 1H); Mass spectrum MJT 369. Example 80 2-Hydroxy-N-{[(4-{[3-imthyl(lthia2olylmethoxy)phenyl]amiiM)}qul yl)oxy]ethyl}acetamide The procedure described in Example 3 was repeated using 4-(chlorornethyll,3- miazole and 2-hydroxy-N-[2-({4-[(4-hydroxy-3-memylphenyl)amino]quinazolin-5- yl}oxy)ethyl]acetamide (obtained as described in Example 79, preparation of starting materials) to give the title compound as a yellow solid in 21% yield; NMR spectrum QDMSOd6) 2.20 (s, 3H), 3.71 (q, 2H), 3.77 (d, 2H), 4.38 (t, 2H), 5.23 (s, 2H), 5.49 (t, IH), 7.08 (d, IH), 7.J3 (d, IH), 7.32 (d, IH), 7.44 (d, IH), 7.57 (dd, IH), 7.69 (t, IH), 7.77 (d, IH), 8.17 (t, IH), 8.42 (s, IH), 9.14 (d, IH), 9.77 (s, IH); Mass spectrum MlT 466. Example 81 Af-{2-[(4-{[3hkro(pyridiD-2-ylmethoxy)phenyl]ainino}quinazolin-5-yI)oxy]-l,l" dimethylethyI}-2-hydroxyacetainkie The procedure described in Example 3 was repealed using 2-(chloromethyl)pyridine and 2ydroxy2{4-[(4ydroxy3-riirylphenyloJ qninazo]ro-5-yl}oxy)-Udiniethyletfay]] acetaniide to give the title compound as a white solid in 16% yield; NMR spectrum (DMSO16) 1.46 (s, 6H), 3.72 (d, 2BX 4.42 (s, 2H), 5.27 (s, 2H), 534 (t, IH), 7.16 (d, IH), 7.24 (d, IH), 737 (m, 2H), 7.50 (m, 2H), 738 (d, IH), 7.73 (t, IH), 7.87 (td, IH), 8.06 (d, IH), 8.50 (s, IH), 8.59 (d, IH), 9.83 (s, IH); Mass spectrum MH+ 508. The 2-hydroxy-JV-[2{4-[(4-hydroxy-3-roethyhnyl)amino]quinazolin-5-yl }oxy- l,l-dimethylethyl]acetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using 2-amino-2-methylpropan-l-ol and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-{ [5-(2- arruno-2-methylpropoxy)quinazoun-4-yl]arnino}-2-methylphenol as a white solid in 78% yield; NMR spectrum (DMSO-d6) 1.34 (s, 6H), 4.23 (s, 2H), 6.97 (d, IH), 7.18 (d, IH), 7.35 (d, IH), 7.52 (dd, IH), 7.73 (t, IH), 7.96 (d, IH), 8.46 (s, IH), 10.50 (s, IH); Mass spectrum MH+360. The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-{[5-(2-amino-2-methylpropoxy)quinazoHn-4-yl]amino}-2- methylphenol to give 2-hydroxy-N-[2-({4-[(4-hydroxy-3-memylphenyl) amino]quinazolin-5- yl)oxy,l-dimethylethyl]acetamide as a light brown solid in 53% yield; NMR spectrum (DMSO-d6) 1.47 (s, 6H), 3.69 (d, 2H), 4.47 (s, 2H), 7.04 (d, 1H), 7.38 (m, 3H), 7.78 (d, 1H), 7.% (t, 1H), 8.18 (t, 1H), 8.80 (s, 1H), 10.40 (s, 1H), 10.67 (s, 1HV. Mass spectrum MH 417. Example 82 2-Hydroxy-A-{(2K)-2-[(4-{[3-methyI-4-(pyridin-2-yImethoxy)phenyl]ainiiio}quinazolin- 5-yDoxy]propyl}acetamide The procedure described in Example 3 was repeated using 2-(chlorcanediyl)pyridine and 2-hydroxy-N-[(2)-2-((4-[(4-hydroxy-3-methyrphenyi) arnino)qumazolin-5- yloxy)propyl]cetaimde to give the tide compound at a white solid in 29% yield; MMR spectrum (DMSOd6) 1.40 (d, 3HX 2.27 (s. 3HX 3.43 (dt, 1H), 3.72 (dt. 1H), 3.80 (4 2HX 4.94 (m. 1H), 5.20 (s, 2H), 5.46 (t, 1H), 7.00 (d, 1H), 7.21 (d, 1H), 7.30 (d, 1HX 734 (dd, 1H), 7.56 (m, 3HX 7.68 (U1HX 7.85 (td, IHX 8.16 (t, 1HX 8-43 (s, IB), 8.58 (d, 1H), 9.94 (s, 1H); Mass spectrum MH** 474. Tie2-hydxy--[(2l2K{4-[(4-hydoxy-3nethylrAenyl)arnino]qlrin yl}oxy)propyl]acetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using (/0-(-l-anrino-propan-2-ol and 4-[(5-fluoroquinazolin^yl)arnino]-2-rnethylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-({5-[(LR)-2- amino-l-methylethoxy]quinazolin-4-yl}amino)-2-mcthylphenol as a brown solid in 65% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.16 (s, 3H), 2,96 (m, 2H), 3.30 (s, 2H), 4.96 (m, 1H), 6.77 (d, 1H), 7.14 (d, 1H), 7.25 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 7.67 (t, 1H), 8.39 (s, 1H), 9.16 (s, 1H), 10.50 (s, 1H: Mass spectrum MH" 325. The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and4{5-[(l/0-2-armno-l-rnethytemoxy]qutnazoUnyl}amino2- methylphenol to give 2-hydroxy-JV-[(2R)-2-({4-[(4-hydroxy-3- methylphenyl)ainino]quinazohn-5-yl}oxy)propyl]acetamide as a dark brown solid in 59% yield; NMR spectrum (DMSQ-d6) 1.41 (d, 3H), 2.17 (s, 3H), 3.43 (dt, 1H), 3.75 (dt, 1H), 3.78 (s, 2H), 5.01 (m, 1H), 6.84 (d, 1H), 7.30 (d, 1H), 7.32 (dd, 1H), 7.39 (d, 1H), 7.46 (d, 1H), 7.95 (t, 1H), 8.22 (t, 1H), 8.75 (s, 1H), 9.54 (d, 1H), 10.78 (s, 1H); Mass spectrum MH 383. Example 83 2-Hydroxy-N-{(2fi)-2-[(4-{[3-metbyl-4-(lr3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yI)oxy)prxpyl}acetainide The procedure described in Example 3 was repeated using 4-(chloromethyl13- thiazote and 24draxy-(2f2{4-[(4-hydroxy qirinazoKn-5- yloxy)propyf)acctamide (obtained as described in Example 82, preparation of starting materials) to give the title compound as a white solid in 13% yield; d6) 139 (d, 3H), 2.21 (s, 3H), 3.42 (dt, 1H), 3.71 (dt, 1H), 3.79 (d, 2H), 4.95 (m, 1H), 5.24 (s, 2H), 5.48 (t, 1H), 7.09 (d, 1H), 7.23 (d, 1H), 729 (d, 1H), 7.54 (d, 1H), 7.62 (dd, 1H), 7.68 (t, 1H), 7.77 (d, 1H), 8.16 (t, 1H), 8.44 (s, 1H), 9.14 (d, 1H), 9.95 (s, 1H); Mass spectrum MH 480. Example 84 Af(2)-2-{[4-({4-[(3-Fluorobenzyl)oxy]-3-methylphenyl}ainino)quinazolin-5- yi]oxy}propyl)2hydroxyacetamkle The procedure described in Example 3 was repeated using l-(chloromethyl3- fluorobenzene and 2-hydroxy-A-[(2)-2-({4-[(4-hydroxy-3-rnethylphenyl)amino] quinazolin- 5-yl}oxy)propyl]acetamide (obtained as described in Example 82, preparation of starting materials) to give the title compound as a light yellow solid in 25% yield; NMR spectrum (DMSO-d6) 139 (d, 3H), 2.25 (s, 3H), 3.42 (dt, IH), 3.72 (dt, IH), 3.81 (d, 2H), 4.94 (m, IH), 5.17 (s, 2H), 5.47 (t, IH), 6.99 (d, IH), 7.16 (td, IH), 7.22 (d, IH), 7.30 (m, 3H), 7.43 (m, IH), 7.56 (d, IH), 7.61 (dd, IH), 7.68 (t, IH), 8.16 (t, IH), 8.43 (s, IH), 9.94 (s, IH); Mass spectrum MH 491. Example 85 2-Hydroxy-N-{(2)-2-[(4-{[3-inethyl(13-thiazol-2-ylimth)xy)phenyl]amino} quinazolin-5-yl)oxy]propyl}acetaniide The procedure described in Example 3 was repeated using 2-(chloromcthyl)-13- thiazole and 2ydroxy- [(2K}-2"{4-[(4 quinazolin-5- yl}oxy)ptopyi)acetaimde (obtained as described in Example 82, preparation of starting materials) to give flic title compound as a light brown solid in 31% yield; NMBjg^ttym (DMSO-d6) 139 (d, 3H), 2.25 (s, 3H), 3.42 (dt, IH), 3.73 (m, IH), 3.79 (d, 2H), 4.94 (m, IH), 5.44 (s, 2H), 5.47 (t, IH), 7.09 (d, IH), 7.23 (d, IH), 730 (d, IH), 7.58 (d, IH), 7.63 (dd, IH), 7.69 (t, IH), 7.77 (d, IH), 7.84 (d, IH), 8.16 (t, IH), 8.43 (s, IH), 9.96 (s, IH); Mass spectrum MH 480. Example 86 {(22-[( yl)oxy]propyl}acetandde The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and AK(2/?)-2-({4-[(4-hydroxy-3-methylphenyl)aminoJ quinazolin-5- yl oxy)propyl]acetamide to give the title compound as a white solid in 43% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.27 (s, 3H), 3.41 (dt, IH), 3.58 (dt, IH), 4.87 (m, IH), 5.20 (s, 2H), 7.01 (d, IH), 7.22 (d, IH), 7.29 (d, IH), 7.35 (dd, IH), 7.55 (m, 2H), 7.58 (dd, IH), 7.69 (t, IH), 7.85 (td, IH), 8.23 (t, IH), 8.45 (s, IH), 8.58 (d, IH), 9.97 (s, IH); Mass spectrum NOT 458. The-[(2R-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazoIin-5- yloxy)propyl]acetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 4-({5-[(l)-2-amino-l-methylethoxy]quinazolin-4-yl}amino)-2- methylphenol (obtained as described in Example 82, preparation of starting materials) to give Af-[(2{4-[(4ydroxy-3-niethylphenyl)amino] quinazolin-5-yl)oxy)propyI]acetamide as a ginger solid in 90% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.76 (s, 3H), 2.17 (g, 3H), 3.41 (d^ IHX 3.62 (dt, IH), 4.96 (m, IH), 6.85 (d, IH), 731 (d, IH), 7.36 (m, 2H), 7.49 (d, IH), 7.96 (t, IH), 8.24 (t, IH), 8.77 (s, IH), 9.57 (s, IH), 10.77 (s, IH); Mass spectrum MH+367. Examples? 2-[(4-{[3-Methyllthiarolylnt yl)oxy]propyl}acetaniide N The procedure described in Example 3 was repeated using 4-(chloromethyl)-l,3- thiazole and -[(2)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5- yl }oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting materials) to give the title compound as a white solid in 20% yield; NMR spectrum (DMSOd6) 1.41 (d, 3H), 1.78 (s, 3H), 2.23 (s, 3H), 3.41 (dt, IH), 3.58 (dt, IH), 4.87 (m, IH), 5.25 (s, 2H), 7.H (d, 1H), 7.21 (d, IH), 7.29 (d, IH), 7.53 (d, IH), 7.63 (dd, IH), 7.69 (t, IH), 7.76 (d, IH), 8.23 (t, IH), 8.44 (s, IH), 9.14 (d, IH), 9.% (s, IH); Mass spectrum MH 464. Example 88 Af-((2V2-{[4-{4-[(3-Fhiorobenzyl)oxy]-3-methylphenyl}amino)quinazolin-5- yl]oxy}propyl)acetamide The procedure described in Example 3 was repeated using l-(chloromethyl)-3- fluocobenzene and N-[(2JO-2K{4-[(4-hydroxy-3-inetbyhph yl}oxy)ptopyacetatmde (obtained at described m Example 86t preparation of starting tnatmrirt to give the tide compounds white solid in 46% viekL NMR spectrum d6) 1.41 (d, 3HX 1.77 (s, 3H), 236 (s, 3H), 3.41 (dt, IHX 3.58 (dt. IHX 4.86 (m, IH), 5.18 (s, 2H), 7.01 (d, IH), 7.16 (Id, IHX 7.22 (d, IHX 730 (m, 3HX 7.42 (m, IHX 754 (d, IHX 7.62 (dd, IH), 7.68 (t, IH), 8.22 (t, IH), 8.43 (s, IH), 9.95 (s, IH); Mass spectrum MH* 475. Example 89 AH(2£V2(4-{[3-MethyIwHltfaiaz yl)oxy]propyl}acetainide The procedure described in Example 3 was repeated using 2-(chloromethyl)-l,3- thiazole and V-[(2R)-2-{4-[(4-hydroxy-3-memylphenyl)amino]quinazolin-5- yl}oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting materials) to give the title compound as a fight brown solid in 25% yield; (DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.25 (s, 3H), 3.42 (dt, IH), 3.60 (dt, IH), 4.88 (m, IH), 5.45 (s, 2H), 7.11 (d, IH), 7.22 (d, IH), 7.31 (d, IH), 7.56 (d, IH), 7.63 (dd, IH), 7.68 (t, IH), 7.76 (d, IH), 7.83 (d, IH), 8.23 (t, IH), 8.43 (s, IH), 9.97 (s, IH); Mass spectrum MIT 464. Example 90 2-Hydroxy-N-methyl-A-{(2)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyI] amino}quinazoKn-5-yl)oxy]propyl}acetamide The procedure described in Example 3 was repealed using 2-(chloromethyl)pyridine and 2-hiroxy--[(2)-2-({4-[(4-hydToxy-3-roethylphenyI) amhx]quinazolin-5- yl )oxy)prDpyi]-^methylacetamide to give the title compound as a light yellow solid in 17% yield; NMR spectrum (DMSCM6 373K) 1.43 (d, 3H), 2.29 (s, 3H), 2^7 (s, 3H), 3.58 (m, IH), 4.08 (m, 3H), 5.11 (m, IH), 5.19 (s, 2H), 7.01 (d, IH), 7.21 (d, IH), 732 (m, 2H), 7.57 (m, 3H), 7.67 (t, IH), 8.83 (td, IH), 8.41 (s, IH), 8.57 (d, IH), 9.81 (s, IH); Mass spectrum MH488. The2-hydroxy-7V-[(2)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5- yl}oxy)propyl]-methylacetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using (2)-l-[allyl(methyl)amino]propan-2-oI (obtained as described in Example 2.3, preparation of starting materials) and 4-[(5-fluoroquinazolin-4-yl) amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-[(5-{ (l/?)-2- [allyl(rnethyl)amino]-l-methylethoxy}quinazoIin-4-yl)amino]-2-methylphenol as a brown oil in 86% yield; NMR spectrum (DMSO-d6) 1.43 (d, 3H), 2.15 (s, 3H), 2.18 (s, 3H), 2.54 (dd, IH), 2.88 (dd, IH), 3.00 (m, 2H), 4.92 (m, IH), 5.01 (d, IH), 5.11 (d, IH), 5.62 (m, IH), 6.77 (d, IH), 7.16 (d, IH), 7.26 (d, IH), 7.35 (s, IH), 7.38 (d, IH), 7.66 (t, IH), 8.37 (s, IH), 9.17 fs, IH), 10.16 (s. IH): Mass spectrum MH 379. The procedure described in Example 2.3 (preparation of starting materials) was repeated using chlorotris(triphenylphosphine)rhodium 00 and 4-[(5-{(l)-2- [a)lyl(methyl)amino]-l-methylethoxy}quinazolin-4-yl)amino]-2-methylphenol to give 2- methyl({5-[(l/fl-methyl-2Kniethylamino)ethoxy]quinazolin-4-yl}ainino)-phenol as a brown foam in 56% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 2.15 (s, 3H), 2.33 (s, 3H), 2.87 (m, 2H), 4.85 (m, IH), 6.77 (d, IH), 7.14 (d, IH), 7.25 (d, IH), 7.43 (s, IH), 7.46 (d, IH), 7.64 (t, IH), 8.38 (s, IH), 9.14 (s, IH), 10.35 (s, IH); Mass spectrum MH 339. The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 2-mediyl-4-({5-[(l/l-meftyl-2-(methylamino) ethoxy]quinazolin-4- yl}anrino)phenol to give 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3- methylphenyl)amino]quinazolin-5-yl}oxy)propyI]-N-methylacetarnide as an orange solid in 81% yield; NMR spectrum (DMSO-d6) 138 (d, 3H), 2.15 (s, 3H), 2.96 (s, 3H), 3.35 (dd, IH), 4.02 (s, 2H), 4.21 (m, 2H), 5.18 (m, IH), 6.83 (d, IH), 7.27 (m, IH), 7.38 (s, IH), 7.46 (d, IH), 7.92 (t, IH), 8.70 (s, IH), 9.52 (s, IH), 10.68 (s, IH): Mass spectrum MH* 397. Example 91 The procedure described in Example 3 was repeated using 4-(chloromethyll,3- thiazole and 2-hydroxy-W-[(2)-2-({4-[(4-hydroxy-3-methylphenyl)arnino] quinazolin-5- yl}oxy)propyl]-Af-methylacetarnide (obtained as described in Example 90, preparation of starting materials) to give the title compound as a white solid in 41% yield; NMR spectrum (DMSO-d6 373K) 1.43 (d, 3H), 2.24 (s, 3H), 2.97 (s, 3H), 3.57 (m, IH), 4.07 (m, 3H), 5.13 (m, IH), 5.25 (s, 2H), 7.09 (d, IH), 7.11 (d, IH), 7.34 (d, IH), 7.57 (m, 2H), 7.69 (m, 2H), 494. Example 92 2-Hydroxy-A-methyl-Ar-((2R)-2-{[4-({3-methyI-4-[(5-methylisoxa2oI-3- y))methoxy]plieny)}ainino)quinazoJin-5-yl]oxy}propyI)acetamide The procedure described in Example 3 was repeated using 3-(chloromethyl}-5- methylisoxazole and 2-hydroxy-A?-[(2)-2{4-[(4-hydroxy-3-methylphenyl)amino] quinazolin-5-yl}oxy)propyl]-N-mediylacetaraide (obtained as described in Example 90, preparation of starting materials) to give the title compound as a white solid in 7% yield; NMR spectrum (DMSCM6 373K) 1.44 (d, 3H), 2.22 (s, 3H), 2.42 (s, 3H), 2.98 (s, 3H), 3.58 (m, IH), 4.17 (m, 3HX 5.11 (m, IH), 5.15 (s, 2HX 629 (s, IH), 7.07 (d, IH), 7.11 (d, IH), 733 (d, IH), 7SJ (m, 2H), 7.69 (t, IH), 8.44 (s, 1HX 9.83 (s, IH); Mass spectrum MH492. Example 93 amino}quinazolin-5-yl)oxy]etbyl}acetainide The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine andJV-[(l/?)-2-({4-[(4-hydroxy-3-nwthylphenyI)arnino]quinazoh"n-5-yl}oxy)-l-methylethyl]- TV-methylacetamide to give the title compound as a tight beige solid in 43% yield; NMR spectrum (DMSO-d6 373K) 1.21 (d, 3H), 1.85 (s, 3H), 2.27 (s, 3H), 2.84 (s, 3H), 4.34 (m, IH), 4.40 (t, IH), 5.07 (m, IH), 5.20 (s, 2H), 7.01 (d, IH), 7.17 (d, IH), 7.33 (m, 2H), 7.42 (d, IH), 7.47 (dd, IH), 7.55 (d, IH), 7.67 (t, IH), 7.82 (td, IH), 8.41 (s, IH), 8.57 (d, IH), 9.50 (s, IH); Mass spectrum MH472. The/V-[(l/?)-2-({4-[(4-hydroxy-3-methylphenyl)ainino]quinazolin-5-yl}oxy)-lmethylethyl]- W-rnethylacetamide used as starting material was prepared as follows: The procedure described in Example 3 (preparation of starting materials) was repeated using (2tf)-2-(:nrethylammo)propan-l-ol (obtained as described in Becker et al., J. Chem. Soc. 1957, 858) and 4-[(5-fluoroqiMna2oHn-4-yl)amino]-2-methylphenol (obtained as described hi Example 3, preparation of starting materials) to give 2-methyl-4-[(5-{ [(2K)-2- (methy]ammo)propyl]oxy }quinazoKn-4-yl)amino]phenol as a brown solid in 80% yield; NMR spectrum (DMSO-d6) 1.16 (d, 3H), 2.14 (s, 3H), 2.34 (s, 3H), 3.04 (m, IH), 3.24 (bs, IH), 4.08 (dd, IH), 4.25 (dd, IH), 6.76 (d, IH), 7.06 (d, IH), 7.26 (d, IH), 7.47 (d, IH), 7.53 (dd, IH), 7.65 (t, IH), 8.39 (s, IH), 9.17 (s, IH), 10.37 (s, IH); Mass spectrum MH 339. To a mixture of triethylamine (420 \|il) and 2-methyl-4-[(5-{[(2-2- (methylamino)propyl)oxy }qoinazc4in-4-yl)amino]phenol (450 mg) in DCM (5 ml) was added acetyi chloride (190 jil). The reaction was stirred for 30 minutes and then quenched with water and extracted with DCM (x2 The residue was dissolved in 7N MeOH/NH3 and stirred at loom temperature for 30 infantes. Solvent was removed mwcuo and water was added. The mixture was extracted with DCM (x2), filtered and men methylacetamide as a pink foam (365 mg, 72%); NMR spectrum (DMSO-d6 373K) 1.41 (d, 3H), 1.86 (s, 3H), 2.17 (s, 3H), 2.83 (s, 3H), 4.36 (m, 2H), 5.04 (m, IH), 6.77 (d, IH), 7.16 (d, IH), 7.29 (m, 3H), 7.67 (t, IH), 838 (s, IH), 8.78 (s, IH), 9.43 (s, IH): Mass spectrum MH 381. Example 94 N-Methyt-]V.{(ll.methyl.2-[(4.{[3-methyl.4.(l,3-thiazol.4- ylmethoxy)phenyllamino}quinazoHn-5-yl)oxy]ethyl}acetamlde The procedure described in Example 3 was repeated using 4-(chloromethyl13- thiazole and N-[(LR-2K{4-[(4-hydroxy-3-memylphenyl)aniino]quinazolin-5-yl}oxy)-lmethylethyl]- Af-methylacetamide (obtained as described in Example 93, preparation of starting materials) to give the title compound as a white solid in 13% yield; NMR spectrum (DMSO-d6 373K) 1.22 (d, 3H), 1.86 (s, 3H), 2.24 (s, 3H), 2.85 (s, 3H), 4.33 (m, IH), 4.42 (t, IH), 5.09 (m, IH), 5.25 (s, 2H), 7.09 (d, IH), 7.18 (d, IH), 7.34 (d, IH), 7.39 (s, IH), 7.50 (d, IH), 7.70 (m, 2H), 8.41 (s, IH), 9.08 (s, IH), 9.51 (s, IH); Mass spectrum MH 478. Example 95 N-{(l)-2-[(4-{[3-ChJoro(lthia2olyImethoxy)phenyl]amino}quinazolin-5-yl)oxy]- l-methylethy)}-2-hydroxy-AT.meihylacetamide -S The procedure described in Example 3 was repeated using4-(cbloromethyl)-13- tbiazote and A4(l2{4(3-cMoro-4 nKthytethyI]-2ydfoxyTynethy)acetainide (obtained as described in Example 54, preparation of starting materials) to give the title compound as a white solid in 64% yield; NMR spectrum (DMSCM6 373K) 1.25 (d, 3H), 2.83 (s, 3H), 3.98 (s, 2H), 4.34 (m, IH), 4.47 (t, IH), 4.98 (m, IH), 5.34 (s, 2H), 7.19 (d, IH), 7.37 (d, 2H), 7.51 (dd, IH), 7.70 (t, IH), 7.74 (d, IH), 7.93 (d, IH), 8.46 (s, IH), 9.08 (s, IH), 9.57 (s, IH); Mass spectrum MH+ 514. Example 96 ybnetboxy)phenyl]amino}quinazolin-5-yI)oxy]ethy]}acetainide The procedure described in Example 3 was repeated using 2-(chIoromethyl)pyridine 2-h) droxy -N- [(lK)-2({ K(4-hydroxy-3-methylphenyl) amino]quinazolin-5-yl}oxy)-lmethylethyl]- JV-methylacetamide to give the title compound as a white solid in 15% yield; NMR spectrum (DMSO-d6 373K) 1.25 (d, 3H), 2.28 (s, 3H), 2.83 (s, 3H), 3.96 (s, 2H), 4.35 (ro, IH), 4.46 (t, IH), 4.97 (m, 1H), 5.19 (s, 2H), 7.01 (d, 1H), 7.18 (d, 2H), 7.33 (m, 2H), 7.44 (m, 1H), 7.56 (d, IH), 7.68 (t, 1H), 7.83 (td, 1H), 8.40 (s, IH), 8.58 (d, 1H), 9.48 (s, 1H); Mass spectrum MH 488. The2-hydroxy-[(l/0-2{4-[(4ydroxy-3-methylphenyl)amino]quinazolin-5- yl}oxyl-methylethyl]-N-methylacetanude used as starting material was prepared as follows: The procedure described in Example 94 (preparation of starting materials) was repeated using acetoxyacetyl chloride and 2-methyl-4-[(5-{ [(2/0-2- (methylamino)propyl]oxy }quinazolin-4-yl)aniino]phenol (obtained as described in Example 93, preparation of starting materials) to give 2-hydroxy-N-[(17)-2-({4-[(4-hydroxy-3- , memylphenyl)ainrao]quiiiazoliiH5-y as an orange foam in 75% yield; NMR spectrum (DMSOd6 373K) 1.25 (d, 3H)y 2.17 (s, 3H), 2.83 (s, 3H), 3.97 (s, 2H), 433 (dd, 1H), 4.45 (t, 1HX 4.95 (m, IH), 6.77 (d, IH), 7.17 (d, 1H), 7.30 (m, 3H), 7.(7 (t, 1H), 8.37 (s, 1H), 8.79 (s, 1HX 9.43 (s, 1H); Massspeclmm Example 97 The procedure described in Example 3 was repeated using 4-(chloromethyl)-l,3- thiazole and 24iydtoxy-N-[(l-2K{4-[(4-hydroxy-3-methylphenyl)amino] quinazolin-5- yl}oxy)-l-methylethyl]-JV-metiiylacetamide (obtained as described in Example 96, preparation of starting materials) to give the title compound as a foam in 29% yield; NMR spectrum (DMSO-d6 373K) 1.26 (d, 3H), 2.24 (s, 3H), 2.83 (s, 3H), 3.97 (s, 2H), 4.35 (m, 1H), 4.46 (t, 1H), 4.95 (m, IH), 5.24 (s, 2H), 7.08 (d, 1H), 7.18 (d, 2H), 7.35 (d, 1H), 7.42 ;(s, 1H), 7.46 (d, IH), 7.70 (m, IH), 8.41 (s, IH), 9.07 (s, IH), 9.50 (s, im: Mass spectrum MH" 494. Example 98 N-{(2)-2-[(4-{[3-Chloro-4-(pyridin-2-yImethoxy)phenyl]aniino}quiDazolin-5- yl)oxy]pit»pyl}-l-faydroxyWV-inethyIcycIopropanecarboxamide The procedure described in Example 1 was repeated using hydroxy-1-cyclopropane carboxylic acid andN-[3horo-4-(pyridin-2-ylmedioxy) phenyl]-5-[(LR)-l-methyl-2- (methylairrino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a foam in 19% yield: NMR spectrum (DMSO-d6) 0.70 (s, 4H), 1.40 (d, 3H), 323 (s, 3H), 336 (m, 1H), 4.19 (m, 1H), 5.15 (m, 1H), 5.29 (s, 2H), 6.20 (s, 1H), 724 On, 2HX. 735 (m, 2H), 7.58 (m, 2H), 7.71 (t, 1H), 7.87 (dt, 1H), 8.09 (d, 1H), 8.44 (s, 1HX 8^8 (d, 1H), 9.86 (s, 1H): Mass spectrum MFT 534. yl)oxy)propyI}-2-hydroxy-ArHi)etfaytpropaiuunkie The procedure described hi Example 1 was repeated using L-(+)-]actic acid and N-[3- chloiX)yridin-2-ylmethoxy)phenyl]-5(l)-l-methyl-2metliylainino)ethoxy]qm 4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the tide compound as a white solid in 35% yield; NMR spectrum (DMSO-d6 373K) 1.07 (d, 3H), 1.45 (d, 3H), 2.98 (s, 3H), 3.22 (m, 1H), 4.19 (m, 1H), 4.43 (m, 1H), 5.15 (m, 1H), 5.27 (s, 2H), 7.22 (m, 2H), 735 (m, 2H), 7.59 (m, 2H), 7.69 (t, 1H), 7.84 (dt, 1H), 8.08.(d, 1H), 8.47 (s, 1H), 8.58 (d, 1H), 9.93 (s, 1H); Mass spectrum MH 522. Example 100 The procedure described in Example 1 was repeated using 2-hydroxy-tso-butyric acid (methylamino)ethoxy]qainazolin-4-anune (obtained as described in Example 2.3, preparation of starting materials) to give the tide compound as a white solid in 28% yield; NMR spectrum (DMSO46 373K) 1.25 (s, 3HX 1.27 (s, 3HX 1.43 (d, 3HX 3.26 (s, 3H), 3.54 (m, 1HX 4.16 (dd, IH), 5.16 (m, IH), 5.28 (s, 2H), 7.23 (m, 2HX 734 (m, 2H), 7 5B (m, 21$, 7.69 (t, 1H), 7.83 (dt, 1H), 8.07 (d, 1H), 8.46 (s, IH), 8.58 (d, 1H), 9.88 (s 1H, Mass spectrum MlT 536. Example 101 The procedure described in Example 1 was repeated using D-(-lactic acid and N-[3nethylarr 4-amine (obtained as described in Example 23, preparation of starting materials) to give the title compound as a white solid in 26% yield; NiyiR spectni (DMSO-d6 373K) 1.15 (d, 3H), 1.44 (d, 3H), 2.97 (s, 3H), 3.16 (m, 1H), 4.05 (dd, 1H), 4.43 (m, 1H), 5.16 (m, 1H), 5.27 (s 2H), 7.23 (m, 2H), 7.35 (m, 2H), 7.59 (m, 2H), 7.70 (t, IH), 7.84 (dt, 1H), 8.09 (d, 1H), 8.47 (s, IH), 8.59 (d, IH), 9.90 (s, IH); Mass spectrum MH 522. Example 102 (2)-A-{(2-2-[(4-{[3-ChJoro-4-(pyridin-2-ylmethoxy)phenyl]amJno}quinazolin-5- yl)oxy]propy]}-2-inetboxy-Ar-methyIpropanarnide The procedure described in Example 1 was repeated using (K)-(+)-2- methoxypropionic acid and JV-[3x;hloro-4-(pyridin-2-ylmemoxy)phenyl]-5-[(l/Z)-l-methyl-2- (methylarnino)ethoxy]quina2olin-4-arnine (obtained as described in Example 23, preparation of starting materials) to give die title compound as a brown gum in 44% yield; NMR spectrum (DMSOd6 373K) 1.11 (d, 3H), 1.37 (d, 3H), 2.97 (s, 3H), 3.09 (s, 3H), 3.38 (m, IH), 4.17 (q, IH), 4.26 (dd, IH), 5.16 (m, IH), 5.28 (s, 2H), 7.24 (m, 2H), 7.33 (d, IH), 7.37 (dd, IH), 736 (d, IH), 7.64 (dd, IH), 7.69 (t, IH), 7.86 (dt, IH), 8.13 (d, IH), 8.44 (s, IH), 859 (d, IH), 9.89 (s, IH); Mass spectrum MH" 536. Example 103 2-Hydroxy-N-methyl-Ar.((2)-2-{[4-({3.methyl[(6-roe4hylpyridin-3- yI)oxy]phenyI}amino)quiiiazoUn-5-yl]oxy}propyl)acetamide The procedure described in Example 1 was repeated using glycolic acid and 5-[(l)-lrnemyl- 2-(memylamino)ethoxy]-{3-methyl[(6-methylpyridin-3-yl)oxy] phenyl}quinazolin-4-amine to give the title compound in 86% yield; NMR spectrum (CDCH) 1.55 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.96 (s, 3H), 3.59 (dd, IH), 4.16-4.07 (m, 3H), 5.08 (m, IH), 6.92 (d, IH), 7.02 (d, IH), 7.09 (d, IH), 7.14 (d, IH), 7.50 (m, 2H), 7.65 (in, 2H), 8.28 (s, IH), 8.61 (s, IH), 9.87 (s IH); Mass spectrum: MH 488. The5-[(1/J)-l-inethyl-2-(methylamino)ethoxy]-N-{3-inethyI-4-[(6-methylpyridin-3- yl)oxy}phenyl }quinazolin-4-amine used as starting material was prepared as follows: Sodium hydride (25.6 g, 60% dispersion in oil, 0.64 mol) was added portion wise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while beeping the temperature below 40°C. At the end of the addition, the mixture was stirred at room temperature for 1 hour and 2-fluoro-5-mtrotoruene (91.3 g, 0.59 mol) in DMA (100 ml) was added slowly. The mixture was stirred at 80°C for 3 hours and then cooled. The solvents were evaporated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant 30% ethyl acetate in petroleum ether) to give 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridinc (141 g, 98%) as an oil; NMR spectrum (CDCfe); 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d, 1H), 7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 832 (s, 1H). A mixture of 2-ineAyl-5iriethvl-4Hiitn)phenoxy)pyridirie (141 g, 0.58 mol) and 10% palladium on charcoal (13 g) in ethyl acetate (200 ml) ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 homes. After jeaction completion, the mixture was purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-njemyl[(6-rnethylpyridin-3-yl)oxy]amlirie (120.6 g 98%) as a white solid; Muss spectrum MH" 215. 3-Methyl-4-[(6-methyrpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4N hydrogen chloride in dioxane (7.55 ml, 30 mmol) were added to a suspension of 4-chloro-5- fluoroqumazoline (5 g, 27.5 mmol; obtained as described in PCT Int Appl. WO2001094341, AstraZeneca) in acetonitrile (100 ml). The mixture was stirred at 80°C for 2 hours. After cooling, the precipitate was washed with acetonitrile. This precipitate was partitioned between DCM and 5% aqueous sodium bicarbonate and the pH was adjusted to 8. The organic layer was washed with brine and dried over MgSO. Evaporation of the solvents gave 5-fluoro-W- {3-memyW-[(6-memylpyridm-3-yl)oxy]phenyl}qumazolm-4-arnine (9.3 g, 94%) as a dark gum which crystallised on standing; NMR spectrum (CDC13); 2.30 (s, 3H), 2.54 (s, 3H), 6.93 (d, 1H), 7.15-7.08 (m, 2H), 7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s, 1H), 8.37 (d, 1H), 8.71 (s, 1H). Sodium hydride (960 rhg, 60% dispersion in oil, 20 mmol) was added portion wise to an ice-cooled solution of (2 -[allyl(methyl)amino]propan-2-ol (3.87 g, 30 mmol, obtained as described in Example 23, preparation of starting materials) and 5-fluoro-/V-{3-methyl-4- [(6-rnethylpyridin-3-yl)oxy]phenyl}quina2»lin-4-aniinc (3.6 g, 10 mmol) in THF (25 ml). The mixture was heated at 65°C for 24 hours. After cooling, the solvents were evaporated under vacuum. The mixture was diluted with DCM, and washed with water and brine. The organic layer was dried over MgSO4. After evaporation of the solvents, the residue was purified by chrornatography on silica gel (eluant: 2 to 4% methanol in DCM) to give 5-{(lJ?)-2- [allyl(mehyl)amino]-l-methylethoxy}-{3-methyl-4-[(6-methylpyridin-3- 470. A mixture of 5-{(l2-[aUyl(methyl)amino]-l-methyleraoxy}-Ar-{3-memyl-4-[(6- methylpyridin-3-yl)oxy]phenyl}quinazolin-4-aniine (2.25 g, 4.8 mmol) and chlorotris(triphenylphospnine)rhodium(I) (463 mg, 0.48 ml) in acetonitrile - water (17 ml : 3 ml) was heated at reflux for 3 hours. After cooling, the solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to give 5-[(U -mediyl-2-(inethyfamino)cthoxy] -AT-{3-mcthyl-4-[(6- methyh?yridm-3-y])oxy]phenyl} quraazoiro-4-amine (1,70 g. 83 %); Mass spectrum: MET E mple 104 Acetyl chloride (24 uj, 0.33 mmol) was added drop wise to a solution of 5-[(lJ?)-lmethyl- 2-(methylamino)ethoxy]-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine (129 mg, 030 mmol, obtained as described in Example 103, preparation of starting materials) and DIPEA (105 ul, 0.6 mmol) in DCM (5 ml). The mixture was stirred at room temperature for 2 hours and diluted with DCM. The solution wa washed with water and brine, and dried over MgSO. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to give the tide compound (84 mg, 60%) as a pale solid; NMR spectrum (CDC13) 1.55 (d, 3H), 2.08 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 3.08 (s, 3H), 3.56 (dd, 1H), 3.93 (dd, 1H), 5.09 (m, 1H)> 6.92 (d, 1H), 7.12 (m, 3H), 7.50 (m, 2H), 7.65 (m, 1H), 7.70 (s, 1H), 8.27 (s, 1H), 8.62 (s, 1H); Mass spectrum: MH 472. Example 105 ATTrimethyl-C yIoxy]pbenyl}anuno)quiiiazolin-5-yl]oxy}propylycinainide Chloroacetyl chloride (33 ul, 0.42 mrool) was added drop wise to a solution of 5- [(ll-methyl-2nM&y)ami yl)oxy)phenyl}qumazolm-4-aQntne (172 mg, 0.40 mmoi, obtained as described in Example 1O3, preparation of starting materials)) andDIPEA (139 pi, 0.8 mmol) in DCM (2 ml). The mixture was stirred at room temperature for 1 hour. THF (S ml) was added to the solution and dunemyiamme was bubbled in the reaction mixture. After 30 minutes, the solvents were evaporated under vacuum. The mixture was diluted with DCM, washed with water and brine, and dried over MgSQ. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 4% 7N ammonia-methanol in DCM) to give die title compound (85 mg, 41%) as a pale solid; NMR spectrum (CDC13) 1.53 (d, 3H), 2.28 (s, 6H), 2.30 (s, 3H), 2.53 (s, 3H), 3.15-3.05 (m, 5H), 3.54 (dd, 1H), 3.95 (dd, 1H), 5.10 (m, 1H), 6.91 (d, 1H), 7.12 (m, 3H), 7.46 (d, 1H), 7.55 (d, 1H), 7.64 (m, 1H), 7.72 (s, 1H), 8.27 (s, 1H), 8.62 (s, 1H); Mass spectrum: MET 515. Example 106 AT-Methyl-V-((21)-2-{[4-«3-methyI-4-[(6-methylpyridin-3- yl)oxy]phenyI}aimno)qiihiazDlin-5-yl]oxy}pr(pyl-2-pyiToHdin-l-yIacetamide The procedure described in Example 105 was repeated using pyrrolidine (4 equivalents) instead of dimethylamine to give the title compound in 57% yield; NMR spectrum (CDCfe) 1.53 (d, 3H), 1.75 (m, 4H), 2.30 (s, 3H), 2.55 (m, 7H), 3.13 (s, 3H), 327 (d, IH), 332 (d, IH), 3 SJ (dd, IH), 3.92 (dd, IH), 5.11 (m, IH), 631 (d, IH), 7.12 (m, 3H), 7.46 (d, IH), 7.54 (d, IH), 7.64 (m, IH), 7.72 (s, IH), 827 (s, IH), 8.62 (s, IH); Mass spectrum: MH 541. Example 17 yl)oxy]phenyl}amiiio)qiiina The procedure described in Example 105 was repeated using morpholine (4 equivalents) instead of diiricthylamine to give the title compound in 63% yield; NMR spectrum (CDC13) 1.53 (d, 3H), 2.30 (s, 3H), 2.48 (m, 4H), 2.53 (s, 3H), 3.15 (m, 5H), 3.53 (dd, IH), 3.65 (m, 4H), 3.97 (dd, IH), 5.11 (m, IH), 6.92 (d, IH), 7.14-7.07 (m, 3H), 7.46 (d, IH), 7.54 (d, IH), 7.63 (m, IH), 7.72 (s, IH), 8.27 (s, IH), 8.62 (s, IH), 9.93 (s, IH); Mass spectrum: MH 557. Example 108 A-MethyI-Ar-((2)-2-{[4-{3-methyl-4-[(6-melhylpyridin-3- y)oxy]phenyI}amino)quinazolin-5-yl]oxy}propyl)-2-(4-iTiethylpiperazin-l-yl)acetaraide The procedure described in Example 105 was repeated using N-methylpiperazine (4 equivalents) instead of dimethylamuie to give die title compound in 68% yield; NMR spectrum (CDC13) 1.53 (d, 3H), 2.25 (s 3H), 2.30 (s, 3H), 25-23 (m, 8H), 253 (s, 3H), 3.15 (m, 5HX 354 (dd, IH), 354 (dd, IH), 5.11 (m, IH), 6.92 (d, IH), 7.14-7ff7 (m, 3H), 7.45 (d, IH), 7.54 (d, IH), 7.64 (m, IH), 7.72 (s, IH), 8.27 (s, IH), 8.62 (s, IH); Mass spectrum: MH Example 109 The procedure described in Example 1 was repeated using glycolic acid and 5-[(lS)-lmethyl- 2-(meoiylamino)emoxy]-N-{3-memyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}quinazoUn-4-amine to give the title compound in 46% yield; NMR spectrum (CDC13) 1.55 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.96 (s, 3H), 359 (dd, IH), 4.164.07 (m, 3H), 5.08 (m, IH), 6.92 (d, IH), 7.02 (d, IH), 7.09 (d, IH), 7.14 (d, IH), 7.50 (m, 2H), 7.65 (m, 2H), 8.28 (s, IH), 8.61 (s, IH), 9.87 (s IH); Mass spectrum: MH 488. The5-[(15)-l-methyl-2^methylamino)ethoxy]-N-{3-methyl-4-[(6-inethylpyridin-3- yl)oxyJphcnyl}quinazolin-4-amine used as starting material was prepared as follows: The procedure described in Example 103, preparation of starting materials, was repeated using (25)-l-[allyl(methyl)amino]propan-2-ol (obtained as described for the Rantipode in Example 2.3, preparation of starting materials) and 5-fluoro-.N-{3-methyl-4-[(6- methy)pyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials) to give 5-{(15)-2-[allyl(methyl)amino]-l-methy]ethoxy}-A {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazoh"n-4-amine in 92% yield as a gum; M««s spectrum: MH 470. The procedure described in Example 103, preparation of starting materials, was repeated using 5-{(lS-2-[aUvl(inethyl)arm methylpyridin-3-yl)oxy]phenyl}qiiiriazolin-4-amine to give 5-[(lS)-l-methyl-2- (inemylamino)ethoxy]-AH3~inemyl- aminein 56% viekk Mass spectrum: MET 430. Example lit The procedure described in Example 104 was repeated using 5-[(lS)-l-methyl-2- (methylamino)ethoxy]-Ar- {3-meuiyl-4-[(6-methylpyridin-3-yl)oxy]phenyl }quinazolin-4- amine (obtained as described in Example 109, preparation of starting materials) and acetic anhydride to give the title compound in 64% yield; NMR spectrum (CDC13) 1.55 (d, 3H), 2.08 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 3.08 (s, 3H), 3.56 (dd, IH), 3.93 (dd, IH), 5.09 (m, IH), 6.92 (d, IH), 7.12 (m, 3H), 7.50 (m, 2H), 7.65 (m, IH), 7.70 (s, IH), 8.27 (s, IH), 8.62 (s, IH); Mass spectrum: MH 472. Example 111 Methyl-((2S2.{[4-({3-methy]-4.[(6-methylpyridin-3- y)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)-2-pyTroIkliii-l-ylacetamlde The procedure described in Example 105 was repeated using 5-[(15l-methyl-2- o)ethoxy-{3-inetty amine (obtained as described in Example 109, preparation of starting materials) and pyrrolidrne (4 equivalents) instead of dimethylainine to give the title compound in 51% yield; NMR spectrum fCDCM 153(d,3H), 175 $aa,4H), 230 (s,3H), 235 (jni.7H), 3.13 (s,3HX 3.27 (d, 1HX 332 (d, IH), 357 (dd, IH), 352 (dd, IH), 5.11 (m, IH), 651 (d, IH), 7.12 (m, 3H), 7.46 (d, IH), 754 (d, 1HX 7.64 On, IH), 7.72 (s, IH), 8.27 (s, IH), 8.62 (s, IH); Mats AAur 541. Example 112 oxy]phenyl)quinmoh5-yl]oxy}prtpyl)butanainid The procedure described in Example 63 was repeated using 5-[(lK2-amino-lmethylethoxy]- 3-rnethyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}qumazoUnamine and (S)-a-hydroxybutyrolactone to give the title compound in 53% yield as a solid; NMR Spectrum: (CDC13) 1.55 (d, 3H), 1.79 (m, IH), 2.05 (m, IH), 2.26 (s, 3H), 2.49 (s, 3H), 3.90- 3.65 (m, 4H), 4.21 (dd, IH), 4.94 (m, IH), 6.96 (m, 2H), 7.11 (d, IH), 7.23 (dd, IH), 7.39 (d, IH), 7.43 (m, IH), 7.60-752 (m, 2H), 7.69 (s, IH), 8.00 (s, IH), 8.55 (s, IH); Mass spectrum: MET 518. The 5-l(l/?)-2-anMno-l-methylethoxy]-AH 3-methyl-4-[(6-methylpyridin-3- ylX)xy]phenyIJquinazolin-4-amine used as starting material was prepared as follows: The procedure described in Example 103 (preparation of starting materials) was repeated using 5-fluoro-7Vr-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl }quinazolin-4- amine (obtained as described in Example 103, preparation of starting materials) and (2R)-laminopropan- 2-ol to give 5-[(lJ?)-2-amino-l-methylethoxy]-A/r-{3-niethyl-4-[(6- methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 77% yield; Mass spectrum: MH416 Example 113 (2SBronx)-2-hydroxy-/V-((2R)-2-{[4-({3-methyl-4-[(6-raethylpyridin-3- yl)oxy]phenyl}amino)quiiia3»lin-5-yI]oxy}propyl)b«tanamide solution of (2S):2y4-dihvdroxv(2)-2-{ yl)oxy]phenyl}aniino)quinazolin-5-yl]oxy }piopyl)butanainib (856 mg. 1.65 mmol, obtained as described in Example 1 12) and carbon tetrabronride (658 mg, 2 mmol) in DCM (10 ml). The mixture was stirred overnight at room temperature. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2% to 5% 7N ammoniamethanol in DCM) to give the title compound (712 mg, 74%) as a solid; NMR Spectrum: (CDC13) 1.53 (d, 3H), 2.07 (m, 1H), 2.28 (s, 3H), 2.38 (m, 1H), 2.52 (s, 3H), 3.51 (t, 2H), 3.80-3.65 (m, 2H), 4.34 (dd, 1H), 4.95 (m, 1H), 6.90 (m, 2H), 7.09 (d, 1H), 7.14 (dd, 1H), 7.28 (m, 1H), 7.50 (m, 3H), 7.63 (s, 1H), 8.23 (s, 1H), 8.44 (s, 1H); Mass spectrum: MlT 580, 582. Example 114 -(2-Chlorothyl)-A""-((2R2-{[4-{3-inethyl-4-[(6-methylpyridin-3- yl)oxy]pheny1}aniinoqui]MaoIin-5-yI]oxy}propyI)urea Cbloroethylisocyanate (116 ul, 1.36 mmol) was added drop wise to an ice-cooled solution of 5-[(lR2-arnino-l-niemyleuK)xy]-W-{3-melhyl-[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine (516 mg, 1.24 mmol, obtained as described in Example 112, pieparation of starting materials) in DCM (10 ml). The mixture was stirred at 0°C for 30 minutes and at room temperature for 1 hour. After evaporation of die solvents, the residue was purified by cfaromatography on stfica gel (ehianf 3% to 5% 7N ammonia-memanol in DCM) to give me tide compound (S84 mg. 74%fc NMR Spectrum: (CDCfe) 3H), 232 (s, 3HX 3.46 (m, IHX 3.57 (m, 4H), 4.00 (m, 1H), 4.76 (m, IHX 640 (m, IHX 6.62 (m, IHX 6.67 (d, 1H), 6.91 (d, IHX 7.08 (d, 1H), 7.12 (dd, 1H), 7.18 (d, 1H), 734 (t, 1H), 7.53 (dd, IH), 7.67 (, 1H), 8.27 (, 1H), 834 (, 1H), 9.82 (s, 1H); Mass spectrum: MET 521. Example 115 2-Hydroxy-N-iMthyl-N(l)- y)oxy]phenyl}amino)quinaa»Bn-5-yroxy}ethyI)acetanilde Acetoxyacetyl chloride (70 ul, 0.64 mmol) was added drop wise to an ice-cooled solution of 5-{ [(2/2)-2inethylarruno)prc^yl]oxy}-N-{3-memyl[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine (250 mg, 0.58 mmol), triethylamine (97 ul, 0.70 mmol) in DCM (7 ml). The mixture was wanned to room temperature and stirred for 2 hours. After evaporation of die solvents under vacuum, the residue was diluted with pyrrolidine (0.50 ml, 6 mmol) and the mixture was stirred at 65°C for 2 hours. After evaporation of the mixture to dryness, the residue was injected on an HPLC column (CIS, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water (containing 5% raethanol and 1% acetic acid) and acetonitrile (gradient). After evaporation of the solvents, the solid was diluted in DCM The solution was washed with aqueous sodium bicarbonate and dried over magnesium sulfate to give the title compound (140 mg, 49%); NMR Spectrum: (CDCI3) 1.34 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.79 (s, 3H), 3.12 (m, 1H), 3.95 (dd, 1H), 4.09 (dd, 1H), 4.30-4.15 (m, 2H), 5.40 (m, 1H), 6.91 (m, 2H), 7.09 (d, 1H), 7.17 (dd, 1H), 7.38 (m, 1H), 7.46 (s, 1H), 7.50 (d, 1H), 7.64 (t, 1H), 8.30 (d, 1H), 8.58 (s, 1H), 9.36 (s, 1H); Mass spectrum: MH488. The5-{[(2/0-2-(methylainino)propyl]oxy}-7l/-{3--rnethyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-aminc used as starting material was prepared as follows: The procedure described in Example 103, preparation of starting materials, was repeated using 5-fluoro-{3-memyl-4-[(6-methyl amine (obtained as described in Example 103, preparation of starting materials) and (2/0-2- (methylammo)propan-l-ol (obtained as described in Becker et aL, J. Chem. Soc. 1957,858) to give 5-{[(2/0-2KmcylanriiK yl)oxy]pheny] }qtraazohn-4-amme in 75% yield; NMR Spectrum: (CDQ3) 1.30 (d, 3H), 2.28 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.20 (m, 1H), 4.09 (m, 1H), 4.21 (m, 1H), 6.89 (m, 2H). 7.14-7.07 (m, 2H), 7.45 (d, 1H), 7.63 (m, 2H), 8.26 (s, 1H), 8.63 (s, 1BD, 103 (bs, 1H); Mass spectrum: MET 430. Example N-Methyl-Ar.((y) 2-{[4-({3-methyl-4-[(6-methylPyridin-3- yl)oxy]phenyl}arohio)quina2olin-5-yl]oxy}ethyl)acetamide Acetic anhydride (66 pj, 0.7O mmol) was added drop wise to a solution of 5-{[(2R)-2- (methylarnino)propyl]oxy}-A-{3-memyM-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4- amine (250 mg, 0.58 mmol, obtained as described in Example 115, preparation of starting materials) and potassium carbonate (161 mg, 1.16 mmol) in acetone (10 ml). The mixture was stirred at room temperature for 2 hours. After evaporation of the solvents, the residue was diluted in DCM The solution was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 5% 7N ammonia-methanol in DCM) to give the title compound (230 mg, 84%); NMR Spectrum: (CDC13) 1.28 (d, 3H), 1.94 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.90 (s, 3H), 4.30-4.10 (m, 2H), 5.38 (m, IH), 6.92 (m, 2H), 7.08 (d, IH), 7.14 (dd, IH), 7.48 (d, 2H), 7.53 (s, IH), 7.64 (t, IH), 8.27 (d, IH), 8.60 (s, IH), 9.51 (s, IH); Mass spectrum: MH 472. Example 117 2-Hydroxy-N-roethyl-AfK(lS)-l-methyl-2^[4-({3-methyl^[(6-methyIpyridin-3- fl)oxy]pbenyl}aniino)quiDazolm-5-yl}oxy}ethvl)acetaniide Hie procedure described in Example 115 was repeated using 5-{[(252- amine to give the title compound in 72% yield; FMft TO-" (CDC13) 1.34 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.79 (s, 3H), 3.12 (m, IH), 3.95 (dd, IH), 4.09 (dd, IH), 4.30-4.15 (m, 2H), 5.40 (m, IH), 6.91 (m, 2H), 7.09 (d, IH), 7.17 (dd, IH), 7.38 (m, IH), 7.46 (s, IH), 7.50 (d, IH), 7.64 (t, IH), 8.30 (d, IH), 8.58 (s, IH), 9.36 (s, IH); Mass spectrum: MH 488. The 5-{[(2S)-2-(memylanaiio)pK yl)oxy]phenyl}quinazolin-4-anrine used as starting material was prepared as follows: The procedure described in Example 103, preparation of starting materials, was repeated using 5-fluoro-AT-{3-niemyl[(6-niemylpyridn-3-yl)oxy]phenyl}quma2Un amine (obtained as described in Example 103, preparation of starting materials) and (2S)-2- (mcthylamino)propan-l-ol (obtained as described in Chacchio et al., Tetrahedron, 1995, 51, 5689) to give 5-{[(22-(metihylaimno)propyl]oxy}-{3-methyW-K6-memylpyridin-3- yl)oxy]phenyl}quinazolin-4-armne in 71% yield; NMR Spectrum: (CDC13) 1.30 (d, 3H), 2.28 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.20 (m, IH), 4.09 (m, IH), 4.21 (m, IH), 6.89 (m, 2H), 7.14-7.07 (m, 2H), 7.45 (d, IH), 7.63 (m, 2H), 8.26 (s, IH), 8.63 (s, IH); Mass spectrum: MH+430. Example 118 N-Methyl-N-((15l-methyl-2-{[4-({3-nM}thyI-4-[(6-methyIpyridin-3- yl)oxy]phenyl}amino)quina2olin-5-yI]oxy}ethyl)acetamide The procedure described in Example 116 was repeated using 5-{ [(252- (methylamino)propyl]oxy}-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}qiima amine (obtained as described in Example 117, preparation of starting materials) and acetic anhydride to give the title compound in 88% yield; NMR Spectrum: (CDC13) 1.28 (d, 3H), 1.94 (s, 3H), 2.30 (s, 3HX 253 (s, 3H), 2.90 (s, 3H), 430-4.10 (m, 2H), 538 (m, 1H), 6.92 (m, 2H), 7.08 (d, lH)t 7.14 (dd, 1HX 7.48 (d, 2H), 753 (s, 1H), 7.64 (t, 1H), 8.27 (41H), 8.60 (s, 1H), 9.51 (s, 1H); Mass spectrum: MET 472. Example 119 Methyl {2-[(4[3-cWoroHpyridto.2-ylMedioxy)phenyl)amii}qurn yl)oxy]ethyl}methykarlMunate N-[3-chloro-4-(pyridin-2-ylrnethoxy)phcnyl]-5-[2-(meliiylanuno)emoxy]quinazoUn amine (obtained as described in Example 1, preparation of starting materials, 217 mg) and DIPEA (0.2 ml) were stirred in DCM (20 ml). Methyl chloroformate (0.043 ml) was added slowly and the resulting solution was stirred for 18 hours. The solution was evaporated and the residue purified by chromatography, eluting with increasing concentrations of methanol in ethyl acetate (5-10%). The appropriate fractions were evaporated to give an oil, which was triturated with acetonitrile to give the title compound as a solid (43 mg, 17%); NMR spectrum (DMSO-d6 @ 373K) 2.88 (s, 3H), 3.30 (s, 3H), 3.75-3.85 (t, 2H), 4.35-4.55 (bs, 2H), 5.30 (s, 2H), 7.10-7.30 (m, 2H), 7.30-7.40 (m, 2H), 7.50-7.60 (m, 2H), 7.70-7.78 (t, 1H), 7.80-7.95 (m, 2H), 8.43 (bs, 1H), 8.75-8.80 (d, 1H), 9.60-9.80 (bs, 1H); Mass spectrum MBT 494.0. Example 120 N42-[(4-{[3-CWoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolui-5-yI)oxylethyl}- AgV-dimethylurea Methyl isocyanate (0.035 ml) was added slowly to a stirred solution of AT-[3-chloro-4- (pyridii-2-yliriethoxy)phenyl]-5-[2-(meth (obtained as described in Example 1, preparation of starting material, 217 mg) in PCM (10 ml). The resulting solution was stored for 2 hours and then evapootod The res&ue was triturated with acetomtnfe and the resulting solid WM washed with ether to give the title compound as a solid (205 mg. 83% ); NMR spectrum fDMSCMtt & 373K) 2.85 (s, 3H), 2.95 (s, 3H), 3.75-3.85 (t, 2H), 43S4.45 (t, 2H), 55 (s, 2H), 550-6.00 (bs, 1H), 7.10-7.15 (d, 1H), 7.15-7.25 (d, 1H), 7.30-7.37 (t, 2H), 7J2-7.60 (m, 2H), 7.65-7.73 (t, 1H), 7.80-7.86 (m, 1H), 7.94- 759 (d, 1H), 8.44 (s, Ifl), 8.55-8.60 (d, IH), 9.80 (s, 1H); Mass spectmm 1493.4. Example 121 N"-(2-Chloroethyl{2-[(4-{[3-chIoro-4-(pyridin-2- ylmethoxy)phenyl]amino}quina2olin-5-yl)oxy]ethyl}-A-methylurea The procedure described in Example 120 was repeated using 2-chloroethyl isocyanate amine (obtained as described in Example 1, preparation of starting materials) to give the tide compound as a solid in 80% yield; NMR spectrum fDMSO-d6 @ 373K) 2.90 (s, 3H), 3.15- 3.25 (q, 2H), 3.43-3.50 (t, 2H), 3.75-3.85 (t, 2H)T 4.35-4,45 (t, 2H), 5.25,6.35 (bs, IH), 7.08- 7.13 (d,lH), 7.13- 730 (ra, IH), 7.35-7.40 (m, 2H), 7.5O-7.65 (m, 2H), 7.65-7.80 (m, IH), 7.80-7.90 (t, IH), 7.95 (d, IH), 8.50 (s, IH), 8.55-8.60 (d, IH), 9.80 (s, IH); Mass spectrum MH 541.3. Example 122 A-{(2)-2-[(4-{[3-Chlon)-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- ylxyJpropyl-methylurea The procedure described in Example 120 was repeated using methyl isocyanate and 5- [(lXV2-aimno-l-methyled)oxy; anrine (obtained as described in Bcample 65, preparation of starting materials) to give the title compound as a solid hi 43% yield; NMR spectrum (DMSO-d6 @ 373K) 1.40-1.45 (d, 3H), 2.50-2.55 (d, 3H), 3.38-3.48 (m, IH), 330-3.60 (m, IH), 4.83-4.92 (m, IH), 5.28 (s, 2H), 5.55-5.65 (bs, IH), 6.00-6.10 (bs, IH), 7.19-7.24 (dd, 2H), 7.31-737 (m, 2H), 7.56-7.62 (m, 2H), 7.66-7.73 (t, IH), 7.81-7.88 (dt, IH), 8.06-8.08 (d, IH), 8.48 (s, IH), 8.55-8.60 (d, IH), 9.95-10.05 (bs, IH); Mass spectrum MH 493.4. Example 123 2-{4-[3-Chloro-4-(pyridfai-2-ylmethoxy)pnylano]quina2»lin-5- yloxy}propylcarbamoyl)methyl]methylcarbamk acid terj-butyl ester 5-[( -2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2- ylmethoxy^)henyl]quinazo]in-4-amine (obtained as described in Example 65, preparation of slatting materials, 868 mg) was stirred in DCM (40 ml) with DIPEA (1 ml). JV-(tertbutoxycarbonyl) sarcosine (400 mg) and HATU (800 mg) were added and mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue was purified by chromatography, eluting with increasing concentrations of methanol in ethyl acetate (0-10%). Evaporation of the appropriate fractions gave the tide compound as a froth (0.50 g); NMR S2ecttunL(DMSO-d6 @ 373k) 1.10 (s,6H), 1.20 (s, 3H), 1.40-1.42 (d, 3), 2.72 (s, 3H), 3.40- 3.60 (d, IH, (masked by H2O), 3.60-3.75 (q, 2H), 3.75-3.8O (d, IH), 4.90-5.00 (bs, IH), 5.30 (s, 2H), 7.28-7.34 (q, 2H), 734-7.40 (m, IH), 7.42-7.46 (d, IH), 7.50-7.62 (m, 2H), 7.85-7.91 (dt, IH), 7.91-7.99 (m, 2H), 8.24-8.34 (bs, IH), 8.57-8.62 (d, IH), 8.75 (s, IH), 10.60-10.70 (bs, IH); Mass spectrum MH607. Example 124 yloxy}propylcarbanioyl)niethyl]niemylc»rbamic acid fat-butyl ester (obtained as described in Example 123,0.50 g) was stirred in trifluoroacetic acid (5 ml) for 20 hours. Volatile material was removed by evaporation and the residue was purified by chromatography, eluting with aqueous ammonia (0.880), methanol, DCM (1:10:90). Evaporation of the appropriate fractions gave the title compound as a solid (60 mg, 15%); (DMSO~d6 @ 373k) 1.47-1.50 (d, 3H), 2.20 (s, 3H), 3.10 (s, 2H), 3.45-3.55 (q, IH), 3.55-3.65 (q, IH), 4.85-5.00 (m, IH), 5.25 (s, 2H),"7.15-7.25 (q, 2H), 7.25-7.30 (m, 2H), 7.55-7.65(t, IH), 7.70-7.80 (m, 2H), 8.20 (s, IH), 8.50 (s, IH), 8.55-8.60 (d, IH), 9.85-9.95 (bs, Iffi: Mass spectrum MH 507. Example 125 2-Hydroxy-N-methyl-2-{[4-{3-meihyl-4-[(6-methylpyridin-3- yi)oxy]pbenyl}amino)quinazolin-5-yl]oxy}ethy])acetamide 5-[2-(MethylamiiK))ethoxy]-]V-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine (32 mg, 0.077 mmol) and glycolic acid (6 mg, 0.085 mmol) were dissolved in DMA (10 ml). HATU (32 mg, 0.085 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated in vacua, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in HO containing 0.2% TFA. The appropriate fraction was evaporated, and the residue dissolved m methanoVDCM (1:1,25 ml). The mixture was neutralised by stirring overnight wimtetnKilkylaninxmii)mcarbone,polyiner bound The mixture was filtered, and die filtrate was evaporated. Crystallisation from ethyl acetate/iso-hexane gave 2-hydroxy-tfinethyl- AH2-{[4K{3-memyl-(6 yl]oxy}ethyl)acetamide as a white crystalline solid (22 mg, 60%); NMR Spectrum (DMSOd6,400 MHz, 373K) 2.26 (s, 3H), 2.48 (s, 3H), 3.02 (s, 3H), 3.95 (t, 2H), 4.02-4.11 (m-3H), 4.55 (t, 2H), 6.96 (d, 1H), 7.20 (d, 1H), 7.23 (m, 2H), 7.38 (d, 1H), 7.65 (dd, 1H), 7.70 (d, 1H), 7.73 (dd, 1H), 8.20 (m, 1H), 8.49 (s, 1H), 9.77 (s, 1H); Mass spectrum MH 473.9 The5-[2memylamino)emoxy]-{3-methyl-[(6-rnemylpyridin-3- yl)oxy]phenyl}quinazolin-4-amine used as starting material was prepared as follows: Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.69 mmol) was suspended in DMA (10 ml) and N-methylethanolamine (56 pi, 0.69 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 20 minutes at ambient temperature, and 5-fluoro-N- {3-methyl-4-[(6-mcthylpyridin-3-yl)oxy]phenyl}quinazolm-4-amine (obtained as described in Example 103, preparation of starting materials, 100 mg, 0.28 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 110°C for 1 hour, then at 125°C for 14 hours. The mixture was cooled to ambient temperature, and acidified with TFA. The mixture was concentrated in vacua, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in HaO. The appropriate fractions were evaporated to a volume such that all of the acetonitrile had been removed. The resulting aqueous solution was basified with concentrated aqueous ammonia, and extracted with DCM (4 x 20 ml). The combined extracts were filtered through a silicone-treated filter paper, and concentrated in -vacua to give 5-[2- (memylarnino)ethoxy]-JV- {3-methyl-4-[(6-methylpyridin-3-yl)oxy]pheriyl }quinazolin-4- amine as a yellow solid (40 rag, 34%); NMR Spectrum (CDC13,400 MHz) 2.20 (s, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.12 (t, 2H), 4.25 (t, 2H), 6.80 (d, 1H), 6.83 (d, 1H), 7.00 (d, 1H), 7.04 (dd, 1H), 7.39 (d, IH), 7.55 (dd, IH), 7.61 (dd, 1H), 7.68 (d, 1H), 8.19 (d, 1H), 8.56 (s, IH), 10.26 (s, IH); Mass spectrum MH 416.0 Example 126 Methyl-tf-(2[4K{3-methy yl]oxy}ethyl)acetaink)e (38 mg, 0.136 mmol) and 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (obtained as described in Example 103, preparation of staring materials, 32 mg, 0.150 mmol) were dissolved in wo-propanol, and the mixture heated to reflux for 1 hour. The mixture was concentrated in vacua, and the residue purified by cinematography, during with 0 to 5.5% (10:1 methanol cone. NH3 (»q)) in ethyl acetate. Evaporation of the appropriate fractions gave AMnethyWv~-(2-{ [4-({3-methyl-4-[(6- mernylpyridm-3-yl)oxy]phenyl}aim^)quina^ as a dry film (24 mg, 39%); NMR Spectrum (DMSO-d6.400 MHz), 373K 1.96 (s, 3H), 2.24 (s, 3H), 2.46 (s, 3H), 2.94 (s, 3H), 3.90 (t, 2H), 4.50 (t, 3H), 6.94 (d, 1H), 7.18 (d, 1H), 7.21 (m, 2H), 7.36 (d,lH), 7.63 (dd, 1H), 7.68 (d, 1H), 7.71 (dd, 1H), 8.17 (dd, 1H), 8.47 (s, 1H), 9.76 (s, 1H); Mass spectrum MH1" 458.4. The JV-{2-[(4^hloroqmnazoUn-5-yl)oxy]emyl}-N-memylacetairiide used as starting material was prepared as follows: Sodium hydride (60% dispersion in mineral oil, 732 mg, 18.3 rnrnol) was suspended in DMA (50 ml) and N-methylethanolamine (734 jil, 9.15 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature, and 5-fluoroquinazolin-4(3None (1.0 g, 6.10 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 8S°C for 90 minutes. The mixture was cooled to ambient temperature, and the resulting slurry poured into methanol (100 ml). Dowex resin (50WX4- 400,25g) was added, and the mixture stirred for 1 hour at ambient temperature. The resin was collected by filtration, and washed with methanol (100 ml). The resin was suspended in a solution of ammonia in methanol (2.3 N, 150 ml), and the mixture stirred for 30 minutes. The mixture was filtered and the residue was washed with ammonia in methanol (2.3 N, 100 ml). The combined filtrates were concentrated in vacuo, and dried in vacua (1 mbar, 60°C) for 16 hours to give 5-[2methylamino)ethoxy]quinazohrn-4(3Jy)-one as an off white solid (1.09 g, 82%); NMR Spectrum fDMSO-d6.400 MHz) 2.36 (s, 3H), 2.85 (t, 2H), 5.11 (t, 2H), 6.97 (d, 1H), 7.14 (d, 1H), 7.61 (dd, 1H), 7.97 (s, 1H); Mass spectrum MH+ 220. 5-[2-(Mcthylammo)etrioxy]quinazolin-43/f)-one (823 mg, 3.76 mmol) was dissolved in pyridine (25 ml), and the solution cooled to 0°C. Acetic anhydride (1.20 ml, 12.70 mmol) was added drop wise; the solution was wanned to ambient temperature aixl stirred for 90 minutes. The mixture was concentrated mvociw, and the resadne purified by cnromatography, eluting with 4% to 7% (10:1 methanol / cone. NH3 in DCM. Evaporation of the appropriate fractions gave ATHaaemyl-N-{2-[(4xo-3,4-dihydxoqumazouii- 5-yl)oxy]ethyl Jacetamide as a white foam (970 mg, 99%); NMR Spectrum (DMSO-d6.400 MHz, 373K) 2.05 (bs, 3H), 2.92 (s, 3H), 3.71 (bt, 2H), 4.20 (bt, 2H), 7.01 (d, 1H), 7.19 (d, 1H), 7.63 (dd, 1H), 7.89 (s, 1H); Mass spectrum M+NH/ 284.0 (ES-) M-H+ 260.0. N-Memyl-{2-[(4xc-3,4Hlihydroquinazoh"n-5-yl)oxyethyl Jacetamide (261 mg, 1.00 mmol) and diwo-propylethylamine (522 (il, 3.00 mmol) were dissolved in DCM (25 ml), and the mixture cooled to 0°C. Phosphorus oxychloride (930 ill, 10 mmol) was added drop wise; the solution was wanned to ambient temperature and stirred for 2 hours. The mixture was cooled to 0°C, and saturated sodium hydrogen carbonate solution (30 ml) was added with vigorous stirring. The stirred mixture was allowed to warm to ambient temperature over 20 minutes. The DCM layer was separated, washed with saturated sodium hydrogen carbonate solution (30 ml), water (30 ml) and brine (30 ml), filtered through a silicone-treated filter paper, and evaporated to give N-{2-[(4hloroquinazoh"n-5-yl)oxy]ethyl}-JV;-methylacetamide as an orange solid (90 mg, 32%); NMR Spectrum (DMSO-d6.400MHz, CDC13) 2.05 (s, 3H), 3.17 (s, 3H), 3.85 (t, 2H), 4.28 (t, 2H), 6.99 (d, 1H), 7.58 (d, 1H), 7.76 (dd, 1H), 8.87 (s, 1H); Mass spectrum 276.4 MR (4-OMe derivative - product quenched with MeOH in instrument). Example 127 {2-[(4-{[3-Chloro(l-methyl-lyrWtiv2-yIethoxy)phenyllamiDo quinazoUn-5- yi)oxy]ethy]}-tf-inethylacetainide The procedure described in Example 126 was repeated using /Sf-{2-[(4- chlwtxjuinazolin-5-ylxy)ethyl}-VHnaethylacetamide (obtained as described in Example 126, preparation of starting materials, 47 nag, 0.170 mmol) and 3-chloro-4-(l-methyl-l-pyridin-2- ylethoxy)aniline (49 mg, 0.187 mmol) to give the title compound in 31% yield; NMR Spectrum (DMSCXd6.400 MHz, 373K) 1,75 (s, 6H), 1.92 (s, 3HX194 (s, 3H), 3.88 (t, 2H), 4.47 (t, 2H), 6.62 (d. 1H), 7.16 (d, IB), 731 (ddd, 1H), 735 (d, 1H), 739 (dd, 1H), 7.70 (dd, 1H), 7.75 (dd, 1H), 7.83 (ddd, 1HX 759 (d, 1H), 8.46 (s, 1H), 858 (dd, 1HX 9.70 (s, 1H); Mass spectrum MH 506.0. The 3-Aloro-41-niethyl-lyridin-2-yletboxy)anilroe used as starting material was prepared as follows: Sodium hydride (60% dispersion in mineral oil, 220 mg, 5.50 mmol) was suspended in DMA (30 ml) and 2-pyridin-2-ylpropan-2-ol (obtained as described in Organometallics, 1997, 16,3303,754 mg, 5.50 mmol) was added under an atmosphere of nitrogen. The mix.ture was stirred for 30 minutes at ambient temperature, then cooled to 0°C. 3-Chloro-4- fluoronitrobenzene (878 mg, 5.00 mmol) was added as a solution in DMA (15 ml); the mixture was wanned to room temperature, and was stirred for 2 hours. The mixture -was concentrated in vacuo, and the residue partitioned between ethyl acetate (75 ml) and -water (75 ml). The aqueous layer was extracted with ethyl acetate (75 ml), and the extractions combined with the organic layer. The combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography, eluting with 0 to 20% ethyl acetate in wo-hexane, giving 2-[l2hloro-4-nitrophenoxy)-l-methylethyl]pyridine as a pale yellow solid (810 mg, 55%); NMR Spectrum (DMSQ-d6.400 MHz, CDCb) 1.91 (s, 6H), 6.40 (d, 1H), 7.25 (ddd, 1H), 7.50 (d, 1H), 7.70 (ddd, 1H), 7.82 (dd, 1H), 8.30 (d, 1H), 8.65 (d, 1H); Mass spectrum MH 293.0.295.0. 2-[l-(2-Chloro-4-nitrophenoxy)-l methylethyljpyridine (800 rag, 2.74 mmol) was dissolved in ethyl acetate (50 ml). The mixture was purged with nitrogen, and platinum on activated carbon (10%, 100 mg) was added. The mixture was hydrogenated for 6 hours using a burette filled with hydrogen. The system was degassed and purged with nitrogen, and the catalyst removed by filtration. The filtrate was concentrated in vacua, and the residue purified by chromatography, eluting with 20% to 30% ethyl acetate in iso-hexane. The appropriate fractions were evaporated to give 3-chloro-4-(l-methyl-l-pyridin-2- ylethoxy)aniline as a straw-coloured oil (452 mg, 63%); NMR Spectrum (DMSO-d6, 400 MHz, CDC13) 1.63 (s, 6H), 3.41 (bs, 2H), 6.25 (dd, 1H), 6.35 (d, 1H), 6.65 (d, 1H), 7.11 (ddd, 1H), 7.63 (ddd, 1H), 7.77 (d, 1H), 8.50 (d, 1H). Example 128 Pharmaceutical compositions , The following illustrates representative frtiannaceirticaldcwagefoansof tbeinveatioa as defined tetem (fee arive ingredient be for therapeutic or prophylactic use in humans: (a) Tablet I nag/tablet Compound X. 100 Lactose Ph.Eur. „ 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b) Injection I (50 mg/ml) Compound X 5.0% w/v 1M Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100%. The above compositions may be prepared by conventional procedures well known in the pharmaceutical art. For example, Tablet I may be prepared by blending the components together and compressing the mixture into a tablet. CLAIMS 1. A quinazoline derivative of the formula I (Formula Removed) wherein: m isO; R1 is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(l-6C)alkoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (1 -6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy, R2 is hydrogen or (l-4C)alkyl; n is 1; R3 is selected from halogeno and (l-4C)aIkyl; X1 is selected from O, S, SO, SO2, N(R7), OC(R7)2, SC(R7)2, CO and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl; Q1 is aryl, or a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1, 2 or 3 heteroaioms independently selected from oxygen, nitrogen and sulfur, and wherein Ql optionally bears one or more substituents, which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (1 -6C)alkyI, (2-8C)alkenyl, (2-8C)alkynyl, (I-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, [2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)aIkynoyI, (2-6C)alkanoyloxy, 2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)aIkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylauuno,(3-6C)aIkynoylamino,N-(l-6C)alkyl-(3-6C)alkynoylamino N-(l-6C)aIkylsulfamoyl,N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonyIamino N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, and a group of the formula: (Formula Removed) wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N- (l-6C)alkylamino-(l-6C)alkyl, N,N-di-[( 1-6C)alkyl]amino-( 1-6C)alkyl, (2-6C)alkanoyIamino-(l-6C)alkyl, N-( 1 -6C)alkyl-(2-6C)alkanoylamino-( 1 -6C)alky 1, (1 -6C)alkoxycarbonylamino-( 1 -6C)alkyl, carbamoyl-( 1 -6C)alkyl, N-( 1 -6C)alkylcarbamoyl-(l -6C)aikyl, N,N-di-[( 1 -6C)alkyl]carbamoyl-( 1 -6C)alkyl, (1 -6C)alkylthio-( 1 -6C)alky 1, (1 -6C)alkylsulfinyl-( 1 -6C)alkyl, (1 -6C)alkylsulfonyl-( 1 -6C)alkyl sulfamoyl(l-6C)alkyl, N-(l-6C)alkylsulfamoyl(l-6C)alkyl, N3N-di-(l-6C)alkylsulfamoyl(l-6C)alkyl,(2-6C)alkanoyl-(l-6C)alkyl,(2-6C)alkanoyloxy-(l-6C)aIkyl or (l-6C)alkoxycarbonyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within -X1-Q1 optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyI substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)aIkylamino and di-[(l-4C)alkylamino]; R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, and wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino]; R6 is selected from hydrogen, (l-3C)alkyl, (2-3C)aIkenyl, (2-3C)alkynyl, (3-5C)cycloalkyl, (3-5C)cycloalkyl-(l-3C)alkyI, heterocyclyl and heterocyclyl-(l-3C)alkyl, wherein any heterocyclyl group within R6 is a 4, 5, 6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclyl group is linked to the group to which it is attached by a ring carbon atom, and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyI, (l-6C)aIkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: (Formula Removed) wherein X3 is a direct bond or is selected from O and N(R11), wherein Ru is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents; and wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; A is selected from a group of the formula Z-(CRI2R13)P- and R14, wherein p is 1, 2 or 3, each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl, and wherein any CH2 or CH3 group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy, Z is selected from hydrogen, OR15, NR,6R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen and (l-6C)alkyI, RM is selected from OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl and wherein R16and R17 are as defined above, or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl or heterocyclyl, and wherein any heterocyclyl group within a Z or R substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy, (l-6C)alkyl and (l-6C)alkoxy, and wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; or a pharmaceutically acceptable salt thereof. 2. A quinazoline derivative as claimed in claim 1, wherein R2 is hydrogen. 3. A quinazoline derivative as claimed in any one of the preceding claims, wherein n is 1 and R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I. 4. A quinazoline derivative as claimed in any one of the preceding claims, wherein R3 is chloro. 5. A quinazoline derivative as claimed in any one of claims 1 to 3, wherein R3 is methyl. 6. A quinazoline derivative as claimed in any one of the preceding claims, wherein X1 is selected from O, S and OC(R7)2 wherein each R7 is, independently, hydrogen or (l-4C)alkyl. 7. A quinazoline derivative as claimed in any one of the preceding claims, wherein X1 is OCH2. 8. A quinazoline derivative as claimed in any one of the preceding claims, wherein Q1 is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl, IH-imidazolyl, lH-pyrazolyl, 1,3-oxazolyl and isoxazolyl. 9. A quinazoline derivative as claimed in anyone of the preceding claims, wherein R6 is (l-3C)alkyl, and wherein anyCH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino. 10. A quinazoline compound as claimed in claim 1 is selected from one or more of the following: N-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2- methoxy-N-methylacetamide; N-{2-[(4-{3-chloro-4-(pyridm-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2- (dimethylamino)-N-methylacetamide; N-{(2R)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5- yl)oxy]propyl}-2-methoxy-N-methylacetamide); 2-hydroxy-N-methyl-N-{2-[(4-{3-methyl-4-(pyrazin-2-ylmethoxy)anilino}quinazolin- 5-yl)oxy]ethyl}acetamide; 2-hydroxy-N-methyI-N-{2-[(4-{3-methyl-4-(l,3-thiazol-4- ylmethoxy)anilino} quinazolin-5-yl)oxy]ethyl }acetamide; 2-hydroxy-N-methyl-N-2-{[4-(3-methyl-4-[(5-methylisoxazol-3- yl)methoxy]anilino)quinazolin-5-yl]oxy}ethyl)acetamide; N- {(2R)-2-[(4- {3 -chloro-4-(pyridin-2-ylmethoxy)anilino} quinazolin-5- yl)oxy]propyl} -2-methoxyacetamide; N-(2-{[4-(3-chloro-4-[(6-methylpyridin-2-yl)methoxy]anilino)quinazolin-5- yl]oxy}emyl)-2-hydroxy-N-methylacetamide; N-((2R)-2- {[4-(3 -chloro-4-[(6-methylpyridin-2-yl)methoxy]anilino)quinazolin-5- yl]oxy}propyl)-2-hydroxy-Ar-methylacetamide; N-2-{t4-(3-chloro-4-[(6-methyIpyridin-2-yl)methoxy]anilino)quinazolin-5- yl]oxy}ethyl)-Ar-rnethylacetamide; N-(2-{[4-(3-chIoro-4-[(2-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}ethyl)-N- methylacetamide; N-(2-{[4-(3-chloro-4-[(3-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}ethyl)-N- methylacetamide; N- {2-[(4- {3-chloro-4-( 1,3 -thiazol-4-ylmethoxy)anilino} quinazolin-5 -yl)oxy] ethyl} - N-methylacetamide; N- {2-[(4- {3-chloro-4-(pyrazin-2-ylmethoxy)anilino} quinazolin-5-yl)oxy]ethyl} -N- methylacetamide; N-{(2R)-2-[(4-{3-chIoro-4-(pyridin-2-'ylmethoxy)anilino}quinazolin-5- yl)oxy]propyl} -2-hydroxyacetamide; N-{2-[(4- {3-chloro-4-(pyridin-2-ylmethoxy)anilino} qumazolin-5-yl)oxy]ethyl} -N- methylacetamide; 2-hydroxy-N-rnethyl-N- {2-[(4-{ 3-methyl-4-(pyridin-2-ylmethoxy)anilino} quinazolin- 5-yl)oxy]ethyl}acetamide; N-{(lR)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l- methy lethy 1} acetamide; N-{(lR)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l- methylethyl} -2-hydroxyacetamide; N-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-N-methylacetamide; N-(2-{[4-(3-criloro-4-[(3-fluorobenzyl)oxy]aniIino)quinazolin-5-yl]oxy}ethyl)-2- hydroxy-iV-methylacetamide; N-{2-[(4-{3-chloro-4-(l,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-N-methylacetamide; N-{2-[(4-{3-chloro-4-(pyrazin-2-yImethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2- hydroxy-N-methylacetamide; N-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)antlino}quinazolin-5- yI)oxy]ethyl} acetamide; N- {(2R)-2-[(4- {3 -chloro-4-(pyridin-2-ylmethoxy)anilino} quinazolin-5- yl)oxy]propyl} acetamide; N-{(2R)-2-[(4-{3-chloro-4-(pyridin-2-yImethoxy)anilino}quinazolin-5- yl)oxy]propyl} -2-hydroxy-N-methylacetamide; N- {(2R)-2- [(4- {3 -chloro-4-(pyrazin-2-ylmethoxy)anilino} quinazolin-5- yl)oxy]propyl} -2-hydroxy-N-methylacetamide; N-((2R)-2-{ [4-(3 -chloro-4-[(3-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy} propyl)- 2-hydroxy-iV-methylacetamide; N-{(2R)-2-[(4- {3 -chIoro-4-( 1,3-thiazol-4-ylmethoxy)anilino} quinazolin-5- yl)oxy]propyl} -2-hydroxy-JV-methylacetamide; N-{(2R)-2-[(4-{3-chloro-4-(pyridiii-2-ylmethoxy)anilino}quinazolin-5- yI)oxy]propyl} -N-methylacetamide; N- {2-[(4- {[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino} quinazolin-5- yl)oxy]ethyl} -N-ethylacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-lyl)oxy]ethyl}-N-ethyl-2-hydroxyacetamide; N-{2-[(4-{[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIin-5-yl)oxy]ethyll}-N-propylacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} -2-hydroxy-N-propylacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] ethyl} -N-isopropylacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-N-isopropylacetamide; N-allyl-N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetamide; N-aIlyl-N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quiiiazolin-5-yI)oxy]ethyI} -2-hydroxyacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-.N-cyclopropylacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-yIraethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N-cyclopropyl-2-hydroxyacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] ethyl} -N-(cyclopropylmethyl)acetamide; N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl}-N-(cyclopropylmethyl)-2-hydroxyacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyI}-N-cyclobutylacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIiii-5-yl)oxy] ethyl} -N-cyclobutyl-2-hydroxyacetamide; N{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] ethyl} -N-( 1 -methyl piperidin-4-yl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} -N-(tetrahydro-2H-pyran-4-yl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] ethyl} -2-hydroxy-N-(tetrahydro-2H-pyran-4-yl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl} -N-(2-hydroxyethyl)acetamide; N- {2-[(4- {[3 -chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5- yl)oxy]ethyl}-2-hydroxy-N-(2-hydroxyethyl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl} -N-(2-methoxyethyl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy] ethyl} -2-hydroxy-N-(2-methoxyethyl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- y l)oxy] ethyl} -N-prop-2-yn-1 -yl acetamide; N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5- yI)oxy] ethyl} -2 -hydroxy -N-prop-2-yn-1 -ylacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIin-5- yl)oxy]ethyl} -2-hydroxy-N-methylpropanamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyI} -N-methyl-tetrahydrofuranyl-2-carboxamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl} -N, 1 -dimethylprolinamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]emyl}-2-hydroxy-N,2-dimethylpropanamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl} -1 -hydroxy-N-methylcyclopropanecarboxamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIin-5- yl)oxy]ethyl}N1-N2-dimethylglycinamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl}-3-hydroxy-N,2,2-trimethylpropanamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]ethyl} -3-hydroxy-N-methylpropanamide; N-{(2S)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl}acetamide; N- {(2S)-2- [(4- {[3 -chloro-4-(pyridin-2-y lmethoxy)phenyl] amino} quinazolin-5- yl)oxy]propyl} -2-hydroxyacetamide; N1-{(2S)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yI)oxy]propyl}-N1-N2-dimethylgIycinamide; N- {(2S)-2- [(4- {[3 -chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5- yl)oxy]propyl}-2-methoxyacetamide; N-{(2S)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl} -2-(methylsulfonyl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl} -2-hydroxyacetamide; N'-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl}-N1-N2-dimethylglycinamide; N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl} -2-methoxyacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yI)oxy]ethyl}-2-(methylsulfonyl)acetamide; N-{(25)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]propyl}-N-methylacetamide; N-{(25)-2-[(4-{[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI} -2-hydroxy-.N-methylacetamide; Nl- {(25)-2-[(4- {[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]propyl} -N1-N2,N2trimethylglycinamide; N-{(25)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl}-2-methoxy-N-rnethylacetarnide; N- {(25)-2- [(4- {[3 -chloro-4-(pyridin-2-ylmethoxy)pheny IJamino} qui nazolin-5-yl)oxy]propyl}-N-methyl-2-(methylsulfonyl)acetaniide; N-{(2R)-2-[(4-{[3-chloro-4-(pyrazin-2-yImethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI}-N-methylacetamide; N- {(2R)-2-[(4-{ [3-chloro-4-(l ,3 -thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxylpropyll-N-methylacetamide; N-((2R)-2-{[4-({3-chloro-4-[(3-fluoroben2yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)-N-methylacetamide; N-((2R)-2-{[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)-N-methylacetamide; N- {(1 R)-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy] -1 -methy lethyl} -2 -hydroxy -N-methylacetamide; N-{(lR)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] -1 -methylethyl} -N-methylacetamide; N- {(1S)-2-[(4-{ [3 -chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]-1 -methylethyl} -2-hydroxy-N-methylacetamide; N- {(lS)-2-[(4- {[3 -chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-lyl)oxy]-1 -methylethyl} -N-methylacetamide; N-{(15)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] -1 -methylethyl} -2-methoxy-N-methylacetamide; N-{(lS}-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] -1 -methylethyl} -2-hydroxyacetamide; N-{(15)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-y l)oxy] -1 -methylethyl} acetamide; Nl-{(lS)-2-[(4-{[3 -chloro-4-(pyridin-2-yImethoxy)phenyl]amino} quinazolin-5 -yl)oxy]-1-methylethyl}-N2-N2-dimethylglycinamide; N1-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino}quinazolin-5-yl)oxy] propy 1} -N2,-N2-dimethylglycinamide; (2S)-N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} -2,4-dihydroxybutanamide; (2R)-N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} -2,4-dihydroxybutanamide; (2R)-N-{(2R)-2-[(4- {[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]propyl} -2,4-dihydroxybutanamide; (2S)-N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI} -2,4-dihydroxybutanamide; (2R)-N- {(2S)2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]propyl}-2,4-dihydroxybutanamide; (25)-N-{(2S)-2-[(4-{[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propy 1} -2,4-dihydroxybutanamide; (25)-N-{(lR)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l -methylethyl} -2,4-dihydroxybutanamide; (2R)-N- {(1 R)-2-[(4-{ [3 -chloro-4-(pyridin-2-yImethoxy)phenyl]arnino }quinazolin-5-yl)oxy] -1 -methylethyl} -2,4-dihydroxybutanamide; (2R)-N- {2-[(4- {[3-chloro-4-( 1,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl} -2,4-dihydroxybutanamide; (2S')-n-{2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2,4-dihydroxybutanamide; (2R)-N- {(1 R)-2-[(4- {[3-chloro-4-( 1,3 -thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]-l-methylethyl}-2,4-dihydroxybutanamide; (25)-N-{(lR)-2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin- yl)oxy]-1 -methylethyl} -2,4-dihydroxybutanamide; N-methyl-N-{2-[(4-{[3-rnethyI-4-(pyridin-2-ylniethoxy)pheny]]amino}quinazolin-5- yI)oxy] ethyl }acetamide; N-methyl-N-{2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl}acetamide; N-methyl-N-(2-{[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino) quinazolin-5-yl]oxy}ethyl)acetamide; 2-hydroxy-N-methyl-N-{2-[(4-{[3-methyl-4-(l,3-thiazoI-2-ylmethoxy)phenyl] amino}quinazolin-5-yl)oxy]ethyl}acetamide; 2-hydroxy-N-{2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5- yI)oxy]ethyl} acetamide; 2-hydroxy-N- {2-[(4- {[3 -methyl-4-(l ,3-thiazoI-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl}acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phetiyl]amino}quinazolin-5-yI)oxy]-l,l- dimethylethyl} -2-hydroxyacetamide; 2-hydroxy-N-{(2R)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyI]amino} quinazolin-5 -yl)oxy]propyl} acetamide; 2-hydroxy-N-{(2R)-2-[(4'{[3-methyI-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]propyl}acetamide; N-((2R)-2-{[4-({4-f(3-fluoroben2yl)oxy]-3-methylphenyl}amino)quinazoIin-5- yl]oxy}propyl)-2-hydroxyacetamide; 2-hydroxy-N-{(2R)-2-[(4-{[3-methyl-4-( 1,3-thiazol-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]propyl}acetamide; N-{(2R)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy] propyl} acetamide; N-{(2R)-2-[(4- {[3-methyl-4-( 1,3 -thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5- yl)oxy]propyl} acetamide; N-((2R)-2-{[4-({4-[(3-fluorobenzyI)oxy]-3-methylphenyl}amino)quinazolin-5- yl]oxy}propyl)acetamide; N-{(2R)-2-[(4-{[3-methyl-4-(l,3-thiazol-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy] propyl} acetam ide; 2-hydroxy-N-methyl-N-{(2R)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl] amino}quinazolin-5-yl)oxy]propyI}acetamide; 2-hydroxy-N-methyl-N-{(2R)-2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI}acetamide; 2-hydroxy-N-methyI-N-((2R)-2-{[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; N-methy\-N- {(1R)-1 -methyl-2-[(4- {[3-methyl-4-(pyridin-2-ylmethoxy)phenyl] amino}quinazolin-5-yl)oxy]ethyl}acetamide; N-methyl-N-{(lR)-l-methyl-2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl} acetamide; N-{(lR)-2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] -1 -methylethyl} -2..........-hydroxy-N-methylacetamide; 2-hydroxy-N-methyl-N {(1 R) .. 1 -methyl-2-[(4- {[3 -methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetamide; 2-hydroxy-N-methyI-N-{(lR)-l-methyl-2-[(4-{t3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetamide; N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yI)oxy]propyl}-1 -hydroxy-N-methylcyclopropanecarboxamide; (25)-N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-N-methylpropanamide; N-{(2R)-2-[(4-{[3-chloro-4-{pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl} -2-hydroxy-N,2-dimethylpropanamide; (2R)-N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-N-methylpropanamide; (2R)-N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ammo}quinazolin-5-yl)oxy]propyl}-2-methoxy-A'-methylpropanamide; 2-hydroxy-N-methyl-N-((2R)-2- {[4-( {3 -methyl-4- [(6-methylpyridin-3 -yI)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; N-methyl-N-((2R)-2-{[4-({3-methyI-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetaraide; N1-N2.N2-trimethyl-N1 -((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl} amino)quinazolin-5-yl]oxy }propyl)glycinamide; 2-hydroxy-N-methyl-N-((2S)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl} amino)quinazoIin-5-yl]oxy} propyI)acetamide; N-methyl-N-((25)-2-{[4-({3-methyI-4-[(6-methylpyridin-3- fl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; (2S)-2,4-dihydroxy-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide; (2S)-4-bromo-2-hydroxy-N-((2R)-2-{[4-({ 3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)quina2olin-5-yl]oxy}propyl)butanamide; N-(2-chIoroethyl)-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyI}amino)quinazolin-5-yl]oxy}propyl)urea; 2-hydroxy-N-methyl-N-((lR)-l-methyl-2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl} amino)quinazolin-5-yl]oxy} ethyl)acetamide; N-methyl-N-(( 1R)-1 -methyl-2- {[4-( {3-methyl-4-[(6-methylpyridin-3 - yl)oxy]phenyI}amino)quinazolin-5-yl]oxy}ethyl)acetarnide; 2-hydroxy-N-methyl-N-(( 1S)-1 -methyl-2- {[4-( {3-methyl-4- [(6-methylpyridin-3- yl)oxy]phenyl }amino)quinazoIin-5-yl]oxy} ethyl)acetamide; N-methyl-N-((lS)-1 -methyl-2- {[4-({ 3 -methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide; methyl-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5- yl)oxy]ethyl }methyl carbamate; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5- yl)oxy] ethyl} -N,N-dimethylurea; N-(2-chIoroethyl)-N-{2-[(4-{[3-chloro-4-(pyridin-2- y lmethoxy)pheny 1] amino } quinazolin-5 -yl)oxy] ethyl} -N-methy lurea; N-{(R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl}-N-methylurea; [((R)-2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)phenyIamino]quinazolin-5- yloxy}propylcarbamoyl)methyl]methylcarbamic acid tert-butyl ester; N1-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl} -N2-methylglycinamide; 2-hydroxy-N-methyl-N-(2- {[4-( {3-methyl-4-[(6-methylpyridin-3- yI)oxy]phenyl}amino)quinazolin-5-yI]oxy}ethyl)acetamide; N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide; and N- {2- [(4- {[3 -chloro-4-( 1 -methyl-1 -pyridin-2-ylethoxy)phenyl]amino} quinazolin-5- yl)oxy]ethyl}-N-methylacetamide; or a pharmaceutical^ acceptable salt thereof. 11. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 as and when used as a medicament. 12. A process for the preparation of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 which comprises: (a) the coupling, conveniently in the presence of a suitable base, of a quinazoline of the formula II: (Formula Removed) wherein R1, R2, R3, R4, R4a, R5, R5a, R6, X1, Q1, m, and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a carboxylic acid of the formula III, or a reactive derivative thereof: (Formula Removed) wherein A has any of the meanings defined in claim 1 except that any functional group is protected if necessary; or (b) for the preparation of those compounds of the formula I wherein X1 is OC(R7)2, SC(R7)2 or N(R7)C(R7)2, the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula IV: (Formula Removed) wherein Xla is O, S or N(R7) and R1, R2, R3, R4, R4\ R5, R5a, R6, R7, A, m, and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the formula V or a salt thereof: (Formula Removed) wherein L1 is a suitable displaceable group and Q1 and R7 have any of the meanings defined in claim 1 except that any functional group is protected if necessary; (c) for the preparation of those compounds of the formula 1 wherein A is R14 and R14 is NHR17 (wherein R17 is as defined in claim 1), the coupling of a quinazoline of the formula II as defined above in (a) with an isocyanate of the formula Ilia: A-NCO Ilia wherein A is R14 as previously defined in this section except that any functional group is protected if necessary; (d) the reaction of a quinazoline of the formula II wherein R6 is hydrogen: (Formula Removed) wherein R1, R2, R3, R4, R4a, R5, R5a, X1, Q1, m, and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with α-hydroxy-γ-butyrolactone wherein any functional group is protected if necessary; or ) the coupling of a quinazoline of the formula VI: (Formula Removed) wherein R1, R4, R4a, R5, R5 R6, A and m have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the formula IIb: (Formula Removed) wherein R2, R3, X1, Q* and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary; (f) for the preparation of those compounds of the formula I wherein X1 is O and Q1 is 2-pyridyI, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyI, 2-pyrazinyl or 3-pyridazinyl, the reaction, conveniently in the presence of a suitable base and a suitable catalyst, of a quinazoline of the formula VII: (Formula Removed) wherein R1, R2, R3, R4, R4a, R5, R5a, R6, A, m and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with 2-bromopyridine, 4-bromopyridine, 2-chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or 3-chloropyridazine; or (g) for the preparation of those compounds of the formula I wherein A is Z-CR12R13)p-, wherein Z is NRI6R17, the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula VIII: (Formula Removed) wherein L1 is a suitable displaceable group and R1, R2, R3, R4, R4a, R5, R5a, R6, R12, R13, X1, Q1, m, n and p have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the formula IXa, or a reactive derivative thereof: (Formula Removed) wherein R16 and R17 have any of the meanings defined in claim 1 except that any functional group is protected if necessary; and thereafter, if necessary: (i) converting a quinazoline derivative of the formula I into another quinazoline derivative of the formula I; (ii) removing any protecting group that is present by conventional means; (iii) forming a pharmaceutically acceptable salt.

Full Text

FIELD OF THE INVENTION
he invention concerns certain novel quinazoline compounds, or pharmaceutically acceptable salts 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.
BACKGROUND OF THE INVENTION
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 BioK 1999,3,459-465).
It 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 of a variety of human cells. These mutated and over-expressed forms of the kinase are present in a large proportion of human tumours (reviewed in Kolibaba et al, Biochimica et Biophysica 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 mis 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 et a/, Oncoeene. 2000,12,5548-5557).
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 the cell.
It is known that the erbB family of receptor tyrosine kinases, which include EGFR, erbB2, erbB3 and erbB4, are frequently involved in driving the proliferation and survival of tumour cells (reviewed in Olayioye etal.. 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.. 2000,21» 25) such as breast cancer (Sainsbury et al., Brit. J. Cancer. 1988,58,458; Guerin ej a]., Oncogene Res.. 1988,3, 21; Slamon etal.. Science. 1989,244.707; Kh"jn et aL, Breast Cancer Res. Treat.. 1994,2j>, 73 and reviewed in Salomon et al., Grit Rev. Oncol. Hematol. 1995,19,183), non-small cell
lung cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J. Cancer. 1986, 54, 265; Reubi etal, Int. J. Cancer. 1990,45, 269; Rusch et al., Cancer Research, 1993, 53, 2379; Brabender etal. Clin. Cancer Res.. 2001, 7,1850) as well as other cancers of the lung (Hendler et al., Cancer Cells. 1989,7, 347; Ohsaki et al.. Oncol. Rep.. 2000, 7,603), bladder cancer (Neal et al., Lancet, 1985, 366; Chow et al.. Clin. Cancer Res.. 2001,7,1957, Zhau et al., Mol 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.. 1987,1,149; Kapitanovic etal.. Gastroenterologv. 2000,112,1103; Ross etal.. Cancer Invest.. 2001,19,554), cancer of the prostate (Visakorpi et al., Histochem. J.. 1992,24,481; Kumar et ai.. 2000,3^, 73; Scheretal.. J. Natl. Cancer Inst.. 2000, 92,1866), leukaemia (Konaka etal.. Cell. 1984, 3J, 1035, Martin-Subero et al.. Cancer Genet Cvtogenet.. 2001, 127.174), ovarian (Hellstrom etal.. Cancer Res.. 2001,61,2420), head and neck (Shiga et 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 (in particular erbB2), it is widely believed that many tumours become clinically more aggressive and so correlate with a poorer prognosis for the patient (Brabender et al, Clin. Cancer Res.. 2001,7, 1850; Ross etal. Cancer Investigation. 2001,19,554, Yu etal.. Bioessavs. 2000,22.7.673). In addition to these clinical findings, a wealth of pre-clinical 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 etal.. 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 et al 2000, Oncogene. 19,5690-5701; Mendelsohn et
al, 2000, Oncogene. 19,6550-6565). In addition to this pre-clinical data, findings using inhibitory antibodies against EGFR and erbB2 (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 die ErbB type 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. Pharm. Des.. 2000,6,933; Elder el ah, Science, 1989,243.811), benign prostatic hyperplasia (BPH) (Kumar eUl., Lit Urol. Nephroi.. 2000,32_,73), atherosclerosis and restenosis (Bokemeyer eta!.. Kidnev Int.. 2000, 58,549). It is therefore expected that inhibitors of erbB type receptor tyrosine kinases will be useful in the treatment of these and other non-malignant disorders of excessive cellular proliferation.
International Patent Applications WO 96709294, WO 96/15118, WO 96/16960, WO 96/30347, WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/03069, WO 97/13771, WO 97/30034, WO 97/30035, WO 97/38983, WO 98/02437, WO 98/02434, WO 98/02438, WO 98/13354, WO 99/35132, WO 99/35146, WO 01/215%, WO 01/55141 and WO 02/18372 disclose that certain quinazoline derivatives which bear an anilino substituent at the 4-position possess receptor tyrosine kinase inhibitory activity.
International Patent Applications WO 97/22596 and WO 98/13354 disclose that certain 4-anilinoqumazoline derivatives that are substituted at the 7-position are inhibitors VEQF or mixed VEOF/EGF receptor tyrosine kinase inhibitors. The anilino group in these applications is substituted with small groups such as halogeno or (l-3C)alkyl.
International Patent Application WO 01/94341 discloses that certain quinazoline derivatives which are substituted at the 5-position are inhibitors of the Src family of non-receptor tyrosine kinases, such as c-Src, c-Yes and c-Fyn. There are no disclosures in WO 01/94341 of 4-anilinoquinazolines wherein the aniline group is substituted in the para position by a substituent containing an aryl or a heteroaryl group.
International Patent applications WO 03/040108 and WO 03/040109 disclose that certain 5-substitued quinazoline derivatives are inhibitors of the erbB family of tyrosine kinase inhibitors, particularly EGFR and erb-B2 receptor tyrosine kinases. All the compounds in these applications carry a ring containing substituent at the 5-position on the quinazoline ring.

Mone of the prior art discloses 4-anilinoquinazolines that are substituted at the 5- position by an |bylaminoethoxy group and which carry an aryl or heteroaryl containing substituent at the para-position on the aniline ring.
STATEMENT OF THE INVENTION
A quinazoline derivative of the formula I:
(Formula Removed)

wherein: m is 0, 1 or 2 ;
each R', which may be the same or different, is selected from hydroxy, (1-6C) alkoxy. (3-7C)
cycloalkyl-oxy and (3-7C) cycloalkyl- (1-6C) alkoxy,
and wherein any CH2 or CH? group within a R1 substituent optionally bears on each said CH2 or CM-
group one or more halogeno or (1-6C) alky! substituents. or a substituent selected from hydroxy and
(1-6C) alkoxy.
R2 is hydrogen or (1-4C) alkyl;
nisO, 1,2, 3 or 4 ;
each R\ which may be the same or different, is selected from cyano, halogeno,'(l- 4C) alkyl.
trifluoromethyl, (1-4C) alkoxy, (2-4C) alkenyl and (2-4C) alkynyl;
X1 is selected from O, S, SO, S02, N(R7), CH(OR7), CON(R7), N(R7) CO, S02N(R7), N(R7) S02, OC
(R7)2, C(R7)20, SC(R7)2, C(R7)2S, CO, C(R7)2N(R7) and N(R7)C(R7)2. wherein each R7, which may be
the same or different, is hydrogen or (1-6C) alkyl;
Q1 is aryl, or heteroaryl,
and wherein Q' optionally bears one or more substituents, which may be the same or different.
selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl. formyl.
mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy. (2-6C) alkenyloxy, (2-
6C)alkynyioxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl. (1-6C) alkylamino. di-|(l-
6C) alkyl]amino, (1-6C) alkoxycarbonvl. N- (I-6C) alkvlcarbamovi. N. N-di-[(l-6C)alk\l)

carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)aIkynoyl. (2-6C)alkanoyloxy. (2-6C) (pkanoylamino,
N-(1-6C) alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3- 6C)alkenoylamino. (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(I-6C) alkylsulfamoyl, N. N-di-[(l-6C) alkyl] sulfamoyl, (l-6C)alkanesulfonylamino. N-(1-6C) alkyl-(l-6C) alkanesulfonvlamino. and a group of the formula: -X2-R8
wherein X2 is a direct bond or is selected from O, CO and N (R9), wherein Ry is hydrogen or (I-6C) alkyl, and R8 is halogeno- (1-6C) alkyl, hydroxy- (1-6C) alkyl. carboxy-(l- 6C) alkyl. (1-6C) alkoxv-(I-6C) alkyl, cyano- (1-6C) alkyl, amino- (I-6C) alkyl. N- (1-6C) alkylamino- (1-6C) alkyl. N. N-di-[(1-6C) alkyl] amino- (1-6C) alkyl, (2-6C) alkanoylamino- (I-6C) alkyl, N- (I-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-[(l-6C) alkyl] carbamoyl- (1-6C) alkyl. (I- 6C) alkylthio- (1-6C) alkyl, (1-6C) alkylsulfinyl- (1-6C) alkyl, (1-6C) alkylsulfonyl- (1-6C) alkyl sulfamoyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl (I-6C) alkyl, N, N- di- (1-6C) alkylsulfamoyl (1-6C) alkyl, (2-6C) alkanoyl- (1-6C) alkyl, (2-6C) alkanoyloxy- (1- 6C) alkyl or (1-6C) alkoxycarbonyl- (1-6C) alkyl,
and wherein any CH2 or CH5 group within-X'-Q1 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. (1-4C) alkoxy, (I-4C) alkylamino and di- [ (1-4C) alkylamino];
R4 R4a,R5 and R5a, which may be the same or different, are selected from hydrogen and (1-6C) alkyl. or
R4 and R4a together with the carbon atom to which they are attached form a (3- 7C) cycloalkyl ring, or R3 and R5a together with the carbon atom to which they are attached form a (3- 7C) cycloalkyl ring. and wherein any CH2 or CH3 group within any of R1, R4'1. R3 and R';1 optionally bears on each said CH2 or CH, group one or more halogeno substituents or a substituent selected from hydroxy, cyano. (I-6C) alkoxy, amino, (2-6C) alkanoyl, (1-6C) alkylamino and di-[(l- 6C) alkylamino]; R6 is selected from hydrogen, (1-6C) alkyl, (2-6C) alkenyl. (2-6C) alkynyl, (3- 7C) cycloalkyl. (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl, (3-7C) cycloalkenyl- (1- 6C) alkyl, heterocyclyl and heterocyclyl-( 1 -6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, 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-[(l-6C) alkyl] amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and from a group of the formula: -X3-R10

wherein X3 is a direct bond or is selected from O, CO, S02 and N (RM). wherein R" is hydrogen or of 4C) aikyl, and R10 is halogeno- (1-4C) alkyl, hydroxy- (1-4C) aikyl, (1-4C) alkoxy- (I-4C) alkyl. cyano- (1-4C) alkyl, amino- (1-4C) alkyl, N- (1-4C) alkylamino- (1-4C) alkyl and N. N-di- [ (I-4C) alkyl] amino- (1-4C) alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents;
and wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 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. (I-6C) alkylsulfonyl, (I-6C) alkylamino, di- f (1-6C) alkyl] amino, N- (1-6C) alkylcarbamoyl. N. N-di- | (I-6C) alkyl] carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino. N- (I-6C) alkyl- (2-6C) alkanoylamino, N- (1-6C) alkylsulfamoyl. N, N-di- [ (1-6C) alkyl] sulfamoyl. (I-6C) alkanesulfonylamino and N- (1-6C) alkyl- (1-6C) alkanesulfonylamino ;
A is selected from hydrogen, a group of the formula Z-(CRl2R13)p-and R14, wherein p is 1,2, 3, or 4. each R12 andR13 which may be the same or different, is selected from hydrogen, (1- 6C) alkyl. (2-6C) alkenyl and (2-6C) alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C) cycloalkyl or (3-7C) cycloalkenyl ring, and wherein any CH2 or CH-, group within any of Ru and R13, optionally bears on each said CH2 or CH3 group one or more halogeno or (I-6C) alkyl substituents or a substituent selected from hydroxy, cyano, (1-6C) alkyl, (1-6C) alkoxy, amino, (2-6C) alkanoyl. (I- 6C) alkylamino and di- [ (1-6C) alkyl] amino,
Z is selected from hydrogen, OR15, NR,6R17, (l-6C)alkylsulfonyl, (I-6C) alkanesulfonyl amino and N-(1-6C) alkyl- (1-6C) alkanesulfonylamino, wherein each of R15, R16 and R1', which may be the same or different, is selected from hydrogen, (1-6C) alkyl, (2-6C) alkenyl. (2-6C) alkynyl and (I-6C) alkoxycarbonyl, or Z is a group of the formula: Q2-X4-
wherein Bis selected from O, N(R18), S02 and S02N (R18). wherein RIS is hydrogen or (1-6C) alkyl. and Q2 is (3-7C) cycloalkyl, (3-7C) cycloalkenyl or heterocyclyl,
R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1- 6C) alkyl. (2-6C) alkenyl and (2-6C) alkynyl, and wherein R16 and RI7 are as defined above, or R14 is a group of the formula: Q3-X5-
wherein X5 is selected from O and N (R20), wherein R20 is hydrogen or (1-6C) alkyl, and Q3 is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heterocyclyl and heterocyclyl- (1-6C) alkyl,

or R'4 is Q4 wherein Q4 is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl. (3-7C) cycloalkenyl. (3-
C) cycloalkenyl- (1-6C) alkyl, heterocyclyl or heterocyclyl-( I - 6C) alkyl.
and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Z or R14 substituent are
optionally separated by the insertion into the chain of a group selected from O. S, SO. SO:, N (R2').
CO,-C=C-and-CsC-, wherein R2' is hydrogen or (1-6C) alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more
substituents, 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) alkynyi. (1-6C) alkoxy.
(1-6C) alkylthio, (1-6C) alkylsulfinyl, (I-6C) alkylsulfonyl, (1-6C) alkylamino. di-[(l-6C) alkylj
amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and from a group of the formula:
-Xf,-R22
wherein X6 is a direct bond or is selected from O, CO, S02 and N (R23), wherein R2, is hydrogen or
(1-4C) alkyl, and R22 is halogeno- (1-4C) alkyl. hydroxy- (I-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl.
cyano- (I-4C) alkyl, amino- (1-4C) alkyl, N- (1-4C) alkylamino- (1-4C) alkyl and N. N-di- [ (1-4C)
alkyl] amino-(1-4C) alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears I or 2 oxo or thioxo
substituents.
and wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a
heterocyclyl ring, optionally bears on each said CH2 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) alkynyi, (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, (I-6C)
alkanesulfonylamino and N- (1-6C) alkyl- (1-6C) alkanesulfonylamino; or a pharmaceutical!}
acceptable salt thereof.

SUMMARY OF THE INVENTION
We have now found that surprisingly certain quinazoline derivatives substituted at the 5-position with a substituent containing an acylaminoethoxy group possess potent anti-tumour activity. 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 EGFR and/or erbB2 receptor tyrosine kinases.
Generally the compounds of the present invention possess potent inhibitory activity against the erbB receptor tyrosine kinase family, for example by inhibition of EGFR and/or erbB2 and/or erbB4 receptor tyrosine kinases, whilst possessing less potent inhibitory activity against other kinases. Furthermore, generally the compounds of the present invention possess substantially better potency against the erbB2 over that of the EGFR tyrosine kinase, thus potentially providing effective treatment for erbB2 driven tumours. Accordingly, it may be possible to administer a compound according to the present invention at a dose that is sufficient to inhibit erbB2 tyrosine kinase whilst having no significant effect upon EGFR (or other) tyrosine kinases. The selective inhibition provided by the compounds according to the present invention may provide treatments for conditions mediated by erbB2 tyrosine kinase, whilst reducing undesirable side effects that may be associated with the inhibition of other tyrosine kinases. Generally the compounds according to the invention also exhibit favourable DMPK properties, for example high bioavailability, and favourable physical properties such as solubility.
Furthermore, many of the compounds according to the present invention are inactive or only weakly active in a hERG assay.
DETAILED DESCRIPTION
According to a first aspect of the invention there is provided a quinazoline derivative of the formula I:

wherein:
m is 0,1 or 2;
each R1, which may be the same or different, is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7)cycloalkyl-(l-6C)alkoxy
and wherein any CH2or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy,
R2   is hydrogen or (l-4C)alkyl;
n    is 0,1,2,3 or 4;
each R3, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alfeenyl and (2-4C)alkynyl;
X1   is selected from O, S, SO, SO2 N(R7), CH(OR7), CON(R7), N(R7)CO, SOzN(R7), N(R7)S02, OC(R7)2, C(R7)2O SCCR7)2, COR-V, CO, C(R7)2N(R7) and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl;
Q1 is aryl, or heteroaryl,
and wherein Ql optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, fonnyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6G)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, H-(l*6C)alkylcarbamoyl, N,N-di-(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyl.(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino,
N-(l-6C)alkylsulfanioyl)N,N-di-[(l-6C)alky1]sulfamoyl, (l-6C)alkanesulfonylamino, N-(l-6C)alkyMl-6C)alkanesulfonylamino, and a group of the formula:
-X2-R8
wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-(l-6C)alkylamino-(l-6C)alkyl,N>N-di-[(l-6C)aIkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, N-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl,carbamoyl-(l-6C)alkyl, N-(l-6C)alkylcarbamoyl(l-6C)alkyl,N,N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkyl,(l-
6C)alkylthio-(l-6C)allcylXl-6C)alkylsulfinyl and wherein any CHfe or CHa group within -X^Q1 optionally bears on each said GHz or CHs group one or more (for example 1,2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino];
R4, R4*, R5 and R5*, which may be the same or different, are selected from hydrogen and(l-6C)alkyl,or
R4 and R4a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, or
R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring,
and wherein any CH2 or CHa group within any of R4, R4*, R5 and R5a optionally bears on each said CHa or CHa group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino];
R6    is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno,
trifluoromethyl, cyano, nitro, hydroxy, amino, fonnyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]arnino, (2-6C)alkanoyl, (2-6C)aJkanoyloxy and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O, CO, SOz and N(Rn), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)aIkyl and N^-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents;
and wherein any CHfe or CHa group within a R6 substituent, other than a CHa group within a heterocyclyl group, optionally bears on each said.
2 or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6Qalkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6Qalkylthio, (l-6Qalkylsulfinyl, (l-6C)alkykulfonyl, (l-6C)alkylamino, di-[(l-6C)allcyl]amino, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)aDcanoylamino, H-(l-6C)alkylsulfamoyl, JLH-di-[Cl-6C)aIkyl]sulfamoyl, (l-6C)alkanesulfonylamino and M-(l-6C)alkyl-(l-6C)alkanesulfonylamino;
A is selected from hydrogen, a group of the formula Z-(CR12R13)p- and R14,
wherein p is 1,2,3, or 4,
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyl ring,
and wherein any CH2 or CHfe group within any of R12 and R13 optionally bears on each said CH2 or CHs group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkylamino and di-[(l-6C)alkyl]amino,
Z is selected from hydrogen, OR15, NR16R17, (l-6C)alkylsu!fonyl, (l-6C)alkanesulfonyIamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, wherein each of
R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)aUcenyl, (2-6C)alkynyl and(l-6C)alkoxycarbonyl,
or Z is a group of the formula:
Q2-X4-
wherein X4is selected from O, N(R18), SO2 and SO2N(R18), wherein R18 is hydrogen or (l-6C)alkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl,
R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above,
or R14 is a group of the formula:
Q3-X5-
wherein X5 is selected from O and NCR20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyI, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl~(l-6C)aIkyl,
or RM is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyHl-6C)alkyl, (3-7C)cycioalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R21), CO, -C=C- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent 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, ammo, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)a!kylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula;
-X"-R22
wherein X6 is a direct bond or is selected from O, CO, SOa and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N (l^C)alkylamino-(l-4C)alkyl andH,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 1 oxo or thioxo substituents,
and wherein any CH2or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)a!kylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyllamino, N-(l-6C)alkylcarbaraoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)aIkanoyloxy, (2-6C)alkanoylamino, N;-(i-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulfamoyl, N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and H-(l-6G)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof.
According to a second aspect of the invention there is provided a quinazoline derivative of the formula I, wherein:
m is 0,1 or 2;
each R1, which may be the same or different, is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycIoalkyl-oxy and (3-7C)cycloalkyl-(l-6C)alkoxy,
and wherein any CH2 or CEb group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy,
R2   is hydrogen or (l-4C)alkyl;
n     is 0,1,2,3 or 4;
each R3, which may be the same or different, is selected from halogeno, (l-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
X1   is selected from O, S, SO, SO* N(R7), CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)S02, OC(R7)2, CCR7)2O, SC(R7)a, C(R7)2S, CO, CCR^CR7) and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl;
Q1 is aryl, or heteroaryl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, catbamoyl, sulfamoyl, formyl, mercapto, (l-6C)alkyl, (2-8Qalkenyl, (2-8C)alkynyl, (l-6G)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsutfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, M-(l-6C)alkylcarbamoyl, £LN-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl,
(3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-U -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-( 1 -6C)a]kyl-(3-6C)alkynoylamino, N-(l-6C)alkylsulfamoyl,N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylammo, N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, and a group of the formula:
-X2-R8
wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)a!kyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-(l-6C)alkylaaiino-(l-6C)alkyl,N,N-di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, N-(l-6C)aIky-(2-6C)alkanoylamino-(l-6C)alkyl, (l-6X^)alkoxycaibonylaniino-(l-6C)alkyl,carbamoyl-(l-6C)alkyl, N(1-6C)alkylcarbamoyl-(l-6C)allcyl,N,N-di-[(l-6C)alkyl]carbamoyKl-6C)alkyl,(l-6C)alkylthio-(l-6C)alkyl, (l-6C)alkylsulfinyl(l-6C)alkyl, (l-6Qalkylsulfonyl-(l-6C)alkyl sulfamoyl(l-6C)alkyl, N-(l-6C)alkylsulfamoyl(l-6C)alkyl, &N-di-(l-6C)alkylsulfamoyl(l-6C)alkyl, (2-6C)alkanoyHl-6C)alkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6Oalkoxycarbonyl-(l-6C)alkyl,
and wherein any CH2 or CHs group within -Xl-Q! optionally bears on each said CK-z or CHb group one or more (for example 1,2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino];
R4, R4*, R5 and R5a, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, or
R4 and R4* together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, or
R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring,
and wherein any CH2 or CHs group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino];
R6    is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyK (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3-R"°
wherein X3 is a direct bond or is selected from O, CO, SOa and NOR.11), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amiiio-(l-4C)alkyl, H-(l-4C)allcylamino-(l-4C)alkyl and H^^-[(l-4C^kyl]ainino-(l-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents;
and wherein any CHj or CHs group within a R6 substituent, other than a CHj group within a heterocyclyl group, optionally bears on each said CHj or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, EN^(l-6C)alkyl3carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, H-(l-6C)alkylsulfamoyl, &£^-[(l^C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l -6C)alkyl-(l-6C)alkanesulfonylamino;
A is selected from hydrogen, a group of the formula Z-(CR12R13)p- and R14,
wherein p is 1,2,3, or 4,
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloaIkenyl ring,
and wherein any CH2 or CHs group within any of R12 and R13 optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl
substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (i-6C)alkylamino and di-[(l-6C)alkyllamino,
Z is selected from hydrogen, OR15, NR16R17, (l-6C)alkylsulfonyl,
(l-6C)alkanesulfonylamino andN-(l-6C)aIkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or Z is a group of the formula:
Q"-X4-
wherein X4is selected from O, N(R18), SC>2 and S02N(R18), wherein R18 is hydrogen or (l-6C)alkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl,
R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 arc as defined above,
or R14 is a group of the formula:
Q3-X5-
wherein X5 is selected from O and NCR20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloalkyKl-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocycIyl-(l-6C)alkyl,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO*, N(R21), CO, -C=C- and -C=C-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)aIkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-XO-R22
wherein Xs is a direct bond or is selected from O, CO, SO2 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)aIkyl, M-(l-4C)alkylamino-(l-4C)alkyl and M,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CH3 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CHaor CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N^i-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, M-(l-6C)alkylsulfamoyl, H,H-di-[(l-6Qalkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino;
or a pharmaceutically acceptable salt thereof.
According to a third aspect of the invention there is provided a quinazoline derivative of the formula I, wherein:
misO, 1 or 2;
each R1, which may be the same or different, is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(l-6C)alkoxy,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy,
R2   is hydrogen or (l-4C)alkyl;
n    is 0,1,2,3 or 4;
each R3, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
X1    is selected from O, S, SO, SO* N(R7), CH(OR7), CON(R7), N(R7)CO, S02N(R7), N(R7)S02, OC(R7)2| CCR^O, SC(R7)2, CQL\S, CO, C(R7>2N(R7) and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl;
Q1 is aryl, or heteroaryl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, fonnyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl,
43"
(l-6C)a1kylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N~(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(I -6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l -6C)alkylsulfamoyl, N,N-di-[( 1 -6C)alkyl]sulf amoyl, (1 -6C)alkanesulfonylamino, N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, and a group of the formula:
-X2-R8
wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, andR8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-(l-6C)alkylamino-(l -6C)alkyl, N,M-di-l(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, M-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl, [l-6C)alkoxycarrx)nylaniinc-(l-6C)alkyl,cart)arnoyl-(l-6C)alkyl, S-(l-6C)alkylcarbamoyHl-6C)ancyl, H,H-di-[(l-6C)alkyl]carbamoyHl-6C)alkyi, (1-6C)alkylthio-(l-6C)allcyl, (l-6C)alkylsulfinyHl-6C)alkyl, (!-6C)aIkylsulfonyHl-6C)alkyl sulfamoyKl-eQalkyl, M-(l-6Qalkylsulfamoyl(l-6X^alkyl» M^i-di-(l-6Oalkylsulfamoyl(l-6C)alkylt (2-6C)alkanoyl-(l-6C)alkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)alkoxycarbonyl-(l-6Qalkyl,
and wherein any CHa or CHs group within -X^Q1 optionally bears on each said CHj or CHs group one or more (for example 1,2, or 3) halogeno or (l-6C)alkyl substitaents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino];
R4, R4*, R5 and R5a, which may be the same or different, are selected from hydrogen and(l-6C)alkyl,
and wherein any CEk or CH3 group within any of R*, R4*, R5 and R5a optionally bears on each said CKfe or CEfo group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino];
R6    is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, ( 6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,

and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and firom a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O, CO, SO2 and N(RU), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)aUeyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and HJi-di-[(l-4C)alkyl]aniino-(l-4C)allcyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents;
and wherein any CHj or CH3 group within a R6 substituent, other than a CKfe group within a heterocyclyl group, optionally bears on each said CHj or CKb group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfcmyl, (l-6C)alkylamino, di-[(l-6C)alkyl]ainino, H-(l-6C)alkylcarbamoyI, && A is selected from hydrogen, a group of the formula Z-(CR12R13)P- and R14,
wherein p is 1,2,3, or 4,
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyl ring,
and wherein any CHz or CHs group within any of R12 and R13 optionally bears on each said CHj or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6Qalkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkylamino anddi-[(l-6C)alkyl]amino,
Z is selected from hydrogen, OR15, NRI6R17, (l-6C)alkylsulfonyl,
(l-6C)alkanesulfonylamino andN-(l-6C)alkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and Rn, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl,
or Z is a group of the formula:
Q2-X4-
wherein X4 is selected from O, N(R18), SO2 and SO^R18), wherein R18 is hydrogen or (l-6C)alkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl,
R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above,
or R14 is a group of the formula:
Q3-X5-
wherein X5 is selected from O and NCR20), wherein R20 is hydrogen or (l-6C)alkyl, andQ3 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycioalkenyl, (3-7C)cycloalkenyHl-6Qalkyl, heterocyclyl and heterocyclyl-(l-6C)aDcyl,
or R14 is Q4 wherem Q4 is (3-7C)cycloalkyl, (3-7C)cycbalkyl-(l-6C)alkyl$ (3-7C)cycIoalkeiiyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyHl-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SCb, N(R21), CO, -C=C- and -CsC-, wherem R21 is hydrogen or (l-6C)alkyl,
and wherem any heterocyclyl group within a Z or R14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-^C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X^-R22
wherein X6 is a direct bond or is selected from O, CO, SOa and NCR23), wherem R23 is
hydrogen or (l-4C)alkyl, andR22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl,
(l-4C)^llcoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, .
N-(l-4C)alkylamino-(l-4C)alkyl and H.N-di-[(l-4C)alkyl]amino-(l-4C)alkyl,

and wherein any heterocyclyl group within a Z or Ru substituent optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CH2or CH3 group within a Z or R14 group, other than a CH-z group within a heterocyclyl ring, optionally bears on each said CHa or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, ammo, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)allcyl]amino, £Hl-6C)alkylcarbamoyl, H»N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulfarnoyl, N^[-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesuIfonylamino and £i-(l-6C)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof.
In this specification the generic term "alky!" includes bom straight-chain and branched-chain alkyl groups such as propyl, isopropyl and text-butyl. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms, for example (l-6C)alkoxy includes methoxy, ethoxy and isopropoxy, (l-6C)alkylamino includes methylamino, ethylamino and isopropylamino and di-[(l-6C)alkyI]amino includes dimethylamino, diethylamino and Ji-isopropyl-Ji-niethylamino,
It 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£) denotes any scalemic or racemic mixture while (R) and (5) denote the enantiomers. In the absence of (/?,5), (R) or (S) 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 S 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 substituents herein (for example Q1) when it is aryl or for the aryl group within a "Q" group is, for example, phenyl or naphthyl, preferably phenyl.
A suitable value for any one of the substituents herein when it is (3-7C)cycloalkyl or for a (3-7C)cycloalkyl group defined herein within, for example a "Q" group or Rl substituent is, for example, cyclopropyl, cyclobutyi, cyclopentyl, cyclohexyU cycloheptyl or bicyclo[2.2. l)heptyl. A suitable value for any one of the substituents herein, when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a substituent is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
A suitable value for any one of the substituents herein when it is heteroaryl or for the heteroaryl group within a "Q" group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulfur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 13,5-triazenyl, 13-benzodioxolyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cirmolinyl or naphthyridinyl.
Particular heteroaryl groups include, for example, pyridyl, pyrimidyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl (more particularly pyridyl, pyrazinyl, thiazolyl and isoxazolyl).
A suitable value for any one of the substituents when it is heterocyclyl or for the heterocyclyl group within a substituent 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 sulfur, which, unless specified otherwise, may be carbon or nitrogen linked, for example oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolinyl,
pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, decahydroisoquinolinyl or decahydroquinolinyl, particularly tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,4-oxazepanyI, thiamorpholinyl, l,l-dioxotetrahydro-4H-l,4-tWazinyl, piperidinyl or piperazinyl, more particularly tetrahydrofuran-2-yl, 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, pipcridin-3-yl, piperidin-2-yI or piperazin-1-yl. A nitrogen or sulfur 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-dioxoimidazolidmyl or 2,6-dioxopiperidinyl.
Particular heterocyclyl groups include, for example, non-aromatic saturated or partially saturated 3 to 7 membered monocydic heterocyclyl rings with 1 ring nitrogen or sulfur heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of such rings include azetidtnyl, oxazepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidmyU tetrahydrothienyl, tetrahydrothiopyranyl or thiomorpholinyl.
Other particular heterocyclyl groups include, for example, 4, 5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl rings containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur such as oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l,4-thiazinyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl or tetrahydrothiopyranyl,
Further particular heterocyclyl groups include, for example 4,5,6 or 7 membered saturated or partially saturated monocyclic heterocyclyl rings containing 1 nitrogen atom and optionally 1 heteroatom selected from nitrogen, oxygen and sulfur such as piperazinyl,
pyrrolidinyl, piperidinyl, particularly pyrrolidin-l-yl, pyrrolidin-2-yl, piperazin-1-yl, piperidino or morphohno.
Other heterocyclyl groups include, for example, non-aromatic saturated or partially saturated 4, 5, 6 or 7 membered monocyclic heterocyclyl rings containing 1 or 2 oxygen atoms such as tetrahydrofuranyl, 1,3-dioxolanyl and tetrahydiopyranyl (for example tetrahydrofuran-2-yl and tetrahydropyran-4-yl).
A suitable value for a substituent herein when it is heterocyclyl-(l-6C)alkyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. The invention comprises corresponding suitable values for other substituents when, for example, rather than a heterocyclyl-(l-6C)alkyl group, an (3-7C)cycloalkyl-(l-6C)alkyl or (3-7C)cycloalkenyl-(l-6C)alkyl is present.
Suitable values for any of the substituents herein, for example the "R" groups (R1 to R23) or for various groups within a Q1, X1 or A group include:-
w hen in this specification reference is made to a (l-4C)alkyl group it is to be understood that such groups refer to alkyl groups containing up to 4 carbon atoms. A skilled person will realise that representative examples of such groups are those listed above under (l-6C)alkyl that contain up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. Similarly, reference to a (l-3C)alkyl group refers to alkyl groups containing up to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl. A similar convention is adopted for the other groups listed above such as (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl and (2-4C)alkanoyl.
When, as defined hereinbefore, in the group of the formula -X"-Q1, and X1 is, for example, a OC(R7)2 linking group, it is the oxygen atom, not the carbon atom, of the OC(R )2 linking group which is attached to the phenyl ring in the formula I and the carbon atom is attached to the Q1 group. Similarly when X1 is a N(R7)C(R7>2 linking group the nitrogen atom of the N(R7)C(R7)2 group is attached to the phenyl ring in formula I and the carbon atom is attached to the Q1 group. A similar convention is applied to other linking groups used herein, for example when A is a group of the formula Z-(CR12R13)p- and Z is Q2-X*- and X4 is SOiNXR18), the SO2 group is attached to Q2 and the nitrogen atom is attached to X4 in formula I.
It is to be understood that references herein to adjacent carbon atoms in any (2-6C)alkylene chain within a group may be optionally separated by the insertion into the chain of a group such as O or OC refer to insertion of the specified group between two carbon atoms in an alkylene chain. For example, when A is R14 and R14 is a 2-pyrrolidin-l-ylethoxy group insertion of a CsC group into the ethylene chain gives rise to a 4-pyrrolidin-l-ylbut-2-ynyloxy group.
When reference is made herein to a CH2or CH3 group optionally bearing on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (l-6C)alkyl substituents present on each said CHa group and there are suitably 1, 2 or 3 such substituents present on each said CHa group.
Where reference is made herein to any CHa or CHa group optionally bearing on each said CHa or CHa group a substituent as defined herein, suitable substituents so formed include, for example, hydroxy-substituted heterocyclyl-(l-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy, hydroxy-substituted heterocyclyl-(l-6C)alkylammo groups such as 2-hydroxy-3-piperidinopropylamino and
2-hydroxy-3-morpholinopropylamino> and hydroxy-substituted (2-6)alkanoyl groups such as hydroxyacetyl, 2-hydroxypropionyl and 2-hydroxybutyryl.
Where reference is made herein to, for example, R4 and R4a together with the carbon atom to which they are attached forming a (3-7C)cycloalkyl ring herein, the ring so formed is a (3-7C)cycloalkylidene group, for example a cyclopropylidene group of the formula:
wherein * represent the bonds from the cyclopropylidene group.
It is to be understood that the quinazoline in formula I is unsubstituted at the 2-position on the quinazoline ring.
It is to be understood that certain compounds of the formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase.
It is also to be understood that certain compounds of the formula I may exhibit polymorphism, and that the invention encompasses all such forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase.
It is also to be understood that the invention relates to all tautomeric forms of the compounds of the formula I forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase.
A suitable pharmaceutically acceptable salt of a compound of the formula I is, for example, an acid-addition salt of a compound of the formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the formula I which is sufficiently acidic, 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.
Particular novel compounds of the invention include, for example, quinazoline derivatives of the formula I, or pharmaceutically acceptable salts thereof, wherein, unless
otherwise stated, each of R\ R2, R3, R4, R4a, R5, R5a, X1, Q1, m, n and A has any of the meanings defined hereinbefore or in paragraphs (a) to (yyyyyy) hereinafter :-
(a) m is 0 or 1 and R1, when present, is located at the 7-position on the quinazoline ring in
formula I;
(b) R1 is selected from hydroxy, (l-6C)alkoxy, hydroxy(l-6C)alkoxy, (l-6C)alkoxy-(l-
6C)aikoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(l-6C)alkoxy,
and wherein any CHior CHb group within a R1 substituent optionally bears on each said CHa or CHs group one or more substituents selected from fluorb and chloro;
(c) m is 0 or 1 and R1, when present, is located at the 7-position on the quinazoline ring
and is selected from (l-6C)alkoxy, cyclopropyl-(l-4C)alkoxy, cyclobutyl-(l-4C)alkoxy,
cyclopentyl-(l-4C)alkoxy and cyclohexyl-(l-6C)alkoxy,
and wherein any CKi or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro substituents, or a substituent selected from hydroxy, methoxy and ethoxy;
(d) m is 1 and R1 is located at the 7-position on the quinazoline ring and is (l-4Qalkoxy,
for example methoxy or ethoxy,
and wherein any CH2 or CHa group within a R1 substituent optionally bears on each said CH2 or CHa group one or more fluoro or chloro substituents, or a substituent selected from hydroxy, methoxy and ethoxy;
(e) m is 1 and R1 is located at the 7-position on the quinazoline ring and is selected from
methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy,
2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, trifluoromethoxy, 2,2-difluoroethoxy and
2,2,2-trifluoroethoxy;
(f) m is 1 and R1 is located at the 7-position on the quinazoline ring and is methoxy;
(g) misO;
(h)   R2 is hydrogen or methyl; (i)    R2 is hydrogen;
(j)    n is 0,1 or 2 and, when present, at least one R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I;
(k)   n is 0, 1 or 2 and, when present, at least one R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from halogeno, (l-4C)alkyl, (l-4C)alkoxy and (2-4C)alkynyl;
(1)    n is 0,1 or 2 and, when present, at least one R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from halogeno and (l-4C)alkyl;
(m)   n is 0 or 1 and, when present, R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from halogeno (particularly fluoro or chloro) and (l-4C)alkyl;
(n)   n is 0 or 1 and, when present, R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from cyano, fluoro, chloro, methyl, methoxy and ethynyl (particularly fluoro, chloro, methyl, methoxy and ethynyl);
(o) n is 1 and R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from halogeno (particulariy fluoro or chloro) and(l-4C)aIkyl;
(p) n is 1 and R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from cyano, fluoro, chloro, methyl, methoxy and ethynyl (particularly fluoro, chloro, methyl, methoxy and ethynyl);
(q) n is 1 and R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I, and wherein R3 is selected from chloro and methyl;
(r)   n is 1, R3 chloro and wheren R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I;
(s) n is 1, R3 is methyl and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I;
(t)    X1 is selected from O, S, OC(R7)2, SC(R7)2, SO, SO2, N(R7), CO and N(R7)C(R7)2 wherein each R7, which may be the same or different, is selected from hydrogen or (l-6C)alkyl;
(u)   X1 is selected from O, S and OC(R7)2 wherein each R7 is, independently, hydrogen or (l-4C)alkyl;

(v)   X1 is selected from S and OC(R7)2 wherein each R7 is, independently, hydrogen or
(l-4C)alkyl;
(w)   X1 is selected from O and OC(R7)a wherein each R7 is, independently, hydrogen or
(l-4C)alkyl (particularly hydrogen or (l-2C)alkyl);
(x) X1 is selected from O, S, OCH2 and OC(CH3)2;
(y) X1 is selected from O, OCH2 and OC(CH3)2;
(z) X1 is selected from O, S and OCH2;
(aa) X1 is O;
(bb) X1 is S;
(cc) X"isOCH2;
(dd) X1 is OaCHbk
(ee)   X1 is selected from O, OCH2 and OCCCHa^, n is 0 or 1 and, when present, R3 is selected from halogeno (particularly chloro) and (l-4C)alkyl (particularly methyl);
(ff)   X1 is OCHa, n is 0 or 1 and, when present, R3 is halogeno, particularly chloro;
(gg) X1 is OCH2> n is 1, R3 is selected from fluoro, chloro and methyl (particularly chloro and methyl), and wherein R3is in a meta-position (3-position) relative to the nitrogen of the aniline group in formula I;
(hh)  X1 is O, n is 1, R3 is selected from fluoro, chloro and methyl (particularly chloro and methyl), and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I;
(ii)   X1 is O, n is 1, R3 is methyl, and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I;
(jj)   X1 is OC(CH3)2, n is 1, R3 is selected from fluoro, chloro and methyl (particularly chloro and methyl), and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I;
(kk)  X1 is OCXCHs^, n is 1, R3 is chloro, and wherein R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I;
(11)   Q1 is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur,

and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylaniino> (3-6C)alkenoylamino, N-(l-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, K-(l-6C)alkyl-(3-6C)alkynoylamino, ]N-(l-6Qalkyl8ulfamoyl, N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino, N-(l-6C)alkyl-(l-6C)alkanesulfonylainino, and a group of the formula:
-X2-R8
wherein X2 is a direct bond or is selected from O, CO and NCR9), wherein R9 is hydrogen or (l-6C)alkyl, andR8 is halogeno-(l-6Qalkyl, hydroxy-(l-6C)alkyl, catboxy-(l-6C)alkyl, (l-o^alkoxy-a-eQalkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-
(2-6C)alkanoylamino-(l-6C)alk:yl, N^l-6C)aUcyH2-^Qalkanoylamino-(l-6C)alkyl,
M-(l-6C)alkylcarbamoyl-(l-6C)alkyl> N^[-di-[(l-6C)alkyl3carbamoyHl-6C)alkyl, (1-6C)alkylthio-(l-6C)alkyl, (l-oOalkylsulfinyHl-eCJalkyl, (l-6C)alkylsulfonyHl-6C)alkyl sulfamoyl(l-6X:)alkyl, S-(l-6C)alkylsulfamoyl(l-6C)alkyl, EH-di-(l-6C)alkylsulfamoyl(l-6C)alkyl, (2-6C)alkanoyl-(l-6C)aIkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)alkoxycarbonyl-(l-6C)alkyl,
and wherein any CEb or CHs group within -Xl-Q* optionally bears on each said CHa or CHb group one or more (for example 1, 2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino];
(mm) Ql is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1 nitrogen heteroatom and optionally 1 additional heteroatom selected from oxygen, nitrogen and sulfur,
and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, as hereinbefore defined in (11),

(nn)   Q1 is phenyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(oo)  Q1 is a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1 nitrogen heteroatom and optionally 1 additional heteroatom selected from oxygen, nitrogen and sulfur,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(PP)  Q1 is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl, IH-imidazolyl, 1H-pyrazolyl, 1,3-oxazolyl and isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(qq)  Q1 is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl and isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(rr)   Q1 is selected from pyridyl, pyrazinyl, 13-thiazolyl and isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(ss)   Q1 is selected from phenyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 1,3-thiazol-4-yl, l,3-thiazol-5-yl, 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(tt)   Q1 is selected from 2-, 3- or 4-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl, l,3-thiazol-5-yl, 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(uu)  Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazoi-2-yl, 1,3-tniazol-4-yl and 3-isoxazolyl,
and wherein Q1 optionally bears one or more oubstitucnts (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);

(vv)   Ql is selected from 2-pyridyI, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 1,3-thiazol-4-yl and 3-isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(ww) Q1 is selected from 2-pyridyl, 2-pyrazinyl, l,3-thiazol-4-yl, l,3-thiazol-5-yl and 3-isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(xx)  Q1 is pyrazinyl (particularly 2-pyrazinyl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(yy) Q1 is isoxazolyl (particularly isoxazol-3-yl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in 00;
(zz) Q1 is pyridyl (particularly 2-pyridyl or 3-pyridyl, more particularly 2-pyridyl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in Ql);
(aaa) Q1 is 13-thiazolyl (particularly l,3-thiazok4-yl or 13-thiazolyl-2-yI), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (11);
(bbb) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, hydroxy, cyano, carboxy, nitro, amino, (l-4Qalkyl, (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)a!kylthio, (1-4C)alkylsulfmyl, (l^C)alkylsulfonyl, (2-4C)alkanoyl, N-(l-4C)alkylamino, & M-di-[(l-4C)alkyl]amino, (l-4C)alkoxycarbonyl, carbamoyl, £Hl-4C)alkylcarbamoyl, Mi M-di-[(l-4C)alkyI]carbamoyl, (2-4C)alkanoyloxy, (2-4C)alkanoylamino, M-(l-4Qalkyl-(2-4C)alkanoylamino, halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, carboxy-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and IiN-di-[(l-4C)alkyl]amino-(l-4C)alkyl;

(ccc)  Q1 is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1 nitrogen heteroatom and optionally 1 additional heteroatom selected from oxygen, nitrogen and sulfur,
and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different as hereinbefore defined in (bbb),
(ddd) Q1 is phenyl,
and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, as hereinbefore defined in (bbb);
(eee) Q1 is selected from pyridyl, pyrazinyl, 1,3-tiiiazolyl and isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, as hereinbefore defined in (bbb);
(fff)  Q1 is selected from phenyl, 2-, 3- or 4-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 13-thiazol-4-yl, l,3-thiazol-5-yl, 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb);
(ggg) Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, 13-thiazol-2-yl, 1,3-thiazol-4-yl and 3-isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb);
(hhh) Q1 is selected from 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl and 3-isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb);
(iii)   Q1 is pyrazinyl (particularly 2-pyrazinyl), which optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, as hereinbefore defined in (bbb);
(ijj)   Q1 is isoxazolyl (particularly isoxazol-3-yl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb);

(kkk) Q1 is pyridyl (particularly 2-pyridyl or 3-pyridyl, more particularly 2-pyridyl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb);
(111)   Q1 is 1,3-thiazoIyl (particularly l,3-thiazol-4-yl or l,3-thiazolyl-2-yl), which optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in (bbb);
(mmm) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from fluoro, chloro, bromo, hydroxy, carboxy, cyano, nitro, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 2-propynyl, methylthio, methylsulfinyl, methylsulfonyl, acetyl, propionyl, methylamino, ethylamino, N,N-diinethylamino, N,N-diethylamino, N-methyl-N-ethylamino methoxycarbonyl, etboxycalbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetoxy, acetamido, fluoromethyl, 2-fluoroethyl, chloromethyl, 2-chloroethyl, hydroxymethyl, 2-hydroxyethyl, methoxyrnethyl, 2-methoxyethyl, cyanomethyl, 2-cyanoethyl, carboxymethyl, 2-carboxymethyl, aminomethyl, methylaminomethyl, ethylaminomethyl, NJN-dimethylaminoniethyl, N,N-diethylaminomethyl, N-methyl-N-emylaminomethyl, 2-aminoethyl, 2-(methylamino)ethyl, 2-(emylamino)ethyl, 2-(N,N-dimeraylamino)ethyl, 2-(NJNf-diethylamino)ethyl, 2-(N-methyl-N-ethylamino)ethyl, carbamoylmethyl, N-methylcarbamoylmethyl and N J«J-dimethylcarbamoylroethyl;
(nnn) Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 1,3-thiazol-4-yl and isoxazol-3-yl,
and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, as hereinbefore defined in (mmm);
(ooo) Q1 is selected from phenyl, 2-pyridyl, 2-pyrazinyl, l,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl,
and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, as hereinbefore defined in (mmm);
(PPP) Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl and isoxazol-3-yl,
and wherein Q2 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (1-4C)alkoxy;
(qqq) Q1 is selected from phenyl, 2-pyridyl, 2-pyrazinyl, l,3-thiazol-4-yl, l,3-thiazol-5-yl and isoxazol-3-yl,
and wherein Q2 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (1-4C)alkoxy;
(rrr)  Q1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 13-thiazol-4-yl and isoxazol-3-yl (particularly phenyl, 2-pyridyl, 3-pyridyl and isoxazol-3-yl),
and wherein Q2 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro) and (l-4C)alkyl (for example methyl);
(sss) Q1 is phenyl which bears 1 or 2 substituents, which may be the same or different, selected from halogeno (particularly fluoro and chloro, more particularly fluoro);
(ttt)   Q1 is selected from 2-fluorophenyl and 3-fluorophenyl; (uuu) Q1 is 3-fluorophenyl; (vvv) Q1 is 2-fluorophenyl;
(www)Q1 is pyridyl (for example 2-pyridyl or 3-pyridyl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (l-4C)alkoxy (particularly (l-4C)alkyl, for example methyl);
(xxx) Q1 is 2-pyridyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (l-4C)alkyl and (l-4C)alkoxy;
(yyy) Q1 is selected from 2-pyridyl, 6-methyl-pyrid-2-yl and 6-methyl-pyrid-3-yl;
(zzz) Q1 is 2-pyridyl;
(aaaa) Q1 is 6-methyl-pyrid-2-yl;
(bbbb) Q1 is 6-methyl-pyrid-3-yl;
(cccc) Q1 is 1,3-thiazolyl (for example 1,3-thiazol-2-yl Or l,3-thiazol-4-yl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (l-4C)alkyl and (l-4C)alkoxy;
(dddd) Q1 is l,3-thiazol-2-yI; (eeee) Q1 is l,3-thiazol-4-yl;
(ffff) Q1 is pyrazinyl (for example 2-pyrazinyl) which optionally bears 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, hydroxy, (l-4C)alkyl and (l-4C)alkoxy;
(gggg) Q1 is 2-pyrazinyl;
(hhhh) Q1 is isoxazolyl (for example 3-isoxazolyl) which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (l-4C)alkyl and (l-4C)alkoxy (particularly (l-4C)alkyl, for example methyl);
(iiii)  Q1 is 5-methyl-isoxazol-3-yl;
Gift) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl (particularly pyridyl, more particularly 2-pyridyl),
and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, cyano, nitro, amino, (l-4C)alkyl, (1-4C)alkoxy, N-(l-4C)alkylamino and &M-di-[(l-4C)alkyl]ainino,
X1 is selected from OCH2,0(CH3>2 and O, and
n is 0 or 1, R3, when present, is located at the meta-position (3-position) relative to the nitrogen in the anilino group, wherein R3 has any of the values defined above (for example R3 is selected from fluoro, chloro and (l-3C)alkyl (such as methyl));
(kkkk) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl (particularly pyridyl, more particularly 2-pyridyl),
and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, cyano, nitro, amino, (l-4C)alkyl, (1-4C)alkoxy, H-(l-4C)alkylamino and &N-di-[(l-4C)alkyl]amino,
X1 is O(CH3)2, and
3
n is 0 or 1, R , when present, is located at the meta-position (3-position) relative to the nitrogen in the anilino group, wherein R3 has any of the values defined above (for example R3 is selected fromfluoro, chloro and (l-SC)alkyl (such as methyl));
(1111)  Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl (particularly pyridyl, more particularly 2-pyridyl),
and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, cyano, nitro, amino, (l-4C)alkyl, (1-4C)alkoxy, H-(l-4C)aUcylamino and N» N-di-[(l-4C)alkyl]amino,
X1 is OCH2, and
n is 0 or 1, R3, when present, is located at the meta-position (3-position) relative to the
1 ^
nitrogen in the anilino group, wherein R has any of the values defined above (for example R is selected from fluoro, chloro and (l-3C)alkyl (such a methyl));
(rnmmm) Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl,
and wherein Q1 optionally bears 1,2, or 3 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, cyano, nitro, amino, (l-4Qalkyl, (1-4C)alkoxy, £J-(l-4C)alkylamino and £L N-di-[(l-4C)alkyl]ainino,
X1 is O, and
n is 0 or 1, R3,when present, is located at the meta-position (3-position) relative to the nitrogen in the anilino group, wherein R3 has any of the values defined above (for example R3 is selected from fluoro, chloro and (l-3C)alkyl (such as methyl));
(nnnn) R4, R4a, R5 and R5*, which may be the same or different, are selected from hydrogen and (l-3C)alkyl (particularly methyl);
(oooo) R4, R4a, R.5 and R5at which may be the same or different, are selected from hydrogen and (l-3C)alkyl (particularly methyl), wherein at least one of R4, R4*, R5 and R5" is (1-3C)alkyl (particularly methyl);
(pppp) R4, R4* and R5 are all hydrogen and R5a is (l-3C)alkyl (particularly methyl); (qqqq) R4, R5 and R5a are all hydrogen and R4a is (l-3C)alkyl (particularly methyl);
(nrr) R4 and R4a are both hydrogen and R5 and R5a are both (l-3C)alkyl (particularly methyl);
(ssss) R4a and R5a are both hydrogen; (tttt)  R4a, R5a and R4 are hydrogen and R5 is (l-6C)alkyl, or R4*, R5a and R5 are hydrogen and R4 is (l-6C)alkyl,
and wherein any CH2 or CH3 group within any of R4 and R5 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy;
(uuuu) R4and R4Aare hydrogen, and R5 and R5a are both (l-6C)alkyl, or R5 and R5a are hydrogen, and R4 and R4* are both (l-6C)alkyl,
and wherein any CH2 or CHa group within any of R4, R4*, R5 and R5a optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)a!koxy;
(ww) R5 and R5a are hydrogen, and
R4 and R4* together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl),
and wherein any CH2 or CHa group within any of R4 and R4* optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy;
(wwww) R4 and R4* are hydrogen, and
R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl),
and wherein any CH2 or CHa group within any of R5 and R5a optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy;
(xxxx) R4, R4a, R5 and R5a are all hydrogen;
GW) R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl,
(2-6C)aikynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkylJamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3~R10
wherein X3 is a direct bond or is selected from O and N(RU), wherein RM is hydrogen or (l-4C)a!kyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl(
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents;
and wherein any CH2 or CHs group within a R6 substituent, other than a CHi group within a heterocyclyl group, optionally bears on each said CH2 or CHb group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6Qalkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (zzzz) R6 is selected from hydrogen, (l-6C)alkyl, hydroxy-(2-6C)alkyl, (l-6C)alkoxy-(2-6C)alkyl, halogeno-(2-6C)alkyl, amino-(2-6C)alkyl, H-(l-6C)alkylamino-(l-6C)alkyl, N^I-di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyI, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O and N(Rn), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents;
(aaaaa) R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)aIkenyl, (2-6C)alkynyl, (3-TQcycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl andheterocyclyl-(l-6C)alkyl,
wherein any heterocyclyl group within R6 is a 4, 5,6 or 7 membered raonocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinylt (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]anrino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O and N(Rn), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyi, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, HKl-4C)alkylamino-(l-4C)alkyl andN,N-di-[(l-4Qalkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents;
and wherein any CHb or CEfe group within a R6 substituent, other than a CHfe group within a heterocyclyl group, optionally bears on each said CHa or CSLj group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (bbbbb) R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycIoalkyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
wherein any heterocyclyl group within R6 is a 4,5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclyl group is linked to the group to which it is attached by a ring carbon atom,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto; (li6C)alkyl, (2-6G)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl,
(l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O and N(R11), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyU (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, M-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)aJkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents;
and wherein any CH2 or CHs group within a R6 substituent, other than a CHa group within a heterocyclyl group, optionally bears on each said CH2 or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (ccccc) R6 is selected from hydrogen, (l-3C)a!kyl, (2-3C)alkenyl, (2-3C)alkynyl, (3-SQcycloalkyl, (3-5C)cycloalkyl-(l-3C)alkyl, heterocyclyl and heterocyclyl-(l-3C)alkyl,
wherein any heterocyclyl group within R6 is a 4,5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclyl group is linked to the group to which it is attached by a ring carbon atom,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifiuoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)aIkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyi, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O and N(R1!), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-(l-4C)alkylamino-(l-4C)alkyl and N,H-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein, any heterocyclyi group within an R* substituent optionally bears 1 or 2 oxo substituents;
and wherein any CHa or CR3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CHa or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl] amino;
(ddddd) R6 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, isopropenyl, allyl, but-2-enyl, ethynyl, 2-propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridmyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropybncthyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, azetidinylmethyl, pyrrolinylmethyl, pyrrolidinylmethyl, morpholinylmethyl, piperidinylmethyl, homoptperidmylxnethyl, piperazinylmethyl, homopiperazinylmethyU dihydropyridinylmethyl, tetrahydropyridmylmeihyl, dihydropyrimidinylmethyl, tetrahydropyrimidinyhnethyl, tetrahydrothienylrnethyl, tetrahydrothiopyranylmethyl, thiomorpholinylmethyl, tetrahydrofuranyhnethyl, tetrahydropyranylmethyl, 2-(azetidinyl)ethyl, 2-(pyrrolinyl)ethyl, 2-(pyrrolidinyl)ethyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl, 2-(homopiperidinyl)ethyl, 2-(piperazinyl)cthyl, 2-(homopiperazinyl)ethyl, 2-(dihydropyridinyl)ethyl, 2-(tetrahydropyridinyl)ethyl, 2-(dihydropyrimidinyl)ethyl, 2- and wherein any GHz or CH3 group within a R6 substituent, other than a CEfe group •within a heterocyclyl group, optionally bears on each said CH2 or CHs group one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, methyl, ethyl, propyl and isopropyl, or a substituent selected from hydroxy, amino, methoxy, ethoxy, rnethylamino, ethylamino, di-methylamino, di-emylamino andH-methyl-H-ethylamino,
and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tlifluoromethyl, vinyl, isopropenyl, I allyl, but-2-enyl, ethynyl, 2-propynyl, butynyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, acetyl, propionyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-- • hydroxyethyl, 2-methoxyethyl and 2-ethoxyethyl;
(eeeee) R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyL 2-methoxyethyl, propyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-methoxypropyl, 2-methoxypropyl, isopropyl, vinyl, isopropenyl, allyl, but-2-enyl, ethynyl, 2-propynyI, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, homopiperidinylmethyl, tetrahydrothiopyranylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, 2-(azetidinyl)ethyl, 2-(pyrrolidinyl)ethyl, 2-(piperidinyl)ethyl, 2-(homopiperidinyl)ethyl, 2-(tetrahydrothienyl)ethyl, 2-(tetrahydrothiopyranyl)ethyl, 2-(thiomorpholinyl)ethyl, 2-(tetrahydrofuranyl)ethyl and 2-(tetrahydropyranyl)ethyl,
and wherein any CH2 group within a cycloalkyl group within R6 optionally bears on each CHz group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy,
and wherein any CEfe or CH3 group within a R6 substituent, other than a GHz group within a heterocyclyl group, optionally beats on each said CH2 or CHb group one or more fluoro substituents,
and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy;
(fffff) R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-methoxypropyl, 2-methoxypropyl, isopropyl, allyl, but-2-enyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, tetrahydrofuranyknethyl, tetrahydropyranylmethyl, 2-(azetidinyl)ethyl, 2-(pyrrolidinyl)ethyl, 2-(piperidinyl)ethyl, 2-(tetrahydrofuranyl)ethyl and 2-(tetrahydropyranyl)ethyl,
( ,.,.  and wherein any CHa group within a cycloalkyl group within R6 optionally bears on each CH2 group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy,
and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy;
(ggggg) R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl and cyclopropylmethyl,
and wherein any CHfe group within a cycloalkyl group within R6 optionally bears on each CH2 group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy,
and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy;
(hhhhh) R6 is selected from hydrogen and (l-3Qalkyl (for example R6 is hydrogen or
methyl);
R6 is hydrogen;
R6 is (l-3C)alkyl (for example methyl); (kWdkk)     R6is(l-3C)alkyl,
and wherein any CHa or CHfe group within aR6 substituent, other than a CHfe group
within a heterocyclyl ring, optionally bears on each said CHa or CH3 group one or more
substituents selected from hydroxy and (l-6C)alkoxy (for example methoxy);
(11111) R6 is (2-6C)alkenyl (for example allyl);
(rnrnmmm)   R6 is (2-6C)alkynyl (for example 2-propynyl);
(nnnnn)     R6 is selected from (3-7C)cycloalkyl and (3-7C)cycloalkyl-(l-6C)alkyl (for example R6 is selected from cyclopropyl, cyclobutyl, cyclopropyl-methyl and cyclobutyl-methyl);
(ooooo)     R6 is heterocyclyl (for example R6 is selected from piperidinyl and tetrahydropyranyl); (PPPPP)     A is selected from a group of the formula Z-(CR12R13)P- and Rw,
wherein pis 1,2,3-,or4y • .-•?•;-.•/,••   K «
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloaJkyl or (3-7C)cycIoalkenyl ring,
and wherein any CEb or CHs group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkylamino and di-[(l-6C)alkyl]amino,
Z is selected from hydrogen, OR15, NRI6R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl,
R14 is selected from OR19 and NR16R17, wherein R19 is selected from (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16and R17 are as defined above,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7Ocycloalkenyl, (3-7C)cycloalkenyI-(l-6Qalkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)aIkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a groap selected from O, S, SO, SO2, N(R21), CO, -OC- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a Z orR14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkyIamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyIoxy and from a group of the formula:
_X6_R22
wherein X6 is a direct bond or is selected from O, CO, SO* and N(R23), wherein R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyllamino-(l-4C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CHfe or CHj group within a Z or R14 group, other than a GH2 group within a heterocyclyl ring, optionally bears on each said CHa or CHj group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino,
carboxy, carbamoyl, sulfamoyl, (2-6C)aIkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio,
(l-6C)a!kylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,
N-(l-6C)alkylcarbamoyI, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl,
(2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino,
N-(l-6C)alkylsulfamoyl, N,N-cii-[(l-6C)alkyl]sulfaraoyl, (l-6C)alkanesulfonylamino and
N-(l-6C)alkyl-(l-6C)alkanesulfonylamino;
(qqqqq) A is selected from a group of the formula Z-(CR12R13)p- and R14,
wherein p is 1,2 or 3,
each R12 and R13, which may be the same or different, is selected-from hydrogen and (l-6C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring,
and wherein any CEfe or CH3 group within any of R12 and R13 optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl and (l-6C)alkoxy,
Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6Qalkyl and (l-6C)alkoxycarbonyl,
R14 is selected from OR19 and NR16R17, wherein Rw is selected from (l-6C)alkyl and wherein R16 and R17 are as defined above,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SOa, N(R21), CO, -C=C- and -DC-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent 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, forrayl, mercapto, (l-6C)aIkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amrao, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
wherein X6 is a direct bond or is selected from O, CO, SO2 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkylaTidNIN-di-[(l-4C)alkyl]ainino-(l-4C)alkyl(
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CKb or CH3 group within a Z or R14 group, other than a CHz group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, M-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)aIk;anoyloxy, (2-6C)alkanoylamino, M-(l-6Qalkyl-(2-6C)alkanoylamino, M-(l-6C)alkylsulfamoyl, &&Kti-[(l-6Qalkyl]sulfamoyl, (l-6C)alkanesulfonylamino and H-(l-6C)alkyl-(l-6C)aIkanesulfonylaimno; (rmr) A is selected from a group of the formula Z-(CR12RI3V and RM»
wherein p is 1,2 or 3 (particularly 1 or 2),
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
and wherein any CHa or CHs group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)aBcoxy (particularly hydroxy),
Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (l-6C)alkoxycarbonyl,
R14 is selected from OR19 and NR16R17, wherein R19 is selected from (l-6C)alkyl and wherein R16 and R17 are as defined above,
or R14 is Q4 wherein Q4 is (S-TQcycloalkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, trifluorximethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy,
and wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy; (sssss) A is selected from a group of the formula Z-(CR12R13)P- and R14,
wherein p is 1,2 or 3 (particularly 1 or 2),
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
and wherein any CHa or CHs group within any of R12 and R13 optionally bears on each said CHi or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy (particularly hydroxy),
Z is selected from hydrogen, OR15, NRl R14 is selected from OR19 and NR16R17, wherein R19 is selected from (l-6C)a!kyl and wherein R16 and R17 are as defined above,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, heterocyclyl or heterocyclyl-(l-6C)alkylt
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, hydroxy, (l-6C)alkyl and (l-6C)alkoxy (particularly (l-6C)alkyi),
and wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CHi or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy (particularly a substituent selected from halogeno and hydroxy); (ttttt) A is selected from a group of the formula Z-(CR12RI3)p- and R14,
wherein p is 1,2,3, or 4,
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyl ring,
and wherein any CKfe or GHj group within any of R12 andR13 optionally bears on each said CHj or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl
substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)a!koxy, amino, (2-6C)alkanoyl, (l-6C)alkylamino and di-[(l-6C)alkylamino],
and wherein Z is selected from hydrogen, OR15, NR16R17, wherein each of R1S, Ri6 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
and wherein R14 is Q4 wherein Q4 is heterocyclyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SOa, N(R21), CO, -C=C- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a Rw substituent 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, fonnyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l~6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino,dK(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
wherein X6 is a direct bond or is selected from O, CO, SOj and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is nalogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-d-4C)aIkylamino-( l-4G)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within an R14 substituent optionally bears 1 or 2 oxo substituents,
and wherein any CEb or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CHa or CHg group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6Qalkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (I-6C)alkylthio, (l-6<: di- n- n h and a is selected from group of the formula z- ru> wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring,
and wherein any CH2 or CHs group within any of R12 and R13 optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy,
and wherein Z is selected from hydrogen, OR15, NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6G)alkynyl,
and wherein R14 is Q4 wherein Q4 is a 4,5,6 or 7 membered saturated or partially saturated monocyclic heterocyclyl ring containing i nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur,
and wherein Q4 optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, trifluoromcthyl, cyano, nitro, hydroxy, amino, mercapto, (l-6Qalkyl, (2-6C)alkenyI, (2-6C)alkynyl, (l-6C)alfcoxy, (l-6C)alkylthio, (l-6C)alkyIsulfinyl, (l-6C)alkylsulfonyl, (l-6C)aIkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)aDcanoyloxy and from a group of the formula:
-X"-R22
wherein X6 is a direct bond or is selected from O and NOR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)aIleyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, E-(l-4C)aIkylamino-(l-4C)alkyl and H,M-di-Kl-4C)alkyl]amino-(l-4C)alkyl,
and wherein Q4 optionally bears 1 or 2 oxo substituents,
and wherein any CH2 or CHa group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said Clfc or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (wwv) A is selected from a group of the formula Z-(CR12R13)p- and R14,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl
ring,
and wherein any CH2 or CH3 group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy,
and wherein Z is selected from hydrogen, OR15, NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
and wherein R14 is Q4 wherein Q4 is a 4, 5,6 or 7 membered saturated or partially saturated monocyclic heterocyclyl ring containing 1 nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, which ring is linked to the carbonyl group in formula I by a ring carbon atom,
and wherein Q4 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, mercapto, (l-6C)aIkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6X3)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X6-R22
wherein X6 is a direct bond or is selected from O and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-(l-4C)alkylamino-(l-4C)alkyl and H,H-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein Q4 optionally bears 1 or 2 oxo substituents,
and wherein any CEfe or GHj group within a Z or R14 group, other than a CHfe group within a heterocyclyl ring, optionally bears on each said CHa or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino; (wwwww) A is a group of the formula Z-(CR12R13)P-,
wherein p is 1 or 2,
each R12 andR13, which may be the same or different, is selected from hydrogen and U-6C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring,
and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (l-6C)alkoxycarbonyl,
and wherein any CEfeor CHs group within any of R12, R13 and Z, optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (xxxxx) A is a group of the formula Z-(CR12R13)p-,
wherein pis 1 or2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)aIkyl and (l-6C)aIkoxycarbonyl,
and wherein any CH2 or CH3 group within any of R12, R13 and Z, optionally bears on each said CH2 or CHs group one or more (for example 1,2 or 3) halogeno, (l-6C)alkyl or hydroxy substituents; (yyyyy) A is a group of the formula Z-(CR12R13V,
wherein pis lor 2,
each R12 and R13, which may be the same or different; is selected from hydrogen and (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom, form a (3-7C)cycloalkyl ring,
and wherein Z is selected from hydrogen, OR15, NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
and wherein any CH2 or CKfe group within any of R12, R13 and Z, optionally bears on each said CH2 or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (zzzzz) A is a group of the formula Z-(CR12RI3)P-,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)aIkyl,

or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl
ring,
and wherein Z is selected from hydrogen and OR15, wherein R15 is selected from
hydrogen and (l-6C)alkyl,
and wherein any CH2 or CH3 group within any of R12, R13 and Z, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy; (aaaaaa) A is a group of the formula Z-(CR12R13)P-,
wherein p is 1 or 2,
each R12 andR13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3~6C)cycloalkyl ring,
and wherein any CHz or CHs group within any of R12 and R13 optionally bears on each said CH2 or CHs group one or more (for example 1,2 or 3) halogeno or (l-4Qalkyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy,
and wherein Z is hydroxy; (bbbbbb) A is a group of the formula Z-(CR12R13)p-.
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl ring,
and wherein Z is NR16R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
and wherein any CH2 or CHs group within any of R12, R13 and Z, optionally bears on each said CHa or CHs group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl suostituente or a substuuent selected from hydroxy and (l-6C)a!koxy; (cccccc) A is a group of the formula Z-(CR12Rl3)p-,
wherein p is 1 or 2,
.;  .,(4,eachR^and RJ3, v^hich may be the same or different,^ selected from hydrpgertand (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
provided (i) that at least one of the R12 or R13 groups is (l-4C)alkyl, or (ii) that an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyU
and wherein any CH2 or CHs group within any of R12, R13 and Z, optionally bears on each said CHz or CEfe group one or more (for example 1, 2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (dddddd) A is a group of the formula ZKCR^R1 V
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloaIkyl ring,
provided (i) that at least one of the R12 or R13 groups is (l-4C)alkyl, or (ii) that an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein Z is selected from hydrogen, OR13, NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)a!kyl, (2-6C)alkenyl and (2-6C)alkynyl,
and wherein any GHz or CHa group within any of R12, R13 and Z, optionally bears on each said CHz or CHa group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6Qalkoxy; (eeeeee) A is Ru, wherein R14 is selected from OR19 and NR16R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl, and wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6G)alkyV
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R 4 group are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(Rai), CO, -C=C- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a R14 group 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, formyU mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)a!kylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
_X6.R22
wherein X6 is a direct bond or is selected from O, CO, SCfe and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-Cl^Qalkyl, H-(l-4C)alkylamino-(l-4C)alkyl and H,S-di-l(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within a R14 group optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CEfe or CHs group within a R14 group, other than a CHj group within a heterocyclyl ring, optionally bears on each said CHa or CHs group one or more halogeno or (l-6C)alkyl substituents or a subsdtuent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, M-(l-6C)alkylcarbamoyl, M,M-di-[(l-6C)alkyl]carbainoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyl-(2-6C)alkanoylamino, M-(l-6C)alkylsulfamoyl, M,M-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino;
(ffffff) A is R14, wherein R14 is selected from OR19 and NR16R17, wherein each of R16 and Rn, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (1-6C)alkoxycarbonyl, and wherein R19 is selected from (l-6C)alkyl,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyi, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within a R14 group 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy,
and wherein any heterocyclyl group within a R14 group optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CH2 or CHs group within a R14 group, other than a CHj group within a heterocyclyl ring, optionally bears on each said CHz or CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (gggggg) A is Ru, wherein R14 is OR19, wherein R19 is (l-6C)alkyl (particularly (l-3C)alkyl, such as methyl);
(hhhhhh) A is R14, wherein R14 is NR16R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (l-6C)alkoxycarbonyl,
and wherein any CEfe or CH3 group within a R16 or a R17 group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6Qalkyl substituents or a substituent selected from hydroxy and (l-6G)alkoxy,
(iiiiii) A is R14, wherein R14 is Q4 wherein Q4 is (3-7Qcycloalkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within a R14 group 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, formyl, mercapto, (l-6Qalkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy,
and wherein any heterocyclyl group within a R1* group optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CH2 or Cfife group within a R14 group, odier than a CH2 group within a heterocyclyl ring, optionally bears on each said CHfeor CHs group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; (jjjjjj) A is Q4 wherein Q4 is a 4,5,6 or 7 membered saturated or partially saturated monocyclic heterocyclyl ring containing 1 nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur,
and wherein Q4 optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, ammo* (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6G)alkoxyi (l-6C)alkylthioy (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula-.
-X6-R22
wherein X6 is a direct bond or is selected from O and N(R23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein Q4 optionally bears 1 or 2 oxo substituents;
(kkkkkk) A is Q4 wherein Q4 is a 5 or 6 membered saturated or partially saturated monocyclic heterocyclyl ring containing 1 nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur,
and wherein Q4 optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxy,
and wherein Q4 optionally bears 1 or 2 oxo substituents;
(111111) A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dmydropyrirnidinyl, tetrahydropyrimidinyl, tetrahydrofuranyl and tetrahydropyranyl,
and wherein A optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, trifluoromethyl, vinyl, isopropenyl, allyl, but-2-enyl, ethynyl, 2-propynyl, butynyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, acetyl, propionyl, hydroxymethyl, methoxymethyl, ethoxymethyl, 2-hydroxyethyl, 2-methoxyethyl and 2-ethoxyethyl;
(mmmmmm) A is selected from cyclopropyl, pyrrolidinyl, piperazinyl, morpholinyl and tetrahydrofuranyl,
and wherein A optionally bears one or more substituents, which may be the same or different, selected from methyl, ethyl, propyl, butyl, isopropyl and isobutyl (particularly methyl);
(nnnnnn)    A is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, tetrahydrofuranyl and tetrahydropyranyl,
and wherein A optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl,
trifluoromethyl, vinyl, allyl, ethynyl, 2-propynyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy and acetyl;
(oooooo)    A is selected from methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl, 1,3-dihydroxypropyl, 2-(hydroxymethyl)prop-2-yl, 2-hydroxy-2-methylpropyl, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 3-methoxypropyl, 1-methoxypropyl, 2-methoxypropyl, 2-methoxyprop-2-yl, 2-(methoxymethyl)prop-2-yl, 2-methoxy-2-methylpropyl, ethoxymethyl, 2-ethoxyethyl, 1-ethoxyethyl, l-hydroxy-3-bromopropyl, (methylsulfonyl)methyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl, 2-aminopropyl, 2-aminoprop-2-yl, 2-(aminomethyl)prop-2-yl, 2-amino-2-methylpropyl, N-methylaminomethyl, 2-(N-methylamino)ethyl, 1-QJ-methylamino)eti\yl, 3-(N-methyIammo)propyl, l-(M-nielhylainino)propyl> 2-(N-methylamino)pn^)yl, 2-(H-methylamino)prop-2-yl, 2-(|i-melhylaniinomethyl)prop-2-yl> [(N-methyl)^-^-butoxycarboi>yl)aniino]mettiyl, 2-Qi-melhylaiiiino)-2-methylpropyl, dimethylaminoinethyl, 2-QiH-diniethylamino)ethyl, l-^LK- (PPPPPP)    A is selected from methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl, 2-(hydroxymethyl)prop-2-yl, 2-hydroxy-2-methylpropyl, methoxynjethyl, 2-methoxyethyl, 1-methoxyeihyl, 3-methoxypropyl, 1-methoxypropyl, 2-methoxypropyl, 2-methoxyprop-2-yl, 2-(methoxymethyl)prop-2-yl, 2-methoxy-2-methylpropyl, ethoxymethyl,
2-ethoxyethyl, 1-ethoxyethyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-arainopropyl, 2-aminopropyl, 2-aminoprop-2-yl, 2-(aminomethyl)prop-2-yl, 2-amino-2-methylpropyl, N-methylaminomethyl, 2-(N-methylamino)ethyl, l-(N-methylamino)emyU 3-(N-methylamino)propyl, l-(N-methylamino)propyl, 2-(N-methylamino)propyl, 2-(N-raethylamino)prop-2-yl, 2-(N-methylaminomethyl)prop-2-yl, 2-(N-methylamino)-2-methylpropyl, H,N-dimethylaminomethyl, 2-(NJN-dimethylamino)ethyl, 1-(£LN-dimethylamino)ethyl, 3-(N,N-dimetoylamino)propyl, l-(NJi-dimethylamino)propyl, 2-(N[,N-dimethylamino)propyl, 2-(N,N-dimemylanimo)prop-2-yl, 2-(N,N-dimethylaminomethyl)prop-2-yl, 2-(M,N-dunemylamino>2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl."cyclohexyl, 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, 1-hydroxymethylcyclopropyl, 1-hydroxymethylcyclobutyl, l-hydroxymethylcyclopentyl, 1-hydroxymethylcyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azen"din-2-yl, azetidin-3-yl, l-methylazetidin-2-yl, l-melhylazetidin-3-yl, pyrrolidin-2-yl, pyrrolidm-3-yI, l-methylpynolidin-2-yl, 1-methyl pyrroUdin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, l-memylpiperidin-2-yl, l-methylpiperidin-3-yl and l-methylpiperidin-4-yl;
(qqqqqq)    A is selected from methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl, 1,3-dihydroxypropyl, 2-(hydroxymethyl)prop-2-yl, 2-hydroxy-2-methylpropyl, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 3-methoxypropyl, 1-methoxypropyl, 2-methoxypropyl, 2-methoxyprop-2-yl, l-hydroxy-3-bromopropyl, (methylsulfonyl)methyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl, 2-aminopropyl, 2-aminoprop-2-yl, 2-(aminomethyl)prop-2-yl, 2-amino-2-methylpropyl, N-methylaminomethyl, 2-(N-methylamino)ethyl, l-(N-methylamino)ethyl, [(N-memyl)-(N-^-butoxycarbonyl)amino]methyl, HJ^-dmiethylaminomethyl, 2-QJ.N-dimethylamino)ethyl, l-(N,N-dimefoylamino)ethyl, methylamino, dimethylamino, ethylamino, diethylamino, (2-chloroethyl)amino, methoxy, ethoxy, cyclopropyl, cyclobutyl, 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxymethylcyclopropyl, 1-hydroxymethylcyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yLtettabydrjDpyran-4-yl; pyrrolidin-2-yl, pyrrolidin-3-ylv l^ ^"^kv>fe ->" "" methylpyrrolidin-2-yl, l-methyIpyrrolidin-3-yl, pyrrolidin-1-ylmethyl, morpholin-4-yl, morpholin-4-ylmethyl, l-methylpiperazin-4-ylmethyl;
(rrrrrr) A is selected from methyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-
hydroxypropyl, 1,3-dihydroxypropyl, 2-(hydioxymethyl)prop-2-yl, methoxymethyl, 1-
methoxyethyl, l-hydroxy-3-bromopropyl, (methylsulfonyl)methyl, aminomethyl, N-
methylaminomethyl, [(N-methyl)-(N-tert-butoxycarbonyl)ainino]methyl, methylamino, (2-
chloroethyl)amino, methoxy, 1-hydroxycyclopropyl, tetrahydrofuran-2-yl, 1-
methylpyrroIidin-2-yl, pyrrolidm-1-ylmethyl, morpholin-4-ylmethyl, l-methylpiperazin-4-
ylmethyl;
(ssssss) A is selected from hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-
hydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl, 2-
(hydroxymemyl)prop-2-yl and 2-hydroxy-2-methylpropyl;
(tttttt) A is selected from methyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyeth.yl
and 2-hydroxyprop-2-yl;
(uuuuuu)    A is selected from methyl and hydroxymethyl;
(www)    A is hydroxymethyl;
(wwwwww) A is a group of the formula Z-(CR!2R13)p-,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-3C)alkyl,
and wherein Z is a group of the formula NRI6R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
and wherein any CHj or CHs group within any of R12, R13 and Z, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents,
and wherein any CH2 or CHa group within any of Ru, R13 and Z which is not attached to a nitrogen atom optionally bears on each said CEfe or CH3 group a substituent selected from hydroxy and (l-6C)alkoxy;
(xxxxxx)    A is selected from aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl, 2-aminopropyl, 2-aminoprop-2-yl, 2-(aminomethyl)prop-2-yl, 2-amino-2-methylpropyl,M-methylaminomethyl, 2-Q5-methylamino)ethyl, l-(H-methylamino)ethyl, 3-(N-methylamino)propyl, l-(JJ-methylamino)propyl, 2-Qi-methylamino)propyl, 2-(H-methylamino)prop^2-yl, 2-QS-methylaminomethyl)prop*2-yl, 2-(tJ-methylamino)-2-methylpropyl, £J,M-oMnethylaminomethyl, 2-(N^f-dimethylamino)ethyl, 1-QI^J-dimethylamino)ethyl, 3-(HJS-dunethylamino)propyl, l-(H,N-dimethylamino)propyl, 2-Qi^i-
dimethylamino)propyl, 2-(N,N-dimethylamino)prop-2-yl, 2-(N,N-
dimethylaminomethyl)prop-2-yl, 2-(N,N-dimethylamino)-2-methylpropyl and [(N-methyl)-
(N-tert-butoxycarbonyl)amino]methyl;and
(yyyyyy)    A is selected from aminomethyl, 2-arainoethyl, N-methylaminomethyl, 2-(N-
methylamino)ethyl, N,N-dirnethylaminomethyl, 2-(N,N-dimethylamino)ethyl and [(N-
memyl)-(N-tejt-butoxycarbonyl)ainino]methyl (particularly A is N,N-dimethylarainomethyl).
A particular embodiment of the present invention is a quinazoline derivative of the formula I of the formula la:

m is 0,1 or 2;
each R1, which may be the same or different, is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyHl-6C)alkoxy,
and wherein any Ofo or CHs group within a R1 substituent optionally bears on each said CHjor CHa group one or more halogeno or (l-6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy,
R3" is selected from cyano, halogeno, (l-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
n is 0,1 or 2;
each R3b, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl (particularly halogeno and (l-4C)alkyl);
X1 is selected from O, S, SO, SO2, N(R7), CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(Rt)S02, OC(R7)2, C(R7)20, SC(R7>2, C(R7)2S, CO, C(R7>2N(R7) and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl;
Ql is aryl, or heteroaryl,
and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, fonnyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyI, (l-6C)alkylamino, di-Kl-eQalkylJamino, (l^C)alkoxycarbonyl, N-(l-6Qalkylcarbamoyl, N^-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyIoxy, (2-6C)alkanoylamino, H-(l-6C)alkyl-(2-6C)alkanoylamino, (S^Qalkenoylamino, 6C)alkenoylarnino, (3-6C)alkynoylamino, H-(l-6C)alkylsulfamoyl, HJS^-Kl^)^yl]sulfamoyl, (l-6C)alkanesulfonylamino, M-(l-6C)alkyl-(l-6C)aIkane8ulfonylanrino, and a group of the formula:
-X2-R8
wherein X2 is a direct bond or is selected from O, CO and NCR9), wherein R9 is hydrogen or (l-6C)alkyl, andR8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)aIkyi, N-(l-6C)alkylamino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, (l-6X^alkoxycarbonylarnino-(l-6C)alkyl, carbamoyl-(l-6C)alkyl, H-(l-6C)alkylcarbamoyl-(l-6C)alkyl, Mii-di--[(l-6QaIkyl]carbainoyl-(l-6C)alkyl, (l-6C)alkylthio-(l-6C)alkyl, (l-6C)alkylsulfinyHl-6C)alkyl, (l-6Qalkylsulfonyl-(l-6C)alkyl
di-(l-6C)alkylsulfamoyl(l-6C)alkyl, (2-6C)alkanoyl-(l-6Qalkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)alkoxycarbonyl-(l-6C)alkyl,
and wherein any CH2 or CH$ group within -O^-Q1 optionally bears on each said CHj or CHa group one or more (for example 1, 2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino];
R4, R4i, R5 and R5*, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, or
R4 and R4a together with the carbon atom to which they are attached form a (3- • 7C)cycloalkyl ring, or
R5 and R5a together with the carbon atom to which they are attached form a (3-
7C)cycloalkyl ring,
and wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino];
R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyU (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsuffinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl)ainino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O, CO, SOa and N(Rn), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, ammo-(l-4C)alkyl, M-(l-4C)alkylamino-(l-4C)alkyl and N,H-di-[(l-4C)alkyl]ainino-(l-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents;
and wherein any CHa or CHa group within a R6 substituent, other than a CHa group
within a heterocyclyl group, optionally bears on each said CHj or CHs group one or more
halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino,
carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio,
(l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,
H-(l-6C)alkylcarbamoyl, M^i-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl,
(2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino,
N ,1 -6C)alkylsulfamoyl, N^J-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and
H-(l-6C)alkyHl-6C)alkanesulfonylamino; v , .   .,,
A is selected from hydrogen, a group of the formula Z-(CR12R13)p- and R14,
wherein p is 1, 2, 3, or 4,
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyI ring,
and wherein any CH2 or CHa group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl» (l-6C)alkoxy, amino, (2-6C)aIkanoyl, (l-6Qalkylamino and di-[(l-6C)alkyl]amino,
Z is selected from hydrogen, OR15, NRi6R17, (l-6C)alkylsulfonyl,
(l-6C)aIkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl, or Z is a group of the formula:
Q2-*4-
wheiein X* is selected from O, N(R18), SO2 and SO^NCR1*), wherein R18 is hydrogen or (l-6Qalkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl,
R14 is selected from hydrogen, OR19 and NR16R17, wherein Rw is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)aIkynyl, and wherein R16 and R17 ate as defined above, or R14 is a group of the formula:
Q3-X5-
wherein X5 is selected from O and NOR20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloaikyHl-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyHl-6C)alkyl,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyKl-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyHl-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R21), CO, -C=C- and -OC-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl,
(l-6C)alkylsulfonyl, (l-6C)alkylammo, di-[(l~6C)aDcyl]amino, (2-6C)allcanoyl, (2-6C)alkanoyloxy and from a group of the formula:
_X6_R22
wherein X6 is a direct bond or is selected from O, CO, SO2 andN(R23), wherein R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l-4C)alkyl, hydroxy-(MC)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and JiN-di-[(l-4C)alkyl]ainino-(l-4C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CH2 or CHs group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sutfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]aminot M-(l-6Qalkylcarbamoyl, Ji^i-di-[(l-6C)alkyl]caibamoyl, (2-6Qalkanoyl» (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6Qalkyl-(2-6C)aIkanoylamino, H-(l-6C)alkylsulfamoyl, N,H-di-[(l-6C)aIkyl]8ulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamhio; or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is a quinazoline derivative of the formula la, wherein: misOorl;
R1 is selected from (l-4C)alkoxy (for example methoxy or ethoxy),
and wherein any CBfe or CHs group within a R1 substituent optionally bears on each said CH2 or CHs group one or more fluoro or chloro substituents, or a substituent selected from hydroxy and (l-3C)alkoxy;
R3* is selected from hydrogen, halogeno, trirluoromethyl, (l-4C)alkyl, (l-4C)a!koxy, (2-4C)alkenyl and (2-4C)alkynyl;
nisO, lor2;
each R3b, which may be the same or different, is selected from halogeno and (1-
4C)alkyl; "
X1 is selected from O, S and OC(R7)2) wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl;
Q1 is aryl, or heteroaryl,
and wherein Q1 optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, ammo, carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6G)aIkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino,di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, M-d-6C)alkylcarbamoyl, N^}-di-[(l-6C)aIkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, H-(l-6Qalkyl-(3-6C)alkenoylamino, (3-6C)alkynoylainino, M-(l-6C)alkyl-(3-6C)alkynoylamino, H-(l-6C)alkylsulfamoyl, H^i-di-Kl-fiQalkyllsulfamoyl, (l-6C)alkanesulfonylamino, HKl-^C)alkyl-(l-6C)alkanesulfonylainino, and a group of the formula:
-X2-R8
wherein X2 is a direct bond or is selected from O, CO and NOR9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6Qalkyl, amino-(l-6C)alkyl, £J-
(2-6C)alkanoylamino-(l-6C)alkyl, N-{l-6C)alkyl-(2-6C)alkanoylamino-(l^C)alkyl, (l-6C)alkoxycarbonylamino-(l-6C)alkyl, carbamoyl-(l -6C)alkyl, H-(l-6C)alkylcarbamoyl-(l-6C)alkyl, HOi-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkyl, (1-
sulfamoyl(l-6C)alkyI, H-(l-6C)alkylsulfamoyl(l-6C)alkyl, di-(l-6C)alkylsulfamoyl(l-6€)alkyl, (2-6C)alkanoyKl-6C)alkyl, (2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)alkoxycarbonyl-(l-6C)alkyl,
and wherein any CHa or CHs group within -X"-Q1 optionally bears on each said CHj or CHa group one or more (for example 1, 2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)alkylamino and di-[(l-4C)alkylamino];
R4, R4", R5 and R5*, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, or
R4 and R4a together with the carbon atom to which they are attached form a (3-
7C)cycloalkyl ring, or
R5 and RSa together with the carbon atom to which they are attached form a (3-
7C)cycloalkyl ring,
and wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino];
R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)aflcenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)aUcylsulfonyl, (l-6X:)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O, CO, SCh and N(Rn), wherein R11 is hydrogen or (l-4QalkyU and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and M,N-di-[(l-4C)alkyl]amino-(l^C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents;
and wherein any CHa or CHa group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (i-6C)alkylsulfonyl, (l-6Qalkylamino, di-t(l-6C)alkyl]amino, H-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylanuno,H-(l-6C)alkyl-(2-6C)alkanoylaimno, H-(l-6C)alkylsulfamoyl, N,H-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and H-(l-6C)alkyl-(l-6C)alkanesulfonylamino;
A is selected from a group of the formula Z-(CR12R13)P- and R14,
wherein pis 1,2 or 3,
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyi ring,
and wherein any CHj or CHa group within any of R12 and R13 optionally bears on each said CH2 or CHs group one or more (for example 1, 2 or 3) halogeno or (l-6C)aBeyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkyl amino and di-[(l-6C)alkylamino],
Z is selected from hydrogen, OR15, NR16R17 and R14 wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
R14 is a 4, 5, 6 or 7 membered saturated or partially saturated monocyclic heterocyclyl ring containing 1 nitrogen or oxygen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur,
and wherein any heterocyclyl group within a R14 substituent 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, formyl, mercapto, (l-6C)aLkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-*C)alkylthio, (l-6Qalkylsulfinyl, (l~6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
wherein X6 is a direct bond or is selected from O, CO, SO7 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyI, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and U^J-di-[(l-4C)a]kyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a R14 substituent optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CH2 or CHs group within a Z group optionally bears on each said CHa or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy^ earbamoyl, sulf amoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, ^-(l-6C)alkyl-(2-6C)alkanoylamino,N-(l-6C)alkylsulfamoyl) N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino;
or a pharmaceutically acceptable salt thereof.
In an embodiment, in the compound of formula la m is 0 or m is 1 and R1 is (1-3C)alkoxy, for example methoxy. Particularly m is 0.
In another embodiment, in the compound of formula la, n is 0 and R3a is selected from halogeno, trifluoromethyl, (l-4C)alkyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl. Particularly R3a is selected from halogeno and (l-3C)alkyl, more particularly R3a is selected from chloro and methyl, still more particularly R3a is chloro. In this embodiment n is suitably 0 or 1. Particularly n is 0.
In another embodiment, in the compound of formula la, X1 is selected from O, S and OC(R7)2, wherein R7 is hydrogen or (l-3C)alkyl, more particularly X1 is selected from O and OC(R\, for example X1 is selected from O, OCH2 and OC(CH3)2. In another embodiment, in the compound of formula la, X1 is selected from S and OC(R7)2, wherein R7 is hydrogen or (l-3C)alkyl, more particularly X1 is QC(R\, for example X1 is OCH2.
In another embodiment, in the compound of formula la, Q1 is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1 nitrogen heteroatom and optionally 1 additional heteroatom selected from oxygen, nitrogen and sulfur,
and wherein Q1 optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different selected from halogeno, hydroxy, cyano, carboxy, nitro, amino, (l-4C)alkyl, (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkylthio, (1-4C)alkylsulfinyl, (l-4Qalkylsulfonyl, (2-4C)al3canoyl, N-(l-4C)alkylamino, ^N-di-Ul-4C)aDcyl]amino, (l-4C)alkoxycarbonyl, carbamoyl, N-(l-4C)alkylcarbamoyl, N» £f-di-[(l-4C)alkyl]carbamoyl, (2-4C)alkanoyloxy, (2-4C)alkanoylamino, H-(l-4C)alkyl-(2-4C)alkanoylamino, halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, carboxy-U^Qalkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N, M-di-[(l-4C)alkyl]amino-(l-4C)alkyl
In another embodiment, in the compound of formula la, Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl, optionally substituted by 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro),

hydroxy, (l-4C)alkyl and (l-4C)alkoxy. For example Q1 is selected from phenyl optionally substituted with 1 or 2 substituents selected from fluoro and chloro or Q1 is selected from 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl, 1,3-thiazol-5-yI and isoxazol-3-yl (particularly 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl and isoxazol-3-yl), and wherein any heterocyclic group in Q1 optionally bears 1, 2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (l-4C)alkoxy.
In another embodiment, in the compound of formula la, Q1 is pyridyl (for example 2-pyridyl or 3-pyridyl, particularly 2-pyridyl), which optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (l-4C)alkoxy. For example, Q1 is particularly pyridyl, optionally substituted by 1 or 2 (l-4C)alkyl substituents (for example by 1 or 2 methyl substituents).
In another embodiment, in the compound of formula la, R4, R4*, R5 and R5a are selected from hydrogen and (l-3Qalkyl, for example R4, R4*, R5 and RSa are selected from hydrogen and methyl.
In another embodiment, in the compound of formula la, R4, R4*, R5 and R51 are all hydrogen.
In another embodiment, in the compound of formula la, R4", R5 and R5a are hydrogen and R4 is (l-3C)alkyl, for example methyl.
In another embodiment, in the compound of formula la, R4, R4* and R5a are hydrogen and R5 is (l-3C)alkyl, for example methyl.
In another embodiment, in the compound of formula la, R4 and R4* are both hydrogen and R3 and R5* are both (l-3C)alkyl, for example methyl.
In another embodiment, in the compound of formula la, R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
wherein any heterocyclyl group within R6 is a 4,5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno,trifluoromethyl, hydroxy, amino, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O and N(Rn), wherein Rn is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and M,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents.
In another embodiment, in the compound of formula la, R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-4C)alkyl, heterocyclyl and heterocyclyl-(l-4C)alkyl,
wherein any heterocyclyl group within R6 is a 4, 5,6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bronto, hydroxy, (l-4C)alkyl, (2-4Qalkenyl, (2-4C)alkynyl and (l-4C)alkoxy,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 oxo substituent,
and wherein any CH2 or CHa group within a R6 substituent, other than a CHa group within a heterocyclyl ring, optionally bears on each said CHfe or CHs group one or more substituents selected from fluoro and chloro, or a substituent selected from hydroxy and (l-4C)alkoxy, (l-6C)alkylamino anddi-[(l-6C)alkyl]amino.
In another embodiment, in the compound of formula la, R6 is selected from hydrogen and (l-4C)alkyl. For example R6 is (l-3C)alkyl such as methyl.
In another embodiment, in the compound of formula la, R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl and cyclopropylmethyl,
and wherein any CHj group within a cycloalkyl group within R6 optionally bears on each CHa group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy,
and wherein any hetetocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chioro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy.
In another embodiment, in the compound of formula la, A is a group of the formula Z-
(CR12R"V
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)a!kyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein any CHa or CEfe group within any of R12 and R13, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyl substituents or a substituent selected from hydroxy and (l-4Qalkoxy,"
and wherein Z is selected from hydrogen, OR15, NR16Rn and (l-6C)alkylsulfonyl( wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-4Qalkyl and (l-4C)aIkoxycarbonyl.
For example, in an embodiment, Z is selected from hydrogen, hydroxy, methoxy, N-methylamino, N,N-dimethylamino, (N-methyl)-(N-tert-butoxycarbonyl)amino and methylsulfonyl (particularly Z is hydroxy).
In another embodiment, in the compound of formula la, A is a group of the formula Z-
(CR12R13y,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein any CH2 or CHa group within any of R12 and R13, optionally bears on each said CHz or CKb group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyI substituents or a substituent selected from hydroxy and (l-4C)alkoxy,
and wherein Z is selected from hydrogen, hydroxy and (l-3C)alkoxy. For example Z is hydrogen or hydroxy, particularly Z is hydroxy.
In another embodiment, in the compound of formula la, A is selected from methyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 2-hydroxyprop-2-yl. Particularly A is hydroxymethyl.
In another embodiment, in the compound of formula la: misO;
R3a is selected from fluoro, chloro and (l-3C)alkyl (for example R3a is chloro or methyl, particularly R3a is chloro);
n is 0;
X1 is selected from O and OCH2 (for example X1 is OCH2);
R4, R4a, R5 and R5a are selected from hydrogen and (l-3C)alkyl, for example R4, R*1, R5 and
R5" are selected from hydrogen and methyl (for example R4* and R5a are hydrogen and one of
R4 and R5 is methyl and the other of R4 and R5 is hydrogen or R4 and R4* are both hydrogen
and R5 and R5* are both methyl); or
R4 and R4* togemer with the carbon atom to which they are attached form a (3-6C)cycloalkyl
ring, or
R5 and R5a together with the carbon atom to which they are attached form a (3-6C)cycloalkyl
ring;
R6 is hydrogen or (l-3C)alkyl, for example R6 is hydrogen or methyl (a particular value for R6
is methyl);
A is a group of the formula Z-(CR12Rl3)p-,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-3C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein Z is selected from hydrogen, hydroxy and (l-3C)alkoxy (for example Z is hydrogen or hydroxy, particularly Z is hydroxy).
In another embodiment, in the compound of formula la:
misO;R is selected from fluoro, chloro and (l-3C)alkyl (for example R3a is chloro or methyl, particularly R3a is chloro);
n is 0;
X1 is selected from O, OCH2 and OC(CH3)2 (for example X1 is OCH2); R4, R4a, R5 and R5a are selected from hydrogen and (l-3C)alkyl, for example R4, R48, R5 and R5a are selected from hydrogen and methyl (for example R4, R4*, R5 and R5a are all hydrogen, or R4* and R5a are both hydrogen and one of R4 and R5 is methyl and the other of R4 and R5 is hydrogen, or R4 and R49 are both hydrogen and R5 and R5a are both methyl);
R6 is selected from hydrogen, (l-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (3-5C)cycloalkyl, (3-5C)cycloalkyl-(l-3C)alkyl and heterocyclyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more (l-6C)alkyl substituents (for example R6 is hydrogen or methyl (a particular value for R6 is methyl)); A is selected from a group of the formula Z-(CR12R13)p- and R14,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
and wherein any CHa or CHa group within any of R12 and R13, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy (particularly hydroxy),
Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl and (l-6C)alkoxycarbonyl,
R14 is selected from OR19 and NR16R17, wherein R19 is selected from (l-6C)alkyl and wherein R16 and R17 are as defined above,
orR14 is Q4 wherein Q4 is (3-7C)cycloalkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more (for example 1,2 or 3) substituents, which may be the same or different, selected from halogeno, hydroxy, (l-6C)alkyl and (l-6C)alkoxy (particularly (l-6C)a!kyl),
and wherein any CHa or CHb group within a Z or R14 group, other than a Cfife group within a heterocyclyl ring, optionally bears on each said CHfe or CHa group one or morehalogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy (particularly a substituent selected from halogeno and hydroxy).
Another particular embodiment of the present invention is a quinazoline derivative of the formula I of the formula Ib:
J

Ib
wherein:
R3" is selected from cyano, halogeno, (l-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
Q1 is aryl, or heteroaryl,
and wherein Q! optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (l-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, cd-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, M-(l-6C)alkylcarbamoyl, &H^-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)alkynoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)aIkenoylamino, H-d-6C)alfcyl-(3-6C)alkenoylamino, C3-6C)alkynoylamino, N-(l-6C)alkyl-(3-6C)alkynoylamino, N-(l^C)alkylsulfamoyl,EN^-[(l-6C)allcyl]sulfamoyl,(l-6C)alkanesulfonylarnino, H-(l-6C)aikyl-(l-6C)alkanesulfonylamino, and a group of the formula:
-X2-R8
wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyi, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (1 -6C)allcoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N-(r-6C)alkylarnino-(l-6C)alkyl,H,H-di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-(l-6C)alkyl, N-(l-6C)alkyl-(2-6C)alkanoylamino-(l-6C)alkyl,
(l-6C)alkoxycarbonylamino-(l-6C)alkyl, carbamoyl-(l-6C)alkyl, N-0-6C)alkylcarbamoyl-(l-6C)alkyl, N^-di-[(l-6C)alkyl]carbamoy]-( l-6C)alkyl, (1-6C)alkylthio-(l-6C)alkyl,(l-6C)alkylsuJfinyl-(l-6C)alkyl, (l-6C)alky]sulfonyl-(l-6C)alkyl sulfamoyl(l-6C)aIkyl, N-(l-6C)aIkylsulfamoyl(l-6C)alkyl, N.N-
di-(l-6C)alkylsulfamoyl(l-6C)aIkyl, (2-6C)alkanoyl-(l-6C)alkyl,(2-6C)alkanoyloxy-(l-6C)alkyl or (l-6C)aIkoxycarbonyl-(l-6C)alkyl,
and wherein any CH2 or CH3 group within -X"-Q1 optionally bears on each said CH2 or CHa group one or more (for example 1,2, or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)aIkylamino and di-[(l-4Qalkylamino];
R4, R4*, R5 and R3a, which may be the same or different, are selected from hydrogen and (l-6C)alkyl,
and wherein any CHfe or CHs group within any of R4, R4*, R5 and R5a optionally bears on each said CHfe or CHs group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)atkanoyl, (1-6C)alkylamino anddi-[(l-6C)alkylamino];
R6 is selected from hydrogen, (l-6C)alkylt (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl andheterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, m"tro, hydroxy, amino, fonnyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O, CO, SOa and N(Rn), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l^C)alkyl, (l-4C)alkoxy-(l-4C)aIkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-(l-4C)alkylamino-(l-4C)alkyl and H,H-di-[(l-4C)alkyl]amino-(l-4C)aUcyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents;
and wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy> carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyI, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N^-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, H-(l-6C)alkyI-(2-6C)alkanoylamino, N-(l-6C)alkylsulfamoyl, N^i-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonyIamino;
A is selected from hydrogen, a group of the formula Z-(CR12Rl3)p- and R14,
wherein p is 1, 2,3, or 4,
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7Qcycloalkyl or (3-7C)cycloaIkenyl ring,
and wherein any CH2 or CH3 group within any of Ru and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (l-6C)alkyIamino and di-((l-6C)alkyl]amino>
Z is selected from hydrogen, OR15, NR16R17, (l-6C)alkylsulfonyl, (l-6G)alkanesulfonylamino andN-(l-6C)alkyl-(l-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (l-6C)alkoxycarbonyl,
or Z is a group of the formula:
Q"-X4-
wherein X4 is selected from O, N(R18), SOa and SO2N(R18), wherein R18 is hydrogen or (1 -6C)alkyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl,
R14 is selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-SQalkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above,
or R14 is a group of the formula:
Q3-X5-
wherein Xs is selected from O and N(R20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl--(l-6C)alkyl,
or R14 is Q4 wherein Q4 is (3-7Qcycloalkyl, (3-7Qcycloalkyl-(l-6C)alkyl, (3-7Ocycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6Qalkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO* N(R21), CO, -C=C- and -GC-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent 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, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl> (2-6C)alkanoyloxy and from a group of the formula:
-X"-R22
wherein X6 is a direct bond or is selected from O, CO, SO2 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, andR22 is halogeno-(l~4C)alkyl, hydroxy-(l^C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, M-(l-4C)alkylamino-(l-4C)alkyl and H,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CEfeor CHa group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CHa or CEfe group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyl, N^-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-£C)alkanoyloxy, (2-6C)alkanoylamino, HKl^Qal^H2-6C)alkanoylamino, N-(l-6C)alkylsulfamoyl, N,,M-di-[(l-6C)alkyl]sulfamoyl, (l-6QaIkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the present invention is a quinazoline derivative of the formula I of the formula lb, wherein:
R3a is selected from hydrogen, fluoro, chloro, trifluoromethyl, (l-3C)alk;yl, (1-3C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
Q1 is selected from phenyl, pyridyl, pyrazinyl, thiazolyl and isoxazolyl, optionally substituted by 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (l-4C)alkoxy;
R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (I~3C)alkyl,
and wherein any CH2 or CH3 group within any of R4, R4*, R5 and R5* optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy and (l-3C)alkoxy;
R6 is selected from hydrogen and (l-4C)alkyl;
A is a group of the formula Z-(CR12R13)P- ,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4Qalkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein any CHa or CEb group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno substituents or a substituent selected from hydroxy, and (l-3C)alkoxy,
Z is selected from hydrogen, OR15 and NR16R17, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
and wherein any CH2or CH3 group within a Z group optionally bears on each said CHa or CH3 group one or more fluoro or chloro substituents or a substituent selected from hydroxy, (2-4C)alkenyl, (2-4C)alkynyl and (l-4C)a!koxy;
or a pharmaceutically acceptable salt thereof.
In an embodiment, in the compound of formula Ib, R3a is selected from hydrogen, chloro and (l-3C)alkyl, particularly R3a is chloro or (l-3C)alkyl (such as methyl), more particularly R3a is chloro.
In another embodiment, in the compound of formula Ib, Q1 is selected from phenyl optionally substituted with 1 or 2 substituents selected from fluoro and chloro, or Ql is selected from 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, l,3-thiazol-4-yl, 1,3-tniazol-5-yl and isoxazol-3-yl (particularly 2-pyridyl, 3-pyridyl, 2-pyrazinyl, l,3-thiazol-2-yl, 1,3-thiazol-4-yl and isoxazol-3-yl),
and wherein Ql optionally bears 1,2, or 3 substituents, which may be the same or different, selected from halogeno (for example fluoro or chloro), hydroxy, (l-4C)alkyl and (1-4C)alkoxy.
In another embodiment, in the compound of formula Ib, Q1 is pyridyl (for example 2-pyridyl or 3-pyridyl, particularly 2-pyridyl).
In another embodiment, in the compound of formula Ib, R4, R4", R5 and R5" are selected from hydrogen and (l-3C)alkyl, for example R4, R4*, Rs and R5a are selected from hydrogen and methyl.
In another embodiment, in the compound of formula Ib, R4, R4*, R5 and R5* are all
hydrogen.
In another embodiment, in the compound of formula Ib, R4*, R5 and R5* are hydrogen and R4 is (l-3C)alkyl, for example methyl.
In another embodiment, in the compound of formula Ib, R4, R4* and R5a are hydrogen and R5 is (l-3C)alkyl, for example methyl.
In another embodiment, in the compound of formula Ib, R4 and R4* are both hydrogen and R5 and R5a are both (l-3C)alkyl, for example methyl.
In another embodiment, in the compound of formula Ib, R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl and cyclopropylmethyl,
and wherein any CHa group within a cycloalkyl group within R6 optionally bears on each CH2 group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy,
and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy.
In another embodiment, in the compound of formula Ib, A is a group of the formula Z-
(CR12R1V,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (MC)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein any CH2 or CH3 group within any of R12 and R13, optionally bears on each said CH2 or CH3 group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy,
and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-4C)alkyl and (l-4C)alkoxycarbonyl.
For example, in an embodiment, Z is selected from hydrogen, hydroxy, merhoxy, N-methylamino, N^-dimethylamino, (N-memylHN-Jert-butoxycarbonyI)amino and methylsulfonyl (particularly Z is hydroxy).
In another embodiment, in the compound of formula Ib, A is a group of the formula Z-(CR12R13)p-,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein any CH2 or CHa group within any of R12 and R13, optionally bears on each said CBfe or CHa group one or more (for example 1,2 or 3) halogeno or (l-4C)alkyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy,
and wherein Z is selected from hydrogen, hydroxy and (l-3C)alkoxy. For example Z is hydrogen or hydroxy, particularly Z is hydroxy.
In another embodiment, in the compound of formula Ib, A is selected from methyl and hydroxymethyl. Particularly A is hydroxymethyl.
In another embodiment, in the compound of formula Ib, A is a group of the formula Z-
(CR12R13V,
wherein p is 1 or 2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyl ring,
and wherein Z is NR16R17, wherein each of R16 and R17, which may be the same or different, is selected from hydrogen and (l-4C)alkyl (for example Z is selected from amino, H-methylamino and N^J-dimethylamino, particularly Z is N^J-dimethylamino).
In another embodiment, in the compound of formula Ib: Q1 is pyridyl (for example 2-pyridyl); R3* is selected from chloro and methyl (particularly R3* is chloro);
R4, R4*, R5 and R5*, which may be the same or different, are selected from hydrogen and
methyl; and
A is a group of the formula ZKCR^R13),-»
wherein pis 1 or2,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-3Qalkyl (for example R12 and R13 are selected from hydrogen and methyl),
and Z is selected from hydrogen, and hydroxy (particularly Z is hydroxy).
A particular embodiment of the present invention is a quinazoline derivative of the formula I of the formula Ic:
(Figure Removed)herein:
R3a is selected from cyano, halogeno, (l-4C)alkyl, triflupromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
n is 0,1 or 2;
each R3b, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
R3a is selected from halogeno and (l-4C)alkyl;
R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (l-6C)alkyl, or
R4 and R4a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, or
R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring,
and wherein any CH2 or CH3 group within any of R4, R4*, R5 and R5* optionally bears on each said CH2 or CH3 group one or more (for example 1, 2 or 3) halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino];
R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloaIkenyl, (3-7Qcycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl] amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
wherein X3 is a direct bond or is selected from 0, CO, SOa and N(R11), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, M-(l-4C)alkylamino-(l-4C)al]cyl and H^-di-[(l-4C)alkyl]amino-(l-4C)alkyi,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents;
and wherein any CHj or CHj group within a R6 substituent, other than a CEfe group within a heterocyclyl group, optionally bears on each said CHa or CHa group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, v crboxy, jarbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio,
(l-6C)alkylsulfinyl, (l-6C)alleylsu]fonyI, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, £Hl-6C)aIkylcarbamoyl, N£-di-[(l-6C)alkyl]cart>amoyl, (2-6C)alkanoyl, (2-6C)a]kanoyIoxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, H-(l-6C)alkyisuIfamoyl, N^{-di-[(l-6C)alkyl]sulfamoyl( (l-6C)alkanesulfonylamino and N-(l-6C)alkyl-(l-6C)alkanesuIfonyIamino;
A is selected from hydrogen, a group of the formula Z-(CRl2R13)p- and R14,
wherein p is 1,2, 3, or 4,
each Ri2 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyI ring,
and wherein any CHa or CHa group within any of R12 and R13, optionally bears on each said CH2 or CEfe group one or more (for example 1,2 or 3) halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (l-6C)alkyl, (l-6C)alkoxy, ammo, (2-6C)alkanoyI, (l-6C)alkylamino and di-[(l-6C)alkyl]amino,
Z is selected from hydrogen, OR15, NRI6R17, (l-6C)alkylsulfonyl,
(l-oX^alkanesulfonylamino andN-(l-6XH)alkyKl-6C)alkanesulfonylamino, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyI, (2-6C)alkynyl and (l-6C)alkoxycarbonyI,
or Z is a group of the formula:
Q2-X*-
wherein X*is selected from O, N(R18), SOz and SOzNfR18), wherein R18 is hydrogen or (l-6C)a!kyl, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl orhetetocyclyl,
R14 ia selected from hydrogen, OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above,
or R14 is a group of the formula:
Q3-X5-
wherein X5 is selected from O andN(R20), wherein R20 is hydrogen or (l-6C)alkyl, and Q3 is (3-7C)cycloalkyl, (3-7C)cycloaIkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl,(3-7C)cycloalkyHl-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituenl are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R21), CO, -C=C- and -C=C-, wherein R21 is hydrogen or (l-6C)alkyl,
and wherein any heterocyclyl group within a Z or R14 substituent 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, ammo, formyl, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6Qalkylamino, di-tCl-eQalkyllamino, (2-6C)alkanoyl, (2-6C)alkanoyIoxy and from a group of the formula:
-X"-R22
wherein X6 is a direct bond or is selected from O, CO, SO2 and NCR23), wherein R23 is hydrogen or (l-4C)alkyl, and R22 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4Qalkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, H-(l-4C)alkylaniino-(l-4Qalky] and H^-di-[(l-4C)a!kyl]amino-(l-4C)alkyl, and wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents,
and wherein any CH2 or CHb group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsuIfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, N-(l-6C)alkylcarbamoyI, &N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylainino, Ji-(l-6C)alkyl-(2-6C)alkanoylamino, JS-(l-6Qalkylsulfamoyl, H.N-di-[(l-6C)alkyl]suIfamoyl, (l-6C)alkanesulfonylamino and £J-(l-6C)alkyl-(l-6C)alkanesulfonylamino; or a pharmaceutically acceptable salt thereof.
In another embodiment, in the compound of formula Ic, n is 0 and R3a is selected from
halogeno, trifluoromethyl, (l-4C)alkyl, (l-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl.
Particularly R3a is selected from halogeno and (l-3C)alkyl, more particularly R3a is selected
from chloro and methyl, still more particularly R3a is chloro. In this embodiment n is suitably
0 or !>.• Particularly .-Q: is Q. .1 ,
In another embodiment, in the compound of formula Ic, R3c is (l-4C)alkyl, particularly methyl.
In another embodiment, in the compound of formula Ic, R4, R4a, R5 and R5a are selected from hydrogen and (l-3C)alkyI, for example R4, R4*, R5 and RSa are selected from hydrogen and methyl.
In another embodiment, in the compound of formula Ic, R4, R4a, R5 and R5a are all
hydrogen.
In another embodiment, in the compound of formula Ic, R4a, R5 and R5a are hydrogen and R4 is (l-3C)alkyl, for example methyl.
In another embodiment, in the compound of formula Ic, R4, R4* and R5a are hydrogen and R5 is (l-SC)alkyl, for example methyl.
In another embodiment, in the compound of formula Ic, R4 and R48 are both hydrogen and R5 and R5" are both (l-3C)alkyl, for example methyl.
In another embodiment, in the compound of formula Ic, Rti is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyHl-6€)alkyl, heterocyclyl and heterocyclyHl-6C)alkyl,
wherein any heterocyclyl group within R6 is a 4, S, 6 or 7 numbered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, and from a group of the formula:
-X3-R10
wherein X3 is a direct bond or is selected from O and N(RU), wherein R11 is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and H^-^-[(l-4C)alkyl]amincKl-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents.
In another embodiment, in the compound of formula Ic, R6 is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyI, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-4C)alkyl, heterocyclyl and heterocyclyl-(l-4C)alkyl,wherein any heterocyclyl group within R6 is a 4, 5, 6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur,
and wherein any heterocyclyl group within an R6 substiruent optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, hydroxy, (MQalkyl, (2-4C)alkenyl, (2-4C)alkynyl and (l-4C)alkoxy,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 oxo substituent,
and wherein any CHa or CH3 group within a R6 substituent, other than a CHj group within a heterocyclyl group, optionally bears on each said CHa or CBb group one or more substituents selected from fluoro and chloro, or a substituent selected from hydroxy and (l-4C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]arnino.
In another embodiment, in the compound of formula Ic, R6 is selected from hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl, isopropyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyranyl and cyclopropylmethyl,
and wherein any CH2 group within a cycloalkyl group within R6 optionally bears on each CHa group 1 or 2 substituents selected from hydroxy, methyl, ethyl, methoxy and ethoxy,
and wherein any heterocyclyl group within R6 optionally bears one or more substituents, which may be the same or different, selected from fluoro, chloro, bromo, oxo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and trifluoromethoxy.
In another embodiment, in the compound of formula Ic, A is a group of the formula Z-
(CR12R13)P-,
wherein p is 1 or 2,
each R12 andR13, which may be the same or different, is selected from hydrogen and (l-4C)alkyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-6C)cycloalkyI ring,
and wherein any CHa or CH? group within any of R12 and R13, optionally bears on each said.CHa or CHa group one or more (for example 1,2 or 3) halogeno or (l-4C)allfyl substituents or a substituent selected from hydroxy and (l-4C)alkoxy,
and wherein Z is selected from hydrogen, OR15, NR16R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (l-4C)a!kyl and (l-4Qalkoxycarbonyl.
For example, in an embodiment, Z is selected from hydrogen, hydroxy, methoxy, N-methylamino, N,N-dimethylamino, (N-methyl)-(N-tert-butoxycarbonyl)amino and methylsulfonyl (particularly Z is hydroxy).
A particular compound of the invention is, for example, one or more quinazoline derivatives of the formula I selected from:
AT-{2-[(4-{3-chloro^Kpyridin-2-ylmemoxy)aiiiUno}qiiinazolin-5-yl)oxy]ethyl}-2-methoxy-N-methylacetamide;
N-{2-[(4-{3 N-{(2J?>2-[(4-{3^hloro-4^yridin-2-ymiethoxy)anilino}quinazomi-5-yl)oxy]prop }~2-meffloxy-tf-inethylacetamide);
2-hydroxy-N-n»myl-^-{2-[(4-{3-methyl^(pyrazin-2-ylmemoxy)anilirH)}quinazolin-5-yl)oxy]ethyl} acetamide;
2-hydroxy-W-mernyl-#-{2-[(4-{3-mernyl-4Kl,3^ yl)oxy]ethyl} acetamide;
2-hydroxy-iV-methyl-JV-(2-{[4-(3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]anilino)quinazolin-5-yl]oxy}ethyl)acetamide; JV-{(2^)-2-[(4-{3^hloix)^(pyiidin-2-ylinfimoxy)anilmo}qiiinazolm-5-yl)oxy]piopyl}-^^
methoxyacetamide; ^K2-{[4-(3-chloro^[(6-memylpyridin-2-yl)methoxy]animio)quma2olm-5-yl]oxy}emyl)-2-
hydroxy-JV-methylacetamide;
^-((2^)-2-{[4-(3 ynoxyJpropylH-hydroxy-W"-methylacetamide-,
^^2-{[4-(3-chloro^[(6^memylpvridin-2-yl)memoxy]anilmo)qumazo^
methylacetamide;
N-(2-{[4^3^hloro-4-[(2-fluorobenzyl)oxy]amlmo)quinazolm-5-yl]oxy}ethyl>^
methylacetamide;
N-(2-{[4 methylacetamide;
/V-{2-[(4-{3-chIoro-4-(l,3-thiazol-4-ylmethoxy)anilino}quinazo)in-5-yl)oxy]ethyl}-N-
rnethylacetamide;
/y_{ 2-[(4- { 3-chloro-4-(pyrazin-2-ylmethoxy)anilino }quinazolin-5-yl)oxy]ethyl }-N-
methylacetamide;
N- { (27?)-2-[(4- { 3-chIoro-4-(pyridin-2-ylmethoxy)anilino } quinazolin-5-yl)oxy]propyl } -2-
hydroxyacetamide; ^-{2-[(4-{3-chIoro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-]V-
methylacetamide; 2-hydroxy-Ar-methyl-A^-{2-[(4-{3-methyl-4-(pyridin-2-yltnethoxy)anilmo}quinazoHn-5-
yl)oxy]ethyl}acetamide;
^-{(l/?)-2-[(4-{3-chloro-4-(pyridiii-2-ylmethoxy)aralino}qiunazolin-5-yl)oxy]-l-
methylethyl}acetamide;
methylethyl }-2-hydroxyacetamide;
W-{2-[(4-{3^hloro^(pyridin-2-yln»*oxy) methylacetamide;
N-(2-{[4-(3-cWc«)^-[(3-fluorobenzyl)oxy]aniUno)qidriazolin-5-yl]oxy}e1hyl>2-hydK)xy-^^ methylacetamide;
N-{2-[(4-{3^Wcm>^(13-thiazol-4-yImethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-^V-methylacetamide;
JV-{2-[(4-{3-cMoro^-(pynizin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-N-methylacetamide;
N-{2-[(4-{3-chlon>-4-(pyridin-2-ylmethoxy)anilmo}quinazolm-5-yl)oxy]ethyl}acetamide;
N-{(2^)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilmo}quinazolin-5-ylX>xy]propyl}acetamide;
JV-{(2jR)-2-[(4-{3-chloro-4-(pyridm-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-N-methylacetamide;
N- { (2/?>2-[(4- { 3-chloro-4-(pyra2in-2-ylmethoxy)anilino } quinazolin-5 -yl)oxy]propyl } -2-hydroxy-]V-methylacetamide;
N-((2/?)-2-{[4-(3-chloro-4-[(3-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}propyl)-2-hydroxy-N-methylacetamide;
AT-{(2R)-2-((4-{3-chloro-4-(l,3-thiazol-4-ylmethoxy)anilino}qumazolm-5-yl)oxy]propyl}-2-hydroxy-N-methylacetamide;
N- {(2R}-2- [(4- {3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl} -N-
raethylacetamide;
N- {2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino} quinazolin-5-yl)oxy]ethyl} -N-
ethylacetamide;
AT-{2-[(4-{[3K;hlQro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoUn-5-yl)oxy]ethyl}-A^
ethyl-2-hydroxyacetamide;
^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5--yl)oxy]ethyl}-^-
propylacetamide;
N-{2-[(4-{[3-chloro-4^yridin-2-ylmethoxy)ph^
hydroxy-^V-propylacetainide;
^-(2-[(4-{ [3^hloro^pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl }-JV-
isopropylacetamide;
N-{2-[(4-{[3^hloro^-(pyridn-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyI}-2-
hydroxy-^V-isopropylacetamide;
N-allyl-^-{2-[(4-{[3-cWoro^(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-
yl)oxy]ethyl} acetamide;
7/-allyl-N-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl} -2-hydroxyacetamide;
^-{2-[(4-{[3K;Woro^ cyclopropylacelamide;
//-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-^V-
cyclopropyl-2-hydroxyacetamide;
N-{2-[(4-{[3-chloro^-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-^^
(cyclopropylmethyl)acetamide;
jV-{2-[(4-{[3-chloit>4-(pyridin-2-ylinethoxy)phenyl]ainino}quinazolin-5-yl)oxy]ethyl}-^-
(cyclopropylmethyl>2-hydroxyacetamide;
N- {2-[(4-{ [3-chloro-4-(pyridin-2-ylmelhoxy)phenyl3amino }quinazolin-5-yl)oxy]ethyl }-N-
cyclobutylacetamide;
N~{2-[(4-{ [3-chloro^-(pyridin-2-ylmethoxy)phenyllamino }quinazolin-5-yl)oxy]ethyl }-N-
cyclobutyl-2-hydroxyacetamide; ^.{2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-AL(l-
methylpiperidin-4-yl)acetamide; jV-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIin-5-yl)oxy]ethyl}-N-
(tetrahydro-2H-pyran-4-yl)acetamide; ^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]ainino}quina2olin-5-yl)oxy]ethyl}-2-
hydroxy-N-(tetrahydro-2H-pyran-4-yl)acetamide;
N- {2-1(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -N-(2-
hydroxyethyl)acetamide;
A/r-{2-[(4-{[3-cWoro^(pyridin-2-ylmethoxy)phenyllamino}quinazolm-5-yl)oxy]ethyl}-2-
hydroxy-N-(2-hydroxyethyl)acetamide;
Wr-{2-[(4-{[3-chloro^(pyridin-2-ylmethoxy)phenyl]anrino}quinazolin-5-yl)oxy]ethyl}-N-(2-
methoxyethyl)acetamide;
N-( 2-[(4- {[3^hl hydroxy-N-(2-methoxyethyl)acetaniide;
AT-{2-[(4-{[3^hloro^-(pyridiii-2-yImethoxy)phenyl]aiiuno}quinazolin-5-yl)oxy]ethyl}-N-
prop-2-yn-l-ylacetamide;
N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino }quinazolin-5-yl)oxy]ethyl} -2-
hydroxy-JV-prop-2-yn-l-ylacetamide;
N-{ 2-[(4-{ [3-chIoro-4-(pyridin-2-ylinethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-N-methylpropanamide;
AT-{2-[(4-{[3^hloro^(pyridin-2-ylmelhoxy)phenyl]arnino}quinazo!in-5-yl)oxy]ethyl}-N-
methyl-tetrahydrofuranyl-2-carboxamide;
A/"-{2-[(4-{[3K;hIoro^(pyridin-2-ylmethoxy)phenyl]aniino}qiunazolin-5-yl)oxy]ethyl}-N,l-
dimethylprolinamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-Ar,2-dimethylpropanamide;
7^-{2-[(4-{[3^hlor(>4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-l-
bydroxy-Ar-methylcyclopropanecarboxamide;
Nl-{ 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl }-
N1 jV2-dimethylglycmamide;
AM 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -3-
hydroxy-M2,2-triraethylpropanamide;
N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-ylX)xy]ethyl} -3-
hydroxy-N-methylpropanamide;
N-{(25)-2-[(4-{[3-chloro-4-(pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl} acetamide;
N-{ (2S)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phcnyl]amino }quinazolin-5-
yl)oxy]propyl}-2-hydroxyacetaniide;
Nl-{ (2S)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phwiyl]amino}quinazolin-5-
yl)oxy]propyl} -JV2 J^-dimethylgiycinamide;
N-{ (25)-2-[(4-{ [3-chl«x>-4-(pyriclin-2-ylinethoxy)phenyl]ainino}quinazolin-5-
yl)oxy]propyl} -2-methoxyacetamide;
N-{ (25>2-[(4-{ [3^hlc>ro-4^pyridin-2-ylinethoxy)phenyl]ainino}quinazolin-5-
yl)oxy]ptopyl} -2-(methylsulfonyl)acetamide;
^-{2-[(4-{[3^hl(m>-4^yri(tin-2-ylinrthoxy)phenyl]aiiriiK)}qomazoUn-^
hydroxyacetamide;
AT1-{2-[(4-{[3^Waro^pyridin-2-yktiethoxy)phenyl]aniiiK>}qira
A^^-dimethylglycinainide;
^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phCTyl]amino}quinazoUn-5-yl)oxy]ethyl}^
methoxyacetaraide;
AT-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]aimno}quinazoUn-5-yl)oxy]e^
(methylsulfcmyl)acetamide;
A/^-{(25)-2-[(4-{[3K;hloix)^(pyridin-2-yImethoxy)phenyl]amino}qumazolin-5-
yl)oxy]propyl}-JV-metihylacetamide;
^-{(25)-2-[(4-{[3^hloK>4^yridin-2-ylniethoxy)phenyl]ainino}quinazolm-5-
yl)oxy]propyl}-2-hydroxy-JV-methylacetamide;
JV1-{(2^2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]aniino}quinazolm-5-
yl)oxy]propyl}-Nl^JV2-trimethylglycinainide;
A^{(2^2-[(4-{[3-cWoro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
ylX>xy]propyl} -2-methoxy-N-methylacetamide;
N- {(25>2-[(4- {[3-chloro-4-(pyridin-2-ylmcthoxy)phenyl]amino }quinazolin-5-
yl)oxy]propyl}-JV-methyl-2-(methylsulfonyl)acetaniide;
N-{ (2K)-2-[(4- { [3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]propyl } -W-methylacetamide; /\r-{(2/?)-2-[(4-{[3-chIoro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl } -AT-methylacetamide;
N-((2R)-2-{ [4-( {3-chloro-4-[(3-fluorobenzyl)oxy]phenyl } amino)quinazolin-5-
yl]oxy } propyl)-W-methyl acetamide;
^-((2/?)-2-{[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}aniino)quinazolin-5-
yl]oxy } propyl)-A^-methylacetamide;
N-{(l/?)-2-l(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]anuno}quinazolin-5-yl)oxy]-l-
methylethyl}-2-hydroxy-?/-methylacetamide;
A^{(l/?)-2-[(4-{[3-chloro^pyridin-2-ylrnetlioxy)phenyl]amino}quinazolin-5-yl)oxy]-l-
methylethyt}-N-methylacetamide;
AT-{(l,S)-2-[(4-{[3-chloro-^pyridin-2-ylmethoxy)phenyl]ainino}quinazolin-5-yl)oxy]-l-
methylethyl}-2-hydroxy-N-methylacetamide;
^-{(15^2-[(4-{[3^hlon>-4^yridin-2-ylmethoxy)phenyl]aiiiino}quina2olin-5-yI)oxyl-l-
methylethyl }-JV-methylacetamide;
N-{(lS)-2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l-
methylethyI}-2-methoxy-N-methylacetamide;
N-{(15)-2-[(4-{[3-chlon>^pyridin-2-ylinethoxy)phenyl]aniino}quinazolin-5-yl)oxy]-l-
methylethyl}-2-hydroxyacetamide;
^-{(15)-2-[(4-{E3-chlon)^(pyridin-2-ylinethoxy)ph«iyl]aniino}quinazoIin-5-yl)oxy]-l-
methylethyl } acetamide;
methylethylJ-^^-dimethylglycinamide1,
JV1-{(2^>2-[(4-{[3^hloro-4-(pyridm-2-ylmethoxy)phenyl]ainino}quina2olin-5-
yl)oxy]propyl } -N2 ^-dimethylglycinamide;
(2S)-AT-{2-[(4-{[3 2,4-dihydroxybutanamide;
(2R)-N-{ 2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl}-
2,4-dihydroxybutanamide;
(2/?)-AH(2/?)-2-[(4-{[3^fopro-4-(pyrid yl)oxy]propyl}-2,4-dihydroxybutanamide;
(2S)-N-{ (2tf )-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-
yl)oxy]propyl} -2,4-dihydroxybutanamide;
(2/?)-A^{(25r)-2-[(4-{[3-ch1oro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl} -2,4-dihydroxybutanamide;
(2S)-N- {(25>2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino }quinazolin-5-
yl)oxy|propyl} -2,4-dihydroxybutanamide;
(25)-JV-{(l/?)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]arnino}quinazo]in-5-yl)oxy)-
1-methylethyl }-2,4-dihydroxybutanamide;
(2R)-^{(l/0-2-[(4-{[3-chlon>4-(pyridm^
1-methylethyl }-2,4-dihydroxybutanamide;
(2/0-#-{2-[(4-{[3-cMoro-4-(l,3-tm"azol-4-ylm^
ylX>xy]ethyl} -2,4-dihydroxybutanamide;
(2S)-N- {2-[(4- {[3-chloro-4-(13-thiazol-4-ylmethoxy)phenyl]amiiio }quinazoIin-5-
yl)oxy]ethyl}-2,4-dihydroxybutanamide;
(2J?)-^-{(l/?)-2-[(4-{[3-cWoro-4^13-^^ol-4-ymiethoxy)pb^ayl]ainino}qi^
yl)oxy]-l-memylemyl}:2t4-dihydhx)xybiitanainide;
(2S)-N-{(lR)-2-[(4-{ [3HJhloro-4K13-miazol-4-ylmeajoxy)phenyl]amino} quinazolin-S-
yl)oxy]-l-methylethyl}-2,4-dihydroxybutanamide;
yV-memyl-N-{2-[(4-{[3-memyl-4-^yridin-2-ylmethoxy)phenyl]anrino}quinazolin-5-
yl)oxy]ethyi} acetamide;
JV-methyl-A^-{2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazoKn-5-
yl)oxy]ethyl }acetamide;
quinazolin-5-yl]oxy}ethyl)acetamide;
2-hydroxy-N-rnethyl-JV-{2-[(4-{[3-methyl-4-(l,3-thia2ol-2-yImethoxy)phenyl]
amino} quinazolin-S-yl)oxy]ethyl} acetamide;
2-hydroxy-N- {2-[(4-{ [3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolm-5-
yl)oxy]ethyl} acetamide;
2-hydroxy-A^{2-[(4-{[3-memyl^(l,3~thiazol^ylmemoxy)phenyl]amino}quinazolin-5-
ylX>xy]ethyl} acetamide;
^-{2-[{4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]aniino}quinazolm-5-y^
dimethylethyl} -2-hydroxyacetamide;
2-hydroxy-A^-{(2/?)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}qoina2olm-5-
yl)oxy]propyl} acetamide; 2-hydroxy-/V-{(2/?)-2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-
5-yl)oxy]propyl} acetamide; N-((2/?)-2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)quiiiazolin-5-
yljoxy }propyl)-2-hydroxyacetamide; 2-hydroxy-N-{(2^)-2-[(4-{[3-methyl-4-(l,3-thiazol-2-ylmethoxy)phenyl]amino}quinazoIin-
5-yl)oxy]propyl} acetamide;
AT-{(2/?)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
y l)oxy]ptopyl} acetamide;
N- {(2K)-2-[(4-{ [3-methyl-4-(l ,3-thiazol-4-ylmethoxy)phenyl]ainino }quinazolin-5-
yl)oxy]propyl} acetamide;
N-((2R)-2- ([4-( {4-[(3-fluorobenzyl)oxy]-3-methylphenyl} amino)quinazolin-5-
yl]oxy }propyl)acetamide;
N- {(2/?)-2- [(4- {[3-methyl-4-(l 3-thiazol-2-ylmethoxy)phenyl]amino }quinazolin-5-
yl)oxy]propy 1} acetamide;
2-hydroxy-AT-niethyl-N-{(2R>2-[(4-{[3-methyl-4-(pyridin-2--ylmethoxy)phenyl]
amino}quinazolin-5-ylX>xy]prq)yl}acetamide;
2-hydroxy-AT-methyl-^-{(2R)-2-[(4-{[3-methyl-4.(U-thiazol-4-
ylmethoxy)phenyl]amino}qumazolin-5-yl)oxy]propyl}acetamide;
2-hydroxy-#-methyl-jV-((2/0-2-{ [4-({ 3-methyl-4-[(5-methylisoxazol-3-
yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide;
A^methyl-//-{(l/?)-l-methyl-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]
ammo }quinazolin-5-yl)oxy]ethyl} acetamide;
N-mefoyl-N- {(IK)- l-methyl-2-[(4- {[3-methyl-4-(l ,3-thiazol-4-
ylmethoxy)phenyl]amino}quinazotin-5-yl)oxy]ethyl}acetamide;
JV-{(l/?)-2-[(4-{[3-chloro^(13-tWazol-4-ylmethoxy)phenyl]amino}quina2olin-5-yl)oxy]-l-
methylethyl} -2-hydroxy-AT-methylacetamide;
2-hydroxy-A^-methyl-AT-{ (l/?)-l-metbyl-2-[(4-{ [3-methyl-4-(pyridin-2-
ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl }acetamide;
ylmethoxy)phenyl]amino}qumazolm-5-yl)oxy]ethyl}acetamide;
N- { (2K)-2-[(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
ylX>xy]propyl}-l-hydroxy-N-methylcyclopropanecarboxamide;
(25)-N-{(2/?)-2-[(4-{[3-chloro-4-(pyridin-2-y]methoxy)phenyl]an)ino}quinazolin-5-
yl)oxy]propyl } -2-hydroxy-N-methylpropanamide;
^-{(2J?)-2-[(4-{[3-chloro-4-(pyridin-2-ylrnethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl } -2-hydroxy-JV,2-dimethylpropanamide;
(2R)-N~ { (lR)-2-[(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino }quinazolin-5-
yl)oxy]propyl } -2-hydroxy-JV-methylpropanamide;
(2/?)-Ar-{(2l?)-2-[(4-{[3^hloro-^(pyridin-2-ylmethoxy)phenyI]ainino}quina2olin-5-
yl)oxy]propyl } -2-methoxy-JV-metfiylpropanamide;
2-hydroxy-Ar-methyl-7V-((2/?)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}ajnino)quinazolin-5-yl]oxy}propyl)acetainidc;
N-mett\y\-N-((2R)-2-{ [4-({ 3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl } amino)quinazolin-
5-yl]oxy}propyl)acetamide;
yl)oxy]phenyl}amino)quinazolin-5-y]]oxy}propyl)glycinamide;
M-methyl-M-((2l?)-2-{[4-({3-rr»thyl^[(6-methylpyridin-3-yl)oxy]phenyl}amino)q^^
5-yl]oxy}propyl)-2-pyrrolidin-l-ylacetamide;
5-yl]oxy}propyl)-2-moiphoKn-4-ylacetaniide;
JV-me%l-/H(2/?)-2-{[4-({3-meAyl^
5-yl]oxy}ptopyl)-2-(4-methylpiperazin-l-yl)acetamide;
2-hydroxy-Ar-methyl-^-((25)-2-{[4-({3-methyl-4-[(6-tnethylpyridin-3-
yl)oxy]phenyl } amino)quinazolin-5-yl]oxy }propyl)acetamide;
A>r-methyl-A/-((2S)-2-{[4-({3-ira^^
5-yl]oxy}propyl)acetamide;
^-methyl-A^((25)-2-{[4-({3-methyl^[(6-methylpyridin-3-yl)oxy]phenyl}anuno^
5-yl]oxy}propyl>2-pyrrolidin-l-ylacetamide;
(25)-2,4-dihydroxy-^V-((2/?)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl } amino)quinazolin-5-yl]oxy}propyl)butanainide;
(25)-4-bromo-2-hydroxy^-((2/?)-2-{[4-({3-tnethyl-4-E(6-methylpyridin-3-
yl)oxy]phenyl } amino)quinazolin-5-yl]oxy }propyl)butanamide;
,V-(2-chloroethyl)-^V-((2^)-2-{[4-({3-raethyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}arnino)quinazolin-5-yl]oxy}propyl)urea;
2-hydroxy-A^-methyl-//-((l^)-l-methyl-2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl} amino)quinazolm-5-yl]oxy }ethyl)acetamjde;
TV-methyl-W-K!/?)-! -raethyl-2- {[4-({ 3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl} amino)quinazoHn-5-yl]oxy }ethyl)acetamide;
2-hydroxy-//-methyl-^-((15)-l-methyl-2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl} ainino)quinazolin-5-yl]oxy }ethyl)acetamide;
7V-methyl-Ar-((15)-l-methyl-2-{[4-({3-niethyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl} atnino)qumazolin-5-yl]oxy }ethyl)acetamide;
methyl-{2-[(4-{[3K;hloro^-(pyridin-2-ylniethoxy)phenyl]ainino}quina2olin-5-
yl)oxy]ethyl }methylcarbamate;
N-{ 2-[(4- {[3-chloro^(pyridin-2-ylme(hoxy)phejiyl]amino}quinazolin-5-yl)oxy]ethyl} -
dimethylurea;
^^2^hloroethyl>-^-{2-[(4-{[3^hl(»o-4^yridin-2-ylmethoxy)phenyl]aniino}qm^
yl)oxy]cthyl }-#-methylurea;
N-{ (2R)-2-[(4-{ [3-chloro-4-(pyridin-2-ylinethoxy)phenyl]ainino }quinazo!in-5-
yl)oxy]propyl} -JV-methylurea;
[((/?)-2-{4-f3^hloro-4^yridin-2-ylmethoxy)phenylaniino]quinazolm-5-
yloxy}propylcarbamoyl)methyl]mcthylcarbamic acid Jraj-butyl ester,
Nl- {(2R)-2-[(4- {[3-chlofo-4-(pyridin-2-yImethoxy)phenyl]amino }quina2»lin-5-
yl)oxy]propyl J-^-methylgJycinamide;
2-hydroxy-JV-methyl-A^-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl} amino)quinazolm-5-yl]oxy }ethyl)acetamide;
Ar-niethyl-JV-(2-{ [4-( {3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl} amino)quinazoIin-5-
yl]oxy}ethyl)acetamide; and
^V-{2-[(4-{[3-chloro-4-(l-methyl-l-pyridin-2-ylethoxy)phenyI]amino}quinazolin-5-
yl)oxy]ethyl} -JV-methylacetamide;
or a pharmaceutically acceptable salt thereof.
A particular compound of the invention is, for example, one or more quinazoline derivatives of the formula la selected from:
A^-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-methoxy-
A/-methylacetamide; //-{2-[(4-{3-chloro-4-(pyridin-2-ylinethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-
(dimethylamino)-JV-methylacetamide;
JV-{(2J?)-2-[(4-{3^hloit)^(pyridin-2-ylm^hoxy)anilino}quinazolin-5-yl)oxy]propyl)-2-
roethoxy-JV-methylacetamide);
2-hydroxy-A/r-methyl-/V-{2-[(4-{3-raetty^
yl)oxy]ethyl } acetamide;
2-hydroxy-AT-nwlhyl-yV-{2-[(4-{3-methyl^(13-thiazol^ylniethoxy)anilino}qumazolin-5-
yl)oxy]ethyl } acetamide;
2-hydroxy-AT-metfiyl-^-(2-{[4-(3-metfiyl-4-[(5-methylisoxazol-3-
yl)methoxy]anilino)quinazoUn-S-yl]oxy}ethyl)acetaniide;
^-{(2J?)-2-[(4-{3^hloro^pyridin-2-ylmeihoxy)aniHno}quina2oIiii-5-yl)o^
methoxyacetamide;
^-(2-{[4^3n;hl hydroxy-JV-methylacetamide;
ylloxyJpropyl^-hydroxy-N-metbylacetamidc;
^-(2-{[4^3^hloro^[(6-methylpyridin-2-yl)methoxy]aiulino)quinazoUn-5-yi]o^^
metiiylacetamide;
N-(2-{ [4^3K;hlon)^-[(2-fluorobenzyl)oxy]anilino)quinazoliii-5-yl]oxy }ethyl)-N-
methylacetamide;
^(2-{[4-(3^Woro^[(3-fluorobenzyl)oxy]aiiilino)quina2olin-5-yl]oxy}ethyl)-N-
methylacetamide; //-{2-[(4-{3^hloro^(l,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-JV-
methylacetamide;
methylacetamide;
A^-{(2/?)-2-[(4-{3^hloro^(pyridin-2-ylmethoxy)aniUno}quinazoUn-5-yl)oxy]propyl}-2^
hydroxyacetamide;
A^{2-[(4-{3^Woro-4-(pyridin-2-ylroethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-^
methylacetamide;
2-hydroxy-N-methyl-N-{2-[(4-{3-methyl-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-
yl)oxy]ethyl} acetamide;
N-{ (l/?>2-[(4-{ 3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l-
methylethyl} acetamide;
N-{(l/?)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l-
methylethyl}-2-hydroxyacetamide;
N- {2-[(4-{ 3-chloro-4-(pyridin-2-ylraethoxy)anilino }quinazolin-5-yl)oxy]ethyl} -2-hydroxy-W-methylacetamide;
N-(2- {[4- ^-{2-[(4-{3^Woro^-(13-thiazol-4-ylmethoxy)anUmo}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-AT-methylacetamide;
N-{2-[(4-{ 3-chlwro-4-(pyrazin-2-yhnethoxy)anilmo }quinazolin-5-yl)oxy]ethyl }-2-hydroxy-A^-methylacetamide;
^-{2-[(4-{3 N-{ (2R)-2-[(4-{ 3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl} acetamide;
JV-{(2/f)-2-[(4-{3^hloio^(pyridiiv2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-^V-methylacetamide;
j/V-{(21?)-2-[(4-{3KJhloro^(pyrazin-2-ylinethoxy)anilino}quinazolm-5-yl)oxy]propyl}-2-hydroxy-JV-methylacetamide;
^(21?)-2-{[4 ^V-{(2/?)-2-[(4-{3-chloro-4-(l,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxy]piopyl}-2-hydroxy-A^-methylacetamide;
JV-{(2^)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]propyl}-^-methylacetamide;
W-{2-[(4~{[3-chloro-4-(pyridin 2-ylmethoxy)phenyl]aimno}quuiazolin-5-yl)oxy]ethyl}-A/r-ethylacetamide;

-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-A"r-ethyl-2-hydroxyacetamide;
A/r-{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]araino}quinazolin-5-yl)oxy]ethyl}-Ar-propylacetamide;
Ar-{2-[(4-{[3-chloro-4-(pyridin-2-ylroethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-W-propylacetamide;
^-{2-[(4-{[3 isopropylacetamide;
^-{2-[(4-{[3^;hloro^-(pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-AMsopropylacetamide;
N-ally\-N~{ 2-[(4- {[3-chloro-4-^>yridin-2-ylmetfioxy)phenyl]amino }quinazolin-5-
yl)oxy]ethyl}acetamide;
yV-allyl-JV-{2-[(4-{[3-chloit)^(jpyridin-2-ylniethoxy)phenyl]amino}quina2olin-5-
yl)oxy]ethyl} -2-hydroxyacetamide;
JV-{2-[(4-{ [3 cyclopropylacetamide;
^-{2-[(4-{[3^hloro^-(pyridin-2-ylmethoxy)phenyl]anMno}quinazoUn-5-yl)oxy]ethyl}-A^
cyclopropyl-2-hydroxyacetamide;
^-{2-[(4-{[3^hloro^-(pyridin-2-ylinettioxy)phenyl]ainino}quinazolin-5-yl)oxy]ethyl}-A/-
(cyclopropylmethyl)acetamide;
N-{2-[(4-{ [3^hloKMl.-(pyridiiH2-ylineftoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl }-A/-
(cyclopropylmethyl>2-hydroxyacetanride;
A^-{2-[(4-{[3-chlorc>^-(pyridin-2-ylniethoxy)phenyl]amino}quinazoIin-5-y^
cyclobutylacetamide; ^{2-[(4-{[3^hloro-4-(pyridin-2-ylniethoxy)phenyl]amino}quinazolin-5-yl)oxy]e^
cyclobutyl-2-hydroxyacetamide;
//-{2-[(4-{[3-4-(pyridin-2-ylme^
methylpiperidin-4-yl)acetamide;
7V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N-
(tetrahydro-2H-pyran-4-yl)acetamide;
/^{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino}quinazolin--5-yl)oxy]ethyl}-2-
hydroxy-^-(tetrahydro-2H-pyran-4-yl)acetamide;
W-{2-[(4-{[3 chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl}-A/-(2-
hydroxyethyl)acetamide;
jV_{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]atnino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-/V-(2-hydroxyethyl)acetamide; Af-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-AT-(2-
methoxyethyl)acetamide; A^-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino}quinazolin-5-yl>)xy]ethyl}-2-
hydroxy-Af-(2-methoxyethyl)acetamide;
N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -N-
prop-2-yn-1 -ylacetamide;
N-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-N-prop-2-yn-l-ylacetamide;
N-{2-[(4-{[3^hloro^(pyridin-2-ylmcthoxy)phenyl]anjino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-^-methylpropanamide;
^-{2-[(4-{[3-chloro-4^pyridin-2-ylraethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N-
methyl-tetrahydrofuranyl-2-carboxamide;
^-{2-[(4-{[3^hloro^-(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl}-^V,l-
dimethylprolinamide;
jV-{2-[(4-{[3 hydroxy-//,2-dimethylpropananiide;
^-{2-[(4-{[3 hydroxy-N-methylcyclopropanecaiboxamide;
jV1-{2-[(4-{[3-chloro^-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-
Nl ^-dimethylglycinamide;
A^-{2-[(4-{[3-chloro^-(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl}-3-
hydroxy-JV,2,2-trimethylpropanamide;
N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]aniino} quinazolin-5-yl)oxy]ethyl} -3-
hydroxy-^V-methylpropanamide;
N- {(2S)-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-
>l)oxy]propyl} acetamide;
A^{(25)-2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phcnyl]anuno}quina2ofIrn-5-
yl)oxy]propyl }-2-hydroxyacetamide;
)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]propyl } -W2^2-dimethylglycinamide;
Af-{ (25>2-[(4~ { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]propyl } -2-methoxyacetamide;
N- { (2S>2-[(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]aniino }quinazoKn-5-yl)oxy]propyl } -2-(methy Isulfonyl)acetamide;
JV-{2-[(4-{[3^hloro-4-(pyridin-2-yImethoxy)phenyl]ainino}qumazolin-5-yl)oxy]ethyl}-2-hydroxyacetamide;
^-{2-[(4-{[3^hloro^pyTidin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-^^-dimethylglycinamide;
A^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]anuno}quinazoIin-5-yl)oxy]ethyl}-2-mcthoxyacetamide;
#-{2-[(4-{ [3-chloro-4-(pyridin-2-yhnetfioxy)phenyl]aTnino }qirinazolin-5-yl)oxy]ethyl}-2-(methylsulfonyl)acetamide;
^-{(25>2-[(4-{[3^hIoro^^yridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]propyl} -N-m^hylacetamide;
yIX>xy]prc^)yl } -2-hydroxy-^V-methylacetamide;
f?-{ (2S)-2-[(4-{ [3^hloro-4~^yridin-2-ylmethoxy)phenyl]aimno}quinazolin-5-
yl)oxy]propyl } -N1 JV^-trintethylgtytinamide;
^-{(2^2-[(4-{[3-chlon>4-(pyridin-2-yli]Mthoxy)phenyl]ainino}quina2o]in-5-
yl)oxylpropyl } -2-methoxy-^V-methylacetanride;
AT-{(25)-2-[(4-{[3-chlon)-4-(pyridin-2-ylmethoxy)pheny]]ainino}quina2olin-5-
yl)oxy]propyl } -JV-methyl-2-(methylsulf onyl)acetamide;
^-{(21?>-2-[(4-{[3^hloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ptopyl}-N-mcthylacetamide;
Ar-{(2/?)-2-[(4-{[3-cMoro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl }-JV-methylacetamide;
N-((2R)-2-{ [4-({ 3-chloro-4- [(3-fluorobenzyl)oxy]phcnyl} amino)quinazoKn-5-
yl]oxy }propyl)-JV-methylacetamide;
N-((2K)-2- { [4-( { 3-chloro-4-[(2-fluorobenzyl)oxy]phenyl } amino)quinazolin«5-
yl]oxy }propyl)-/V-methylacetamide;-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]-l-methylethyl} -2-hydroxy-N-methylacetarnide;
jV-{(l/?)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl>oxy]-l-methylethyl} -W-methylacetamide;
yV-{(15)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l-methylethyl} -2-hydroxy-N-methylaeetamide;
^-{(15)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l-methylethyl}-]V-methylacetainide;
N- {(lS)-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]-l-methylethyl}-2-methoxy-N-methylacetamide;
N-{(lS)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]-1-methylethyl}-2-hydroxyacetamide;
A^{(15>2-[(4-{[3^hloro^(pyridin-2-ylinethoxy)phenyl]aniino}qumazolin-5-yl)oxy]-l-methylethyl} acelamide;
7V1-{(15>2-[(4-{[3^Mon>^(pyridin-2-ylmethoxy)phenyl]aimiK»}quinazolin-5-yl)oxy]-l-methylethyll-A^JS^-dimelhylglycinaraidc;
^1-{(2/?>2-[(4-{[3^hloro^-(pyridin-2-ylmethoxy)phenyl]ainino}qiiinazolin-5-yl)oxy]propyl} -N2 ^-dimethyl glycinamide;
(25>^-{2-[(4-{[3^hloKh4-(pyiidin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy^^ 2,4-dihydroxybutanamide;
(2R)-N-{ 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl }-2,4-dihydroxybutanamide;
(2J?)-^-{(2^)-2-[(4-{[3-chloro-4-(pyridiiv2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI}-2,4-dihydroxybutanamide;
(2S>-^-{(2/?)-2-[(4-{[3 (2^)-AT-{(2^-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl}-2,4-dihydroxybutanamide;
(25)-^V-{(25)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy3propyl}-2,4-dihydroxybutanamide;
(2S)WVr{(l/?)-2-[(4«{[3-cMoro^-(pyiidin-2-ylmethoxy)phenyI]amino}quinazdin^ l-methylethyl}-2,4-dihydroxybutanamide;
(2/?)-A^-{(l/?)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]araino}quinazolin-5-yl)oxy]-
i-methylethyl}-2,4-dihydroxybutananude;
(2/?)-A^-{2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylraethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl}-2,4-dihydroxybutanamide;
(25)-^V-{2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]ainino}quinazolin-5-
yl)oxy]ethyl } -2,4-dihydroxybutanamide;
(2/?)-AT-{(lJ?)-2-[(4-{[3-chloro^(I,3^iazol^ylmethoxy)phenyl]amino}quinazolin-5-
ylX>xy]-l-methylethyl}-2,4-dihydroxybutanamide;
(2S)-A^-{(l/?)-2-[(4-{[3^hloro^l,3-thiazol^ylmethoxy)phcnyl]amino}quinazolin-5-
yl)oxy] -1-methylethyl } -2,4-dihydroxybutanamide;
^-methyl-^-{2-[(4-{[3-methyl-^(pyridin-2-ylmethoxy)phenyl]amino}quinazolm-5-
yl)oxy]ethyl } acetamide;
#-methyl-#-{2-[(4-{[3-methyl^(13^azol^y
yl)oxy]ethyl } acetamide;
A^methyl-^-(2-{[4-({3-methyl^[(5-methylisoxazol-3-yl)meAoxy]phOT
quinazolin-5-yl]oxy}ethyl)acctamidc;
2-hydioxy-^methyl-Ap-{2-[(4-{[3-inethyl-^(13-thiazol-2-ylinethoxy)phenyl]
atnino}quinazolin-5-ylX>xy]ethyl } acetamide;
2-hydroxy-^-{2-[(4-{[3-n»thyI^(pyridin-2-ylmethoxy)phenyl]anriiio}quinazoUn^
yl)oxy]ethyl}acetamide;
2-hydroxy-^-{2-[(4-{ [3-methyl-4-(l^-thiazol-4-ylmethoxy)phenyl]amino } quinazolin-5-
yl)oxy}ethyl}acetaniide;
^-{2-[(4-{[3^pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l,l-
dimethylethyl } -2-hydroxyacetamide;
2-hydroxy-tf-{ (2R ^>-2-[(4-{ [3-methyl^(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-
yl)oxy]propyl } acetamide;
2-hydroxy-^{(2J?)-2-t(4-{[3-methyl^(13-thiazol^ylmethoxy)phenyl]aniino}quinaro
5-yl)oxy]propyl}acetamide;
/K(2/?)-2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}ainino)quinazolin-5-
yl]oxy}propyl)-2-hydroxyacetamide;
5-yl)oxy]propyl } acetamide;
V-{(2/?)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl )ox y ]propy 1} acetamide; N-{(2/?)-2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylrnethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl} acetamide;
N-((2/?)-2-{[4-({4-[(3-nuorobenzyl)oxy]-3-methylphenyl}amino)quinazolin-5-
yl]oxy} propyl)acetamide;
N- {(2K)-2-[(4- {[3-methyl-4-(l ,3-thiazol-2-ylmethoxy)phenyl] amino} quinazolin-5-
yl)oxy]propyl} acetamide;
2-hydroxy-/^-methyl-//-{(2/?)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]
amino} qumazolin-5-yl)oxy]propyl} acetamide;
2-hydroxy-^-methyl-^-{(2^>2-[(4-{[3-methyl-4-(l,3-thia2ol-4-
ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]propyl} acetamide;
2-hydroxy-JV-methyl-AT-((2/?)-2-{[4-({3-methyl-4-[(5-methylisoxazol-3-
yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide;
AT-methyl-^-{(l/?)-l-methyl-2-[(4-{[3-methyl-4-(pyridin-2-ylinethoxy)phenyl]
amino }quinazolin-5-yl)oxy]ethyl }acetamide;
Ar-methyl-Ar-{(l/?>l-methyl-2-[(4-{[3-methyl-4-(l,3-thiazol-4-
ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetamide;
JV-{(17?)-2-[(4-{[3^Woro^(13-thJazol^ylmethoxy)phenyl]aniino}qmnazolin-5-yl)oxy]-l-
methylethyl}-2-hydroxy-N^-methylacetamide;
2-hydroxy-//-methyl-JV-{(l/?>l-melhyl-2-[(4-{[3-methyl-4-(pyridin-2-
ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetainide;
2-hydroxy-A^-methy]-^-{(l^>-l-methyl-2-[(4-{[3-methyl-4-(l,3-thiazol-4-
ylmethoxy)phenyl]ainino}quinazolin-5-yl)oxy]ethyl}acetamide;
Af-{(2^>2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl}-l-hydroxy-N-methylcyclopropanecarboxamide;
(25)-AT-{(2^)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino}quinazolin-5-
yl)oxy]propyl} -2-hydroxy-JV-methylpropanamide;
N- {(2/?)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-
yP )xy]propyl}-2-hydroxy-JV,2-dimethylpropanamide;
yi;u-y]propyl}-2-hydroxy-N-methylpropanamide;
(2R)-N- {(2tf)-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-
yl)oxy]propyl}-2-methoxy-#-methylpropanamide;
methyl-{ 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amiiio }quinazolin-5-
yl)oxy]ethyl }methylcarbamate;
N-{ 2-[(4- {[3-ch]oro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -
dimethyJurea;
AT-(2-chloroethyl)-#- {2-[(4-{ [3-chloro-4-(pyridin-2-yimethoxy)phenyl]aniino }quinazolin-5-
yl)oxy]ethyl }-W-methylurea;
A^{(2/?)-2-[(4-{[3-cWoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl }-yV-methylurea;
[((/?>2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)phenylamino]quinazolin-5-
yloxy}propylcarbamoyl)roethyl]methylcarbaniic acid teg-butyl ester;
^-{(2/?)-2-[(4-{[3K;hIoix)-4^yridin-2-ylineAoxy)phenyl]amino}quinazolin-5-
ylX>xy]propyl}-AT2-methylglycinamide; and
N-{ 2-[(4-{ [3^hlwt)^l-methyl-l-pyiidin-2-yletlioxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl }-7V-methylacetamide;
or a pharmaceutically acceptable salt thereof.
A particular compound of the invention is, for example, one or more quinazoline derivatives of the formula Ib selected from: JV-{2-[(4-{3-chloro^-(pyridin-2-yliM^ A^-methylacetamide;
N- {2-[(4- {3-chloro-4-(pyridin-2-yhnethoxy)anilino }quinazolin-5-yl)oxy]ethyl} -2-(dimethylamino)-yV-methylacetamide; A^{(21?>2-[(4-{3^Woro^(pyridin-2-yhnethoxy)amlino}quinazolin-5-yl)oxy]propyl}-2-
mcthoxy-A^-methylacetamide);
2-hydroxy-AT-methyl-Ar- {2-[(4- {3-methyl-4-(pyrazin-2-ylmethoxy)anilino}quinazoUn-5-
yl)oxy]ethyl} acetamide;
2-hydroxy-^methyl-AT-{2-[(4-{3-methyl-^(13-tWazol-^ylmethoxy)anilino}quina2olin-5-
yl)oxy]ethyl} acetamide;
2-hydroxy-A^-methyl-Ar-(2-U4~(3-memyl-^[(5-methylisoxazol-3-
•UitW   * yl)methoxy]anilino)quinazolin-5-yl]oxy}ethyl)acetamide;
N- { (2/?)-2-[(4- { 3-chloro-4-(pyridin-2-ylmethoxy)anilino } quinazolin-5-yl)oxy]propyl } -2-
methoxyacetamide; JV-(2-{[4-(3-chloro-4-[(6-raethylpyridin-2-yl)methoxy]anilino)quinazolin-5-yl]oxy}ethyl)-2-
hydroxy-Af-methylacetamide; AT-((2/?>2-{[4-(3-chloro-4-[(6-methylpyridin-2-yl)methoxy]anilino)quinazolin-5-
yl]oxy}propyl)-2-hydroxy-A/r-methylacetamide; AT methylacetamide;
^.(2-{[4-(3K;hloro-4-[(2-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}ethyl)-//-
methylacetamide;
methylacetamide;
^.{2-[(4-{3^hloro^(l,3-thiazd^ylmethoxy)anilino}quinazolin-5-ylX>xy]ethyl}-JV-
methylacetamide;
^-{2-[(4-{3^hloro-4^yrazin-2-ylinethoxy)anilino}qirinazolin-5-yl)oxy]eAyU
methylacetamide;
JV"-{(2/Z)-2-[(4-{3^hloro^(pyridin-2-ylmethoxy)amlmo}quinazoUn-5-yl)oxy]piopyl}-2-
hydroxyacetamide;
^-{2-[(4-{3-4^yridin-2-ylmethoxy)aniUno}quinazolin-5-yl)oxy]ethyl}-N-
methylacetamide;
2-hydroxy-JV^methyl-^r-{2-[(4-{3-methyl^(pyridin-2-ylmethoxy)anilino}quinazolin--5-
yl)oxy]ethyl } acetamide;
N-{(l/?)-2-[(4-{3-chloro-4-(pyridin-2-ylmeflioxy)anilino}quinazolin-5-yl)oxy]-l-
raethylethyl } acetamide;
Ar-{(ll?)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l-methylethyl }-2-hydroxyacetamide;
A-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-W-methylacetamide;
^-(2-{[4-(3-chloro-4-[(3-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}ethyl>2-hydroxy-JV-methylacetamide;
N-{ 2-[(4-{ 3-chloro-4-(l ,3-thiazol-4-ylmethoxy)anilino } quinazolin-5-yl)oxy]ethyl } -2-
h j drox y-JV-methyl acetamide;
A/-{2-[(4-{3-chloro-4-(pyrazin-2-ylinethoxy)anilino}quinazolin-5-yl)oxylethyl}-2-hydroxy-TV-methylacetamide;
N- {2-[(4- {3-chloro-4-(pyridin-2-ylmethoxy)anilino} quinazolin-5-yl)oxy]ethyl} acetamide;
N- {(2R)-2-[(4~ {3-chloro-4-(pyridin-2-yImethoxy)anilino }quinazolm-5-yl)oxy]propyl} acetamide;
N- {(2/?)-2-[(4- {3-chloro-4-(pyridin-2-ylinethoxy)aralino} quinazolin-5-yl)oxy]propyl} -2-hydroxy-^V-methylacetaniide;
N-{(2/f)-2-[(4-{3^hloro^Kpyrazin-2-yhnethoxy)anilino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-A^-methylacetainide;
N-((2R)-2-{ [4-(3^hloro^[(3-fhicm)benzyl)oxy]anilino)quinazolin-S-yl]oxy }propyl)-2-hydroxy-M-naethylacetamide;
hydroxy-A^-methylacetaniide;
^-{(2/?>2-[(4-{3^Woro^(pyridin-2-ylmethoxy)aniUno}qiuna2oUn-5-yl)oxy3propyl}-^^ methylacetamide;
JV-{2-[(4-{[3K;hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quitiazolin-5-yl)oxy3ethyl}-A/f-ethylacetamide;
N-{2-[(4-{[3^hloit>^(pyridin-2-ylnwthoxy)phenyl]amino}quinazoUn-5-yl)oxy] ethyl-2-hydroxyacetamide;
^-{2-[(4-{[3^hlorcHt-(pyridin-2-ylinethoxy)phenyl]aimno}quinazoUn-5-yl)oxy]ethyl}-N-propylacetamide;
^-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]ainino}quina2olin-5-yl)oxy]ethyl}-2-hydroxy-N-propylacetamide;
^-{2-[(4-{[3^hIoro^(pyridin-2-ylmethoxy)phenyl]amino}qiMnazolra-5-yl)oxy]ethyl}-^^ isopropylacetamide;
AT-{2-[(4-{[3^hloi^4-(pyridin-2-ylme1hoxy)phenyl]amino}quinaz»lin-5-yl)oxy]ethyl}-^^ hydroxy-JV-isopropylacetamide;
Ar-allyl-Ar-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} acetamide;
I ^-aIIyl-A^{2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quina2olin-5-yl)oxy]ethyl} -2-hydroxyacetamide;
^-{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl3amino}quinazolin-5-yl)oxy]ethyl}-A/-
cyclopropylacetamide;
A^-{2-[(4-{[3-chloro-4-(pyridin-2-yimethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-A":-
cyclopropyI-2-hydroxyacetamide;
Af-{2-[(4-{[3-chloro-4-(pyridin-2-ylrnethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N-
(cyclopropylmethyl)acetamide;
^V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl}-N-
(cyclopropyImethyl)-2-hydroxyacetamide;
/V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-//-
cyclobutylacetainide;
AT-{2-[(4-{[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy3ethyl}-JV-
cyclobutyl-2-hydroxyacetamide;
N- {2-[(4-{ [3-chloro-4-(pyridin-2-ylniethoxy)phenyl]aniino }quinazolin-5-yl)oxy]ethy]} -N-(l -
methy]piperidin-4-yI)acetamide;
^-{2-[(4-{[3^hloro^pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5-yl)oxy]etiiyl}-JV-
(tetrahydro-Z&-pyran-4-yl)acetamide;
Y-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]aniiiio}quina2olin-5-yl)oxy]ethyl}-2-
tiydroxy-^tetrahydro-^-pyran^-yOacetamide;
V-{ 2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)pheTiyl]amino }quinazolin-5-yl)oxy]ethyl} -#-(2-
liydroxyethyl)acetaniide;
V-{2-[(4-{[3^hloro^(pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-yl)oxy]ethyl}-2-
tiydroxy-^^-hydroxyethyOacetamide;
iV-{2-[(4-{[3xy]ethyl}-W-(2-
methoxyethyl)acetamide;
^{2-[(4-{[3^Woro^(pyridin-2-ylmethoxy)phenyI]amino}qiiinazolin-5-yl)oxy]ethyl}-2-
tiydroxy-^-(2-methoxyethyl)acetamide;
IV- {2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl} -W-
prop-2-yn-l-ylacetamide;
V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl}-2-
(iydroxy-AT-prop-2-yn-l-ylacetamide;
V-{2-[(4-{[3-chloro-4-(pyridin-2-ylmelhoxy)phenyl]amino}quinazolra-5-yl)oxy]ethyl}-2-
nydroxy-A?-methylpropanamide;
-chloro-4-(pyridin-2-ylniethoxy)pheaiyl]amino}quinazolin-5-yl)oxy]ethyI }-N-methyl-tetrahydrofuranyl-2-carboxainide;
N-(2-[(4-{ [3-chloio-4-(pyridin-2-ylinethoxy)phenyl]amino }quinazolin-5-yl)oxy]ethyl } -AU-dimethylprolinamide;
A^-{2-[(4-{[3n;hIoro-4-(pyridin-2-ylinethoxy)phenyl]anjino}quinazoMn-5-yl)oxy]e^yl}-2-hydroxy-^,2-dimethylprc^>anamide; AM2-[(4-{[3^hlon>-4^yridiii-2-ylinedioxy^^^ hydroxy-A^-methylcyclc^rqpanecaiboxainide;
Nl ^-diinethylglycinamide;
N- { 2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yI)oxy]ethyl } -3-
hydroxy-/V^,2-tnmetfaylpiopanamide;
N-{2-[(4-{ [3-chloro-4-(pyridin-2-yhnethoxy)phenyl]amino }quinazoKn-5-yl)oxy]ethyl }-3-
hydroxy-JV-methylpropanamide;
tf-{(25>-2-[(4~{[3^:hloro-4^yricfo^
yl)oxy]propyl}acetamide;
A^- { (25>2-[(4-{ [3-chIoro-4-(pyridin-2-ylmethoxy)phenyriamino }quinazolin-5-
y!X>xy]propyl}-2-bydroxyacetarmde;
yl)oxy]piopyl } -A^ ^-dimrthylglycinamide;
Ar-{(25>2-[(4-{[3- yl)oxy]propyl }-2-methoxyacetamide;
N- { (25)-2-[(4- { [3-chloro-4-(pyridin-2-ylmeAoxy)ph«iyI]amino }quinazolia-5-
yl)oxy]ptopyl } -2-(methylsulf onyl)acetamide;
A/-{2-[(4-{[3^hlon)^(pyridin-2-ylinethoxy)phenyl]ainino}quinazolin^
hydroxyacetamide;
A^1-{2-[(4-{[3^(pyridin-2-ylmethoxy)phenyl]ainiiM)}quinazoUn-5-yl)^^
A^^-dimethylglycmaniide;
A^{2-[(4-{[3^hloro^(pyri(tii^2-ylinethoxy)phenyl]aniino}quitiazolin-5-y
methoxyacetamide;
A^-{2-[(4-{[3K:Moro-4^yridin-2-yln»thoxy)phenyl3amino}quinazolin-5^
(mcthylsulfonyl)acetamide;
N-{ (25>2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino}quina2olin-5-
ylX>xy]propyl}-N-methylacetanaide;
N- { (25)-2-t(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ainino } quinazolin-5-
yI)oxy]propyl}-2-hydroxy-A/-methylacetamide;
Nl-{(25)-2-[(4-{[3^hlofo^p>ddin-2-yln^oxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl }-Nl ^^-trimethylglycinamide;
N-{(25)-2-[(4-{[3^Uoix>^pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-
yl)oxy]propyl}-2-niethoxy-N-methylacetamide;
N-{ (25)-2-[(4-{ [3^h)oro^pyridin-2-ylmethoxy)phenyl]aniino}quinazolin-5-
yl)oxy]propyl}-^-raethyl-2Knjethylsulfonyl)acetamide;
N-{(2/?>2-[(4-{[3^Woro^(pyrazin-2-ylineAoxy)phenyllainino}quinazoliii-5-
yl)oxy]propyl}-N-methylacetamide;
yl)oxy]ptopyl}-JV-methylacetainide;
// yl]oxy}propyl)-N-methylacetamide;
N-((2K)-2-{ [4-{{3-chloro-4-[(2-flucMX>ben2yl)oxy]phenyl } amino)quinazolin-5-
yl]oxy}propyl)-JV-inettiylacetainide;
^-{(!J?)-2-[(4-{[3^hloro-4^yridin-2-ylmethoxy)phenyl]anuno}quina2oUn-^
methylethyi}-2-hydroxy-JV-methylacetamide;
^-{(lU)-2-[(4-{ [3-chloro-4-Q)yridin-2-yImethoxy)phenyl]ainino }quinazolin-5-yl)oxyH-
methylethyl}-N-methykcetamide;
^-{(lS)-2-[(4-{[3 methylethyl}-2-hydroxy-^V-niethylacetamide;
N-{(15>2-[(4-{[3^WorcMKpyridin-2-yln»thoxy)phenyl]amino}quinazolin-5-yl)oxy]-l-
methylethyl}-N-methylacetamide;
methylethyl } ^-methoxy-AT-methylacetamide; A/"-{(lS>2-[(4-{[3^Woro^-(pyridin-2-y^ methylethyl }-2-hydroxyacetamide;
/^{(^^^^^-{p^jilpro^Xpyrictin^TylniethoxyJphenyllai^^ methylethyl } acetamide;
ridm-2-y^ methylethyl }-N* J^-dimethylglycinainide;
yl)oxy]propyl }-
(2S)-/V-{2-[(4-{[3-chIoro-4-(pyridin-2-yline^
2,4-dihydroxybutanamide;
(2JQ-AH2-[(4-{[3- 2,4-dihydroxybutanamide;
(2K)-tf-{(2ff)-2-[(4-{ [3^hloro^(pyridin-2-ylmethoxy)phenyl]anuiio}quina2olin-5-
yl)oxy]propyl}-2,4-dihydroxybutananride;
(25)-A^-{(2J?)-2-[(4-{[3^hloro-4^>ddin-2-ylmethoxy)phenyl]arnino}quinazolin-5-
yl)oxy]propyl }-2,4-dihydroxybutanamide;
(2J?>AT-{(25>2-[(4-{[3^hloro-4^yridin-2-ylmethoxy)phenyl]aniino}quuiazolin-5-
yl)oxy]propyl}-2,4-dihydroxybutanamide;
(2S>JV-{(2S)-2-[(4-{[3^hlo!ro-4^yridiii-2-ylnieflioxy)phCT
yl)oxy]propyl}-2,4-dihydroxybiitanainide;
(25>-^{(l/?>2-[(4-{[3^hlon>4^yridin-2-yhnethoxy)phenyl]an^
1-methylethyl }-2,4-dihydroxybutanamide;
(2R)-^-{(lJ?)-2-[(4-{P4^yridin-2-ylmettioxy)phenyl]ainino}qiim
1 -methylethyl } -2,4-dihydroxybutanamide;
(2^)-AT-{2-[(4-{[3-chloro-4-(l,3-tfiiazol-4-ylmethoxy)phenyl]aniino}quinazolin-5-
yl)oxy]ethyl } -2,4-dihydroxybutanamide;
(25^-^{2-[(4-{[3-cMoro-4-(l,3-tfuazol-4-ymiethoxy)phenyl]ainiiK)}qm
yl)oxy]ethyl }-2,4-dihydroxybutanamide;
(2fl)-JH(ll?)-2-[(4-{[3-cUoro-^^
yl)oxy]-l-methylethyl}-2,4-dihydroxybutanamide;
(25)-^-{(l/?)-2-[(4-{ [3-chloio-4- yl)oxy]-l-methyletfiyl}-2,4-dihydroxybutanaimde;
^-methyl-^{2-[(4-{[3-mcthyl-4-^yridii^2-yhnethoxy)phenyl]anuno}quinazol^^
ylX>xy]ethyl }acetamide;
A^methyl-7V-{2-[(4-{[3-ine^yl-4-(13-thiazol-4-yhiiethoxy)phenyy
yl)oxy]ethyl Jacetamide;
-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl Jamino)
quinazolin~5-yl]oxy } ethyl)acetamide;
2-hydroxy-Ar-methyl-N-{2-[(4-{[3-inefliyl-4-(l,3-thiazol-2-ylmethoxy)phenyl]
amino } quinazolin-5-yl)oxy]ethyl } acetamide;
2-hydioxy-N- { 2-[(4-{ [3-methyl-4-(pyridin-2-yhnethoxy)phenyl]ainino } quinazolin-5-
yl)oxy]ethyl}acetamide;
2^ydroxy-^-{2-[(4-{[3-methyW-(13-thiazol^ylmethoxy)pbenyl]ainino}quinazoU
yl)oxy]ethyl} acetamide;
//-{2-[(4-{[3^hlon>-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l,l-
dimethylethyl}-2-hydroxyacetamidc;
2-hydroxy-JV-{(2^)-2-[(4-{ [3-metfiyl-4-(pyridin-2-ylinethoxy)phenyl]amino} quinazolin-5-
yl)oxy]propyl } acetamide;
2-hydroxy-AH (2R)-2-[(4-{ [3-methyl-4-(l ,3-thiazol-4-ylmethoxy)phenyl]ammo } quinazolin-
5-yl)oxy]propyl}acetamide;
JV^(2J?)-2-{[4^{4-[(3-fluorobenzyl)oxy]-3-meAyiphenyl}aimno)qi^
yl]oxy }propyl>2-hydroxyacetamide;
2-hydroxy-^-{ (2J?)-2-[(4-{ [S-methyl-^Cl^-tiiiazol^-ylmethoxy^henyllamino} quinazolin-
S-yl)oxy]propyl}acetamide;
^-{(2R)-2-[(4-{[3-methyl^(pyridin-2-ylinethoxy)phenyl]ainino}quina^
yl)oxy]propyl} acetamide;
yl)oxy]propyl}acetamide;
N-((2J?)-2-{[4K{4-[(3-fluon^nzyl)oxy]-3-methylphenyl}anuno)quinazolin-5-
yl]oxy}propyl)acetainide;
^-{(2/J)-2-[(4-{[3-methyl^(13-thiazoI-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl}acetainide;
2-hydroxy-JV-methyl-/V-{ (2/?>-2-[(4-{ [3-methyl-4-(pyridin-2-ylmethoxy)phenyl]
amino }qumazolin-5-yl)oxy]propyl}acetainide;
2-hydroxy-JV-methyl-Ar-{(2/Z)-2-[(4-{[3-methyl-4-(13-thiazol-4-
ylmethoxy)phenyl]amino }quinazolm-5-yl)oxy]propyl }acetamide;
^-hydroxy^methyl^((2R)-2-{[4K{3-methyl^£(5^nw%lisa»^ .
yl)methoxy]phenyl}amino)quina2olin-5-yl]oxy}propyl)acetamide;
l-#-{ (l/?)-l-methyl-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl] amino}quinazolin-5-yl)oxy]ethyl}acetamide; N-methyl-AM (I* H-methyl-2-[(4-{ [3-methyl-4-(l,3-thiazol-4-ylmethoxy)phcnyl]aniino}quinazo]in-S-yl)oxy]ethyl}acetamide;
A^-{(l/?)-2-[(4-{[3^hloro^l,3-thiazol^ylmethoxy)phenyl]amino}quinazolm-5-yl)oxy]-l-methylethyl}-2-hydroxy-N-methylacetamide; 24iydroxy-JV-methyl-^-{ (lK)-l-methyl-2-[(4-{ [3-methyl-4-(pyridin-2-ylmethoxy)phenyl]anrino}quinazolin-5-ylX»xy]ethyl}acetamide;
y!inethoxy)phenyl]ainino}quinazoUn-5-yl)oxy]ethyl}acetamide;
N-{ (2K)-2-[(4-{ [3^hloro-4- yl)oxy]propyl}-l-hydroxy-JV-methylcyclopropanecarboxaniide;
yl)oxy]propyl }-2-hydroxy-/^-methy)propanamidc;
#-{(2/?>2-[(4-{[34^pyri yl)oxy]propyl }-2-hydroxy-^,2-dimethylpropanamide;
(2/0-^-{(2/?>2-[(4-{[3-2-ylmethoxy)phenyl]ainii»
ylJoxyipropylJ^-hydroxy-^-methylpropananufc;
(2R)-N-{ (2R)-2-[(4-{ [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-
yl)oxylpropyl}-2-methoxy-]V-methylpropanamide;
methyl-{2-[(4-{[3-^^oro^(pyridin-2-ylinethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl }methylcarbamate;
JV-{2-[(4-{[3^Woro^^pyridin-2-yliiMthoxy)phenyl]ainino}quinazolin-5-yl)oxy]eA
dimethylurea;
-( 2-[(4-{ [3-chloro-4-(pyridiii-2-ylmethoxy^ienyl]ainino }quinazolin-5-}-A^-methylurea;
N-{ (2iR)-2-[(4- { [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl }-W-methylurea;
[((JO-2-{4-[3 yloxy}propylcarbamoyl)methyl]methylcaibamic acidtgtt-butyl ester; and
A^-{(2R)-2-[(4-{[3-chloro4-(^yriditt-2-ylmethoxy)phenyl]am^ "
yl)oxy]propyl}-^-methylglyeinaniide;
or a pharmaceutically acceptable salt thereof.
A particular compound of the invention is, for example, one or more quinazoline derivatives of the formula Ic selected from:
2-hyroxy-N-methyl-N-((2R)-2-{[4K{3-methyl-4-[(6-methylpyridin-3-yl)oxy3phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; A^nMrnyl-AK(2fl)-2-{ [4K{3-methy 5-yl]oxy}propyl)acetamide;
yl)oxy]phenyl}aniino)quinazolin-5-yl]oxy}propyl)glycinainide;
^inefoyl-AK(2/0-2-{[4^{3-merayl^[^
5-yl]oxy}propyl)-2-pvrrolidin-l-ylacetamide;
tf-inemyl-#K(2/0-2-{[4 5-yl]oxy}propyl>2-morpholin-4-ylacetamide;
M-inemyl-M{(2#)-2-{[4^{3-inemyl^
5-yl]oxy}propyl)-2-(4-methylpiperazin-l-yl)acetamide;
yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ptopyl)acetamide;
N-methyl-^V-((25)-2-{ [4-({3-methyl-4-[(6-methyipyndin-3-yl)oxy}phenyl} amino)quinazolin-
5-yl]oxy}piopyl)acetamide;
^-methyl-N-((25)-2-{[4^{3-methyl^[(6-methylpvridin-3-yl)oxy]phenyl}aniino)qumazolin-
5-yl]oxy}propyl>2-pyrrolidin-l-ylacetamide;
(25)-2,4Ktihydroxy-A^((2«)-2-{[4 y!X>xy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide;
yl)oxy]phenyl}amino)quinazolin-S-yl]oxy}propyl)butanamide; ^^^hloKKJthyl^KC^^tL^iS-incmyW-Ke-mcTOylpyridi yl)oxy]phenyl } amino)quinazolin-5-yl]oxy }propyl)urea;
^ yl)oxy]phenyl } amino)quinazolin-5-yl]oxy }ethyl)acetamide;
yl)oxy]phenyl} amino)quinazolin-5-yl]oxy }ethyl)acetamide; yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide;
N-methyl-N-((1S)-l-methyl-2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy}phenyl} amino)quinazoJin-5-yl]oxy} dhyl)acetaniide;
2-hydroxy-N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetarnide; and
N-meftyl-N-(2-{[4-({3-methy1-4-[(6^methylpyridin-3-yl)oxy]phenyl}aniirK))quinazolin-5-
yl]oxy}ethyl)acetamide;
or a pharmaceutically acceptable salt thereof.
A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Suitable processes include, for example, those illustrated in International Patent Applications WO 96/15118, WO 01/94341, WO 03/040108 and WO 03/040109. Such processes, when used to prepare a quinazoline derivative of the formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, R1, R2, R3, R4, R4*, R5, R5*, R6, X1, Q1, A, m, and n have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
Process fa) the coupling, conveniently in the presence of a suitable base, of a quinazoline of the formula II:

(Figure Removed)wherein R1, R2, R3, R4, R4", R3, R5t, R6, X1, Q1, m, and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a
carboxylic acid of the formula HI, or a reactive derivative thereof:
A-COOH III
wherein A has any of the meanings defined hereinbefore except that any functional group is protected if necessary;
or
Process (b)   for the preparation of those compounds of the formula I wherein X1 is OC(R7)2, SC(R7)2or N(R7)C(R7)2, the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula IV:
IV
wherein Xu is O, S or N(R7) and R1, R2, R3, R4, R4*, R5, R5a, R6, R7, A, m, and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the formula V or a salt thereof:
wherein L1 is a suitable displaceable group and Q1 and R7 have any of the meanings defined hereinbefore except mat any functional group is protected if necessary;
Process fc) for the preparation of those compounds of the formula I wherein A is R14 and R14 is NHR17 or Q3-X5- (wherein R17 and Q3 have any of the meanings defined hereinbefore and X5 is NH), the coupling of a quinazoline of the formula II as defined above with an isocyanate of the formula EHa:
A-NCO
ma
wherein A is R14 as previously defined in this section except that any functional group is protected if necessary,
Recess (d) the reaction of a quinazoline of the formula II wherein R6 is hydrogen: (Figure Removed)n
wherein R1, R2, R3, R4, R4A, R5, R5A, X1, Q1, m, and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with o-hydroxy-Y-butyrolactone (for example (S)-(-)-α-hydroxy-γ-butyrolactone or (RH+)-«r hydroxy-Y-butyrolactone) wherein any functional group is protected if necessary;
or
Process (e) the coupling of a quinazoline of the formula VI:
herein R1, R4, R4a, R5, R5a, R6, A and m have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the formula

wherein R2, R3, X1, Ql and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary;
Process (ft   for the preparation of those compounds of the formula I wherein X1 is O and Q1 is 2-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl or 3-pyridazinyl, the reaction, conveniently in the presence of a suitable base and a suitable catalyst, of a qumazolme of the formula VII:

(Figure Removed)wherein R1, R2, R3, R4, R4A, R5, R5A, R6, A, m and n have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with 2-bromopyridine, 4-bromopyridine, 2-chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or 3-chloropyridazine; or
Process (g)   for the preparation of those compounds of the formula I wherein A is Z-(CR12R13)P-, wherein Z is NR16Rn, the reaction, conveniently in the presence of a suitable base, of a quinazolhie of the formula VIII: wherein L1 is a suitable displaceable group and R1, R2, R3, R, R4,R5, R5, R6, Ru,
R13, X1, Q1, m, n and p have any of the meanings defined hereinbefore except that any
functional group is protected if necessary, with a compound of the formula IXa, or a reactive
derivative thereof:
H-NR16R17
IXa
wherein R16 and R17 have any of the meanings defined hereinbefore except that any
functional group is protected if necessary;
and thereafter, if necessary:
(i) converting a quinazoline derivative of the formula I into another quinazoline derivative of
the formula I;
(ii) removing any protecting group that is present by conventional means;
(Hi) forming a pharmaceutically acceptable salt
Specific conditions for the above reactions are as follows:
Process fa)
The coupling reaction is conveniently carried out in the presence of a suitable coupling
agent, such as a carbodiimide, or a suitable peptide coupling agent, for example O-(7-
a2abenzolriazol-l-yl)-NJN[N"-tetramemyluronium hexafluoro-phosphate (HATU) or a
carbodiimide such as dicyclohexvlcaibodiimide, optionally in the presence of a catalyst such
as dimethylaminopyridine or 4-pvrrolidinopyridine.
The coupling reaction is conveniently carried out in the presence of a suitable base. A
suitable base is, for example, an organic amine base such as, for example, pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylethylamine,
M-methyhnorpholine or diazabicyclo[5.4.0]vmdec-7-ene, or, for example, an alkali or alkaline
earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate,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 methylene
chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan,
an aromatic solvent such as toluene, or a dipolar aprotic solvent such as
HJirnethylformamide, NJimethylacetamide, Ji-mettiylpvrroUdin-2-one or
dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for
example, from 0 to 120°C, conveniently at or near ambient temperature.
By the term "reactive derivative" of the carboxylic acid of the formula HI is meant a
carboxylic acid derivative mat will react with the qvrinazoline of formula n to give the
corresponding amide. A suitable reactive derivative of a carboxylic acid of the formula HI is,
for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid
and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example
an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl
chloroformate; an active ester, for example an ester formed by tile reaction of the acid and a
phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an
alcohol such as methanol, ethanol, isopropanol, butanol or JJ-hydroxybenzotriazole; an acyl
azide, for example an azide formed by the reaction of the acid and azide such as
diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of
an acid and a cyanide such as diethylphosphoryl cyanide; or an acetoxyacetylchloride. The
reaction of such reactive derivatives of carboxylic acid with amines (such as a compound of
the formula II) is well known in the art, for example they may be reacted in the presence of a
base, such as those described above, and hi a suitable solvent, such as those described above.
The reaction may conveniently be performed at a temperature as described above.
Preparation of Starting Materials for Process (a)
Compounds of formula ID (and reactive derivatives thereof) are commercially
available compounds or they are known in the literature, or they can be prepared by standard
processes known in the art.
The quinazoline of the formula II may be obtained by conventional procedures. For
example, as illustrated in Reaction Scheme 1:
wherein L2 and L3 are suitable displaceable groups, provided that L3 is more labile
than L2, and R1, R2, R3, R. R4, R5, R5, R6, X1, Q1, m, and have any of the meanings
defined hereinbefore except that any functional group is protected if necessary during the
reaction set out above, which protecting groupCs) are removed if necessary at an appropriate
stage in Reaction Scheme 1. For example, instead of using the compound of formula lid in
step (ii) of Reaction Scheme I, the compound nd" (including a protecting group) could be
used:
followed by removal of the protecting group, by an appropriate method known to a
person skilled in the art.
A suitable displaceable group L2 is for example haiogeno or a sulfonyloxy group, for
example fluoro, chloro, methylsulfonyloxy or toluene-4-sulfonyloxy group, particularly
fluoro. A suitable displaceable group L3 is, for example, haiogeno (such as fluoro or chloro)
or an alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfmyl, alkylsulfonyl,
arylsulfonyl, alkylsulfonyloxy or arylsulfonyloxy group, for example a chloro, bromo,
methoxy, phenoxy, pentafluorophenoxy, methylthio, methanesulfonyl, methanesulfonyloxy or
toluene-4-sulfonyloxy group. Preferably L2 and L3 are bom haiogeno, for example L2 is
fluoro and L3 is chloro.
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 inert solvent
such as diethyl ether or dioxane) or hydrochloric acid.
Alternatively the quinazoline derivative of the formula Ha, wherein L3 is haiogeno
(for example chloro), may be reacted with the compound of the formula lib in the absence of
an acid or a base. In this reaction displacement of the haiogeno leaving group L3 results in the
formation of the acid HL3 in-situ and the autocatalysis of the reaction.
Alternatively, the reaction of the quinazoline derivative of formula Ila with the
compound of formula lib may be carried out in the presence of a suitable base. A suitable
base is, for example, an organic amine base such as, for example, pyridine, 2,64utidhie,
collidine, 4-dimethylaminopYridine, triethylamine, di-isopropylethylamine,
N-methylmorpholine or diazabicyclo[S.4.0]undec-7-ene, or, for example, an alkali or alkaline
earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate,
calcium carbonate, or, for example, an alkali metal hydride, for example sodium hydride.
The above reactions are 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 methylene chloride, chloroform or carbon
tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as
tolviene, or a dipolar aprotic solvent such as N-dimethylformamide,
H,H-diniethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The above
reactions are conveniently carried out at a temperature in the range, for example, 0 to 250°C,
conveniently in the range 40 to 80°C or, preferably, at or near the reflux temperature of the
solvent when used.
Step (u)
The reaction a quinazoline of the formula lie and the alcohol of the formula Ud is
suitably carried out in the presence of a suitable base, for example a strong non-nucleophilic
base such as an alkali metal hydride, for example sodium hydride, or an alkali metal amide,
for example lithium di-isopropylamide (IDA).
The reaction of the quinazoline of the formula Die and the alcohol of the formula Hd is
conveniently carried out in the presence of a suitable inert solvent or diluent, for example a
halogenated solvent such as methylene chloride, 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 M-dimethylibnnamide, fimemyiaeetamide,
N-methylpyrrolidin-2-one or dimemylsulfoxide. The reaction is conveniently carried out at a
temperature in the range of, for example, 10 to 250°C, preferably in the range 40 to 150°C.
Conveniently, mis reaction may also be performed by heating the reactants in a sealed vessel
using a suitable heating apparatus such as a microwave heater.
Conveniently, the reaction a quinazoline of the formula He and the alcohol of the
formula nd is performed in the presence of a suitable catalyst, for example a crown ether
such as lS-crown-5.
Starting Materials for Reaction Scheme 1
The quinazoline of formula Ha may be obtained using conventional methods, for
example, when m is 0, L2 is fluoro and L3 is halogeno (for example chloro), 5-fluoro-
3,4-dihydroquinazolin-4-one may be reacted with a suitable halogenating agent such as
thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and
triphenylphosphine. The S-fluoro-3,4-dihydroquinazoline starting material is commercially
available or can be prepared using conventional methods, for example as described in J. Org.
Chem., 1952,17,164-176.
Compounds of the formula Ob are commercially available compounds or they are
known in the literature, or they can be can be prepared by standard processes known in the art
For example, the compound of the formula lib in which R2 is hydrogen and wherein X1 is O,
S, SO, SOi, N(R7), OC(R7)2, SC(R7)2 or N(R7)C(R7)2 may be prepared in accordance with
HX1Q1 reduction
Reaction Scheme 2
wherein L4 is a suitable displaceablc group as hereinbefore defined (for example
halogeno such as chloro) and Q1, X1, R3 and n are as hereinbefore defined, except any
functional group is protected if necessary, and any protecting group that is present in Reaction
Scheme 2 is removed if necessary at an appropriate stage of Reaction Scheme 2 by
conventional means.
Notes for Reaction Scheme 2
Step (i): The compounds of the formula HJ^Q1 are commercially available, or they
are known in the literature, or can be prepared using well known processes in the art For
example compounds of the formula QCHaOH may be prepared using known methods, for
example by reduction of the corresponding ester of die formula Q"COOR, wherein R is, for
example (l-6C)alkyl, or benzyl, with a suitable reducing agent, for example sodium
borohydride, followed by ester hydrolysis.
The reaction in step (i) is conveniently carried out in the presence of a suitable base
and in the presence of a suitable inert diluent or solvent Suitable reaction conditions,
solvents and bases for use in step (i) are analogous to those used in Process (b) described
below.
Step (ii): The reduction of the nitro group in step (ii) may be carried out under
standard conditions, for example by catalytic hydrogenation over a platinum/carbon,
palladium/carbon or nickel catalyst, treatment with a metal such as iron, titanium chloride, tin
n chloride or indium, or treatment with another suitable reducing agent such as sodium
dithionite.
Compounds;6f therformulalib wherein X1 is C)C(R7)2, SC2 ot N(R7)CCR7
for example, be prepared in accordance with Reaction Scheme 3:
(0
Reaction Scheme 3
wherein L1 is a suitable leaving group as defined hereinafter in relation to Process (b),
X1 is as hereinbefore defined in Process (b), and R3, R7, Ql, X1 and n are as hereinbefore
5 defined except any functional group is protected if necessary, and any protecting group that is
present in Reaction Scheme 3 is removed if necessary at an appropriate stage of Reaction
Scheme 3 by conventional means.
Notes for Reaction Scheme 3
Step (i): Analogous conditions to those used in Process (b)
10 Step (ii): Analogous conditions to those used in Reaction Scheme 2.
Other suitable methods for preparing compounds of the formula lib are disclosed in
for example WO 03/040108 and as illustrated by the examples herein.
Compounds of the formula lib wherein X1 is OC(R7)2 may also be prepared by
coupling the appropriate starting nitro phenol in Reaction Scheme 3 (XlkH is OH) with a
IS compound of the formula QC(R7)2OH, conveniently hi die presence of a suitable dehydrating
agent A suitable dehydrating agent is, for example, a carbodiimide reagent such as
dicyclohexylcarbodiimide or H3-diinethy]ammopropyl3-«mylcarbodiimide or a mixture of
an azo compound such as diethyl or cti-tert-butyl azodicarboxylate and a phosphine such as
triphenylphosphine. The reaction is conveniently carried out in the presence of a suitable
20 inert solvent or diluent, for example a haiogenated solvent such as methylene chloride,
chloroform or carbon tetrachloride and at a temperature in the range, for example, 0 to iSO°C,
preferably at or near ambient temperature.
The alcohols of the formula Od used in Reaction Scheme 1 are commercially available
compounds or they are known in the literature, or they can be can be prepared by standard
25 processes known in the art For example, alcohols of the formula nd may be prepared in
accordance with Reaction Scheme 4:
catalyst R48 deprotect
lid1
Reaction Scheme 4
wherein Pg is a suitable amine protecting group such as allyl, and R4, R4, R5 R5 and
R6 arc as hereinbefore defined.
5 Notes for Reaction Scheme 4
Step f i): The coupling and ring opening reaction is conveniently earned out in the presence of
a suitable metal catalyst such as ytterbium(ni) trifluoromethanesulfonate. The reaction is
suitably earned out in the presence of an inert solvent or diluent such as dioxane. The
reaction is preferably carried out at an elevated temperature, for example from SO to about
10 150°C.
Step (ii): The protecting group Pg may be removed using conventional methods, for example
when Pg is an allyl group by metal catalysed cleavage. A suitable catalyst is, for example,
chlorotris(triphenylphosphirie)rhodium (I).
As previously discussed, in embodiments, the alcohol of the formula lid" in Reaction
15 Scheme 4 may be used directly in Process (a) (or in the preparation of the intermediates used
in Process (b) described below), m mis embodiment the amine protecting group, Pg, may be
removed at a convenient stage in the process prior to coupling the acid of the formula HI.
The quinazoline of the formula H may alternatively be obtained a conventional
procedure, for example as illustrated in Reaction Scheme la:
wherein L1 and L2 are suitable displaceable groups and R1, R2, R3, R4, R4, R5, R5i, R6,
X1, Q1, m and n have any of the meanings defined hereinbefore except that any functional
group is protected if necessary during the reaction set out above, which protecting group(8)
are removed if necessary at an appropriate stage in Reaction Scheme la.
A suitable displaceable group L2 is for example a halogeno or a sulfonyloxy group, for
example a fluoro, chloro, tnethylsulfonyloxy or toluene-4-sulfonyloxy group, particularly
fluoro. Preferably L2 is halogeno, for example L2 is fluoro.
A suitable displaceable group L1 in die compound of the formula DC" is for example a
halogeno or a sulfonyloxy group, for example a fluoro, chloro, methylsulfonyloxy or toluene-
4-sulfonyloxy group. A particular group L1 is fluoro, chloro or methylsulf onyloxy,
particularly chloro.
Notes for Reaction Scheme la:
Step frt: Analogous conditions to those used in step (ii) of Reaction Scheme 2.
Step fit): Conducted using a suitable conversion reaction. For example when L1 is chloro,
step (ii) is conducted using an appropriate chlorinating agent, for example thionyl chloride.
Step (iiiV. The reaction of the compound of formula lie with the amine of formula Ilf may
conveniently be carried out in the presence of a suitable base. A suitable base is, for example,
an organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,
triethylamine, di-isopropylethylamine, N-memylmorpholine or
diazabicyclo[5.4.0]undec-7-ene, or an alkali or alkaline earth metal carbonate such as sodium
carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or an alkali metal
hydride such as sodium hydride. Alternatively, the reaction may use an excess of the amine
of formula Ilf in place of the aforementioned suitable base.
If necessary, the reaction may conveniently be carried out in the presence of a suitable
catalyst, for example tetrabutylammonium iodide.
The reaction of the compound of the formula and the amine of the formula is
conveniently carried out in the presence of a suitable inert solvent or diluent, for example an
ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a dipolar
aprotic solvent such as tLK-dimethylformamide, N,fc[-dimethylacetamide,
M-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a
temperature in the range of, for example, from 25 to 150°C, conveniently at about 100°C.
Starting Materials for Reaction Scheme Iq
Compounds of formula He may be prepared using conventional procedures, for
example as discussed above in relation to Reaction Scheme 1.
Compounds of formulae lie and are commercially available compounds or they are
known in the literature, or they can be prepared by standard processes known in the art.
Process (b)
A suitable displaceable group L1 in the compound of the formula V is for example a
halogeno or a sulfonyloxy group, for example a fluoro, chloro, methylsulfonyloxy or toluene-
4-sulfonyloxy group. A particular group L1 is fluoro, chloro or methylsulfonyloxy.
The reaction of the quinazoline of formula IV with the compound of formula V is
conveniently carried out in the presence of a suitable base. Suitable bases include, for
example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, di-isopropylethylamine, N-mernylmorpholine or
diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate,
for example sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or,
for example, an alkali metal hydride, for example sodium hydride. A particular base is an
alkali or alkaline earth metal carbonate, for example potassium carbonate.
The reaction of the quinazoline of the formula IV and the compound of the formula V
is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a
halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether
such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a dipolar
aptotic solvent such as H-dimethylformamide, dimeraylacetamide,
K-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a
temperature in the range of, for example, from 25 to 100°C, conveniently at or near ambient
temperature.
The reaction of the quinazoline of the formula IV and the compound of the formula V
is conveniently carried out hi the presence of a suitable catalyst, for example a crown ether
such as 18-crown-6.
Preparation of Starting Materials for Process (b)
Compounds of the formula V are commercially available compounds or they ate
known in the literature, or they can be can be prepared by standard processes known in the art
The quinazoline of the formula IV may be prepared using conventional methods, for
example, when Xu is O, in accordance with Reaction Scheme 5:
in Reaction Scheme 5 or as a reactive derivative of the compound of formula HI. Suitable
reactive derivatives of the compound of formula HI are described in relation to Process (a)
above.
Preparation of Starting.
Compounds of formulae Ha and lid may be obtained by conventional procedures, as
discussed above.
Anilines of the formula IVa are commercially available compounds or they are known
in the literature, or they can be can be prepared by standard processes known in the art
Process
The reaction of a compound of the formula H with an isocyanate of the formula ma 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 methylene chloride, chloroform or
carbon tetrachloridc, an ether such as tetrahydroforan or 1,4-dioxan, an aromatic solvent such
as toluene, or a dipolar aptotic solvent such as H£~dimemylf ormamide,
&N-dimethylacetamidc, Ji-methylpyrrohdin-2-one or dimethylsulfoxide. The reaction is
conveniently carried out at a temperature in the range, for example, from 0 to 50°C
Preparation, of Starting Materials for Process (c)
The quinazolme of formula H may be obtained by conventional procedures, as
discussed above.
The compounds of formula IHa are commercially available compounds or they are
known in the literature, or they can be can be prepared by standard processes known in the art
Process (dt
The reaction of the compound of formula U and Orhydroxy-Y-butyrolactone is
conveniently carried out in the presence of a suitable inert solvent or diluent, for example
xylene, toluene or dichlorobenzene (particularly xylene). The reaction is conveniently carried
out at a temperature in the range, for example, 100 to 180°C.
Prearation of Startin Materials forProcess
The quinazolme of formula II may be obtained by conventional procedures, as
discussed above.
The a-hydroxy-Y-butyrolactones are commercially available compounds or they are
known in the literature, or they can be can be prepared by standard processes known in the art.
Process (e)
The reaction of the compounds of formula VI and of formula lib is conveniently
carried out using analogous conditions to those described above for Step (i) of Reaction
Sdierne 1.
The quinazoline of formula VI may be obtained by conventional procedures, as
discussed above.
The compounds of formula lib may be obtained by conventional procedures, as
discussed above.
Process (f)
A suitable catalyst for the reaction of a quinazoline of the formula VII and 2-
chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or 3-chloropyridazinc is for example
a crown ether such as 18-crown-6.
A suitable catalyst for the reaction of a quinazoline of the formula VII and 2-
bromopyridine or 4-bromopyridine is a palladium catalyst, for example a catalyst formed in
situ by the reaction of bis(dibenzylideneacetone)palladium and 9,9-dimethyl-4,5-
bis(diphenylphosphino)xanthene.
The reaction is conveniently carried out in the presence of a suitable base. A suitable
base is, for example, an alkali or alkaline earth metal carbonate, for example sodium
carbonate, potassium carbonate, cesium carbonate or calcium carbonate.
The reaction is conveniently performed in a suitable inert solvent or diluent, for
example an ether such as tetrahydrofuran or 1,4-dioxane, or a dipolar aprotic solvent such as
acetonitrile.
Suitably the reaction is carried out at a temperature of, for example 0 to 180°C,
particularly 20°C to the reflux temperature of the solvent/diluent Conveniently the reaction
may also be carried out by heating the reactants in a sealed vessel using a suitable heating
apparatus such as a microwave heater.
Preparation of Starting Materials for Process (f)
The quinazoline of formula VII may be obtained by conventional procedures, as
discussed above.
The 2-bromopyridine, 4-bromopyridine, 2-chloropyrimidine, 4-chloropyrimidine, 2-
chloropyraztne and 3-chloropyridazine reagents are commercially available compounds or
they are known in the literature, or they can be can be prepared by standard processes known
in the art.
Rocess
The reaction of the compound of formula VHI and the arnine of formula IXa is
conveniently carried out using analogous conditions to those used in step (iii) in Reaction
Scheme la.
Preparation of Starting Materials for Process (g)
The quinazoline of formula VIQ may be obtained by conventional procedures, as
discussed above.
The amines of formula IXa are commercially available compounds or they are known
in the literature, or they can be can be prepared by standard processes known in the art
The quinazoline derivative of the formula I may be obtained from the above processes
in the form of the tree base or alternatively it may be obtained in the form of a salt, such as an
acid addition salt. When it is desired to obtain the free base from a salt of the compound of
formula I, the salt may be treated with a suitable base, for example, an alkali or alkaline earth
metal carbonate or hydroxide, for example sodium carbonate, potassium, carbonate, calcium
carbonate, sodium hydroxide or potassium hydroxide, or by treatment with ammonia for
example using a methanolic ammonia solution such as 7N ammonia in methanol.
The protecting groups used in the processes above may in general be chosen from any
of the groups described in the literature or known to the skilled chemist as appropriate for the
protection of the group in question and may be introduced by conventional methods.
Protecting groups may be removed by any convenient method as described in the literature or
known to the skilled chemist as appropriate for the removal of the protecting group in ,
question, such methods being chosen so as to effect removal of the protecting group with
minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience,
in which "lower", as in, for example, lower alkyl, signifies that the group to which it is
applied preferably has 1 to 4 carbon atoms. It will be understood that these examples are not
exhaustive. Where specific examples of methods for the removal of protecting groups are
given below these are similarly not exhaustive. The use of protecting groups and methods of
deprotection not specifically mentioned are, of course, within the scope of the invention.
A carboxy protecting group may be the residue of an ester-forming aliphatic or
arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably
containing 1 to 20 carbon atoms). Examples of carboxy protecting groups include straight or
branched chain (l-12C)aIkyl groups (for example isopropyl, and tort-butyl):
lower alkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl and
isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl,
propionyloxymethyl, butyryloxymethyl andpivaloyloxymethyl); lower
alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and
1-cthoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl,
2-nitrobenzyl, 4-nitrobcnzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyi groups (for
example trimethylsilvl and j^-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups
(for example trimethylsilylcthyl); and (2-6C)alkenyl groups (for example allyl). Methods
particularly appropriate for the removal of carboxyl protecting groups include for example,
acid-, base-, metal- or enzymically-catalysed cleavage.
Examples of hydroxy protecting groups include lower alkyl groups (for example
tejl-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example
acetyl); lower alkoxycarbonyl groups (for example tert-butoxvcarbonvlV.
lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl
groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl and4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example
trimethylsilyl and lerj-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
Examples of ammo protecting groups include formyl, aryl-lower alkyl groups (for
example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and
2,4-dimethoxybenzyl, and triphenylmethyl); lower alkenyl groups (for example allyl)
di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example
tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower
alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); lower alkanoyloxyalkyl groups (for
example pivaloyloxymethyl); trialkylsilyl (for example trimethylsilyl and
igt-butyldimethylsilyl); alkyh"dene (for example methylidene) and benzylidene and
substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for
example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as
2-nitrobenzyloxycarbonyl and allyl, hydrogenation for groups such as benzyl and
photolytically for groups such as 2-nitrobenzyloxycarbonyl. For example a tertbutoxycarbonyl
protecting group may be removed from an amino group by an acid catalysed
hydrolysis using trifluoroacetic acid.
The reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March,
published by John Wiley & Sons 1992, for general guidance on reaction conditions and
reagents and to Protective Groups in Organic Synthesis, 2"1 Edition, by T. Green et aL, also
published by John Wiley & Son, for general guidance on protecting groups.
It will be appreciated 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 prior to or immediately
following the processes mentioned above, and as such are included in the process aspect of
the invention. Such reactions and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation
of substituents and oxidation of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples of aromatic substitution
reactions include the introduction of a nitro group using concentrated nitric acid, the
introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as
aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group
using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts
conditions; and the introduction of a halogeno group,
When a pharmaceutically acceptable salt of a quinazoline derivative of the formula I is
required, for example an acid-addition salt, it may be obtained by, for example, reaction of
said quinazoline derivative with a suitable acid using a conventional procedure.
As mentioned hereinbefore some of the compounds according to the present invention
may contain one or more chiral centers and may therefore exist as stereoisomers (for example
when R4 is alkyl and R4* is hydrogen). Stereoisomers may be separated using conventional
techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated
by separation of a racemate for example by fractional crystallisation, resolution or HPLC. The
diastereoisomers may be isolated by separation by virtue of the different physical properties
of the diastereoisomers, for example, by fractional crystallisation, HPLC or flash
chromatography. Alternatively particular stereoisomers may be made by chiral synthesis from
chiral starting materials under conditions which will not cause racetnisation or epimerisation,
or by derivatisation, with a chiral reagent When a specific stereoisomer is isolated it is
suitably isolated substantially free of other stereoisomers, for example containing less than
20%, particularly less than 10% and more particularly less than 5% by weight of other
stereoisomers.
In the section above relating to the preparation of the quinazoline derivative of
formula I, the expression "inert solvent" refers to a solvent which does not react with the
starting materials, reagents, intennediates or products in a manner which adversely affects the
yield of the desired product.
Persons skilled hi the art will appreciate that, in order to obtain compounds of the
invention in an alternative and hi some occasions, more convenient manner, the individual
process steps mentioned hereinbefore may be performed in a different order, and/or the
individual reactions may be performed at a different stage in the overall route (i.e. chemical
transformations may be performed upon different intennediates to those associated
hereinbefore with a particular reaction).
Certain intennediates used in the processes described above are novel and form a
further feature of the present invention. Accordingly there is provided a compound of the
Formula IV as hereinbefore defined, or a salt thereof. The intermediate may be in the form of
a salt of the intermediate. Such salts need not be a pharmaceutically acceptable salt. For
example it may be useful to prepare an intermediate in the form of a pharmaceutically nonacceptable
salt if, for example, such salts are useful in the manufacture of a compound of
Biological Assays
The inhibitory activities of compounds were assessed in non-cell based protein
tyrosine kinase assays as well as in cell based proliferation assays before their in vivo activity
was assessed in Xenograft studies.
a) Protein Tyrosine Kinase phosphorylation Assays
This test measures the ability of a test compound to inhibit the phosphorylation of a
tyrosine containing polypeptide substrate by an erb receptor tyrosine kinase enzyme.
Recombinant intracellular fragments of EGFR, erbB2 and erbB4 (accession numbers
X00588, X03363 and L07868 respectively) were cloned and expressed in the
baculovirus/SGl system. Lysates were prepared from these cells by treatment with ice-cold
lysis buffer (20mM N^-hydroxyethylpipcrizine-N"-cdianesulfonic acid (HEPES) pH7.5,
ISQmM NaCl, 10% glycerol, 1% Triton X-100, LSrnM MgCl2, ImM ethylene
glycol-bis(j}-aminoethyl ether) N"T.N""-letraacetic acid (EOTA), plus protease inhibitors
and then cleared by centrifugation.
Constitutive kinase activity of these recombinant proteins was determined by their
ability to phosphorylate a synthetic peptide (made up of a random co-polymer of Ghitamic
Acid, Alanine and Tyrosine in the ratio of 6:3:1). Specifically, Maxisorb™ 96-well
immunoplates were coated with synthetic peptide (0.2|ig of peptide in a 200|d phosphate
buffered saline (PBS) solution and incubated at 4°C overnight). Plates were washed in SOmM
HEPES pH 7.4 at room temperature to remove any excess unbound synthetic peptide. EGFR
or erbB2 activities were assessed by incubation in peptide coated plates for 20 minutes at
room temperature in lOOmM HEPES pH 7.4 at room temperature, adenosine trisphosphate
(ATP) at Km concentration for the respective enzyme, 10mM MnCl2O.lmM Na3VO4,
0.2mMDL-dithiothreitol (DTT), 0.1% Triton X-100 with test compound in DMSO (final
concentration of 2.5%). Reactions were terminated by the removal of the liquid components
of the assay followed by washing of the plates with PBS-T (phosphate buffered saline with
0.5% Tween 20).
The immobilised phospho-peptide product of the reaction was detected by
immunological methods. Firstly, plates were incubated for 90 minutes at room temperature
with anti-phosphotyrosine primary antibodies that were raised in the mouse (4O10 from
Upstate Biotechnology). Following extensive washing, plates were treated with Horseradish
Peroxidase (HRP) conjugated sheep anti-mouse secondary antibody (NXA931 from
Amersham) for 60 minutes at room temperature. After further washing, HRP activity in each
well of the plate was measured colorimetrically using 22"-Azino-di-[3-ethylbenzthiazoline
sulfonate (6)] diammonium salt crystals (ABTS™ from Roche) as a substrate.
Quantification of colour development and thus enzyme activity was achieved by the
measurement of absorbance at 405nm on a Molecular Devices ThennoMax microplate reader.
Kinase inhibition for a given compound was expressed as an IC50 value. This was determined
by calculation of the concentration of compound mat was required to give 50% inhibition of
phosphorylation in this assay. The range of phosphorylation was calculated from the positive
(vehicle plus ATP) and negative (vehicle minus ATP) control values.
b) EGFR driven KB cell proliferation assay
This assay measures the ability of a test compound to inhibit the proliferation of KB
cells (human naso-pharangeal carcinoma obtained from the American Type Culture
Collection (ATCQ).
KB cells were cultured in Dulbecco"s modified Eagle"s medium (DMEM) containing
10% foetal calf serum, 2 mM glutamine and non-essential amino acids at 37°C in a 7.5% CO?
air incubator. Cells were harvested from the stock flasks using
Trypsin/emylarmnediaminetetraacetic acid (EDTA). Cell density was measured using a
haemocytometer and viability was calculated using trypan blue solution before being seeded
at a density of 1.25xl03 cells per well of a 96 well plate in DMEM containing 2.5% charcoal
stripped serum, ImM glutamine and non-essential amino acids at 37°C in 15% CCh and
allowed to settle for 4 hours.
Following adhesion to the plate, the cells are treated with or without EGF (final
concentration of Ing/ml) and with or without compound at a range of concentrations in
dimethylsulfoxide (DMSO) (0.1% final) before incubation for 4 days. Following the
incubation period, cell numbers were determined by addition of SOjil of 3-(4,5-
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (stock Smg/ml) for 2 hours.
MTT solution was then tipped off, the plate gently tapped dry and the cells dissolved upon the
^dition of lOOuJ of DMSQ,
Absorbance of the solubilised cells was read at 540nm using a Molecular Devices
ThermoMax microplate reader. Inhibition of proliferation was expressed as an ICso value.
This was determined by calculation of the concentration of compound that was required to
give 50% inhibition of proliferation. The range of proliferation was calculated from the
positive (vehicle plus EOF) and negative (vehicle minus EOF) control values,
c) Cellular EGFR phosphorylation assay
This assay measures the ability of a test compound to inhibit the phosphorylation of
EGFR in KB cells (human naso-pharangeal carcinoma obtained from the American Type
Culture Collection (ATCC).
KB cells were cultured in Dulbecco"s modified Eagle"s medium (DMEM) containing
10% foetal calf serum, 2 rnM glutamine and non-essential amino acids at 37°C in a 7.5% CO
air incubator. Cells were harvested from the stock flasks using
Trypsin/ethylaminediaminetetraacetic acid (EOTA). Cell density was measured using a
haemocytometer and viability was calculated using trypan blue solution before being seeded
at a density of 2X105 cells per well of a 6 well plate in DMEM containing 2,5% charcoal
stripped serum, 2mM glutamine and non-essential ammo acids at 37°C in 7.5% CO and
allowed to settle for 72 hours.
Following the 72 hour incubation period, the stripped serum containing media was
then replaced with serum-free media (DMEM containing 2mM glutamine and non-essential
amino acids) and incubated at 37°C in 7.5% CQ for 72 hours. Following this incubation
period, the cells were treated with or without compound at a range of concentrations in
dimethylsulfoxide (DMSO) (0.1% final) in serum free DMEM. Following incubation forl.5
hours at 37°C in 7.5% CO the cells were treated with EOF (final concentration of lu,g/ml)
and incubated at 37°C in 7.5% CO for 3 minutes. The media was then removed and the cells
washed twice hi ice cold Phosphate Buffered Saline before lysis of the cells with 1ml of ice
cold lysis buffer containing 120mM NaCl2,25mM HEPES, pH 7.6,5mM BGlycerophosphate,
2.5mM MgCfc, ImM EGTA, 0.2mM EDTA, ImM Na3VO4,1% Triton X-
100, lOOmM NaF, ImM DTT, IraMPMSF, 10g/ml Leupeptin and lOu.g/ml Benzamidine.
The lysates were centrifuged in a microfuge at 13000 rpm for 15 minutes and the supematants
taken before analysis by sandwich Elisa,
Nunc Maxisorb F96 Immunoplates were coated with EGFR capture antibody (sc-120,
Santa Cruz Biotechnology, Inc.) by incubation at a concentration of 0.16jig/ml in lOOul of
50mM carbonate/bicarbonate buffer, pH 9.6. The plates were incubated at 4°C overnight with
a gentle shaking action. Following overnight incubation, the plates were washed extensively
with PBS containing 0.05% Tween before blocking with Superblock (Pierce). 100,1 of lysate
was then added to each well and incubated overnight at 4°C before extensive washing with
PBS containing 0.05% Tween.
The immobilised EGFR was then probed with an anti-phosphotyrosine HRP
conjugated antibody (4G10, Upstate Biotechnology Inc.) at a dilution of 1 in 800 in PBS
containing 0.05% Tween plus 0.5% Bovine Serum Albumen. After further washing, HRP
activity hi each well of the plate was measured colorimetrically using Tetra Methyl Benzidine
(TMB) from Bushranger (Roche Applied Sciences) in phosphate-citrate-perborate buffer
containing 10% DMSO as a substrate. This reaction was stopped by the addition of lOOul of
1M HzSQ after 12 minutes and quantified by measurement of the absorbance at 450nm using
a Molecular Devices ThermoMax microplate reader.
Inhibition of EGFR phosphorylation for a given compound was expressed as an ICso
value. This was determined by calculation of the concentration of compound that was
required to give 50% inhibition of phosphorylation hi this assay. The range of
phosphorylation was calculated from the positive (vehicle plus EOF) and negative (vehicle
minus EOF) control values.
d) Clone 24 phospho-erbB2 cell assay
This unmunofluorescence end point assay measures the ability of a test compound to
inhibit the phosphorylation of erbB2 in a MCF7 (breast carcinoma) derived cell tine which
was generated by transfecting MCF7 cells with the full length erbB2 gene using standard
methods to give a cell line that overexpresses full length wild type erbB2 protein (hereinafter
"Clone 24* cells).
Clone 24 cells were cultured in Growth Medium (phenol red free Dulbecco"s
modified Eagle"s medium (DMEM) containing 10% foetal bovine serum, 2 mM glutamine
and 1.2mg/ml G418) in a 7.5% CQz air incubator at 37°C. Cells were harvested from T75
stock flasks by washing once in PBS (phosphate buffered saline, pH7.4, Gibco No. 10010-
015) and harvested using 2mls of Trypsin (1.25mg/mlethylaminediaminetetraacetic acid
(EDTA) (0.8mg/ml) solution. The cells were resuspended in Growth Medium. Cell density
was measured using a haemocytometer and viability was calculated using Trypan Blue
solution before being further diluted in Growth Medium and seeded at a density of IxlO4 cells
perwell(in lOOul) into clear bottomed 96 well platek (Packard, No. 6005182).
3 days later, Growth Medium was removed from the wells and replaced with lOOul
Assay Medium (phenol red free DMEM, 2mM glutamine, 1.2mg/ml G418) either with or
without erbB inhibitor compound. Plates were returned to the incubator for 4hours and then
20ul of 20% formaldehyde solution in PBS was added to each well and the plate was left at
room temperature for 30 minutes. This fixative solution was removed with a multichannel
pipette, lOOjil of PBS was added to each well and then removed with a multichannel pipette
and then 50ul PBS was added to each well Plates were then sealed and stored for up to 2
weeks at 4°C.
Immunostaining was performed at room temperature. Wells were washed once with
200^1 PBS / Tween 20 (made by adding 1 sachet of PBS / Tween dry powder (Sigma, No.
P3563) to 1L of double distilled HjO) using a plate washer then 200ul Blocking Solution (5%
Marvel dried skimmed milk (Nestle) in PBS Tween 20) was added and incubated for 10
minutes. Blocking Solution was removed using a plate washer and 200^1 of 0.5% Triton X-
100 / PBS was added to permeabalise the cells. After 10 minutes, the plate was washed with
200|il PBS / Tween 20 and men 200|il Blocking Solution was added once again and incubated
for 15 minutes. Following removal of the Blocking Solution with a plate washer, 30ul of
rabbit polyclonal anti-phospho ErbB2 IgO antibody (epitope phospho-Tyr 1248, SantaCruz,
No. SC-12352-R), diluted 1:250 in Blocking Solution, was added to each well and incubated
for 2 hours. Then mis primary antibody solution was removed from the wells using a plate
washer followed by two 200ul PBS / Tween 20 washes using a plate washer. Then 30ul of
Alexa-Fluor 488 goat anti-rabbit IgO secondary antibody (Molecular Probes, No. A-11008),
diluted 1:750 in Blocking Solution, was added to each well. From now onwards, wherever
possible, plates were protected from light exposure, at this stage by sealing with black
backing tape. The plates were incubated for 45 minutes and then the secondary antibody
solution was removed from the wells followed by two 200ul PBS / Tween 20 washes using a
plate washer. Then PBS was added to each plate, incubated for 10 minutes and then
removed using a plate washer. Then a further lOOul PBS was added to each plate and then,
without prolonged incubation, removed using a plate washer. Then SOuJ of PBS was added to
each well and plates were resealed with black backing tape and stored for up to 2 days at 4°C
before analysis.
The Fluorescence^ signal is each well was measured using an Acumen Explorer, ,
Instrument (Acumen Bioscience Ltd.), a plate reader that can be used to rapidly quantitate
features of images generated by laser-scanning. The instrument was set to measure the
number of fluorescent objects above a pre-set threshold value and this provided a measure of
the phosphorylation status of erbB2 protein. Fluorescence dose response data obtained with
each compound was exported into a suitable software package (such as Origin) to perform
curve fitting analysis. Inhibition of erbB2 phosphorylation was expressed as an ICso value.
This was determined by calculation of the concentration of compound that was required to
give 50% inhibition of erbB2 phosphorylation signal.
e) In vivo BT-474 Xeno graft assay
This assay measures the ability of a test compound to inhibit the growth of a BT-474
tumour cell xenograft (human mammary carcinoma obtained from Dr Baselga, Laboratorio
Recerca Oncologica, Paseo Vail DHebron 119-129, Barcelona 08035, Spain) in Female
Swiss athymic mice (Alderley Park, nu/nu genotype) (Baselga, J. et al (1998) Cancer
Research, 58,2825-2831).
Female Swiss athymic (nu/nu genotype) mice were bred and maintained in Alderley
Park in negative pressure Isolators (PFI Systems Ltd.). Mice were housed in a barrier facility
with 12hr light/dark cycles and provided with sterilised food and water ad libitum. All
procedures were performed on mice of at least 8 weeks of age. BT-474 tumour cell
xenografts were established in the hind flank of donor mice by sub-cutaneous injections of
IxlO7 freshly cultured cells in lOOul of serum free media with 50% Matrigel per animal. On
day 14 post-implant, mice were randomised into groups of 10 prior to the treatment with
compound or vehicle control that was administered once daily at O.lml/lOg body weight
Tumour volume was assessed twice weekly by bilateral Vernier calliper measurement, using
the formula (length x width) x V(Iength x width) x (fl/6), where length was the longest
diameter across the tumour, and width was the corresponding perpendicular. Growth
inhibition from start of treatment was calculated by comparison of the mean changes in
tumour volume for the control and treated groups, and statistical significance between the two
groups was evaluated using a Students t test.
f) hERG-encoded Potassium Channel Inhibition Assay
This assay determines the ability of a test compound to inhibit the tail current flowing
through the human ether-a-go-go-related-gene (Herg)encoded potassium channel.
Human embryonic kidney (HEK) cells expressing the hERG-encoded channel were
grown in Mimhium Essential Medium Eagle (EMEM; Sigma-Aldrich catalogue number
M2279), supplemented with 10% Foetal Calf Serum (Labtech International; product number
4-101-500), 10% Ml serum-free supplement (Egg Technologies; product number 70916) and
0.4 mg/ml Geneticin 0418 (Sigma-Aldrich; catalogue number G7034). One or two days
before each experiment, the cells were detached from the tissue culture flasks with Accutase
(TCS Biologicals) using standard tissue culture methods. They were then put onto glass
coverslips resting hi wells of a 12 well plate and covered with 2 ml of the growing media.
For each cell recorded, a glass coverslip containing the cells was placed at the bottom
of a Perspex chamber containing bath solution (see below) at room temperature (~20 °C).
This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately
after placing the coverslip in the chamber, bath solution was perfused into the chamber from a
gravity-fed reservoir for 2 minutes at a rate of ~ 2 ml/min. After this time, perfusion was
) stopped.
A patch pipette made from borosilicate glass tubing (GC120F, Harvard Apparatus)
using a P-97 micropipette puller (Sutter Instrument Co.) was filled with pipette solution (see
hereinafter). The pipette was connected to the headstage of the patch clamp amplifier
(Axopatch 200B, Axon Instruments) via a silver/silver chloride wire. The headstage ground
was connected to the earth electrode. This consisted of a silver/silver chloride wire embedded
in 3% agar made up with 0.85% sodium chloride.
The cell was recorded in the whole cell configuration of Hie patch clamp technique.
Following "break-in", which was done at a holding potential of -80 mV (set by the amplifier),
and appropriate adjustment of series resistance and capacitance controls, electtophysiology
software (CUunpex, Axon Instruments) was used to set a holding potential (-80 mV) and to
deliver a voltage protocol. This protocol was applied every 15 seconds and consisted of a 1 s
step to 440 mV followed by a 1 s step to -50 mV. The current response to each imposed
voltage protocol was low pass filtered by the amplifier at 1 kHz. The filtered signal was men
acquired, on line, by digitising this analogue signal from the amplifier with an analogue to
digital converter. The digitised signal was then captured on a computer running Clampex
software (Axon Instruments). During the holding potential and the step to + 40 mV the
current was sampled at 1 kHz. The sampling rate was men set to 5 kHz for the remainder of
the voltage protocol.
The compositions, pH and osmolarity of the bath and pipette solution are tabulated
below.
0.4 ing/ml Geneticin 0418 (Sigma-Aldrich; catalogue number G7034). One or two days
before each experiment, the cells were detached from the tissue culture flasks with Accutase
(TCS Biologicals) using standard tissue culture methods. They were then put onto glass
coverslips resting in wells of a 12 well plate and covered with 2 ml of the growing media.
For each cell recorded, a glass coverslip containing the cells was placed at the bottom
of a Perspex chamber containing bath solution (see below) at room temperature (-20 °C).
This chamber was fixed to the stage of an inverted, phase-contrast microscope. Immediately
after placing the coverslip in the chamber, bam solution was perfused into the chamber from a
gravity-fed reservoir for 2 minutes at a rate of ~ 2 ml/mm. After mis time, perfusion was
stopped.
A patch pipette made from borosilicate glass tubing (GC120F, Harvard Apparatus)
using a P-97 micropipette puller (Sutler Instrument Co.) was filled with pipette solution (see
hereinafter). The pipette was connected to the beadstage of the patch clamp amplifier
(Axopatch 200B, Axon Instruments) via a silver/silver chloride wire. The headstage ground
was connected to the earth electrode. This consisted of a silver/silver chloride wire embedded
in 3% agar made up with 0.85% sodium chloride.
The cell was recorded in the whole cell configuration of the patch clamp technique.
Following "break-in, which was done at a holding potential of -80 mV (set by the amplifier),
and appropriate adjustment of series resistance and capacitance controls, electrophysiology
software (Clampex, Axon Instruments) was used to set a holding potential (-80 mV) and to
deliver a voltage protocol. This protocol was applied every IS seconds and consisted of a 1 s
step to 440 mV followed by a 1 s step to -50 mV. The current response to each imposed
voltage protocol was low pass filtered by the amplifier at 1 kHz. The filtered signal was then
acquired, on line, by digitising mis analogue signal from the amplifier with an analogue to
digital converter. The digitised signal was then captured on a computer running Clampex
software (Axon Instruments). During the holding potential and the step to + 40 mV the
current was sampled at 1 kHz. The sampling rate was then set to 5 kHz for the remainder of
the voltage protocol.
The compositions, pH and osmolarity of the bath and pipette solution are tabulated
below.
Salt
NaCl
Kd
MgCl2
Cad2
HEPES
glucose
Na2ATP
EGTA
Pipette (raM)
Parameter
pH
pH adjustment with
Osmolarity (mOsm)
Pipette
7.18-7.22
1MKOH
275-285
Bath
7.40
IMNaOH
285-295
The amplitude of the hERG-encoded potassium channel tail current following the
step from +40 mV to -50 mV was recorded oo-tine by Clampex software (Axon Instruments).
Following stabilisation of the tail current amplitude, bath solution containing the vehicle for
the test substance was applied to the cell. Providing the vehicle application had no significant
effect on tail current amplitude, a cumulative concentration effect curve to the compound was
then constructed.
The effect of each concentration of test compound was quantified by expressing the
tail current amplitude hi the presence of a given concentration of test compound as a
percentage of that in the presence of vehicle.
Test compound potency (ICso) was determined by fitting the percentage inhibition
values making up the concentration-effect to a four parameter Hill equation using a standard
data-fitting package. If the level of inhibition seen at the highest test concentration did not
exceed 50%, no potency value was produced and a percentage inhibition value at mat
concentration was quoted.
Although the pharmacological properties of the compounds of the formula 1 vary with
structural change as expected, in general activity possessed by compounds of the formula I,
may be demonstrated at the following concentrations or doses in one or more of the above
tests (a), (b), (c) and (d)
Test (a):- ICso in the range, for example, 0.001 - 5
Test (b):- ICso in the range, for example, 0.001 - 5 µM;
Test (c):- ICso in the range, for example, 0.001 - 5 µM;
Test (c):- ICso in the range, for example, 0.001 - S µM;
Test (d):- activity in the range, for example, 1-200 mg/kg/day;
No physiologically unacceptable toxicity was observed in Test (d) at the effective dose
for compounds tested of the present invention. Accordingly no untoward toxicological effects
are expected when a compound of formula I, or a pharmaceutically acceptable salt thereof, as
defined hereinbefore is administered at the dosage ranges defined hereinafter.
By way of example, Table A illustrates the activity of representative compounds
according to the invention. Column 2 of Table A shows ICso data from Test (a) for the
inhibition of EGFR tyrosine kinase protein phosphorylation; column 3 shows ICso data from
Test (a) for the inhibition of erbB2 tyrosine kinase protein phosphorylation; and column 4
shows ICso data for inhibition of phosphorylation of erbB2 in a MCF7 derived cell line in Test
(d) described above:
According to a further aspect of the invention mere is provided a pharmaceutical
composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically
(Table Removed) acceptable 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, or aqueous or oily solutions or suspensions), for administration by inhalation (for
example as a finely divided powder or a liquid aerosol), for administration by insufflation (for
example as a finely divided powder) or for parenteral administration (for example as a sterile
aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing
or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using
conventional pharmaceutical excipients, well known in the art Thus, compositions intended
for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or
preservative agents.
The amount of active ingredient mat 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, a formulation intended for oral
administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active
agent (more suitably from O.S to 100 mg, for example from 1 to 30 mg) compounded with an
appropriate and convenient amount of excipients which may vary from about 5 to about 98
percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a quinazoline
derivative of the formula I will naturally vary according to the nature and severity of the
conditions, the age and sex of the animal or patient and the route of administration, according
to well known principles of medicine.
In using a quinazoline derivative of the formula I for therapeutic or prophylactic
purposes it will generally be administered so that a daily dose in the range, for example, 0.1
mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general
lower doses will be administered when a parenteral route is employed. Thus, for example, for
intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body
weight will generally be used. Similariy, for administration by inhalation, a dose in the range,
for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration is
however preferred, particularly in tablet form. Typically, unit dosage forms will contain
about 0.5 mg to 0.5 g of a compound of this invention.
We have found that the compounds of the present invention possess anti-proliferative
properties such as anti-cancer properties that are believed to arise from their erb-B,
particularly EOFR and more particularly erbB2 receptor tyrosine kinase inhibitory activity.
Furthermore, certain of the compounds according to vie present invention possess
substantially better potency against the erbB2 receptor tyrosine kinase, than against other
tyrosine kinases enzymes, such as EGFR tyrosine kinase. Such compounds possess sufficient
potency against the erbB2 receptor tyrosine kinase mat they may be used in an amount
sufficient to inhibit erbB2 receptor tyrosine kinase whilst demonstrating little, or significantly
lower, activity against other tyrosine kinases such as EGFR. Such compounds are likely to be
useful for the selective inhibition of erbB2 receptor tyrosine kinase and are likely to be useful
for the effective treatment of, for example etbB2 driven tumours. Accordingly, the
compounds of the present invention are expected to be useful m the treatment of diseases or
medical conditions mediated alone or in part by and erb-B, particularly erbB2 receptor
tyrosine kinases, i.e. the compounds may be used to produce a erb-B, particularly an erbB2,
receptor tyrosine kinase inhibitory effect in a warm-blooded anirnalm need of such treatment
Thus the compounds of the present invention provide a for the treatment of maHgnant
cells characterised by inhibition of the erb-B, particularly erbB2 receptor tyrosine kinase.
Particularly die compounds of the invention may be used to produce an anti-proliferative
and/or pro-apoptotic and/or anti-invasive effect mediated alone or in part by the inhibition of
erb-B, particularly ertB2, receptor tyrosine kinases. Particularly, the compounds of the
present invention are expected to be useful in the prevention or treatment of those tumours
that are sensitive to inhibition of an erb-B, particularly the erbB2, receptor tyrosine kinase that
are involved in the signal transduction steps which drive proliferation and survival of these
tumour cells. Accordingly the compounds of the present invention are expected to be useful
in the treatment and/or prevention of a number of hyperprolif erative disorders by providing an
anti-proliferative effect These disorders include, for example psoriasis, benign prostatic
hyperplasia (BPH), atherosclerosis and restenosis and, in particular, erb-B, more particularly
erb-B2, receptor tyrosine kinase driven tumours. Such benign or maHgnant tumours may
affect any tissue and include non-solid tumours such as leukaemia, multiple myeloma or
lyrnphpma, and also solid tumours, for example bile duct, bone, bladder, brain/CNS, breast,
colorcctal, cervical, endometrial, gastric, head and neck, hepatic, lung, muscle, neuronal,
oesophageal, ovarian, pancreatic, pleural/peritoneal membranes, prostate, renal, skin,
testicular, thyroid, uterine and vulval tumours.
According to this aspect of the invention there is provided a quinazoline derivative of
the formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament.
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 thereof, as
defined hereinbefore 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 mere is provided 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 phannaceutically acceptable salt thereof, as
hereinbefore defined.
According to a further aspect of the invention there is provided a quinazoline
derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in the
production of an anti-proliferative effect 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 thereof, as
defined hereinbefore in the manufacture of a medicament for use in the production of an
anti-proliferative effect which effect is produced alone or m part by inhibiting erbB2 receptor
tyrosine kinase in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention mere is provided a
method for producing an anti-proliferative effect which effect is produced alone or hi part by
inhibiting erbB2 receptor tyrosine kinase 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 phannaceutically acceptable salt thereof, as
hereinbefore defined.
According to a further aspect of the invention there is provided a quinazoline
derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in the
production of an anti-proliferative effect which effect is produced alone or in part by
inhibiting erbB2 receptor tyrosine kinase in a warm-blooded animal such as man.
According to a further aspect of the present invention mere is provided the use of a
quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as
defined hereinbefore: in the manufacture of a medicament for use in the treatment of a disease
or medical condition (for example a cancer as mentioned herein) mediated alone or in part by
erb-B, particularly erbB2, receptor tyrosine kinase.
According to a further feature of this aspect of the invention there is provided a
method for treating a disease or medical condition (for example a cancer as mentioned herein)
mediated alone or in part by erb-B, particularly erbB2, receptor tyrosine kinase 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
pharmaccuticaliy acceptable salt thereof, as defined hereinbefore.
According to a further aspect of the invention mere is provided a quinazoline
derivative of the formula I, or a pharmaceutically acceptable salt thereof, for use in the
treatment of a disease or medical condition (for example a cancer as mentioned herein)
mediated alone or hi part by erb-B, particularly erbB2, receptor tyrosine kinase.
According to a former aspect of the invention mere is provided the use of a
quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof , as
defined hereunbef ore in the manufacture of a inediwiment for use in the prevention or
treatment of those tumours which are sensitive to inhibition of erbB2 receptor tyrosine kinase
that is involved in the signal transduction steps which lead to the proliferation of tumour cells.
According to a further feature of mis aspect of me invention there is provided a
method for the prevention or treatment of those tumours which are sensitive to inhibition of
erbB2 receptor tyrosine kinase, that is involved in the signal transduction steps which lead to
the proliferation and/or survival of tumour cells 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 thereof, as
defined hereinbefore.
According to a further aspect of the invention there is provided a quinazoline
derivative of the formula I, or a pharmaceutically acceptable salt thereof, for use in the
prevention or treatment of those tumours which are sensitive to inhibition of the erbB2
receptor tyrosine kinase, mat is involved hi the signal transduction steps which lead to the
proliferation and/or survival of tumour cells. According to a further aspect of the invention
mere is provided tile use of a quinazoline derivative of the formula I, or a pharmaceutically
acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in
providing a erbB2 receptor tyrosine kinase inhibitory effect
According to a further feature of this aspect of the invention there is provided a
method for providing an erbB2 receptor tyrosine kinase inhibitory 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 phannaceutically
acceptable salt thereof, as defined hereinbefore.
According to a further aspect of the invention there is provided a quinazoline
derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in providing
an erbB2 receptor tyrosine kinase inhibitory effect
According to a further aspect of the invention there is provided the use of a
quinazoline derivative of the formula I, or a phannaceutically acceptable salt thereof, as
defined hereinbefore in the manufacture of a medicament for use m providing a selective
erbB2 kinase inhibitory effect
According to a further feature of this aspect of the invention there is provided a
method for providing a selective erbB2 kinase inhibitory 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 phannaceutically
acceptable salt thereof, as defined hereinbefore.
According to a further aspect of the invention mere is provided a quinazoline
derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in providing
a selective erbB2 kinase inhibitory effect.
By "a selective exbB2 kinase inhibitory effect" is meant that the quinazoline derivative
of Formula I is more potent against erbB2 receptor tyrosine kinase than it is against other
kinases. In particular some of the compounds according to the invention are more potent
against erbB2 receptor kinase than it is against other tyrosine kinases such as other erb-B
receptor tyrosine kinases, particularly EGFR tyrosine kinase. For example a selective erb-B2
kinase inhibitor according to the invention is at least 5 times, preferably at least 10 times,
more preferably at least 100 times more potent against erbB2 receptor tyrosine kinase than it
is against EGFR tyrosine kinase, as determined from the relative ICso values in suitable assays
(for example the by comparing the ICso value from the Clone 24 phospho-erbB2 cell assay
(assay d) described above which measure the inhibition of erb~B2 phosphorylation hi cells)
with the ICso from the KB cellular EOFR phosphorylation assay (assay c) described above
which measures the inhibition of EGFR phosphorylation in cells) for a given test compound
as described above).
According to a further aspect of the present invention mere is provided the use of a
quinazoHne derivative of the formula I, or a phannaceutically acceptable salt thereof, as
defined hereinbefore in the manufacture of a medicament for use in the treatment of acancer,
for example a cancer selected fiom leukaemia, multiple myeloma, lymphoma, bile duct, bone,
bladder, brain/CNS, breast, colorectal, cervical, endometrial, gastric, head and neck, hepatic,
lung, muscle, neuronal, oesophageal, ovarian, pancreatic, pleural/peritoneal membranes,
prostate, renal, skin, testicular, thyroid, uterine and vulval cancer.
According to a further feature of mis aspect of the invention mere is provided a
method for treating a cancer, for example a cancer selected fiom selected from leukaemia,
multiple myeloma, lymphoma, bfle duct, bone, bladder, brain/CNS, breast, colorectal,
cervical, endometrial, gastric, head and neck, hepatic, lung, muscle, neuronal, oesophageal,
ovarian, pancreatic, pleural/peritoneal membranes, prostate, renal, skin, testicular, thyroid,
uterine and vulval 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 quinazohne derivative
of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
According to a further aspect of the invention there is provided a quinazoline
derivative of the formula I, or a phannaceutically acceptable salt thereof, for use in the
treatment of a cancer, for example a cancer selected from leukaemia, multiple myeloma,
lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, cervical, endometrial,
gastric, head and neck, hepatic, lung, muscle, neuronal, oesophageal, ovarian, pancreatic,
pleural/peritoneal membranes, prostate, renal, skin, testicular, thyroid, uterine and vulval
cancer.
The anti-proliferative treatment defined hereinbefore may be applied as a sole therapy
or may involve, hi addition to the quinazoline derivative of the invention, conventional
surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of
the following categories of anti-tumour agents:
As mentioned above the size of the dose required for the therapeutic or prophlyactic treatment
of a particular disease will necessarily be varied depending upon, amongst other things, the
host treated, the route of administration and the severity of the illness being treated.
The anti-proliferative treatment defined hereinbefore may be applied as a sole therapy
or may involve, in addition to the quinazoline derivative of the invention, conventional
surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of
the following categories of anti-tumour agents :-
(i) antiproUferative/antineoplastic drugs and combinations thereof, as used in medical
oncology, such as aflcylating agents (for example cis-platin, carboplatin, cyclophosphamide,
nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for
example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,
methotrexate, cytosine arabinoeide and hydroxyurea; antitumour antibiotics (for example
anthracyclines like adriamycLn, bfeomytin, doxorubicin, daunomycin, epirubicin, idarubicin,
mitomycin-C, dactinomycin and mimramycin); antimitotic agents (for example vinca
alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and
taxotere); and topoisomcrase inhibitors (for example epipodophyllotoxins tike etoposide and
teniposide, amsacrinc, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene,
raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example
fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone
acetate), LHRH antagonists or LHRH agonists (for example goseretin, Icuprorelin and
buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example
as anastrozole, letrozole, vorazole and exemestane) and inhibitors of So-reductase such as
fmasteride;
(hi) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors
like marimastat and inhibitors of urokinase plasminogen activator receptor function);
(iv) inhibitors of growth factor function, for example such inhibitors include growth factor
antibodies, growth factor receptor antibodies (for example the anti-erbB2 antibody
trastuzumab [Herceptin™] and the anti-erbBl antibody cetuximab [C22S]), famesyl
transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for
example other inhibitors of the epidermal growth factor family (for example EGFR family
tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-
morpholinoptopoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-methynylienyl)-6,7-
bis(2rinelhoxyedK)xy)quinazoliii-4-amiiie (erlotinib, OSI-774) and 6-acrylamido- -(3-cWoio-
4-fluoroph«iyl)-7-{3-morpholinopropoxy)qmnazolin-4-amine (CI 1033)X for example
inhibitors of the platelet-derived growth factor family and for example inhibitors of the
hepatocyte growth factor family;
(v) antiangiogenic agents such as those which inhibit die effects of vascular endothelial
growth factor, (for example the anti-vascular endothelial cell growth factor antibody
bevacizumab [Avastin™], compounds such as those disclosed in International Patent
Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and
compounds that work by other mechanisms (for example linomide, inhibitors of integral
ovfte function and angiostatin);
(vi) vascular damaging agents such as CombietastatinA4 and 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)antigens therapies, for example those which redirected to the targets listed above, such
as ISIS 2503, an anti-rasantisense;
(viii) gene therapy approaches, inchiding for example approaches to replace aberrant genes
such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial
nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapy approaches, inchiding for example ex-vivo and in-vivo approaches to
increase the immunogenicity of patient tumour cells, such as transfection with cytoldnes such
as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor,
approaches to decrease T-cell energy, approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines
and approaches using anti-idiotypic antibodies.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or
separate dosing of the individual components of the treatment. Such combination products
employ the compounds of this invention within the dosage range described hereinbefore and
the other pharmaceutically-active agent within its approved dosage range.
According to this aspect of the invention there is provided a pharmaceutical product
comprising a quinazoline derivative of the formula I as defined hereinbefore and an additional
anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.
Although the compounds of the formula I are primarily of value as therapeutic agents
for use in warm-blooded animals (including man), they are also useful whenever it is required
to inhibit the effects of the erbB receptor tyrosine protein kinases. Thus, they are useful as
pharmacological standards for use in the development of new biological tests and in the
search for new pharmacological agents.
The invention will now be illustrated by the following non limiting examples in
which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (°C); operations were carried out at room or
ambient temperature, mat is, at a temperature in the range of 18-25°C;
(ii) organic solutions were dried over anhydrous magnesium surf ate; evaporation of solvent
was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals;
4.5-30mmHg) with a bath temperature of up to 80°C;
(iii) chromatography means flash chromatography on silica gel; thin layer chromatography
(TLC) was carried out on silica gel plates;
(iv) in general, the course of reactions was followed by TLC and / or analytical LC-MS, and
reaction times are given for illustration only;
(v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or
mass spectral data;
(vi) yields are given for illustration only and are not necessarily those which can be obtained
by diligent process development; preparations were repeated if more material was required;
(vii) when given, NMR data is in the form of delta values for major diagnostic protons, given
in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard,
determined at 300 MHz using perdeuterio dimethyl sulfoxide (DMSO-de) as solvent unless
otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t,
triplet; q, quartet; m, muMplet; b, broad;
(viii) chemical symbols have their usual meanings imits and symtols arc used;
(ix) solvent ratios are given in volume:volume (v/v) terms; and
(x) mass spectra were run with an electron energy of 70 electron volts in the chemical
ionization (CI) mode using a direct exposure probe; where indicated ionization was effected
by electron impact (El), fast atom bombardment (FAB) or electrospray (ESP); values for m/z
are given; generally, only ions which indicate the parent mass are reported; and unless
otherwise stated, the mass ion quoted is (MH)+ which refers to the protonated mass ion;
reference to M1" is to the mass ion generated by loss of an electron; and reference to M-H is
to the mass ion generated by loss of a proton;
(xi) unless stated otherwise compounds containing an asymmetrically substituted carbon
and/or sulfur atom have not been resolved;
(xii) where a synthesis is described as being analogous to that described in a previous example
the amounts used are the mUlimolar ratio equivalents to those used in the previous example;
(xiii) all microwave reactions were carried out in a CEM Discover™ microwave synthesis or
CEM Mam microwave synthesiser,
(xiv) preparative high performance fiqmd chromatography (HPLQ was performed on a
Otlson instrument using the following conditions:
Column: 21 mm x 10 cm Hichrom RPB
Solvent A: Water0.1% trifluoroacetic acid.
Solvent B: Acetonitrile 4- 0.1% trifluoroacetic acid
Flow rate: 18ml/min
Run time: 15 minutes with a 10 minute gradient from 5-95% B
Wavelength: 254 nm, bandwidth 10 nm
Injection volume 2.0-4.0 ml;
(xv) the following abbreviations have been used:
HATU OX7-Azabe«zotriazol-
Hexafluoro-Phosphate; and
THF tetrahydrofuran;
DMF tyN-dimethylformamide;
DMA MAWirnethylacetamide;
DCM dichloromethane;
DIPEA N,N-diisopropylethylamine;
DMSO dimethylsulfoxide;
DPA Isopropyl alcohol; and
ether diethyl ether.
Example 1
ntethyteeeiainide
A mixture of HATU (197 mg), diisopropylcthylamine (90 pi), acetic acid (22 ul) and
AK3hlcfO-4din-2-ymiethoxy)pleny
(150 mg) in DCM (20 ml) was stirred for 2 hours. The solution was washed with water, then
brine and concentrated in vacua. The residue was purified by chromatography using DCM-
5% methanol as eluent to give the title compound as a white solid (114 mg. 69%Y NMR
ffiecjoffi (DMSO-d6) 1.95 (&, 3H), 3.00 (ft, 3H), 3.89 (t, 2H), 4.48 (m, 2H), 5.29 (s, 2HX 7.18
(d, 1H), 7.24 (d. 1H), 735 (m, 2H), 7 59 (m, 2H), 7.72 (dd, ttiQ, 7.85 (dt, 1H), 7.96 (d, 1H),
8.46 (ft, 1H), 858 (m, 1H), 9.70 (bs, 1H); Mass spectrum MH 478.5.
The N-[3:hloTO-4^yridm-2-yhnethoxy)phenyl]-5-[2-
(me%lainiiK))ethoxy]qumazoliiHl-amine used as starting material was prepared as follows:
DMF (0.2 ml) was added to a suspenaon of 5-fluoro-3,4-dihydro-3flr-quinazolin-4-one
(1.64 g) in thionyl chloride (10 ml) and the mixture was stirred and heated at 80°C for 6
hours. Volatile material was removed by evaporation and the residue was azeotroped with
toluene (20 ml). The resulting solid was added portion wise to a vigorously stirred mixture of
saturated sodium bicarbonate (50 ml), crushed ice 50 g) and DCM (50 ml) such that the
temperature was kept below 5°C. The organic phase was separated, dried and concentrated to
give 4-cMoro-5-fluoroquinazoline (1.82 g, 99%) as a solid which was used without
purification; NMR spectrum (CDC) 7.35 - 7.45 (rn, 1H), 7.85 - 7.95 (m, 2H), 9.0 (s, 1H).
4-Chloro-5-fluoroquinazoline (6.75 g) was added to a stirred solution of 3-chloro-4-(2-
pyridylmethoxy)aniline (9.27 g, obtained as described in Example 15-21 (note u) of WO
96/15118) in IP A (200 ml), and the solution was stirred and heated at reflux for 8 hours. The
solution was allowed to cool to ambient temperature overnight and the precipitated solid was
filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol
(400 ml) and the mixture was heated on a steam bath until the entire so d had dissolved. The
solution was basified by careful addition of aqueous ammonia (0.880), and the mixture was
concentrated to remove methanol. Water (300 ml) was added and the mixture was extracted
with DCM (600 ml). The extract was washed with water, and brine, and dried. The solvent
was removed by evaporation to give a solid, which was re-precipitated from a mixture of
ethyl acetate, tetrahydrofuran and isohexane to give A^-[3-chloro-4-(pyridin-2-
ylmethoxy)phenyl]-5-fluoroquma2Xtoamine as a beige solid (6.75 g, 48%); NMR
spectrum (DMSO-d6) 5.3 (s, 2H), 7.2 - 7.3 (d, IH), 7.35 - 7.5 (m, 2H), 7.5 - 7.65 (m, 3H), 7.8
- 7.95 (m, 3H), 8.55 (s, IH), 8.55 - 8.6 (d, IH), 9.1 - 9.2 (bs, IH); Mass spectrum MH+ 381.
Sodium hydride (60% dispersion in mineral oil, 0.63 g) was added to 2-
(methylainino)ethanol (055 ml), 15-crown-5 (100 ul) and JV-[3-chloro-4-(pyridin-2-
ylinedioxy)pnenyl]-5-fluoroquinazolin-4-amine (1,5 g) in DMA (25 ml) and the reaction
heated at 100°C for 2 hours. The reaction was cooled, quenched with saturated aqueous
ammonium chloride solution to pH 7-8. Addition of a small amount of saturated aqueous
sodium hydrogen carbonate solution resulted in the formation of a precipitate, which was
filtered, washed with water and dried The sotid was purified by chroniatography using DCM
- 5% methanol / 7N ammonia as eluent to give N-l3^Moro^pvridm-2-ylmethoxy)phenyIJ-
5-[2Kmemylamino)eAoxy]qinnazolm-4-ariiine as a yellow solid (0.27 g, 45%); NMR
spectrum (DMSO-d6) 2.AQ (s, 3H), 3.02 (t, 2H), 4.35 (t, 2H), 5.28 (s, 2H), 7.12 (d, IH), 7.25
(d, IH), 7.31 (d, IH), 7.37 (m, IH), 7.57 (d, IH), 7.71 (dd, IH), 7.85 (m, 2H), 8.10 (d, IH),
8.51 (s, IH), 8.58 (m, IH), 10.57 (bs, IH): Mass spectrum MET 436.5.
Example 2
Using an analogous procedure to mat described in Example 1 the appropriate
quinazoline was reacted with the appropriate acid to give the compounds shown in Table I:
(Table Removed)mettexy-Aneiliyiacetatttkle. Prepared by reacting methoxyacetic acid and AH3-chkwo-4-
(pyridiiH2-ylmethoxy)phenyl}-52-( (prepared as
described in Example in 52% yield: NMR spectrum
(DMSO-d6) 3.00 (a, 3H), 3.23 (s» 3HX 3.90 (t, 2H), 4.04 (&, 2H), 430 (t, 2H), 5.29 (s, 2H),
7.17 (d, 1H), 7J23 (d, 1H), 735 (m, 2H), 7 .59 (dd, 1H), 7.72 (dd, 1H), 7.85 (dt, 1HX 7.99 (d,
1H), 8.45 (&, 1H), 838 (m, 1H), 9.70 (bs, 1H); Mas SQ85.
[2] 2-[(4-{3-Oikro-4yridi2-ytoirtlKxy)
(dlmethylainfaioVA-methylftcetaiBide. Prepared by reacting M-dimethylglycine and N-[3-
cWoro-4-(pyridin-2-)dirttthoxy)phenji]-5-[2-(methylamino)etb
(prepared as described in Example 1, preparation of starting materials) in 13% yield; NMR
spectrum (DMSO-d6) 2.68 (s, 6H), 3.05 (s, 3H), 3.97 (m, 2H), 4.05 (s, 2H), 4.53 (m, 2H),
5.29 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H), 7.37 (m, 2H), 7.60 (d, 1H), 7.65 (d, 1H), 7.54 (t, 1H),
7.86 (dt, 1H), 8.02 (d, 1H), 8.50 (s, 1H), 8.58 (m, 1H), 9.70 (bs, im; Mass spectrum MHT
521.6.
[3]
yl)oxy]propyl}-2-methoxy-N-nieayla«etainide). Prepared by reacting methoxyacetic acid
andJV-Ploro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(l/?)-l-methyl-2-
(methylamino)ethoxy]quinazolin-4-amine in 31% yield; Mass spectrnrp MH 522.4.
The JV-[3- -4-(pyridfo-2-yta
(roethylaniino)etiioxy]qmnazdin-4- used as starting material was prepared as follows:
(2K2-methyloxirane (13.76 g) was added to a suspension of Amethylprop-2-en-lamine
(25 ml) and ytterbium(III) trifle wromethanesulfonate (100 mg) in dioxane (100 ml) and
heated to 140°C for 1 hour under microwave irradiation. The solution was concentrated in
vacua and the residue partitioned between water (100 ml) and ethyl acetate (200 ml). The
organic extract was dried and solvent removed in vacua yielding (2K)~1-
[allyl(methyl)amino]propan-2-ol as a yellow oil (8.8 g, 29%); NMR spectrum (CDC13) 1.20
(d, 3H), 2.33 (s, 3H), 2.27-2.46 (m, 2H), 3.05 (m, 1H), 3.23 (m, 1H), 3.88 (m, 1H), 5.19 -
5.29 (m, 2H), 5.90 (m, 1H); Mass spectrum M 129.
(2^1-[aUyl(memyl)amino]propan-2-oJ was reacted with -[3-cnloro-4-(pyridin-2-
ylmethoxy)ohenyl]-5-fluoroquinazoHn-4-amine using an analogous procedure to mat
ylmethoxy)phenyl]-5-
[2thylainrno)ethoxy]qirinazolrn4-amine, to give 5--2-[allyl(methyl)amino]-lmethylethoxy}-
-2-yIraethoxy in 53% yield;
NMR spectrum (DMSO-d6) 1.45 (d, 3H), 2.17 (s, 3H), 292 - 3.07 (m, 2H), 4.93 (m, 1H),
5.00 (d, 1H), 5.10 (d. 1H). 530 (s, 2H), 5.64 (m, 1H), 7J20 - 7.40 (m, 4H), 7.58 (m, 2H), 7.71
(dd, 1H), 7.85 (dd, 1H), 7.98 (m, 1H), 8.47 (s, 1H), 8.58 (d, 1H), 10.32 (bs, 1H).
ylrnethoxy)phenyllquinazolin-4-amine was heated in acetonitrile/water in the presence of
chlorotris(triphenylDhosphine)rhodium (I) using an analogous procedure to mat described
below in Example 4-11 (preparation of starting materials) to give N-[3-chloro-4-(pyridin-2-
yln»thoxy)pheny]]-5-[(ll-iriethyl-2Kmethylamino)ethyl]quina2olin-4-amine in 15 %
yield; Mass spectrum M" 450.
[4)
methylethyl}&cetamide. Prepared by reacting 5-{ -2-aminopropyl]oxy } --[3-chloro-4-
(pyridin-2-ylmemoxy)phenyl]quinazolin-4-amine and acetic acid in 99% yield; NMR
spectrum CDMSO-d6) 1.20 (d, 3H), 1.70 (s, 3H), 4.2 - 4.3 (tn, 2H), 4.4 (m, 1H), 5.35 (s, 2H),
7.3 - 7.6 (m, 6H), 7.8 (m, 1H), 7.85 - 8.00 (m, 2H), 8.15 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H);
Mass spectrum MH4 478.
The 5-{ 2-animopropyl]oxy}-Ar-[3hloro-4-(pyridin-2-
ylmethoxy)phenyl]qumazolin-4-amine used as starting material was prepared by reacting (R)-
(-)-2-amino-l-prooanol and #-[3Moro-4-(pyridm-2-ytoethoxy)ph -
4-amine using an analogous procedure to that described in Example 1 (for the preparation of
to give 5-{[(2)-2-aminopropyl]oxy}-N-[3-cMcro-4-(pyridin-2-
ylmethoxy)phenyl}quinazolin-4-amine in 63% yield; NMR spectrum (DMSO-d6) 1.20 (d,
3H), 3.4 (m, 1H), 4.0 (t, 1H), 4.2 (dd, 1H), 5.3 (s, 2H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3 (m, 2H),
7.6 (d, 1H), 7.7 (m, 2H), 7.9 (m, 1H), 8.25 (d, 1H), 8.5 (s, 1H), 8.6 (d, 1H); Mass spectrum
MH436.
[5] JVK012-[(4K3-aiIoropyr
methyleihyl}-2-hydroTyftceianiide. Prepared by reacting glycohc acid and 5-{ [(2/0-2-
aminopfopyl]oxy}-N-[3-chlon-4-(pyre in 93%
yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 3.6 - 3.8 (m, 2H), 4.3 (m, 2H), 4.5 (m, 1H),
) 1.78 (s, 3H), 3.62 (m, 2H), 434 (t, 2H). 5.29 (s, 2H), 7.14 (d, 1HX 7.24 (d, 1H),
735 (m, 2H), 7 J7 (m 2H), 7.72 (t, 1H), 7.87 (t, 1H), 8.01 (d, 1H), 855 (bs, 1H), 8.48 (s, 1H),
8.59 (m, 1H) 9.87 (bs. 1H); Mass spectrum MET 464.
amine used as a starting material was prepared by reacting ethanolanrine andAr-[3-chlQro-4-
(pyridin-2-ylmethoxy)pbenyl]-5-fluoroquinazolin-4-amine using an analogous procedure to
that described in Example 1 for the preparation of -[3-chloro-4-(pyridin-2-
ylmethoxy)renyl]-5-[2Kmetaylammo)euioxy]quirtazolin-4-amine to give 5-(2-
amiiK)euxy)--[3K:Uon)(pyridin-2-ylniethoxy)phem in 49% yield;
NMR spectrum (DMSO-d6) 3.12 (t, 2H), 3.29 (2H obscured under water), 4.28 (t, 2H), 5.28
(s, 2H), 7.12 (d, 1H), 721 (d, 1H), 7.34 (m, 2H), 7.57 (d, 1H), 7.71 (m, 2H), 7.87 (t» 1H), 8.23
(d, 1H), 8.51 (s, 1H), 858 (d, Iffi: Mass spectrum MH 422.
[7] tf-{(2tf)-2(4.{3-ChlorcMHpyrMrn-yl
yl)oxy]propyl}--methylacetaniide. Prepared by reacting acetic acid with ^-[3-chloro-4-
(pyridin-2-ymiethoxy)phenyl]-5--l-methyI-2-(metliylarnmo)ethoxy]qum
(prepared as described in Example 2-3) to give the title product in 50% yield; NMR spectrum
CDCb)-L47 (d, 3H), 2.00 (s, 3H), 3.00 (s, 3H), 3.45 (m lH) 3.93 (m, 1H) 5.00 (m, 1H),
5.25 (s, 2H), 6.98 (m, 2H), 7.40 (m, 1H), 7.49 (m, 1H), 7.59 (m, 2H), 7.70 (m, 1H), 7.90 (s,
1H), 8.53 (s, 2H), 9.82 (bs, 1H); Mass spectrum MBf 492.5.
Examples
2-Hydroxy--methyl-A-{2-[(4-{3-iW5thyM-(pyridin-2-yImethoxy)anilino}quinazolin-5-
yl)oxy]ethyl}acetainide
2-Hydroxy--[2{4-[4ydroxy-3-methylanibiK]quinazolin-5-yl}oxy)ethyl]-A/-
methYlacetamtde (100 mg), picolyl chloride hydrochloride (60 mg) and potassium carbonate
(120 mg) were stirred in DMF (5 ml) to which was added 18-crown-6 (1O mg). The reaction
was stirred at room temperature for 2 days. The DMF was removed in vacua, water (5 ml)
was added and then the suspension was extracted with DCM (2x5 ml). The DCM fraction
was purified by chromatography using 25 - 5 % of 10:1 DCM/methanol containing 0^%
ammonia (0.880) as eluent. The appropriate fractions were evaporated, and the residue was
precipitated from DCM / diethyl ether to give the titte product as a fight yellow solid (28 m&
23%); NMRspectnim (DMSO-do,100°C) 2J29 (s, 3H), 3.00 (s, 3H), 3.9O (t, 2H), 4.16 (s,
2H), 4 JO (t, 2H), 520 (s, 2H), 7.01 (d, 1H), 7.16 (d, 1H), 734 (d, 2H), 7.51 (m, 2H), 7.55 (d,
1H), 7.79 (t, 1H), 7.83 (td, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.62 (s, 1H); Mass spectrum MH
474.
The2-hydroxy-N-[2{4-[4-hydroxy-3-mcthy}anilino}quinazoIin-5-yl}oxy)cthyl]-Nmethylacetamide
used as starting material was prepared as follows:
4-Chloro-5-fluoroquinazoline (6.76 g) was dissolved in uro-pxopanol (200 ml) and 4-
amino-2-methylphenol (5.00 g) was added. The mixture was heated under reflux for 2 hours,
causing a yellow solid to precipitate. The mixture was cooled to ambient temperature and the
solid was collected by filtration. The solid was dissolved in a boiling mixture of methanol
(500 ml) and water (100 ml) to give a brown solution. With vigorous stirring, the solution
was basified with aqueous ammonia (0.880,10 ml), causing a light brown solid to precipitate.
The mixture was concentrated in vacua to such a volume that all of the methanol had been
removed, leaving the product as a suspension in aqueous solution. The suspension was ,
cooled; the solid was collected by filtration, triturated with ethyl acetate and dried over P&s
in a vacuum oven to give 2-memyl4-[(5-fluoroquinazoHn-4-yl)amino]phenol as a light brown
solid (8.18 g, 82%); NMR spectrum (DMSO-d6) 3.30 (s, 3H), 6.78 (d, IH), 7.28 (m, 2H),
7.38 (dd, IH), 7.57 (d, IH), 7.78 (m, IH), 8.43 (s, IH), 8.88 (d, IH), 9.22 (s, IH); Mags
spectrum MH 270.
A solution of N-mcthylanrinoethanol (0.80 g) in DMA (5 ml) was added dropwise to a
suspension of sodium hydride (60% dispersion in mineral oil, 0.43 g) in DMA (20 ml). The
reaction was stirred for 30 minutes then 15-crown-5 (50 mg) was added, followed by 2-
methl[(5-fliK)roquinazohnyl)ammo]phenol (1.00 g). The reaction was heated at 110°C
for 2.5 hours. The reaction was cooled, quenched with saturated ammonium chloride, and
concentrated in vacua. Saturated sodium bicarbonate solution was added causing
precipitation of a solid which was collected by filtration, washed with water and precipitated
from ethyl acetate to give 2nneAyl{5-[2rnetiiylamino)etnoxy)unazolin-4-
yl }amino)phenol as a grey solid (0.60 g, 50%); NMR spectrum (DMSO-d6) 2.16 (s. 3H), 238
(s, 3H), 3.01 (t, 2H), 432 (t, 2H), 6.87 (d, IH), 7.07 (d, IH), 7.18 (d, IH), 7.45 (d, IH), 7.65
(dd, IH), 7.66 (t, IH), 8.41 (s, 1HX1036 (s, IH); Mass spectrum M 325.
AsotoikmofglYcolk acid(100mg)mDMF(2inl)wM
(400 mg) in DMP
(4 ml) and die mixture held under sonkatton for 5 minutes, A solution of HATU (519 mg) in
DMF (2ml) was then added and the solution was stirred at ambient temperature for 16 houra,
and men concentrated in vacua. The residue was treated wim water to precipitate a brown
solid that was collected by filtration, and washed with water to give 2-hydroxy--[2-({4-[4-
hydroxy-3-niemylaiiih"no]quira as a brown solid
(406 mg, 86%); NMR spectrum DMSO-d6) 2.15 (s, 3H), 2.94 (s, 3H), 3.87 (m, 2H), 4.04 (s,
2H), 4.48 (m, 2H), 6.81 (d, IH), 7.20 (dd, IH), 7.25 (d, IH), 7.35 (m, 2H), 7.92 (t, IH), 8.64
(s, IH), 9.46 (s, IH), 10.49 (s, IH); Mass spectrum M 383.
Example 4
Using an analogous procedure to mat described in Example 3 the appropriate 4-(4-
hydroxyanilino)qumazoline was reacted with the appropriate compound of the formula Ql-
CHa-L1 to give the compounds shown in Table 2 below, wherein Q1 is a specified in
PMR spectrum (DMSO-d6, 100°C) Z22 (s, 3H), 2.41 (s, 3H), 3.00 (s, 3H). 3.92 (t, 2H), 4.05
(s, 2H), 4.48 (t, 2H), 5.15 (s, 2H), 628 (s, 1H), 7.05 (d, 1H), 7.16 (d, 1H), 7.34 (d, 1H), 7.48
(m, 2H), 7.68 (t, 1H), 8.42 (s, 1H), 9.62 (s, 1H);
[4]
yl)oxy]pTOpyl}-2-mcfaoxyafcrflniide. Prepared by reacting N-[(22-({4[3-chloro-4- -
hyditxyarrilino]quinazoUn-5-yl}oxy)propyl]-2-methoxvacetarm and picolyl chloride
hydrochloride in 43% yield; NMR spectrum (DMSO-46) 1.19 (d, 3H), 3.10 (s, 3H), 3.21 (dt,
1H), 3.72 (m, 1H), 3.77 (s, 2H), 4.93 (m, 1H), 5.29 (s, 2H), 7.22 (d, 2H), 7.24 (d, 2H), 7.32 (d,
1H), 736 (dd, 1H), 7.58 (m, 2H), 7.71 (t, 1H), 7.86 (td, 1H), 8.15 (d, 1H), 8.19 (t, 1H), 8.47
(s, 1H), 8.59 (d, 1H), 9.97 (s, 1H) Mass spectrum MH 508.
The M-[(22{4-[3hloro-4^ydroxyanUiiio]quinazolin-5-}oxy)propyl]-2-
methoxyacetamide used as starting material was prepared as follows:
(/O-l-amino-2-propanol was reacted with 2-dilon-4-[(5-flucBX)quinazolin-4-
yl)aminojphenol (prepared as described in Example 44, preparation of starting materials)
using an analogous process to mat described Example 1 for the preparation of A^-[3-chloro-4-
(pyridin-2-ymioxy)phenyl]-5-[2rnethylamino)ethoxy]qdnazoUnamine) to give 4-({5-
[2-anu"no-l-rnemylettioxy]quinazolmyl}anuiK)2-Worophenol in 64% yield; NMR
spectrum (DMSO-d6) 1.39 (d, 3H), 2.88 - 3.03 (m, 2H), 3.72 - 3.85 (m, 1H), 6.95 (d, 1H),
7.15 (d, 1H), 7.29 (d, 1H), 7.45 - 7.52 (m, 1H), 7.69, (t, 1H), 8.05 (s, 1H), 8.45 (s, 1H) Mass
spectrum MH345.
4K{5^(l/f)-2~Amiiio-l-memylethoxy) was
reacted with memoxyacetic acid using an analogous process to mat described in Example 3
(preparation of starting materials) to give A4(2tf)-2-({4-[3-chloro-4-
in 83% yield; NMR
spectrum (DMSQ-do) 1.4 (d, 3H), 3.1 (s, 3H), 335 - 3.45 (m, 1H), 3.72 - 3.85 (m, 3H), 4.95 -
5.05 (m, 1H), 7JK (d, 1H), 731 (d, 1H), 7.4 (dd, 1H), 7.48 (d, 1H), 7.81 (m, 1H), 7^5 (t, 1H),
8.25 (t, 1H), 8.8 (s, 1H), 1039 (s, 1H), 10.74 (s, 1H) Mass spectrum MET 417.
[5] -{2-[(4-{3-aUoro(pyrkiin-2-yhnetlMxy)
hydroxy-AT-methylacetamkle. Prepared by reacting picolyl chloride hydrochloride and
66% yield; NMR spectmm (DMSO-d6) 2.96 (s, 3H), 3.91 (t, 2H), 4.04 (d, 2H), 4.26 (t, 1H),
4.40 (t, 2H), 5^8 (s, 2H), 7.14 (d, 1H), 722 (d, 1H), 732 (d, 1H), 735 (m, 1H), 7.57 (m, 2H),
7.70 (m, 1H), 7.86 (m, 1H), 7.95 (s, 1H), 8.42 (s, 1H), 8.58 (d, 1H), 9.73 (bs, 1H); Mass
spectrum MH" 494.
TheA[2-({4-[(3hloro44iydroxyphenyl)ammo]quinazolm-5-yl}oxy)ethyl]-2-
hydroxymediylacetamide used as a starting material was prepared as follows:
4-Chloro-5-fluoroquinazoline was reacted with 4-amino-2-chlorophenol using an
analogous process ;to that described in Example 3 for the preparation of " 3-
fluoroquinazolin-4-yl)amino]phenol, to give 2-chloro-4-[(5-fluoroquinazolin-4-
yl)amino]phenol in 85% yield; NMR spectrum (DMSO-d6) 6.97 (d, 1H), 7.38 (dd, 1H), 7.42
(dd, 1H), 7.59 (d, IH), 7.73 (d, IH), 7.81 (dd, IH), 8.51 (s, 1H), 9.03 (d, IH), 10.07 (bs, 1H);
Mass spectrum MH 290.
2-ChlcMx-4-[(5-fluoroquina2olin-4-yl)pheno] was reacted with Nraethylaminoethanol
using an analogous process to that described in Example 3 for the
preparation of 2-niethyl-4{5-[2hylanMno)ethoxy]quinazolin-4-yl}amino)phenol, to
give 2-CWoro{5-[2methylamirK)ethoxy]quinazolinyl}aniino)phenol in 96% yield;
NMR spectrum (DMSO-d6) 2,41 (s, 3H), 3.05 (t, 2H), 4.36 (t, 2H), 6.97 (d, IH), 7.12 (d, IH),
731 (d, IH), 7.63 (IH, dd), 7.70 (t, IH), 7.96 (s, IH), 8.47 (s, IH) 10.47 (bs, IH); Mass
spectrum MH345.
2Moro-4{5-[2-(inethylanuno)ethoxy]qmM was reacted
with glycohc acid using an analogous procedure to that described in Example 3 to give AT-[2-
({4-[3-ChlorcMMiydroxyanih^JqninazoKn-5-yl }oxy)ethyl]-2-4iydroxy--memylacetamide in
58% yield; NMR spectrum (DMSO-d6) 2.96 (s, 3H), 3.90 (t, 2H), 4.05 (m, 3H), 4.41 (t, 2H),
6.97 (d, IH), 7.14 (d, IH), 734 (m, 2H), 7.70 (t, IH), 7.79 (d, IH), 8.40 (s, IH), 9.64
hrdroxyWV-inethyiacclunide. Prepared by reamg3-fhx)rooenzylc
the title product in 59% yield: NMR spectrumMSO-d6 at 100°Q 2.91 (s,3H),3.83 (t,2H),
3.99 (bs, 3H), 4.42 (t, 3H), 5.17 (s, 2H), 7.00 - 7.30 (m, 6H), 736 (m, IH), 7.50 (dd, IH), 7.63
(t, IH), 7.89 (d, IH), 838 (s, IH), 9.62 (bs, IH); Mass spectrum MH 511.
[7] 2-[(43-Chtorol3-thlazol
2"hydroxyA/r-methylacetainide. Prepared by reacting 4-(chlorometiiyl)-l,3-thiazole
hydrochloride and -[2K{43hlcm4-hydioxyaniltao]quinazolin-5-yl}oxy)etfiyl]-2-
hydroxy-N-mediylacetamide to give the title product in 54% yield; NMRspecrpi (DMSOd6
at 100°C) 2.99 (s, 3H), 3.91 (t, 2H), 4.07 (bs, 3H), 4.50 (t, 2H), 5.34 (s, 2H), 7.17 (d, IH),
7.30 (d, IH), 7.36 (d, IH), 7.59 (dd, IH), 7.72 (m, 2H), 7.96, (d, IH), 8.46 (s, IH), 9.08 (d,
IH), 9.70 (bs, IH); MW PTm MH 500.
[8]
oxy}etfayl2-hydroxy-2V-mediylacetamide. A mixture of methanesulfonyl chloride
(0.034 ml), triethylanrine (0.077 ml) and (6-methylpyridin-2-yl)methanol (44 mg) waa stirred
in DCM (10 ml) overnight The solution was concentrated m vacua and DMF (20 ml) was
added, followed by the addition of JV-[2-({4-[3-chloro-4-hydroxyanilino]quinazolin-5-
rl}oxy)ethyl]-2-hydroxy-N-inethylacctainide (125 rag) and potassium carbonate mgj ana
he mixture stiired for 2 days. The solution was concentrated MI vacuo and water (50 ml) was
idded and die mixture extracted with DCM (60 ml). The extract was dried and concentrated
n vacuo and the residue purified by chromatography using DCM -10% methanol (2M
anmonia) to give the title compound as a white solid (99 mg, 54%); NMR spectrum (DMSO-
16 at 100°Q 2.50 (s, 3H obscured by DMSO), 2.99 (s, 3H), 3.92 (t, 2H), 4.06 (bs, 3H), 4.49
[t, 2H), 5.22 (s, 2H), 7.13 - 7.26 (m, 3H), 7.37 (m, 2H), 7.57 (dd, IH), 7.72 (m, 2H), 7.98 (d,
IH), 8.46 (s, IH), 9.70 (bs, 1HV. Mass spectrum MH 508.
[9] AT.{2-[(43ro-4yraziiH2
hydroxy-tf-methylacetamide. Prepared by reacting pyrazin-2-yhnethyl sulfonate with N-[2-
({4-[(3^htoreHWiydroxyphcyl)airnno
methvlacetamide to give the title product in 60% yield: NMR spectrum (DMSO-d6 at 100°Q
2.99 (s, 3H), 3.91 (t, 2HX 4.07 (bs, 3H), 4.49 (t, 2h), 537 (s, 2H), 7.17 (d, IH), 7.29 (d, IH),
736 (d, IH), 7.60 (dd, IH), 7.72 (t, IH), 7.99 (d, IH), 8.46 (s, IH), 8.64 (m, 2H), 8.50 (hydroxyaniuno]q/nnazolm-5-yl}cay)propyl]acetarnide and picolyl chloride hydrochloride in
76% yield; NMR spectrum (DMSO-d6) 1.40 (d, 3H), 1.78 (s, 3H), 3.39 (m, IH), 3.62 (m,
IH), 4.87 (m, IH), 5.29 (s, 2H), 7.21 - 7.40 (m, 4H), 7.57 (m, 2H), 7.71 (t, IH), 7.87 (m, IH),
8.12 (d, IH), 8.22 (t, IH), 8.49 (s, IH), 8.58 (d, IH), 10.00 (bs, IH): Mass spectrum MH 478.
-2-({4-[3^Mon-44iyaroxyanittno]
used as starting material was prepared by reacting 4-({5-[( 2-amino-lmemylethoxy]
quinazoUnyl}amino-2-chlorophenol (prepared as described in Example 4-4)
with acetic acid using an analogous procedure to that described in Example 3 for the
preparation of 2-hydroxy--rnethyl-.JV-{2-[(4-{3-methyl-4-yridin-2-
ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}acetarriide, to giveN-[-2-({4-[3-chloro-4-
hydroxyanilino]quinazolin-5-yl}oxy)propyl]acetamide in 28% yield; NMR spectrum (DMSOd6)
1.40 (d, 3H), 1.78 (s, IH), 3.40 (m, IH), 3.62 (m, IH), 4.87 (m, IH), 6.99 (d, IH), 7.23 (d,
IH), 7.31 (d, IH), 7.41 (dd, IH), 7.71 (t, IH), 7.97 (d, IH), 8.22 (t, IH), 7.49 (s, IH), 9.99 (s,
10;0&fe.itHfcMassspeeijfumMHt387.
-2-[(4-{3-ailoropyridin-2-ylmetho
yl)oxy]propyl}-2-hydroxy-A-methyIacetamide. Prepared by reacting AT-[(2/J2-({4-
chloro-4-hydroxyanilmo]quinazolin-5-yl }oxy)pix)pyl]-2-hydioxy-JV-metiiylacetainide and
picolyl chloride hydrochloride in 61% yield; NMR spectrum (DMSO-d6 at 100°C) 1.44 (d,
3H), 2.99 (s, 3H), 3.51 (m, IH), 4.07 (m, 2H), 4.13 (m, IH), 5.12 (m, IH), 5.28 (s, 2H), 7.23
(m, 2H), 7.34 (m, IH), 7.60 (m, 2H), 7.70 (t, IH), 7.85 (t, IH), 8.08 (d, IH), 8.47 (s, IH), 8.58
(bd, IH), 9.87 (bs, IH): Mass spectrum MH 508.
TheAH(2£)-2K{4-[3hlorohydroxyar
hydroxy-tf-raethviacetamide used as a starting material was prepared as follows:
2Atoro(5-fluoropnazohnyl) phenol (2 g) was added to a stirred
solution of (2KH-[aUyl(methyl)arnino]propan-2-ol (2.24 g, prepared as described in Example
2-3) in DMA (100 ml) and sodium hydride (60% dispersion in oil, 692 rag), and the mixture
heated to 110°C for 16 hours. The mixture was concentrated in vacua men a saturated
solution of sodium bicarbonate C200 ml) was added and extracted with DCM (300 ml). The
extract was washed with brine, dried and concentrated mvocuo and the residue purified by
cnromatognphy using DCM - 10% memanol / 2N ammonia as ehieat to give 4-[(5-{(lR2-
[aDyl(met)ryl) as a yellow
solid (1.88 g, 68%); M^ spectrum (DMSO46) 1.43 (d, 3H), 2.17 (s, 3H), 254 (dd, IH),
2.97 (m, 3H), 4.94 (m, IH), 5.00 (dd, IH), 5.10 (dd, 1HX 5.63 (m, IH), 6.98 (d, IH), 7.18 (d,
IH), 7.29 (d, IH), 7.42 (dd, IH), 7.69 (t, IH), 7.84 (d, IH), 8.44 (s, IH), 10.01 (bs, IH), 10.26
(s, IH); Mass spectrum MH+ 399.
mg) in acetonitrile/water (5:1,4 ml), and the mixture heated to 130°C for 10 minutes by
microwave irradiation. The cooled mixture was subjected to ion exchange chromatography
and product eluted with methanol / 2M ammonia yielding 2-chloro-4-{ 5-[(lft)-l-
(methyianiino)ethoxy]quinazolin-4-yl}amino)phenol as a brown solid (776 mg, 100%);
spectrum (DMSO-d6) 1.40 (d, 3H), 2.33 (s, 3H), 2.87 (m, 2H), 3.29 (IH obscured by water),
4.88 (m, IH), 6.97 (d, IH), 7.14 (d, IH), 7.28 (d, IH), 7.55 (dd, IH), 7.68 (t, IH), 7.95 (d,
IH), 8.45 (s, IH), 10.51 (bs, IH); Mass spectrum MH359.
AK(2/?2K{4-[(3hloro-4ydroxyphCTyl)anti
hydroxy-tf-methyiacetamide starting material was prepared by reacting 2-chloro-
an analogous procedure to that described in Example 3 for the preparation of 2-hydroxy-JV-[2-
({4-[4-hydroxy-3-meuylam"lmo]quinazo to give
2/2-({4-[3-chloro-4-hydroxyanilino]quinazolin-5-yl}oxy)propyl]-2-hydroxy-Nmethylacetamide
in 57% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.91 (m, 1H), 2.97
(s, 3H), 3.39 (dd, 1H), 4.04 (d, 2H), 4.16 (m, IH), 4.39 (m, IH), 5.08 (mt 1H), 6.98 (d, IH),
7.27 (m, 2H), 7.47 (dd, IH), 7.70 (t, IH), 7.97 (d, IH), 8.43 (s, IH), 9.85 (s, IH), 9.99 (bs,
IH); Mass spectrum MH 417.
[12] N(2R)-2-[(4-{3-Ch-(pyrazin-2-ylinethoxy)anilino}quinazoKn-5-
y!)oxy]propyl}-2-hydroxy-A-metbylacetaniide. Prepared by reacting pyrazin-2-ylmethyl
sulfonate and JV-[(2R)-2K{4-[3^hloro^hydroxyaniIino)quinazolin-5-yl}oxy)propyl]-2-
hydroxy-methylacetamide to give the title product in 20% yield; NMR spectrum (DMSOd6)
1.41 (d, 3H), 2.98 (, 3H), 3.42 (dd, IH), 4.06 (m, 2H), 4.23 (m, IH), 4.41 (m, IH), 5.12
(m, IH), 5.39 (s, 2H), 7.25 - 7.38 (m, 3H), 7.72 (m, 2H), 8.15 (d, IH), 8.48 (s, IH), 8.68 (d,
2H), 8.87 (s, IH), 9.% (s, IH); Mass spectrum MET 509.
[13] AK(213-24[431oro[(6-methy
Prepared by reacting (6-methyIpyridin-2-
hydoroxy-tfHnethylacetanude, using an analogous procedure to that described in Example 4-8
(in-situ formation of (6-methyh-2-yl)methyl memanesulf onate), to give the title product
in 48% yield; NMR spectrum (DMSO-46) 1.40 (d, 3H), 2.50 (3H obscured by DMSO), 2.98
(s, 3H), 3.37 (dd, IH), 4.06 (d, IH), 4.22 (m, IH), 4.41 (t, IH), 5.10 (m, IH), 526 (s, 2H),
7.20 - 7.30 (m, 3H), 7.33 (d, IH), 7.37 (d, IH), 7.67 (dd, IH), 7.70 - 7.80 (m, 2H), 8.15 (d,
IH), 8.48 (s, IH), 9.95 (s, IH); Mass spectrum MH+ 522.
[14] N-((2R)-2[4-(3loro[(3-4hiort
yQoxy}propyl)-2-hydroxy-/Vroetibylacetaniide. Prepared by reacting l-(chloromethyl)-3-
fluoroDOT2eneandA-[-2-({4-[3hlorohydroxyaniUno]quinazolin-5-yl}oxy)propyll-2-
hydroxy-AT-methylacetaniide to give the title product in 61% yield; NMR spectrum (DMSOd6)
1.40 (d, 3H), 2.98 (s, 3H), 3.37 (dd, IH), 4.06 (d, 2H), 4.22 (m, IH), 4.41 (t, IH), 5.1 1 (m,
IH), 5.28 (s, 2H), 7.19 (m, IH), 7.22 - 7.38 (m, 5H), 7.47 (m, IH), 7.68 (dd, IH), 7.72 (t, IH),
8.13 (d, IH), 8.48 (s, IH), 9.94 (s, IH); Mass spectrum MH 525.
[15] A^-{(2/?)-2-[(4-{3.Chlon(lthiazol ylmethoxy)}quinazolin-5-
yl)oxy]propyl}-2-hydroxy-N-mhylacetamide. Prepared by reacting 4-(chloromethyl)-l,3-
ydrpchlpride and WX21)-2r({4H[(3WoroT4ydroxyamUno]
yl}oxy)propyl]-2-hydroxy-N-methylacetamide to give the title product in 61% yield; NMR
spectrum (DMSO-d6) 1.41 (d, 3H), 2.98 (s, 3H), 3.38 (dd, IH), 4.06 (d, 2H), 4.22 (m, IH),
4.42 (t, 1H), 5.11 (m, IH), 5.34 (s, 2HX 7.28 (d, IH), 7.34 (m, 2H), 7.69 (dd, IHX 7.73 (t,
IH), 7.82 (s, IH), 8.12 (d, 1H), 8.48 (s, IH), 9.18 (d, IH), 9.95 (s, 1HV. Mass spectrum MH
514.
[16]
Prepared by reacting (6-methy]pyridin-2-yl)roethanol
and -[2-({4-[3-chloro4-hydroxyanilino]quinazoKn-5-yl }oxy)e4hyl]-M-methylacetainide
using the procedure described in Example 4-8 (in-situ formation of (6-methylpyridin-2-
yl)methyl methanesulfonate), to give the title product in 67% yield; NMR spectrum (DMSOd6)
1.94 (s, 3H), 3.06 (s, 3H), 3.27 (s, 3H), 3.84 - 3.96 (m, 2H), 4.35 - 4.45 (m, 2H), 5.24 (s,
2H), 7.16 (d, IH), 7.20 - 7.27 (m, 2H), 732 - 7.40 (m, 2H), 7.58 (dd, IH), 7.70 - 7.79 (m,
2HX 7.92 (d, IHX 8.45 (s, IH), 9.74 (s, IH); Mass spectrum MH 492.
The N-[2K{44(3-chlorc-4-hydroxyairiliiK)lqmnazolin-5-yl}oxy)
methylacetamide used as starting nwterial wa» prepvtd ae follows:
Acetic acid wat reacted with 2{5-I2pCnelbyiaiKnio)etlio
yi}amiiK)phenol (prepared as described in Exampte 4-5, prepaiatk)n of sorting njaterials)
using an analogous proceduie to tiiat described in Eumpfe 3 for the preparation of 2-
methylacetamide, to give the title product in 56% yield; (EMSO-d6) l.%(s,
3H), 2.48 (B, 3H), 3.84 (m, 2H), 436 (t, 2H), 6.96 (d, IH), 7.14 (d, IH), 732 (m, 2H), 7.70
(m, 2H), 8.40 (s, IH), 9.62 (bs, IH), 10.01 (be, 1HV. Mass spectrum MH 370.
[17] JVKM[4-(3-Oiloro[
rnethylacetamide. Prepared by reacting 2-fluorobenzyl chloride with -[2-({4-[(3-chloio-4-
hydroxyanilino]quinazolin-5-yl}oxy)ethy}]-N-methylacetamide, to give the title product in
71% yield; NMR spectrum (DMSO-d6) 1.94 (B, 3H), 3.05 (s, 3H), 3.89 (t, 2H), 4.40 (t, 2H),
5.27 (s, 2H), 7.17 (d, IH), 7.22 - 739 (m. 4H), 7.41 - 7.48 (m, IH), 7.56 - 7.65 (m, 2H), 7.73
(dd, IH), 7.90 (d, IH), 8.44 (s, IH), 9.74 (s, KB: Mass spectrum MH 495.
[18] Af2-{[4-(3-ChJoro[(3-fliKroben2yl)oxylanmiio)quhiazoli
methylacetamide. Prepared by reacting 3-fluorobenzyl chloride and -[2-{4-[3-chloro-4-
hydroxyanilino]quinazolin-5-yl}oxy)ethyl]-N-to give the title product in 80% yield; NMR
spectrum (DMSO-d6) 1.94 and 1.97 (each s, together 3H), 2.90 and 3.05 (each s, together
3H); 3.89 and 3.91 (each t, together -2H), 4.40 and 4.55 eteh t, t6gemer2H), SMQ&aate
7.14 - 7.27 (m, 3H), 7.29 - 739 (m, 3H), 7.45 - 7.51 (m, IH), 7.53 - 7.60 (m, IH), 7.73 and
7.76 (each t, together 1H), 7.91 and 8.04 (each d, together 1H), 8.45 and 8.50 (each s, together
lh), 9.73 and 9.77 (each s, together 1H); Mass spectrum NOT 495.
JV-rnethytecetamide. Prepared by reacting 4-(chloromethyl)-13-thiazole and AT-[2-({4~[3-
chk)rohydroxyanilino]quinazolin-5-yl}oxy)ethyl]--niediyiacetarnide to give the tide
product in 67% yield; NMR spectrum (DMSO-d6) 1.94 and 1.96 (each s, together 3H), 2.90
and 3.05 (each s, together 3H), 3.89 and 3.92 (each t, together 2H), 4.40 and 4.55 (each t,
together 2H), 5.35 (s, 2H), 7.16 and 7.24 (each d, together 1H), 7.34 and 7.37 (each d,
together 2H), 7.56 and 7.59 (each dd, together 1H), 7.73 and 7.76 (each t, together 1H), 7.83
(s, 1H), 7.90 and 8.02 (each d, together 1H), 8.44 and 8.50 (each s, together 1H), 9.16 (d, 1H),
9.73 and 9.76 (each s, together 1H); Mass spectrum NOT 484.
[20] tf[(43loro(pyizin-2-yu
naethybcetaraide. Prepared by reacting pyrazm-2-ylinethyl methanesulf onate (prepared as
described in Example 4-1, preparation of starting material) and N-[2-({4-[3-cUoro~4-
-5- to give the title product in
6X)NMR spectrum (DMSO-dfr 1.94 and 1.96 (each 8, together 3H), 2.90 and 3.05
(each s, together 3H), 3.89 and 332 (each t, together 2H), 4.40 and 4.55 (each t, together 2HX
5.40 (s, 2H), 7.16 and 724 (each d, together 1H), 729 - 7.39 (m, 2H), 7.58 and 7.60 (each dd,
together 1H), 7.73 and 7.76 (each t, together 1H), 7.93 and 8.05 (each d, together 1H), 8.44
and 8.51 (each s, together 1H), 8.68 (d, 1H), 8.69 (d, 1H), 8.87 (s, 1H), 9.74 and 9.77 (each s,
together 1H); Mass spectrum MH479.
[21] tfH(2t)-2-[(4K3-£Iiloro
yl)oxy]propyl}-2"hydroxyacetamlde. Prepared by reacting //-[(2K)-2-({4-[3-chIoro-4-
hydroxyaniUno]quinazo]m-5-yl}oxy)pTOpyl]-2-hydroxyacetamide and picolyl chloride
hydrochloride to give the title product in 61% yield; NMR spectrum (DMSO-d6) 1.39 (d,
3H), 3.45 - 3.47 (m, 1H), 3.70 - 3.83 (m, 3H), 4.86 - 4.99 (m, 1H), 5.29 (s, 2H), 5.48 (t, 1H),
7.20 - 7.27 (m, 2H), 7.28 - 739 (m, 2H), 7.54 - 7.64 (m, 2H), 7.71 (t, 1H), 7.87 (t,lH), 8.11 -
8.21 (m, 2H), 8.48 (s, 1H), 8.59 (d, 1H), 9.98 (s, 1H) Mass spectrum MH" 494.
hydroxyacetamide used as starting material was prepared as follows:
(prepared as described in Example 4-4, preparation of starting materials) was reacted with
glycolic acid using an analogous procedure to that used in Example 1 for the preparation of N{
2-[(4-{3XCMt(pyridin-2-ylmethoxy)amlino}quinazolin-5-yl)oxy]ethyl}
methylacetamide, to give the title product in 61% yield; NMRspertmm (DMSO-d6) 139 (d,
3H), 3.70 - 3.80 (m, 3H), 4.90 - 4.97 (m, 1H), 7.0 (d, 1H), 7.26 - 7.31 (m, 2H), 7.41 (dd, 1H),
7.75 (t, 1H), 7.92 (d, 1H), 8.16 (t, 1H), 8.53 (s, 1H), 10.09 (s, 1H), 10.15 (s, 1H)
spectrum MH 403.
amine (58 mg) in DCM (3 nl) was treated with acetyl chloride (15 mg) and DIPBA (39 mg)
and stined over The solution purified by duromatognphyusingDCMtolO%7N
ammonia in methanol in DCM to give after trituration with dtethyl ether N-{2-((4-{[3-chtoro-
4-(pyridtn-2-ylmetfaoxy)phenyl] amino}qiMnazolin-5-yi)oxy]ethyl}-N-ethylacetamide (39 mg,
61%); NMR spectrum (DMSO-d6) 1.12 (t, 3H), 1.98 (s, 3H), 3.37 - 3.42 (m, 2H), 3.87 (t,
2H), 4.39 (t, 2H), 5.31 (s, 2B), 7.16 (d, 1H), 7.22 - 7.28 (m, 1H), 7.33 - 7.39 (m, 2H), 7.55 -
7.61 (m, 2H), 7.71 - 7.75 (m, 1H), 7.87 - 7.91 (m, 1H), 7.94 (d, 1H), 8.45 (s, 1H), 8.61 (d,
1H), 9.80 (s, 1HV. Mass spectrum MIT 492.
TheN-[3hloro-(pyridm-2-ylraethoxy)phenyl]-5-[2Kethylaniino)ethoxy]
quinazolin-4-amine used as starting material was prepared as follows:
Ethylenc glycol (150 ml) was treated with sodium hydride (60% in oil, 3.15 g) and the
exotherra controlled to about 10 °C with an ice-bath. A/r-[3-Chloro-4-(pyridin-2-
ylmethoxy)phenyl]-5-fluoroquinazobn-^arnine (obtained as described in Example 1,
preparation of starting materials, 12 g) was added in small portions and trie mixture heated at
,420 °C for 1 hour. The slurry was, copied, poured chloride....
(1.5 litres) and the solid collected and dried to give 2-[(4-{[3-chloro-4-(pyridin-2-
ylmethoxy)phOTyl]ammo}quinazx) -5-yl)oxy]etharK)l (12.6 g, 95%);
(DMSO-d6) 3.89 - 3.98 (m, 2H), 4.33 (t, 2H), 5.27 (s, 2H), 5.37 (t, 1H), 7.13 (d, 1H), 7.23 (d,
1H), 7.31 - 7.38 (m, 2H), 7.57 (d, III), 7.68 - 7.75 (m, 2H), 7.83 - 7.90 (m, 1H), 8.26 (d, 1H),
8.54 (s, 1H), 8.58 (d, 1H), 10.41 (s, 11H); Mass spectrum MH 422.
To a stirred solution of the 2-[(4-{ [3-chlc-4-(pyridm-2-ylmemoxy)phenyl]
amiDo}quinazolin-5-yl)oxy]ethanol (20 g) in DCM (200 ml) and THF (200 ml) was added
thionyl chloride (20 ml) at ambient temperature. The solution was men heated under reflux
for 2 hours. The solution was cooled and product filtered off to give 5-(2-chloroethoxy)--[3-
chloro-4^yridin-2-yhTietrK)xy)rAenyl]quinazolin-4-amine as its hydrochloride salt (25 g,
98%); NMR spectrum (DMSQ-d6) 4.20-4.40 (t, 2H), 4.60-4.80 (t, 2H), 5.40 (s, 2H), 7.20-
7.60 (m, 3H), 7.60-7.80 (m, 3H), 7.90-8.10 (m, 3H), 8.60-8.70 (d, 1H), 8.9 (s, 1H), 10.65-
10.83 (bs, 1H); Mass spectrum MH 441.
5^-Chkmjerhoxy) [3-chloro-4-(pyridm
(0.400 g) nd ethyiamine (1.2 g) were heated at 50 °C overnight and then the solution
The procedure described in Example 1 was repeated using glycotic acid and AT-[3-
chloro-4-(pyridin-2-ymiemoxy)phenyl]-5-[2-(emylamino)ethoxy]quinazoHn-4-an^
(obtained as described in Example 5, preparation of starting materials) to give the title
compound in 70% yield; NMR spectrum (DMSO-d6) 1.10 (t, 3H), 3.29-3.45 (m, 2H), 3.80-
, 7.30-7.40 (m, 2H), 7.60 (d, 2H), 7.70-7.78 (m, 1H), 7.82-7.92 (M, 1H), 7.95 (s, 1H), 8.43
(s, 1H), 8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH508.
17-t
The procedure described in Example 1 was repeated using glycolic acid and JV-[3-
chloro-4yridin-2-ylinethoxy)phenyl]-5-[2-propvlam
(obtained as described in example 7, preparation of starting materials) to give the title
compound in 26% yield; NMR spectrum (DMSO-d6) 0.84 (t, 3H), 1.53 -1.65 (m, 2H), 3.26
(t, 2H), 3.95 (t, 2H), 4.14 (d, 2H), 438 (t, IH), 4.47 (t, 2H), 4.53 - 4.58 (m, IH), 5.36 (s, IH),
117
7.24 (d, 1H), 7.31 (d, 1H), 7.39 - 7.44 (m, 2H), 7.63 - 7.67 (m, 2H), 7.76 - 7.81 (m, 1H), 7.92
- 7.96 (m, 1H), 8.05 (s, 1H), 8.51 (s, 1H), 8.66 (d, 1H), 9.87 (s, 1H); Mass spectrum MH 522.
Example 9
isopropylacetamide
The procedure described in Example 5 was repeated using -[3-chloro-4-(pyridin-2-
2rand acetyl chloride to
rive the title compound in 49% viektNMR gpectrum (DMSO-d6 1.19 (d 6HX 2.07 (s. 3H).
3.77 (t, 2HX 4.06 - 4.14 (m. 1H), 434 (t, 2HX 531 (, 2HX 751 (d, 1H), 77 (d, 1H), 732 -
739 (m, 2H), 7J7 - 7.63 (m, 2H), 79 - 7.75 (m. 1H), 7.86 - 7.91 (m, 1H), 8.01 (d, 1H), 8.46
(s, 1H), 8.60 (d, 1H), 10.00 (s, IIP: MM spectrum MlT 506.
The AT-[3-chkiro-4yridnv2-y!methoxy)rAenyl]-5H[2
edioxy]quinazolin-4-amine used as starting material was prepared as described in Example 5
(preparation of starting materials) using 52hloroethoxy)-[3-hloro-4-(pyridin-2-
ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 5, preparation of
starting materials) and isopropylamine; Mass spectrum MH 464.
Example 10
AM2-[(4-{[3-Oiloro(pyridin-2-yniietto
hydroxy-AMsopropylacetamide
The procedure described in Example 1 was repeated using glycolic acid and JV-[3-
chloro-4yridin-2-ylmethoxy)phenyl]-5-[2ylamino)ethoxy]quinazolin
(obtained as described in Example 9, preparation of starting materials) to give tne nue
compound in 11% yield; NMR spectrum (DMSO-d6) 1.19 (d, 6H), 3.81 (t, 2H), 3.93 - 4.01
(m, 1H), 4.14 - 4.18 (m, 2H), 4.35 - 4.47 (m, 3H), 5.31 (s, 2H), 7.21 - 7.29 (m, 2H), 7.32 -
7.40 (m, 2H), 7.56 - 7.63 (m, 2H), 7.70 - 7.76 (m, 1H), 7.86 - 7.91 (m, 1H), 8.04 (s, 1H), 8.47
(s, 1H), 8.60 (d, 1H), 10.02 (s, 1H); Mass spectrum MH+ 522.
Example 11
The procedure described in Example 5 wat repeated u
N^3-chloro-4iidiiH2-yliD6thQxy)pheny)]qra and acetyl chloride to give
the title compound in 47% viekL NMR spectrum OMtSO-d6 1.95 (t. 3ID. 3.86 (U 2H). 4.02 -
4.06 (m, 2HX 438 (t, 2H), 5.07 - 5.18 (m, 2H), 531 (s, 2H), 5.82 - 552 (m, 1HX 7.14 (d, 1H),
7.25 (d, 1H), 7.32 - 7.40 (m, 2H), 7.55 - 7.61 (m, 2H), 7.70 - 7.75 (m, 1H), 7.86 - 753 (m,
2H), 8.44 (s, 1H), 8.61 (d, 1H), 9.76 (s, IIP: Mass spectrum MH* 504.
The 5-[2^aUylaniino)ethoxy]--[3hloro(pyridin-2-ylinethoxy)pbenyl]
quinazolin-4-amine used as starting material was prepared as described in Example 5
(preparation of starting materials) using 52-cWoroettioxy--[3-chloro-4-(pyridin-2-
ylmethoxy)phenyl]quinazolin-4-aniine (obtained as described in Example 5, preparation of
starting materials) and allylamine; MflMWftrum 462.
Example 12
y!)oxy]ethyI}-2-hydroxyacetamkie
The procedure described in Example 1 was repeated using gjycdic acid and 5-[2-
(obtained as described in Example 11, preparation of starting materials) to give the title
compound in 24% yield; NMR spectrum (DMSO-d6) 3.79 - 4.19 (m, 6H), 438 - 4.63 (m,
3H), 5.06 - 5.19 (m, 2H). 531 (s, 2H), 5.69 - 5.90 (m, 1HX 7.16 (d, 1H), 7.25 (d, 1H), 733 -
739 (m, 2HX 7.56 - 7.63 (m, 2HX 7.70 - 7.76 (m, 1HX 7.86 - 7.91 (m, 1H), 13% (s, 1H), 8.45
(s, 1H), 8.61 (d, 1H), 9.80 (s, 1HV. Mass spectmm MET 520.
Example 13
cydopropylacaniide
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-
yknethoxy)phenyl]-5-[2-(cyclopropylamino)ethoxy]quinazolm-4-amine and acetyl chloride to
give the title compound in 38% yield; NMR spectrum (DMSO-d6) 0.76 - 0.82 (m, 4H), 2.06
(s, 3H), 2.76 - 2.83 (m, 1H), 3.87 (t, 2H), 4.42 (t, 2H), 531 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H),
732 - 7.40 (m, 2H), 7.56 - 7.61 (m, 2H), 7.70 - 7.75 (m, 1H), 7.86 - 7.92 (m, 1H), 7.94 - 7.96
(m, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.76 (s, 1H); Mass spectrum MH 504.
The (pyridin-2-yhiiethoxy)phenyl]-5-[2-(cyclopropylaniino)
ethoxy]quinazolin-4-amine used as starting material was prepared as described in Example 5
(preparation of starting materials) using 5-(2-chloroemoxy)-[3-chloro-4-(pyridin-2-
ylmethoxy)phenyl]quinazolin-4-aniine (obtained as described in Example 5, preparation of
starting materials) and cyclopropanamtne; Mass spectrum MH 462.
Example 14
tf-{2-[(4[3-Chkro-4yridta-2-ybae
cydopropyl-2-hydroxyacetandde
The proceduie described in Example 1 was repeated using glycolic acid and [3
quinazolin~4-amine
(obtained as described in Example 13, pjepmtion of starting materials) to give the title
compound in 19% yield; SMRm (DMS(d6) 0.73-0 JO ODB.4HX 2.73 -i80(m,
IH), 3.90 (t, 2H), 4.24 (s, 3HX 4.44 (t, 2H), 5.31 (s, 2H), 720 (d, IH), 7.25 (d, IH), 735 (d,
IH), 736 - 7.40 (m. IH), 737 - 7.62 OBI, 2H), 7.71 - 7.76 (m, IH), 7.86 - 7.92 (m, IH), 8.01
(d, IH), 8.46 (s, IH), 8.61 (d, IH), 9.80 (s, IH); Mass spectrum MH 520.
Example 15
(cydopropylmethyDacetamide
The procedure described in Example 5 was repeated using [3-chloro-4-(pyridin-2-
ylrnethoxy)phenyl3-5-{2-[(cycloprcylmethyl)ammo]ethoxy}quina2olin^amine and acetyl
chloride to give the title compound in 58% yield; FIMR gpretfflm (DMSO-d6) 0.16 - 0.27 (m,
2H), 0.36 - 0.52 (m, 2H), 0.97 -1.06 (m, IH), 2.00 (s, 3H), 324 - 3.29 (m, 2H), 3^3 - 4.02
(m, 2H), 433 - 4.56 (m, 2H), 5.31 (s, 2H), 7.13 - 7.18 (m, IH), 7.21 - 7.29 (m, IH), 731 -
7.40 (m, 2H), 7.54 - 7.62 (m, 2H), 7.69 - 7.79 (m, IH), 7.86 - 7.92 (m, IH), 7.93 - 7.96 (m,
IH), 8.44 (s, IH), 8.61 (d, IH), 9.81 (s, IH); Mass spectrum MET 518.
The 3Moro-4-(pyridin-2-yme
amino]ethoxy}quinazoiin-4-amiiie used as starting material was prepared as described in
Example 5 (preparation of starting materials) using 5-(2-chloroethoxy)-W-[3-chloro4-
i
(pyridin-2-ylmethoxy)phenyl}quinazo)in-4-amine (obtained as described in Example 5,
preparation of starting materials) and (cyclopropylmethyl)amine; Mass spectrum MH 476.
Example 16
(cydopropylroethyl)-2-hydroxya
The procedure descntodm Example 1 was repeated using glycohc acid
cUofo-4yricim-2-ylinethoxy)p ethoxy}quinazolin-
4-amine (obtained as described in Example 15, preparation of starting materials) to give the
title compound in 23% yield; NMR spectrum (DMSO-d6) -0.04 - 0.04 (m, 2H), 0.13 - 0.29
(m, 2H), 0.74 - 0.83 (m, IH), 2.98 (d, IH), 3.66 - 3.80 (m, 2H), 3.85 - 3.93 (m, 2H), 4.12 -
4.32 (m, 4H), 5.08 (s, 2H), 6.95 (d, IH), 7.02 (d, IH), 7.09 - 7.17 (m, 2H), 7.30 - 7.40 (m,
2H), 7.47 - 7.54 (m, IH), 7.63 - 7.68 (m, IH), 7.73 - 7.82 (m, IH), 8.21 - 8.29 (m, IH), 8.37
(d, IH), 9.62 (s, IH): Mass spectrum MH4^ 534.
Example 17
AH2-[(4[3-CWoropyridra-2-ylmetto
cyclobutylacetamlde
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-
ylinethoxy)phenyl]-]quma2olinamine and acetyl chloride to
give the title compound in 42% yield; NMR spectrum (DMSO-d6) 1.50 - 1.65 (m, 2H), 2.01
(s, 3H), 2.12 - 2.21 (m, 4H), 3.94 (t, 2H), 4.28 - 4.38 (m, 3H), 5.31 (s, 2H), 7.19 (d, 1H), 7.26
(d, 1H), 732 - 7.40 (m, 2H), 7.57 - 7.62 (m, 2H), 7.69 - 7.76 (m, 1H), 7.86 - 7.91 (m, 1H),
7.97 (s, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.90 (s, 1H); Mass spectrum MH+ 518.
TheN-[3hJoro-4yridin-2-ylmethoxy)phenyl]-5-[2cvclobutylarnino)
ethoxyJqumazolin-4-amine used as starting material was prepared as described in Example 5
(preparation of starting materials) using Hhlorocthoxy)-N-[3-chIoro-4-(pyridin-2-
ylrnetrK)xy)phenyl)quinazoliii^amine (obtained as described in Example 5, preparation of
starting materials) and cyclobutanamine; Mfttf ypectrun MH 476.
Example 18
The procedure described in Example 1 was repeated using glycolic acid and
cWro-4yridin-2-ylmethoxy) phcjiyl]-52cyclobutyl
(obtained as described in Example 17, preparation of starting materials) to give the title
compound in 22% yield; NMR spectrum (DMSO-d6) 1.49 1.65 (m, 2H), 2.08 - 2.27 (m,
4H), 3.97 (s, 2H), 4.12 (d, 2H), 4JM) - 4.29 (m, 1H), 432 - 4.43 (m, 3H), 5.31 (s, 2H), 7.21 (d,
1H), 7.26 (d, 1H), 7.33 - 7.40 (m, 2H), 7.57 - 7.63 (m, 2H), 7.71 - 7.76 (m, 1H), 7.86 - 7.92
(m, 1H), 8.02 (s, 1H), 8.47 (s, 1H), 8.60 (d, 1H), 9.92 (s, 1H); Mass spectrum MH534.
Example 19
The procedure described in Example 5 was repeated using 2V-[3-chloro-4-(pyridin-2-
ylroethoxy)phenyl]-5-{2-[(l-methylpiperidii4-yl)amino]ethoxy} quinazolin-4-amine and
acetyl chJoridc to give die tide compound in 41% yield; NMR spectrum (DMSO-d6) 1.62 -
1.90 (m, 4H), 2.09 (s, 3H), 2.15 - 2.43 (m, 4H), 2.79 - 3.13 (m, 3H), 3.76 - 3.83 (m, 2H), 3.86
- 3.92 (m, 1H), 430 - 4.47 (m, 2H), 531 (s, 2H), 7.21 (d, 1H), 7.26 (d, 1H), 732 - 7.40 (m,
2H), 7.57 - 7.61 (m, 2H), 7.69 - 7.75 (m, 1HX 7 J6 - 7.92 (m, 1H), 7.98 - 8.00 (m, 1H), 8.46
(8,1H), 8.61 (4 1IQ, 9.95 (s, 1HV. MMS spectrum MlT 561.
The J^3^diloro-4pyndii2-y)metyl)unino)ethoxy}quinazoliiK4-ainine used at starting material was ptepated as deacnbed in
Example 5 (preparation of starting using 5-2-diloroeaioxy)-W-[3-chloro-4-
(pyridin-2-yIrnethoxyphenyl]quinazoUn-4^Bnine (obtained as described in Euunple 5,
preparation of starting materials) and l-mettoylpiperidin-4-amine; Mass spectrum
Example 20
The procedure described in Example 5 was repeated using A[3-chloro-4-(pyridin-2-
ylnwthoxy)phenyl]-5-[2-(tetrahydK)-2H-pyranylanuno)ethoxy] quinazolin-amine and
acetyl chloride to give the tide compound in 68% yield; NMR spectrum (DMSOd6) 1.49 -
1.71 (m, 2H), 1.75 - 1.98 (m, 2H), 2.11 (s, 3H), 3.36 - 3.45 (m, 2H), 3.78 - 3.96 (m, 5H), 4.26
- 4.46 (m, 2H), 5.31 (s, 2H), 7.22 (d, 1H), 7.26 (d, 1H), 7.33 (d, 1H), 7.35 - 7.40 (m, 1H), 7.56
- 7.63 (m, 2H), 7.69 - 7.75 (m, 1H), 7.86 - 7.91 (m, 1H), 7.99 - 8.03 (m, 1H), 8.46 (s, 1H),
8.61 (d, 1H), 9.98 (s, 1H); Mass spectrum MH~ 548.
ylanimo)etboxy]quinazolin-4-amine used as starting material was prepared as described in
Example 5 (preparation of starting materials) using 5-(2-chloroethoxyN-[3-chloro-4-
(pyridin-2-ylnietiioxy)phenyI]quinazolin-4-amine (obtained as described in Example 5,
preparation of starting materials) and tetrahydro-2/f-pyran-4-amine;;
The procedure described in Example 1 was repeated using glycolic acid and N-{3-
ylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 20, preparation of
starting materials) to give the title compound in 12% yield; NMR spectrum (DMSO-d6) 1.53
- 1.69 (m, 2H), 1.77 - 2.07 (m, 2H), 3.34 - 3.42 (m, 2H). 3.73 - 3.92 (m, 5H), 4.14 - 4.25 (m,
2H), 4.31 - 4.54 (m, 3H), 5.31 (s, 2H), 721 - 7.29 (m, 2H), 732 - 7.40 (m, 2H), 7.57 - 7.63
(m, 2H), 7.70 - 7.76 (m, 1H), 7.86 - 7.91 (m, 1H), 8.03 (s, 1H), 8.47 (s, 1H), 8.61 (d, 1H),
9.99 (s, 1H); Mass spectrum MIT 564.
IfcS
Example 22
(2-hydroxyethyl)acetainkie
The procedure described in Example 5 was repeated using 2-({2-[(4-{[3-chloro-4-
(pyridin-2-ylmethoxy)phcnyl]ainiiK)}quinazolin-5-yl)oxy]ethyl}amino) ethanol and acetyl
chloride to give the title compound hi 21% yield; NMR spectrum (DMSO-d6) 2.00 (s, 3H),
3.43 (t, 2H), 3.54 - 3.59 (m, 2H), 3.88 - 3.97 (m, 2H), 4.41 (t, 2H), 4.85 (t, 1H), 5.31 (s, 2H),
7.16 (d, 1H), 7.25 (d, 1H), 733 (d, 11, 735 - 7.40 (m, 11, 7 J7 - 7.62 (m, 2H), 7.70 - 7.75
(m, 1HX 7.86 - 7.92 (m, 1H), 7.96 (d, 1HX 8.45 (s, 1H), 8.61 (d, 1HX 9.83 (s, 1H); Mass
spectrum MH^" 508.
The 2K{2-[(4-{[3n;Moro-4Kpyridtn-2-y]raethoxy
yl)oxy]ethyl}aniino)ethanol used as starting material was prepared as described in Example 5
(preparation of starting materials) using 5K2^hloroethoxy-Ar-[3-chksro-4-(pyridin-2-
ylmethoxy)pbenyI]quinazotin-4-amine (obtained as described in Example 5, preparation of
starting materials) and 2-aminoethanol; Mass spectrum MET 466.
Example 23
V2-[(4-{[3-CWort-4yridto-2-ylmetb
hydroxy-N-(2-hydroxyethyl)acetamkle
-ChJoro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-
yl)oxy]ethyl}amino)etfianol (obtained as described in Example 22, preparathrti of starting
materials) (0.208 g) in DCM (10 ml) was treated with 2-chloro-2-oxoethyl acetate (0.091 g)
and DIPEA (0.173 g) and stirred for 30 minutes. 7N Ammonia in methanol (20 ml) was added
and the solution stirred overnight The mixture was evaporated and purified by
chromatography using DCM to 8% 7N ammonia in methanol in DCM to give die title
compound in 30% yield; NMR spectrum (DMSO-d6) 3.37 (t, 2H), 3.56 (t, 2H), 3.95 (t, 2H),
4.11 - 4.17 (m, 2H), 4.25 (t, IH), 4.44 (t, 2H), 4.91 (t, IH), 531 (s, 2H), 7.17 (d, IH), 7.25 (d,
IH), 7.32 - 7.40 (m, 2H), 759 (d, 2H), 7.70 - 7.76 (m, IH), 7.86 - 7.91 (m, IH), 8.00 (d, IH),
8.46 (s, IH), 8.61 (d, IH), 9.85 (s, IH); Mass spectrum MH+ 524.
Example 24
(2-methoxyethyl)acetainide
The procedure described in Example 5
ytanetiKxy)phenyl]-5-{2-[(2-metha and acetyl
chloride to give the title compound in 30% yield; lMK^EKtQflBCDMSO-d6) 1.99(s,3H),
3.24 (», 3H), 3.46 - 3.51 (m, 2H), 3.52 - 3.57 (m, 2H), 3.88 - 3.98 (m, 2H), 437 - 4.43 (m,
2H), 531 (s, 2H), 7.17 (d, IH), 7.26 (d, IH), 734 (d, IH), 7.35 - 7.40 (m, IH), 7.55 - 7.63 (m,
2H), 7.71 - 7.78 (m, IH), 7.86 - 7.92 (m, IH), 7.94 (d, IH), 8.46 (s, IH), 8.61 (d, IH), 9.86 (s,
IH); A%g spectrum MH 522.
TTie//-[3-cWoro(pyridin-2-ylmethoxy)phenyl]-5-{2-[(2-medioxyethyl)
amino]ethoxy }quinazolin-4-amine used as starting material was prepared as described in
Example 5 (preparation of starting materials) using 5-(2-chloroettioxyJV-[3-chloro-4-
(pyridin-2-ylinethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 5,
preparation of starting materials) and rc-methoxyBthyrVamine; MaM spectrum MH*480.
Example 25
hydroxyWV2Hroethoxyethyl)acetaniide
The procedure described in Example 1 was repeated using glycolic acid and N-[3-
4-(pyridin-2-ylmethoxy)phenyl]-5-{ 2-[(2-methoxyethyl)amino]ethoxy} quinazolin-4-
amine (obtained as described in Example 24, preparation of starting materials) to give the title
compound in 27% yield; NMR spectrum (DM5O-d6) 3.18 (s, 1H), 3.24 (s, 2H), 3.48 (s, 3H),
3.55 - 3.60 (m, lift 3.86 - 3.98 (m, 2H), 4.10 - 4.15 (m, 2H), 432 (t, 1HX 4.43 (t, 1H), 4.51 -
4SI (m, lift, 531 (s, 2HX 7.17 (d, lift 7.25 (d, lift 733 - 7.40 (m, 2HX 757 - 7.63 (m,
2HX 7.71 - 7.76 (m, 1H), 7.86 - 7.91 (m, 1HX 7.99 - 8.05 (m, 1H), 8.46 (s, 1H), 8.60 (d, IB),
9.84 (s, 1H); Mass spectrum MIT 538.
The procedure described in Example 5 was repeated using Ar-[3-chloro-4-(pyridin-2-
ylmethoxy)phenyl]-5-[2-(rMX^2-yn-l-ylarnmo)ethoxy] and acetyl
chloride to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 2.03 (s, 3H),
3.27 (s, 1H), 3.93 - 4.04 (m, 2H), 4.24 - 4.32 (m, 2H), 4.43 (t, 1H), 4.56 - 4.63 (m, 1H), 5.31
(s, 2H), 7.13 (d, 1H), 7.25 (d, 1H), 7.34 (d, 1H), 7.35 - 7.41 (m, 1H), 7.52 - 7.63 (m, 2H), 7.70
- 7.79 (m, 1H), 7.86 - 7.93 (m, 2H), 8.44 (s, 1H), 8.61 (d, 1H), 9.69 (s, liT); Mass spcctrtim "
The -[3hlor&4Kpyridin-2-ylinethoxy)enyl)-5-[2-(prop-2-yn-lylamtno)
ethoxy]quinazoiin-4-amine used as starting material was prepared as described in
Example 5 (preparation of starting materials) using 5-{2-chloroethoxy/-[3-chIoro-4-
(pyridin-2-ylmethoxy)phenyl]qiraiazlirHanaine (obtained as described in Example 5,
preparation of starting materials) and prop-2-yn-l-amine; Mass spectrum MET 460.
Example 27
AK2-[(4[3-Oiloropyridi
The procedure described in Example 1 was repeated using grycolic arid an
qnmazolin-4-
amme (obtained as described in Example 26, pcepratkof starting materials) to give tbe title
compound in 26% yield; NMRgpectnm (DMSOd6) 3.98 (s, 2H), 4.16 (s, 2H)t 4.28 (s, 2H),
4.47 (s, 1H), 4 J5 - 4.66 (m, 1H), 531 (s, 2H), 7.12 - 7.21 (m, 1H), 1.25 (d, 1H), 7.32 - 7.40
(m, 2H), 7.59 (d, 2H), 7.70 - 7.78 (m, 1H), 7.86 - 7.92 (m, 1H), 7.97 - 8.06 (m, 1H), 8.43 -
8.51 (m, 1H), 8.61 (d, 1H), 9.76 (s, MB: Masa spectrum MH" 518.
Example 28
ftM2~[(4[3-OiIonHl-pyridm
hydroxyl-A-methylpropanamide
The procedure described in Example 1 was repeated using 2-hydrdxypropahbtc acid "
amine (obtained as described in Example 1, preparation of starting materials) to give the title
compound in 56% yield: NMR spectrum (DMSO-d6) 1.08 (d, 3H), 3.11 (s, 3H), 3.82 - 4.12
(m, 2H), 4.36 - 4.47 (m, 3H), 432-4.72 (m, IH), 5.31 (s, 2H), 7.18 (d, 1H), 7.25 (d, 1H),
7.34 (d, 1H), 735 - 7.40 (m, 1H), 7.52 - 7.62 (m, 2H), 7.70 - 7.76 (m, IH), 7.86 - 7.91 (m,
1H), 7.94 - 7.97 (m, IH), 8.44 (s, 1H), 8.61 (d, 1H), 9.75 (s, 1H); Mass spectrum MH508.
Example 29
The procedure described in Example 1 was repeated using tetrahydrofuran-2-
carboxytic acid and [3htoro-4-(pyikiiiv-2-ylmcthoxy)pbenyl]-5-[2-
(metfaylamiiK)ethoxy]quinazoiin-4-amiiie (obtained as described in Example 1, preparation of
starting materials) to give the tide compound in 89% yield: NMR spectrum (DMSO-d6) 1.64
- 1.94 (m, 4H), 3.09 (s, 3H), 3 SI - 3.70 (m, 2H), 3.82 - 3.97 (m, 2H), 4.42 (t, 2HX 4.60 - 4.66
(m, 1H), 5.31 (s, 2H), 7.16 (d, 1H), 7^3 (d, 1H), 7.33 (d, 1H), 735 - 739 (m, 1H), 7 J2 - 7.57
(m, 1H), 7.59 (d, 1H), 7.70 - 7.75 (m, 1H), 7.85 - 7.91 (m, 1H), 7.92 (d, 1H), 8.42 (s, IH),
8.61 (d, IH), 9.70 (s, IH); Mass spectrum
Example 30
{2-[(4-{[3-CbJoro(pyim-2-yliMthoxy)phenyl]ajmno}quiiiazolln-5.yI)oxy]ethyl}-
V,l-dimethylprolinainide
The procedure described in Example 1 was repeated using l-methylproline and -[
cWoro-4yridin-2-ylniethoxy)phenyl]-5-[2-(methylamino)cthoxy] quinazoUnamin
(obtained as described in Example 1, preparation of starting materials) to give the title
compound in 38% yield; NMR spectrum (DMSO-d6) 1.55 - 1.68 (m, 3H), 1.92 - 2.03 (m,
2H) 2.12 (s, 2H), 329 (s, 6H), 3.87 - 4.03 (m, 2H), 4.40 - 4.61 (m, 2H), 5.31 (s, 2H), 7.17 (d,
1H), 7.22 (d, 1H), 7.33 (d, 1H), 735 - 7.39 (m, 1H), 7.57 - 7.63 (m, 2H), 7.69 - 7.75 (m, 1H),
7.86 - 7.91 (m, 1H), 8.05 (d, 1H), 8.43 (s, 1H), 8.60 (d, 1H), 9.76 (s, 1H); Mass spectrum
MIT 547.
Example 31
The procedure described in Example 1 was repealed usng 2-hydroxy-2-
memyhjffopanoic acid and JH3-clfoco-4-
(methylainino)etiKny]quiruaoli]i^Hi(nine (obtained as described in Example 1, preparation of
starting materials) to give the tide compound in 39% yield; HMRjsj2e£trj^(DMSO-d6) 1.20
(s, 6H), 3.34 (s, 3H), 3.89 (s, 2H), 4.43 (s, 2H), 5.27 (s, 1H), 531 (s, 2H), 7.18 (d, 1H), 74
(d, 1H), 732 - 7.40 (m, 2H), 7.53 - 7.57 (m, 1H), 7.58 (d, 1H), 7.70 - 7.76 (m, 1H), 7.86 -
7.91 (m, 2H), 8.43 (s, 1H), 8.59 - 8.61 (m, 1H), 9.75 (s, 1H); Mass spectrum MH522.
Example 32
AT2-[(4-{[3hloro(pyrldln-2-ylmethoxy)phenyl]ainiiio}quiiiazolinhydroxy-V-methylcyclopropanecarboxamide
The procedure described in Example 1 was repeated using 1-
hydroxycyclopropanecarboxylic acid and AT-[3-chloro-4-(pyridin-2-ylmethoxy) phenyl]-5-[2-
(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of
starting materials) to give die title compound in 54% yield; NMR spectrum (DMSO-d6) 0.68
- 0.80 (m, 4H), 3.30 (s, 3H), 3.84 - 3.96 (m, 2H), 4.37 - 4.49 (m, 2H), 5.31 (s, 2H), 6.16 - 6.23
(m, IH), 7.14 - 7.21 (m, IH), 7.24 (d, IH), 7.32 - 7.40 (m, 2H), 7.51 - 7.56 (m, IH), 7.59 (d,
IH), 7.71 - 7.76 (m, IH), 7.86 - 7.91 (m, 2H), 8.40 - 8.47 (m, IH), 8.61 (d, IH), 9.68 - 9.75
(m, IH); Mass spectrum MH4" 520.
Example 33
The procedure described in Example 1 was repeated using tf-methylgjycine and AT-Pchlcro-
4^yrklm-2-ylinetixy)phenyI]-5 quinazolin-4-amine
(obtained at described in Example 1, preparation of starting materials) to give the title
compound in 25% yield; NMR spectrum (DMSO-d6) 3.06 (s, 2H), 3.30 (s, 6H) 3.90 (t, 2H),
4.33 - 4.42 (m, 3H), 531 (s, 2H), 7.16 (d, IH), 7.24 (d, IH), 7.34 (d, IH), 7.35 - 7.40 (m, IH),
7.53 - 7.57 (m, IH), 7.60 (d, IH), 7.70 - 7.75 (m, IH), 7.86 - 7.92 (m, IH), 7.93 (d, IH), 8.43
(s, IH), 8.61 (d, IH), 9.74 (s, IH); Ma^g spectrum MR 507.
Example 34
A4M(4-{[3-CWoro-4Kpyittin-2-ylmeto
hydroxy-JV2-trimethylpropanamide
The procedure described in Example 1 was repeated using 3-hydroxy-2,2-
dimethylpropanoic acid and N-[3^hloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-
(methylamino)ethoxy]quina2olin-4-amjne (obtained as described in Example 1, preparation of
starting materials) to give the title compound in 25% yield; NMR spectrum (DMSO-d6) 1.07
(s, 6H), 3.15 (s, 3H), 3.35 (d, 2H), 3.91 (t, 2H), 4.41 - 4.48 (m, 3H), 5.30 (s, 2H), 7.18 (d, IH),
7.24 (d, IH), 7.34 (d, IH), 735 - 739 (m, IH), 7.56 - 7.61 (m, 2H), 7.71 - 7.76 (m, IH), 7.86
- 7.91 (m, IH), 7.98 (d, IH), 8.45 (s, IH), 8.60 (d, IH), 9.81 (8, IH); Mass spectrum MH+
536.
Example 35
hydroxy--methylpropanamide (AZ12240261)
The procedure described in Example I was repeated using 3-hydnxypropnoic acid
and A[3-chlofo4-(pyridi2-ylin
amiiie(obtaiiied a* described in Example l,pie
compound in 24% yield; NMR spectrum (DMSO-do) 2.13 - 2.26 (m, 2H), 2.65 - 2.79 (m,
2H), 3.30 (s, 3H), 3.87 - 3.97 (m, 2H), 4.13 - 4.25 (m, IH), 434 - 4.61 (m, 2H), 531 (s, 2H),
7.15 (d, IH), 7.25 (d, IH), 7.32 - 739 (m, 2H), 7.53 - 7.57 (m, IH), 7.60 (d, 1HX 7.70 - 7.76
(m, IH), 7.86 - 7.92 (m, 2H), 8.42 (s, IH), 8.61 (d, IH), 9.70 (s, IH); Mass spectrum MH
508.
The procedure described in Example 1 was repeated using acetic acid and 5-[(15)-2-
aniino-l-methyletnoxy]-[3-chlon-4-(pyridin-2-yljnethoxy)phenyl] quinazolin-4-armne to
give the title compound in 60% yield; NMR spectrum (DMSO-d6) 1.40 (d, 3H), 1.80 (s, 3H),
3.40 (m, 1H), 3.62 (m, 1H), 4.85 (m, 1H), 5.30 (s, 2H), 7.23 (m, 2H), 7.30 (d, 1H), 736 (m,
1H), 7.57 (m, 2H), 7.71 (t, 1H), 7.87 (td, 1H), 8.12 (d, 1H), 8.22 (t, 1H), 8.49 (s, 1H), 8.58 (d,
1H)T 10.00 (s, 1H); Mass Spectrum MH 478.
The5-[(lS2-aimno-l-inemylethoxy]-
pnenyl]qumazoUn-4-amine used as starting material was prepared as follows:
The procedure described in Example 1 (preparation of starting materials) was repeated
using (SX+H-amino-2-propanol and 5-fluoro-7^-[3-chloro-4-{pyridin-2-
ylmethoxy)phenylJquinazolin-4-arnine (obtained as described in Example 1, preparation of
"nting materials) to give 5-[(15-2-amino-l-mylemoxy]--[3Woro-4-(pyridin-2-
ylmethoxy)phenyl}quinazolin-4-amine in 46% yield; NMR spectrum (DMSCNJ6) 1.39 (d,
3HX Z96 (m, 2H), 4.79 (m, l8 (s, 2H), 7.17 (d, 1H), 71 (d, 1H), 7.29 (d, 1H), 735
(m, IH), 7.56 (d, 1H), 7.64 (dd, 1H), 7.70 (t, 1H), 7.86 (dt, 1H), 8 JO (d, 1H), 8.48 (s, 1HX
8.58 (d, 1H), 10.60 (bt. IHh MM Spectmm NflT 435.
Example 37
fl)oxy]propy]}-2-hydroxyacetamide
The procedure described in Example 1 was repeated using glycolic acid and 5-[(15)-2-
amino- l-methylethoxy]-JV-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl] quinazolin-4-amine
(obtained as described in Example 36, preparation of starting materials) to give the title
compound in 47% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 3.41 (m, 1H), 3.74 (m,
1H), 3.78 (d, 2H), 4.92 (m, 1H), 5.29 (s, 2H), 5.48 (t, 1H), 7.23 (dd, 2H), 7.31 (d, lH),-7.35
(m, 1H), 7.58 (m, 2H), 7.70 (t, 1H), 7.87 (td, 1H), 8.13 (d, 1H), 8.17 (t, 1H), 8.47 (s, 1H), 8.58
(d, 1H), 9.98 (s, 1H); Mass Spectrum Mlf 494.
Example 38
The procedure described in Example 1 was repeated using MJV-dimethylglycine and
-inethyleth()xy]-M
amine (obtained as described in Example 36, preparation of starting materials) to give the
title compound in 49% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.07 (s, 6H), 2.80 (s,
2H), 3.41 (m, 1H), 3.73 (m, 1H), 4.93 (rnlH), 5.29 (s, 2H), 7.23 (m, 2H), 730 (d, IB). 735
(t, 1HX7J8 On, 2HX 7.70(1, H),7.86(td, 1H), 8.12 Cm, 211X8.47(5,1H), 8^8 (d, 1H), 9.96
(s, 1HX Mass Spectrum MH521.
Example 39
yl)oxy]propyl}-2-metfaoxyarrtamide
The procedure described in Example 1 was repeated using memoxyacetic acid and 5-
[(lS2-amino-l-methylethoxy]-AT-[3nloix-4yridin-2-ylme(hx)xy)phenyl]quinazolm
amine (obtained as described in Example 36, preparation of starting materials) to give the
title compound in 53% yield; NMR spectrum (DMSO-d6) 139 (d, 3H), 3.20 (s, 3H), 3.40 (m,
1H), 3.72 (m, IH), 3.75 (s, 2H), 4.93 (m, 1H), 529 (s, 2H) 7.23 (m, 2K), 7.3t (d, H; T.58
(m, 2H), 7.7O (t, IH), 7.86 (dt, IH), 7.95 (s, IH), 8.12 (d, IH), 8.19 (t, IH), 8.47 (s, IH),
(m, IH), 9.97 (s, IH); Mass Spectrum MET 508.
Example 40
The procedure described in Example 1 was repeated using methanesulfonylacetic acid
and 5-[(lS-2-amiiio-l-inethyletlKxy
yhnethoxyhenyl]qomiizolin-4«nine (obtained as described in Example 36, preparation of
starting materials) to give the tide compound in 72% yield: NMR spectrum (DMSOdSH 42
(d, 3H), 3.02 (s, 3H). 3.49 (m, ffi). 3 .76 On, 1HX 4.06 (s, 2H), 4.89 (m,ffiX 5.28 (s, 2HX 7.22
(m, 2HX 734 (m, 2H), 76 (d, 2H), 7.72 (t, 1HK 76 (A, 1HK 8.15 (d, 1H), 8.48 fclH),
8.71 (t,
Example 41
WM(4[3a)lonHKpjnri
hydroxyacetamide
The procedure described in Example 1 was repeated using glycolic acid and 5-(2-
aininoethoxy)-N-[3hlaro(pyridin-2-ylmethoxy)phenyl]quinazoUn-amine (obtained as
described in Example 2.6, preparation of starting materials) to give the title compound in 60%
yield; NMR spectrum (DMSO-d6) 3.71 (q, 2H), 3.78 (d, 2H), 4.36 (t, 2H), 5.28 (s, 2H), 5.49
(t. 1H), 7.13 (d, 1H), 7.21 (d, 1H), 7.32 (d, 1H), 7.35 (m, 1H), 7.56 (m, 2H), 7.7JI (tr 1IJ), 7.87
(dt, 1H), 7.98 (d, 1H), 8.18 (t, 1H), 8.45 (s, 1H), 8.58 (d, 1H), 9.82 (s, 1H); Mass Spectrum
Example 42
The procedure described in Example 1 was repeated using M-dimethylglycine and 5-
as described in Example 2.6, preparation of starting materials) to give the title compound in
31% yield; NMR spectrum (DMSOd6) 2.08 (s, 6H), 2.79 (s, 2H), 3.68 (q, 2H), 4.36 (t, 2H),
5.29 (8, 2HX 7.13 (d, 1HX 7.21 (d 1HX 7.34 On, 2H), 7.55 (m, 2HX 7.70 (t, IH), 7.86 (dt,
IH), 7.98 (d, IH), 8.11 (t, IH), 8.45 (t IH), 838 (d, IH), 9.80 (s, 1HV. Mass SpectmrnMET
507.
methoxyiicetainicie
The procedure described in Example 1 was repeated using methoxyacetic acid and 5-
-[3hlorD(pyddm-2-ymiemoxy)phenyQquinazol
as described in Example 2.6, preparation of starting materials) to give the tide compound in
50% yield; NMR spectrum (DMSO-d6) 3.20 (s, 3H), 3.68 (m, 2H), 3.73 (s, 2H), 4.38 (t, 2H),
5.29 (s, 2H), 7.14 (d, IH), 7.21 (d, IH), 7.34 (m, 2H), 7J5 (t, IH), 7.71 (t, IH), 7.86 (t, IH),
7.97 (d, IH), 8.17 (m, IH), 8.44 (s, IH), 8.58 (d, IH), 9.81 (s, IH); Mass Spectrum MH494.
Example 44
(methykulfonyftecetamide
The procedure described in Example 1 was repeated using methanesulfonylacetic acid
(obtained as described in Example 2.6, preparation of starting materials) to give the title
compound in 51% yield: NMR spectrum (DMSOdfl 2,99 (s, 3HX 3.74 (m, 2H), 4.04 (s, 2H),
434 (t, 2HX 529 (s, 2H), 7.13 (d, IHX 722 (d, IHX 735 (m, 2HX 7.55 (m, 2HX 7.71 (t, IHX
7.87 (dt, IH), 8.03 (d, IHX 8.46(8, IHX 88(d, IHX 876 (t,!H), 9.79 (s,lH); Mass
Spectrum MET 542.
yl)oxy]propy1}-A^-methy
The procedure described in Example 1 was repeated using acetic acid and A-[3-
ernoxy)phenyl]-5-[(lSH-
quinazolm-4-amine (obtained as described for the R-antipode in Example 23, preparation of
starting materials, using (2S2-methyloxirane) to give the title compound in 51% yield; NMI
136(d,3H), 14(s,3H)3.03(s,3H),332(lHobscuredbyH2OX -
4.20 (m, IH), 5.08 (m.lH), 5.30 (s, 2H), 723 (m, 2H), 7.34 (rn, 2H), 7.57 (d, IH), 7.68 (m,
2H), 7.87 (dt, IH), 8.11 (d, IH), 8.46 (s, IH), 8.59 (d, IH), 9.94 (s, IH); JVbss Spectrum MH
492.
Example 46
The procedure described in Example 1 was repeated using glycoticatid8ndtf-[3-
cbJoro-4-(pyridin-2-ylmethoxy)
rtbaxylquinazolin-4-«mine (obtained as described for the R-antipodem Example 23,
ptepaiation of starting material^ to pve the titlecoinpouiKlm53% viekkNMRspectrom
(DMSO-d6) 1.39 (d, 3H), 296 (s. 3H), 336 (dd, IH), 4.04 (d, 2H), 4.21 (m, IH), 437 (t,
IH), 5.09 Cm, IH), 5^9 (s, IH), 7J5 On, 2H), 735 (m, 2H), 737 (d, IH), 7.65 (dd, IH), 7.70
(t, IH), 7.87 (dt, IH), 8.12 (d, IH), 8.46 (s, IH), 8.58 (d, IH), 9.93 (s, IH); Mass Spectrum
MH+508.
Example 47
ulM
The procedure described in Example 1 was repeated using AAW-dimethylglycme and
N-[3KW(wo-4pyridin-2-yteicthoxy)phenyl]-5-[(lSV
(methylarano)ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in
Example 2.3, preparation of starting materials) to give the title compound in 27% yield;
StMR spectrum (DMSO-d6) 1.37 (d, 3H), 2.06 (s, 6H), 3.08 (s, 3H), 323 (dd, IH), 3.25 (s,
H), 4.26 (dd, IH), 5.10 (m, IH), 5.29 (s, 2H), 7.23 (m, 2H), 7.30 (d, IH), 7.35 (m, IH), 756
;s, IH), 7.68 (m, 2H), 7.87 (dt, IH), 8.13 (d, IH), 8.44 (s, IH), 8.58 (d, IH), 9.90 (s, IH);
Mass Spectrum MfT 535.
Example 48
The procedure described in Example 1 was repeated using methoxvacetic acid and Nsthoxylquinazolin-
4-amine (obtained as described for the R-antipode in Example 23,
preparation of starting materials) to give die title compound in 39% yield; gpectiniT11
JMSO-d6) 1.38 (d, 3H), 2.99 (s, 3H), 3.16 (s, 3H), 3.27 (IH obscured by H2O), 4.03 (s, 2H),
1.23 (m, IH), 5.1 1 (m, IH), 529 (s, 2H), 724 (m, 2H), 730 (d, IH), 735 (m, IH), 7 .57 (d,
IH), 7.65, (dd, IH), 7.71 (t, IH), 7.86 (dt, IH), 8.12 (d, IH), 8.44 (s, IH), 8.58 (d, IH), 9.90
[s, IH); Mass Spectrum MH522.
The procedure described in Example 1 was repeated using methanesutfonylacetic acid
and tf-[3-ctooro-4yridin-2-ylin
(mediylamino)eftoxy]quinazolin-4-amine (obtained as described for the R-antipode in
Example 23. preparation of stinting material to give the title compound in 61% vickUNMR
sjggm 0MSOd6) 138 (d, 3H), 195 (s, 3H), 3.15 (s, 3HX 337 (dd, H),430(in,lH),
4.41 (d, 2HX 5.11 Cm. IH), 5.29 (s, 2H), 724 (m, 2H), 730 (d, IH), 735 (m, IH), 737 (d,
IH), 7.64 (dd, IH), 7.70 (t, IH), 7.86 (dt, IH), 8.11 (d, IH), 8.45 (s, IH), 838 (d. IH), 9.88
(s, IHk Mass Spectrum MH 570.
oxy]propyI}-N-methylacetaniide
The procedure described in Example 4.1 was repeated using JV[(2/0-2-({4-[(3-chloro-
4^ydroxyphenyl)amino]quinazoUn-5-yl}oxy)propyl]--methylacetamide and pyrazin-2-
ylmcthyl methanesulfonate to give the title compound in 61% yield; NMR spectrum (DMSOd6)
13 (d,3H), 1.95 (s, 3H), 3.03 (s, 3H),337 (IH obscured by HiO), 4.21/(dd\tlH), 5.08
(m, IH), 537 (s, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 8.11 (d, IH), 8.46 (s, IH), 8.66 (m, 2H),
8.85 (s, IH), 9.94 (s, 1HV. Mass Spectrum MH 493.
The A-[(2)-2-({4-[(31oTohydroxyphenyl)arninquiiiazolin-5-yl}oxy) propyl]-
JV-metbylacetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using acetic acid and 2-chlonv4-({ 5-[( -l-methyl-2-(methylamino) ethoxy]quinazolin-4-
yl}ammo)phenol (obtained as described in Example 4.11, preparation of starting materials) to
give JV-[(2R)-2-({4-[(3-chloro4-hydroxyphenyl) amino)quinazolin-5-yl }oxy)propyl]-ATmemylacetamide
in 45% yield: NMR spectrum 0MSO-d6) 1.37 (d, 3H), 1.94 (s, 3H), 3.03
(s, 3H), 3.31 (dd, 1H), 4.15 (dd, 1H), 5.06 (m, 1H), 6.97 (d, 1H), 7.23 (d, 1H), 7.29 (d, 1H),
7.46 (dd, 1H), 7.69 (m, 1H),7.95 (d, 1H), 8.42 (s, 1H), 9.98 (bs, 1H); Mass Spectrum MET
401.
Example 51
The procedure described in Example 3 was repeated using N-[(22-({4-[(3-chloro-4-
hydroxypheiiyl)amino]qiiinazolin-5-yl}oxy)rjropyl]-N^nethylacctamide (obtained as
described for in Example 50, preparation of starting materials) and 4-(chloromethylthiazole
hydrochloride to give the titk compound in 17% yield; NMR spectrum (DMSO-d6) 1.36 (d,
3H), 1.94 (s, 3H), 3.02 (s, 3H), 3.3O (1H obscured by EfeO), 4.21 (dd, 1H), 5.09 (m, 1H), 5.33
(s, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 7.81 (s, 1H), 8.08 (s, 1H), 8.47 (s, 1H), 9.13 (s, 1H), 9.96
(s, IHfc Mass Spectrum MH498.
Example 52
The procedure described in Example 3 was repeated using 7-[(2R)-2-({4-[(3-chloro-4-
hydroxyphenyl)uBmo]qi)mazoli (obtained as
described for in Example 50, preparation of starting niaterials) and 3-fluorobenzyl chloride to
give the title compound in 87% yield: NMRspectmm (DMSO-d6) 136 (d, 3H), 153 (a, 3H),
3.04 (t,3HX 3.27 (fflobtconxl by HbO), 4-22 (ddlH), 5.07 (m, 1HX5J25 (2H)7.16
1H), 79 (m, 5H), 7.45 (m, 1HX 75 (dd, 1H), 7.71 (t, IH), 8.09 (d, 1HX 8.46 (1HX 9.93
(s, 1H);
yl]oxy}propyl)-inetiiyl
The procedure described in Example 3 was repeated using -[(2R2-({4-[(3-chloro-4-
hydroxyphenyl)amino]quiiuizolin-5-yl}oxy)prcoyl]-N-riiethylacetami (obtained as
described for in Example 50, preparation of starting materials) and 2-fluorobenzyl chloride to
give the title compound in 72% yield; flMR spectrum (DMSO-d6) 137 (o\ 3HX 1.94 (s, 3H),
3.04 (s, 3H), 3.30 (1H obscured by HO), 4.20 (dd, 1H), 5.07 (m, 1H), 5.25 (s, 2H), 7.27 (m,
5H), 7.43 (m, 1H), 7.59 (t, 1H), 7.67 (dd, 1H), 7.70 (t, 1H), 8.07 (d, 1H), 8.45 (s, 1H), 9.93 (s,
1H); Mass Spectrum MET 509.
Example 54
The procedure described in Example 3 was repeated using picolyl chloride
spectnimrDMSOd61.19fd.3H. 2.79 fa.3HL 3.87- 4.26 fm.3Hl4.38- 4.48 fm.2H).
5.11 - 5.22 (m, 1H), 5.29 (s, 2H), 7.18 - 7.25 (m, 2H), 732 - 738 (m, 2H), 7.48 (d, 1HX 7^8
1HX 938 (s, 1H); Mass
spectrum MHf 5083.
The Ar-[(l)-2-({4-[(3-chloTO^hydroxyphenyl)amiiHlquinazolin-5-yl}oxy)-lmethylethyl)-
2-hydroxy-N-methylacetainide used as starting material was prepared as
follows:
The procedure described in Example 3 (preparation of starting materials) was repealed
using (2/0-2-methylainino)propan-l-ol (obtained as described in Becker et al., J. Chem. Soc.
1957, 858) and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in
Example 4.5, preparation of starting materials) to give 2-chloro-4-[(5-{[(2R2-
(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol in 100% yield; NMR spectrum
(DMSO-d6) 1.20 (d, 3H), 2.40 (s, 3H), 3.30 (m, 1H), 4.25 (dd, 1H), 4.35 (dd, 1H), 7.00 (d,
1H), 7.10 (d, 1H), 7.30 (d, 1H), 7.60 (dd, IH), 7.70 (t, 1H), 7.90 (d, 1H), 8.50 (s, 1H); Mass
spectrum MH 359.1
The procedure described in Example 3 (preparation of starting materials) was repeated
using gjycollc adid and 2-cnloro-4[(5-{ [(2/0-2KiMrnyiarniho
yl)amino]phcnol to give JV-[(l/Z)-2-({4-[(3-chloro-4-hydroxyphenyl) amino]quinazolin-5-
yl}oxyl-methylethyl]-2-hydroxy-N-methylacetannde in 100% yield; Mass spectrum MH4"
416.9.
Example 55
AM(l)-2(4[3-Chloroyridki-2-ylii
methyiethyl}-N-methylacetamide
The procedure described in Example 3 was repeated using picolyl chloride
hydrochtoride tnd/(lK)-2{4-[(3
methyfethyO-AtaiediyUcetra
(DMSO-d6) 1.18 (d, 3H), 1.83 (s, 3H), 2,84 (s, 3HX 4.19 - 4.43 (m, 2H), 5.14 - 5.24 (m, IH),
530 (s, 2H), 7.16 - 7 .27 On, 2H), 732 - 738 (m, 2H), 7.45 - 7 JO (m, IH), 7 J8 (d, IH), 7.72
(t, IH), 7.87 (t, 2H), 8.43 (s, IH). 859 (d, IH), 9.53 (s, IH); MH 4923.
mediylethyl]-M-methylacetainide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using acetic acid and 21oro4-[(5-{[(2/0-2methylamino)propyl]oxy} quinazolin-4-
yl)amino]phenol (obtained as described in Example 54, preparation of starting materials) to
give M[(l«)-2{4-[(3hloio-4-hydioxyphenyl)amino] quinazolin-5-yl}oxy)-l-methylethyl]-
-methylacetamide in 100% yield; Mass spectrum MH" 401.
Example 56
methylethyl}-2-hydroxy-/V-incfliylftrrtmtde
The procedure described in Example 3 was repeated using picolyl chloride
hydrochloride and JV-[(15)-2K{4-[(3hIMt4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)- methylethyl]-
2-hydroxy-^-methylacetainide to give the tide compound in 57 % yield; NMR
spectrum (DMSO-d6) 1.20 (dd, 3H), 2.80 (d, 3H), 3.10 (m, 1H), 3.80-4.20 (m, 2H), 4.20-4.50
(m, 2H), 5.15 (m, 1H), 5.30 (s, 2H), 7.20 (m, 2H), 7.30 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H),
7.70 (m, 1H), 7.80-7.95 (m, 2H), 8.40 (d, 1H), 8.60 (d, 1H), 9.60 (s, 1H); Mass spectrum MET
508.2.
The (152-({4-[(31oio4-hydroxyphenyl)arnino]qiiinazolin-5-yl }oxy)-lmethylethyi]-
24iydroxy-#-methylacetarnide used as starting material was prepared as
follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using (25)-2-(inethylamino)propan-l-ol (obtained as described in Chacchio et al.,
Tetrahedron, 1995,51,5689) and 2-chloro-4-[(5-fluoroqurna2olin-4-yI)amino] phenol
(obtained as described in Example 4.5, preparation of starting materials) to give 2-chloro-4-
[(5-{[(22Kmethylaramo)propyI in 100% yield; NMR
spectrum (DMSO-d6) 1.20 (d, 3H), 2.40 (s, 3HX 3.20 (m, 1H), 4.15 (dd, 1H), 4.30 (dd, 1HX
7.00 (d, IB), 7.10 (d, 1H), 730 (d, 1H), 7.60 (dd, 1H), 7.70 (t, 1H), 8.00 (d, 1H), 8.50 (s, 1H);
Mflft* Tpecftum MET 359.4.
The procedure described in Example 3 (preparation of starting materials) was repeated
using glycolic acid and 2-chloro-4-[(5-{ [(25)-2-(methylamino)propyl]oxy} quinazolin-4-
yl)amino]phenol to give-[(15)-2-({4-r(3-chloro-44iydroxyphenyl) amino]quinazolin-5-
yl}oxy)-l-methylethyi]-2-hydroxy-W-methylacetamide in 48% yield; Mass spectrumMH
4173.
Examples
The procedure described in Example 3 was repeated using picolyl chloride
hydrochloride and N-[(152{4(3hloro-4ydroxypheiiyl)amino]quinazolin-5-yl}oxy)-lmethyIethyl]-
N-methylacetamide to give the title compound in 34 % yield; NMR spectrum
(DMSO-d6, 373K) 120 (d, 3H), 1.85 (s, 3H), 2.80 (s, 3H), 3.00 (m, IH), 4.30 (m, IH), 4.40
(m, 1HX 5.30 (s, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.50 (d, IH), 7.60 (d, IH), 7.70 (t, IH),
7.80 (m, IH), 7.90 (d, IH), 8.40 (s, IH), 8.60 (d, IH), 9.6O (s, IH); Mass spectrum MH
492.2.
metiiylethyl]-N-methylacetarnide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using acetic acid and 2hloro4-[(5-{[(252-(rrieuiylaniin.o)propyl]oxy} quinazolin-4-
yl)anuno]phenol (obtained as described in Example 56, preparation of starting materials) to
give tf-[(lS)-2{4-[(3-criro-4ydrOT qainazoUn-5-yl}oxy)-l-methylethyl
N-methytecetamkte in 27% yield; MaASjejaMB MH 4013.
Example 58
The procedure described in Example 3 was repeated using picolyl chloride
methylethyl]-2-mcthoxy-methylacetamide to give the title compound in 39% yield; HM&
sj£c£uin_(DMSO-d6, 373K) 1.20 (m, 3H), 2.80 (s, 3H), 3. 10 (s, 3H), 3.90 (m, 2H), 4.20 (m,
IH), 4.50 (m, IH), 5.10 (m, IH), 530 (s, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.50 (d, IH), 7.60
(d, IH), 7.70 (t, IH), 7.90 (t, IH), 7.95 (s, IH), 8.40 (s, IH), 8.60 (d, IH), 9.60 (s, IH);
spectrum MH 522.2.
TteJV"-[(lSV2{4-[(3blcco-44iydroxyphenyl)aniino]quinaz
rnethylemyl]-2Hiiethoxy-JV^memylacetamide used as staxting material was obtained as
follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using methoxyacctic acid and 2-chloro-4-[(5-{[(2lS2-(methylamino)propyl] oxyjquinazolin-
4-yl)amino]phenol (obtained as described in Example 56, preparation of starting materials) to
give A[(12{4-[(3-cUonydroxyphenyl)ainino] quinazoIin-5-yl }oxy)-l -methylethyl)-
2-methoxyWV-methvIacetaniide in 49% yield; Mass spectrum MH 429.2.
Example 59
A4(lS2(4-{[3-toro(pyridin-2-ylro
methytethyl}-24tydroxyacetamide
The procedure described in Example 3 was repeated using picoiyi chloride
vphCTyl)anM
methylethyl}-2ydraxyacetauide to give the titteconipoundin57%yield;
(DMSO-d6) 1.23 (d, 3H), 3.64 - 3.81 (m, 2H), 4.24 - 436 (m, 2H), 4.45 - 4.59 (m, IH), 5.29
(s, 2H), 5.45 (t, IH), 7.13 - 7.23 (m, 2H), 7.35 (t, 2H), 7.49 - 7.53 (m, IH), 7.56 - 7 39 (m,
IH), 7.72 (t, IH), 7.87 (t, IH), 7.99 - 8.02 (m, 2H), 8.46 (s, IH), 8.59 (d, IH), 9.75 (s, IH);
Mass spectrum MH493.95.
The HKlS)-2K{4-[(3Moiohydroxy
methylediyl]-2-hydroxyacetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using (2S)-2-aminopropan-l-ol and 2-chloro-4-[(5-fluoroquinazohn-4-yl) aminojphenol
(obtained as described in Example 4.5, preparation of starting materials) to give 4-[(5-{[(25)-
2-aniiiK)propyl]oxy}quinazoIin-4-yl)ammoJ-2-chlorophenol in 54% yield; NMR spectrum
(DMSO-d6); 1.30 (d, 3H), 3.30 (bs, 2H), 3.80 (m, IH), 4.40 (m, 2H), 7.00 (d, IH), 7.20 (d,
IH), 7.30 (d, IH), 7.50 (dd, IH), 7.70 (t, IH), 8.00 (d, IH), 8.45 (s, IH); Mass spectrum MH
345.1.
The procedure described in Example 3 (preparation of starting materials) was repeated
using glycolic acid and 4-[(5-{[(25)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-
chlorophenol to give JV-[(lS)-2-({4-[(3-chkwo-4-hydroxyphenyl)amino] quinazolm-5-
yl}oxy)-l-!nethylethyl]-2-hydroxyacetamide hi 73% yield: Mass spectrum MH*403.0.
Example 60
tnetbytetbyDacetamkle
The procedure described in Example 3 was repeated using picolyl chloride
bydrochloride aodNH(l{44(3-dikoydraxyt
1.21 (s, 3H), 1.73 (s, 3H), 4.12 - 430 (m. 2H), 433 - 4.43 (m, 1B 59 (s, 2, 7.15 - 7.25
(m, 2HX 735 (t, 2HX 7.51 - 7.59 (m, 2 7.72 (t, 1HX 7.87 (t, 1HX 7.99 (s. 1HX 8.14 (d,
1H), 8.48 (, 1H), 8.59 (d, 1H), 9.80 (s, 1H); MSSStBHB MlT 478.0.
methylethyl]acetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using acetic acid and 4-[(5-{[(22-anopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol
(obtained as described in Example 59, preparation of starting materials) to give N-[(152-({4-
K3-chloco-4-hydroxyphenyl)amino] qumazoUn-5-yl}oxy)-l-rnethylethyl]acetainidein 100%
yield: Mass spectrum MET 387.0.
Example 6
N1-{(152-[(4-{[3-Chk)ro-4-(pvridin-ylirictlxy)phenyIlair
methylethylJ-NV-dimethylglydnamide
The procedure described in Example 1 was repeated using JVWV-dimethylglycine and 5-
{[(2S)-2-ainiiiopixpyl)oxy}--[3-cW
to give the title compound in 42% yield; NMR spectrum (DMSCM6) 1.21 (d, 3H), 2.05 (s,
6H), 2.60-2.80 (m, 2H), 4.20-4.40 (m, 2H), 4.40-4.60 (m, IH), 5.30 (s, 2H), 7.15 (m, IH),
722 (m, IH), 735 (m, 2H), 7.54 (m, 2H), 7.70 (t, IH), 7.90 (t, IH), 7.98 (m, 2H), 8.48 (s,
IH), 8.59 (d, IH), 9.76 (s, IH): Mass spectrum MH 521.4.
The 5-{[(252-aminop!ropyl]oxy}TAH3-Woro-(pyrklin-2-
ylmethoxy)phcnyl]quinazolin-4-amine used as starting material was prepared as follows:
The procedure described in Example 2.4 (preparation of starting materials) was
repeated using (25)-2-aminopropan-l-ol and H;3-chloro-4-yridin-2-yhnethoxy)phenyl]-5-
fluoroquinazolin-4-amine (obtained as described in Example 1, preparation of starting
materials) to give 5-{[(25-2-aminopnyl]oxy}-[3-chloro-4-(pyridin-2-
The procedure described hi Example 3 was repeated using JVl-[(2ft)-2-({4-[(3-chloro-
4^ydroxyphenyl)arrdno]quina2oUn-5-yl}oxy)propyl]-A-diinethylglycinamide and picolyl
chloride hydrochloride to give the title compound in 59% yield; NMR spectrum (CDCM 1.47
(d, 3H), 2.11 (s, 6H), 2.88 (s, 2H), 3.50-3.63 (m, IH), 3.64-3.78 (m, IH), 4.76-4.90 (m, IH),
523 (s, 2H), 6.92-7.00 (m, 2H), 7.13-7.19 (m, IH), 736-7.49 (m, 2H), 7.52-7.72 (m, 4H),
7.90 (d, IH), 8.55 (m, 2H), 9.82 (s, IH): Mass spectrum MH 521.0.
imethylglycinamide amide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using 4-({5-[(12-amino-l-methylemoxy]quina2to-4-yl}amino)-2-chlorophenol (obtained
as described in Example 4.4, preparation of starting materials) and AJV-dimethylglycine to
give A-[(2R2-({4-[(3-chloro-4-hydroxyphenyl)amino] quinazolin-5-yl}oxy)propyl]-WaVachmethylglycinamide
amide in 11% yield; NMR spectrum (CDC13) 1.46 (d, 3H), 2.09 (s, 6H),
2.84 (d, 2H), 3.52-3.75 (m, 2H), 4.77-4.89 (m, IH), 6.89-6.99 (m, 2H), 7.27 (dd, IH), 7.40
(dd, IH), 7.51-7.61 (m, 2H), 7.80 (d, IH), 8.52 (s, IH), 9.76 (s, IH); Mass spectrum
Example 63
(obtained as described in Example 2.6, preparation of Parting materials, 0.5 g 1.19 imnol)
was heated to 130°C in xylene (20 ml) until it had dissolved (S(-a-hyd«oxy-YbutyroUctone
(0.10 ml, 131 mmo!)was added and the mixture was stirred at 13CPC for 3
hows. Mote (SX-)ydroxy-Y4Myrolacone (0.05 ml, 0.66 msnol) was added and the
mixture was heated for a further 2 hours. The resultant precipitate was fUtered off white the
mixture was hot, washed with diethyl ether (3 x 10 ml) and dried to give the title compound
as a solid (430 mg, 69%); NMR spectrum (DMSO-d6) 138-1.55 (m, IH), 1.69-1.85 (m, IH),
337-3.50 (m, 2H), 3.61-3.77 (m, 2H), 3.89-4.00 (m, IH), 4.28-4.45 (m, 3H), 59 (s, 2H),
5.51 (d, IH), 7.13 (d, IH), 7.22 (d, IH), 7.28-7.41 (m, 2H), 7.49-7.62 (m, 2H), 7.71 (t, IH),
8.01 (d, IH), 8.14-8.25 (m, IH), 8.45 (s, IH), 8.59 (d, IH), 9.82 (s, im: Mass spectrum MH*
523.9.
Example 64
(2JJN-{2-[(
yl)oxylethyl)-2,4-dlhydro7cybutaiiaiiilde
The procedure described in Example 63 was repeated using 5-{2-aniinoethoxy)-N-[3-
chkMO-4yridin-2-ylmexy)pheiiyl]qiiinazolin-4-arijine (obtained as described in Example
2.6, preparation of starting materials) and (RH+^hydroxy-y-butyrolactone to give the title
compound in 55% yield; NMR spectrum (DMSO-d6) 1.38-1.55 (m, 1H), 1.69-1.85 (rn, 1H),
3.37-3.50 (m, 2H), 3.61-3.77 (m, 2H), 3.89-4.00 (m, 1H), 4.28-4.45 (m, 3H), 5.29 (s, 2H),
5.51 (d, 1H), 7.13 (d, 1H), 7.22 (d, 1H), 7.28-7.41 (m, 2H), 7.49-7.62 (m, 2H), 7.71 (t, 1H),
8.01 (d, 1H), 8.14-8.25 (m, 1H), 8.45 (s, 1H), 8.59 (d, 1H), 9.82 (s, 1H); Mass spectrum
523.9.
Example 65
(2)(2Jt)-24(4[3-Chloro4
yl)oxy3prpyl}-2y4-dihydroxybnhiiuimid
The procedure described mExanir& 63 was repeated
niethylethoxy][3-chloio-4-(pyiidb2-yh and CRH+)-
o-hydroxy-y-butyrolactone to give the title compound in 54% yield; NMR spectrum CPMSOd6)
139 (d, 3H), 1.43-1 SJ (m, 3H), 1.71-1.86 (m, 1H), 333-3.53 (m, 3H), 3.65-3.79 (m, 1H),
3.88-4.00 (m, 1H), 4.36 (t, 1H), 4.85-4.96 (m, 1H), 5.29 (s, 2H), 5.45 (d,lH), 7.24 (d, 2H),
728-7.41 (m, 2H), 7.59 (t, 2H), 7.71 (t, 1H), 7.87 (t, 1H), 8.10-821 (m, 2H), 8.48 (s, 1H),
8.59 (d, 1H), 9.99 (s, 1H); Mass spectrum MIT 537.9.
The5-[)-2-ainino-l-methylemoxy]-[3-cWoio-4-(pyridin-2-ylmethoxy)
phenyl]quinazolin-4-amine used as starting material was prepared as follows:
Benzaldehyde (1.46 ml, 14.3 mmol) was added to a solution of 4-({5-[()-2-aminol-
methylethoxy]quinazolin-4-yl}amino2-chlorophenol (obtained as described in Example
4.4, preparation of starting materials, 4.5 g, 13.08 mmol) in DMF (50 ml) and the mixture was
stirred for 20 minutes. Potassium carbonate (723 g, 52.32 mmol), picolyl chloride
hydrochloride (2.57 g, 15.70 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (18~crown-6
catalytic amount) were added and the reaction mixture was stirred vigorously for 16 hours.
The reaction mixture was concentrated, the residue was stirred in water (250 ml) and the
precipitated solid was filtered off. The solid was dissolved in 1M HC1 (150 ml) and the
butyrolactone to give the title compound in 62% yield; NMR spectrum (DMSO-d6) 1.31-1.47
(m, 4H), 1.64-1.77 (m, IH), 333-3.50 (m, 3H), 3.71-3.84 (m, IH), 3.90-4.00 (m, IH), 4.32 (t,
IH), 4.87-4.98 (m, IH), 5.29 (s, 2H), 5.48 (d, IH), 7.18-7.27 (m, 2H), 7.28-7.40 (m, 2H),
7.54-7.64 (m, 2H), 7.87 (dt, IH), 8.10-8.21 (m, 2H), 8.47 (s, IH), 8.59 (d, IH), 9.95 (s, IH);
Mass spectrum MH 537.9.
Example 61
The procedure described in Example 63 was repeated using 5-[(lS)-2-ainroo
ylethcy)-fl43-chk»ro-4-{p (obtaaed as
described in Example 36, preparation of starting Materials) and (S xydaaiyfbutyiDiactone
to give the title compound in 60% yield;
3H), 1.43-1.57 (m, 3H), 1.71-1.86 (m, 1HX 333-3.53 (m, 3H), 3.65-3.79 (m, 1HX 3.88-4.00
(m, IH), 436 (t, IH), 4.85-4.96 (m, IH), 5.29 (s, 2H), 5.45 (d,lH), 7.24 (d, 2H), 7.28-7.41
(m, 2H), 7.59 (t, 2H), 7.71 (t, IH), 7.87 (t, IH), 8.10-8.21 (m, 2H), 8.48 (s, IH), 8.59 (d, IH),
9.99 (s, IH): Mass spectrum MH* 537.9.
Example 69
(257V-{(l)-2-[(4-{[3-aikro-4-(pvrklin-2-yliTeUioxy)phenyI]aniiM
ytxyl-l-methylethyll-lAdihydroxybutanamide
The procedure described in Example 63 was repeated using 5-{ [(2K)-2-
y}-JV-[3-chloKHHpyridin-2
as described in Example 2.4, preparation of starting materials) and (S(-)-a-hydroxy-Ybntyrolactone
to give the title compound in 79% yield; NMR spectrum (DMSO-d6 400MHz)
1.24 (d, 3H), 1.30-1.41 (m, IH), 1.63-1.74 (m, IH), 3.32-3.46 (m, 2H), 3.91-3.98 (m, IH),
4.24 (dd, IH), 4.31 (t, IH), 438 (t, IH), 4.47-4.57 (m, IH), 5.30 (s, 2H), 5.43 (d, IH), 7.16 (d,
IH), 7.23 (d, IH), 7.31-7.41 (m, 2H), 7.56 (dd, IH), 7.60 (d, IH), 7.73 (t, IH), 7.89 (dt, IH),
755 (d, IH), 8.06 (d, IH), 8.48 (s, IH), 8.61 (d, IH) 9.79 (s, IH): Mass spectrum MH* 538.0.
Example 70
yl)oxy]-l-ineaylethy2,4-dihydroxybutaiiamkk
The procedure described in Example 63 was repeated using 5-{ [(2/0-2-aminopropyl]
(obtained as described
in Example 2,4, preparation of starting materials) and (RH+)-butyrolactooe to
IH), 1.72-1.86 (m, IH), 338-3.51 (m, 2H), 3.83-3.93 (m, IH). 4.20-4.40 (m, 3H), 4.42-4.55
(m, 1HX 5.29 (s, 2H), 539 (d, IH), 7.14 (d, IH), 7.21 (d, IH), 730-7.40 (m, 2H), 7.47-7.55
(m, IH), 7.58 (d, IH), 7.72 (t, IH), 7.87 (t, IH), 757 (d, IH), 8.01 (s, IH), 8.46 (s, IH), 8.59
(d, IH), 9.74 (s, IH): Mass spectrum MH 538.0.
Example 71
yl)oxy]ethyl2Adihydroxybutanamide
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)- V-[3-
chloro(13-thiazol-4-ylmethoxy)phenyl]quinazolm-4-amine and (RH+hydroxyjybutyrolactone
to give the title compound in 69% yield; NMR spectrum (DMSO-d6 400MH2)
1.44-1.55 (m, IH), 1.73-1.85 (m, 1H), 3.41-3.52 (m, 2H), 3.65-3.77 (2ll)," 3.93-4.02 (hX
IH), 431-4.48 (m, 3H). 538 (s, 2H), 5.50 (d, IH), 7.17 (d, IH), 7.33 (t, 2H), (7-60 (dd, IH),
1.24 (d, 3H), 1.30-1.41 (m, IH), 1.63-1.74 (m, IH), 3.32-3.46 (m, 2H)
4.24 (dd, IH), 4.31 (t, IH), 4.38 (t, IH), 4.47-4.57 (m, IH), 5.30 (s, 2H
IH), 7.23 (d, IH), 7.31-7.41 (m, 2H), 7.56 (dd, 1H),7.60 (d, IH), 7.73
7.95 (d, IH), 8.06 (d, IH), 8.48 (s, IH), 8.61 (d, IH) 9.79 (s, IH); M§s_
Example 70
(2V.{(l)-2-[(4-{[3-Chkro-4.(pyrklin-2-ytmetboxy)phenyl]amL
yl)oxy]-l-methylethyl}-2,4-dihydroxylatanainide
The procedtm described in 63 was repeated uabg 5-
OKy}-3-di]o(o-4-
in Example 2.4, preparation of starting materials) and (RM+)-tt-hydrcr
^ the title compound in 77% viekthMRgpec
IH), 1.72-1.86 (BO, IH), 338-3.51 (m, 2HX 3.83-3.93 (m, IH), 4.20-4.
(m, IHX 5.29 (s, 2H), 539 (d, IH), 7.14 (d, IHX 7.21 (d, IH), 730-7.~
(m, IH), 7.58 (d, IH), 7.72 (t, IH), 7.87 (t, IH), 757 (d, IH), 8.01 (s,
(d, IH), 9.74 (s, IH); MafffRPWhim MH 538.0.
Examine 71
(2{2-[(4-{[3-ChIor(4-(13-thiazol-4-yhnethoxy)phenynaminc
yl)oxy]ethyl}2vt-dihydroxybutanainide
The procedure described in Example 63 was repeated using 5—
chloro4-(13-thiazol-4-yhT»thoxy)phenyl]quinazolin-4-arnine and (EL
butyrolactone to give the title compound in 69% yield; NMRspectrur
1.44-1.55 (m, IH), 1.73-1.85 (m, 1 H), 3.41-3.52 (m, 2H), 3.65-3.77 C
IH), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, IH), 7.17 (d, IH), 7.33
1.24 (d, 3H), 1.30-1.41 (m, 1H), 1.63-1.74 (m, 1H), 3.32-3.46 (m, 2H), 3.91-3.98 (m, 1H),
4.24 (dd, 1H), 4.31 (t, 1H), 4.38 (t, 1H), 4.47-4.57 (m, 1H), 5.30 (s, 2H), 5.43 (d, 1H), 7.16 (d,
1H), 7.23 (d, 1H), 7.31-7.41 (m, 2H), 7.56 (dd, 1H), 7.60 (d, 1H), 7.73 (t, 1H), 7.89 (dt, 1H),
7.95 (d, 1H), 8.06 (d, 1H), 8.48 (s, 1H), 8.61 (d, 1H) 9.79 (s, 1H); Mass spectrum MH 538.0.
Example 70
(pyridin-2-yImetboxy)phenyI]amino}quinazolin-5-
yl)oxy]-l-nietbykthyl}-2,4dlhydroxybutananiide
The procedure described in Example 63 was repeated using 5-{ [(22-ainmopropyl]
oxy)-tf-(3-cfaloiD-4-pyiklfo-2-yh (obtained as described
in Example 2.4, preparation of starting materials) and butyiolac*one to
give ttetrttecompotmdm 77% vidd:NMR spectrum
1H), 1.72-1.86 (m, 1H), 338-3.51 (m, 2S& 3.83-3.93 (m» 1H), 4JO-*.40 (m, 3HX 4.42-45
(m, 1HX 5.29 (s, 2H), 539 (d, 1H), 7.14 (d, 1HX 7^1 (d, 1H), 73O-7.40 (m, 2H), 7.47-735
(m, 1H), 7 J8 (d, 1H), 7.72 (t, 1H), 7.87 (t, 1H), 7.97 (d, 1H), 8.01 (s> 1H), 8.46 (s, 1H), 8.59
(d, 1H), 9.74 (s, 1H); Mass spectrum MlT 538.0.
Example 71
(2fi)-Ar.{2.[(44[3-Chloro(lthiazol-4-ylmethoxy)phenyl]amino}qumazolln.5-
yl)oxy]ethyl}-2,4-dihydnxybutananiide
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-N-[3-
chloro4-(13-thiazol^ylmethoxy)phenyl]quinazolm-4-amine and (RX+)-oc-hydroxy-Ybutyrolactone
to give the title compound in 69% yield; NMR spectrum (DMSO-d6 400MHz)
1.44-1.55 (m, 1H), 1.73-1.85 (m, 1H), 3.41-3.52 (m, 2H), 3.65-3.77 (m, 2H), 3.93-4.02 (m,
1H), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, 1H), 7.17 (d, 1H), 7.33 (t, 2H), (7.60 (dd, 1H),
7.74 (t, 1H), 7.83 (s, 1H), 8.02 (s, 1H), 8.20 (t, 1H), 8.48 (s, 1H), 9.17 (s, 1H), 9.85 (s, 1H);
Mass spectrum MH529.9.
The 5-(2-aminoethoxy)-jiV-[3-chloro-4-(l ,3-thiazol-4-ylmethoxy)phenyl] quinazoIin-4-
amine used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example
4.5, preparation of starting materials) and ethanolamine to give 4-{ [5-(2-
aminoethoxy)quinazolin-4-yl]amino}-2-chlorophenol in 84% yield NMR spectrum (DMSOd6)
3.12 (t, 2H), 4.27 (t, 2H), 6.96 (d, 1H), 7.11 (d, 1H), 7.31 (d, 1H), 7.53 (dd, 1H), 8.08 (d,
1H), 8.47 (s, 1H); Mass spectrum MH 331.0.
The procedure described in Example 65 (preparation of starting materials) was
repeated using 4-{[52-arnmcthoxy)quinazolin-4-yl]amino}-2-chlorophenol and 4-
(chloromethyl)-13-thiazok; hydrochloridc to give 5-(2-aminoenV)xy)-N-[3-ch]oro-4-(l,3-
Wazol^ylmethoxy)ptKMyl)quiiiazolin-4-amiDe in 91% yield; NMR spectrum (DMSO-d6
400MHz) 3.02-3.19 (bs, 2H), 4.22-436 (m, 2H), 533 (s. 2H), 7.14 (d, 1H), 7J7-7.40 (m,
2H), 7.67-7.86 (m, 3H), 8.23 (s, 1H), 8J2 (&, 1H), 9.15 (s, 1H) (3 exchangeaWes); Mass
MH 427.9.
Example 72 ,

(25Ar-{2-[(4-{[3-Clilon-4K13-thiazol-4-ylmetboxy)phenyl]arniiM}quinflzo
yl)oxy]ethyl}-2,4-dihydroxybutanamide
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-AT-[3-
chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in
Example 71, preparation of starting materials) and (SH-)-a-hydroxy-Y-butyrolactone to give
the title compound in 66% yield; NMR spectrum (DMSO-d6 400MHz) 1.44-1.55 (m, 1H),
1.73-1.85 (m, IH), 3.41-3.52 (m, 2H), 3.65-3.77 (m, 2H), 3.93-4.02 (m, 1H), 4.31-4.48 (m,
3H), 5.38 (s, 2H), 5.50 (d, 1H), 7.17 (d, 1H), 7.33 (t, 2H), (7.60 (dd, 1H), 7.74 (t, 1H), 7:83 (s,
1H), 8.02 (s, 1H), 8.20 (t, 1H), 8.48 (s, 1H), 9.17 (s, 1H), 9.85 (s, 1H); Mass spectrum MET
529.9.
Example 73
(2K)-AM(l)-2-l(4-{[3-Coro
yDoxyl-l-methylethylj-dibydroxybutanamide
The procedure described in Example 63 was repeated using 5-{[(2R}-2-
}-N-[3-chloro-4-(13~tra"azol
(R)-(+) a-hydroxy-Y-butyrolactoDe to give the title compound in 73% yield; NMR spectrum
(DMSO-d6) 1.22 (d, 3H), 1.46-1.61 (m, 1H), 1.72-1.87 (m, 1H), 3.40-3 .54 (m, 2H), 3.84-3.97
(m, 1H), 4.19-4.41 (m, 3H), 4.42-4.58 (m, 1H), 535 (s, 2H), 5.40 (d, 1H), 7.14 (d, 1H), 7.25-
738 (m, 2H), 753 (dd, 1H), 7.72 (t, 1H) 70 (d, 1HX 7.92-8.05 (m, 2H), 8.47 (s, 1H), 9.14
(d, 1H), 9.75 (s, 1H); Massspcctmm MH 543.
phenyl](yHnazofin-4-aTnine used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using 2-Koro[(5-fluoroquinazolin-4-yi)arnino phenol (obtained as described in Example
4.5, preparation of starting materials) and (2R2-aminopropan-l-ol to give 4-[(5-{ [(22-
arninopropy]]oxy}quinazolin-4-yl)amino]-2-chlorophenol in 100% yield; NMR spectrum
(DMSO-d6) 1.16 (d, 3H), 3.29-3.44 (m, 1H), 3.98 (dd, 1H), 4.22 (dd, 1H), 6.96 (d, 1H), 7.09
(d, 1H), 7.30 (d, 1H), 7.58 (dd, 1H), 7.69 (t, 1H), 8.10 (d, 1H), 8.47 (s, 1H) (4 exchangeables);
Mass spectrum MH" 344.9.
The procedure described in Example 65 (preparation of starting materials) was
repeated using 4-[(5-{[(2)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol and
4-(cMoromethylH,3-thiazole hydrochloride give 5-{[(2 2-aminopropyl]oxy}-JV-[3-chlon-
4-(l,3-tWazol-4-ylmemoxy)phenyl]qumazolin-4-amine in 65% yield; NMR spectrum
(DMSO-d6) 1.17 (d, 3H), 3.33-3.45 (m, 1H), 4.00 (dd, 1H)), 4.24 (dd, 1H), 5.32 (s, 2H), 7.11
(d, 1H), 7.30 (d, 1H), 733 (d, 1H), 7.67-7.82 (m, 3H), 8.23 (d, 1H), 8.51 (s, 1H), 9.14 (d, 1H);
Mass spectrum MH 441.9.
Example 74
(25)-V-{(l)-2-[(4-{[3-Chloro-4-(llhiazol-4-ylmethoxy)phenyl]amino}quinazoHn-5-
yl)oxy]-l-inetbylethyl}-2,4ihydroxybutanamide
The procedure described in Example 63 was repeated using 5-{[(2)-2-
(obtained as described in Example 73, preparation of starting materials) and (S)-(-)-ahydroxy-
Y-butyrolactone to give the title compound in 58% yield; NMR spectrum (DMSOd6)
1.23 (d, 3H), 1.27-1.40 (m, 1H), 1.60-1.62 (m, 1H), 3.33-3.46 (m, 2H), 3.87-3.97 (m, 1H),
4.19-4.41 (m, 3H), 4.42-4.58 (m, 1H), 5.35 (s, 2H), 5.40 (d, 1H), 7.14 (d, 1H), 7.25-738 (m,
2H), 7.53 (dd, 1H), 7.72 (t, 1H), 7.80 (d, 1H), 7.92-8.05 (m, 2H), 8.47 (s, 1H), 9.14 (d, 1H),
9.75 (s, 1H); Mf TTO MR 543.
Example 75
N-Methylyl)
oxy]ethyl}acetamlde
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine
andM[2-({4-[(4-hydnxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-
methylacetamide to give the title compound as a white solid in 11% yield; NMR spectrum
(DMSO-d6 373K) 1.94 (s, 3H), 2.28 (s, 3H), 3.00 (s, 3H), 3.88 (t, 2H), 4.46 (m, 2H), 5.20 (s,
2H), 7.01 (d, 1H), 7.16 (d, 1H), 7.34 (m, 2H), 7.51 (m, 2H), 7.55 (d, 1H), 7.68 (t, 1H), 7.83
(td, 1H), 8.41 (s, 1H), 8.58 (d, 1H), 9.63 (s, 1H); Mass spectrum MH 458.
TheW-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyI]-7V1-
methylacetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using acetic acid and 2-rneAyl-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol
(obtained as described in Example 3, preparation of starting materials) to give JV-[2-({4-[(4-
hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy) ethyl]-methylacetamide as alight
brown solid in 100% yield; NMR spectrum (DMSO-d6) 1.90 (s, 3H), 2.16 (s, 3H), 3.02 (s,
3H), 3.85 (t, 2H), 4.45 (t, 2H), 6.82 (d, 1H), 7.18 (dd, 1H), 7.25 (d, 1H), 7.34 (m, 2H), 7.92 (t,
1H), 8.65 (s, 1H), 9.45 (s, 1H), 10.52 (s, 1H); Mass spectrum Mlf 367.
Example 76
tf-Methyl-N2-[(4-{[3-meroyl
ethyl acetwnld
The procedure described in Example 3 was repeated using 4-{cMorornethyl)-13-
thiazole and AT-[2K{4(4ydroxy-3-rnethylrjhenyl)MnirK)]quiMZoUn-5ethyQ-tfmethylacetamide
(obtained as described in Example 75, preparation of starting materials) to
give the title compound as an off-white solid in 5% yield; NMR spectrum (DMSO-d6 373K)
1.94 (s, 3H), 2.24 (s, 3H), 2.99 (s, 3H), 3.87 (t, 2H), 4.46 (m, 2H), 5.25 (s, 2H), 7.08 (d, 1H),
7.17 (d, 1H), 7.35 (d, 1H), 7.47 (d, 1H), 7.54 (dd, 1H), 7.70 (m, 2H), 8.41 (s, 1H), 9.07 (d,
1H), 9.63 (s, 1H); Mass spectrum MH 464.
Example 77
N-Mcthyl-NK2-{l4-({3-methylw4.[(5-rn€thylisoxazol-3-yl)roethoxy]phenyl}arnirio)
quinazolin-5-yl]oxy}ethyl)acetaniide
The procedure described in Example 3 was repeated using 3-(chloromethyl5-
methylisoxazole and N-[2{4-[(4-hydroxy-3-memylphenyl)arnino]quinazolin-5-
yl}oxy)ethyi]-W-methylacetamide (obtained as described in Example 75, preparation of
starting materials) to give the title compound as a white solid in 14% yield; NMR spectrum
(DMSO-d6 373K) L95 (s, 3H), 2.23 (s, 3H), 2.43 (s, 3H), 3.57 (s, 3H), 3.88 (t, 2H), 4.47 (m,
2H), 5.15 (s, 2H), 6.29 (s, IH), 7.05 (d, IH), 7.15 (d, IH), 7.34 (d, IH), 7.48 (d, IH), 7.54 (dd,
IH), 7.69 (t, IH), 8.42 (s, IH), 9.64 (s, IH); Mass spectrum MH+ 462.
Example 78
2-Hydroxy--methyl-Af-{2-[(4-{[3-roethyl-4-(l,3-thiazoI-2-ylmetboxy)phenyl]
amino}quina2oUn-5-yl)oxy]ethyl}acetam}de
The procedure described in Example 3 was repeated using 2-(chloroinethyl)-13-
yl }oxy)ediyl]-Amemytacetamide (obtained as described in Example 3, preparation of starting
materials) to give the title compound as a wbite solid in 38% yield; NMR spectrum (DMSOd6
373K) 2.27 (s, 3H), 2.98 (s, 3H), 3.91 (t, 2H), 4.07 (s, 2H), 4.47 (t, 2H), 5.44 (s, 2H), 7.09
(d, IH), 7.16 (d, IH), 734 (d, IH), 7.54 (m, 2H), 7.67 (t, IH), 7.70 (d, IH), 7.83 (d, IH), 8.41
(s, IH), 9.63 (s, IH); Mass spectrum MfiT 480.
Example 79
2-Hydnxy-A-{2-[(4-{[3-methyl(pyridm-2-ylmethoxy)phenyl]andno}quinazoliri-5-
yl)oxy]ethyl}acetamide
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine
and 2-hydroxy-JV-[2-({4-[(4-hydroxy-3-methylphenyl)ainino] quinazolin-5-
yl}oxy)ethyl]acetamide to give the title compound as a yellow solid in 27% yield; HMfi
spectrum (DMSO-d6) 2.27 (s, 3H), 3.71 (q, 2H), 3.77 (d, 2H), 4.38 (t, 2H), 5.20 (s, 2H), 5.49
(t, 1H), 6.98 (d, 1H), 7.14 (d, 1H), 7.31 (d, 1H), 7.35 (dd, 1H), 7.45 (d, 1H), 7.56 (m, 2H),
7.68 (t, 1H), 7.85 (td, 1H), 8.17 (t, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.75 (s, 1H); Mass
spectrum MH 460.
The2-hydroxy-JV-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-
yl }oxy)ethyl]acetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using ethanolamine and 4-[(5-fluoroquinazolin-4-yl)amino]-2-rnethylphenol (obtained as
described in Example 3, preparation of starting materials) to give 4-{ [5-(2-
aminoethoxy)qiimazolin-4-yl]arnrno}-2--methylphenol as a grey solid in 23% yield; NMR
spectrum (DMSO16) 2.14 (s, 3H), 3.09 (d, 2H), 3.28 (s, 2H), 4.25 (t, 2H), 6.77 (d, 1H), 7.08
(d, 1H), 7.28 (d, 1H), 7.46 (dd, 1H), 7.55 (d, IH), 7.66 (t, 1H), 8.40 (s, 1H), 10.31 (s, 1H);
Mass spectrum MH 311.
The pnxxlureedm Example 3 (pnjar
using glycolic acid and 4-{ [S42-umiioetixxxy)qum to
give 2vdroxy-2{4-[(4ydroxy-3-n«thylphenyl)amino] quinazolin-5-
yl}oxy)ethyl]acetamide as m light brown sobdm 58% yield; NMR^ecmffin(DMSO-d6) 2.16
(s, 3H), 3.69 (q, 2H), 3.76 (d, 2H), 4.43 (t, 2H), 6.82 (d, 1H), 730 (m, 4H), 750 (t, 1H), 8^0
(t, 1H), 8.66 (s, 1H), 9.42 (s, 1H), 10.55 (s, 1H); Mass spectrum MJT 369.
Example 80
2-Hydroxy-N-{[(4-{[3-imthyl(lthia2olylmethoxy)phenyl]amiiM)}qul
yl)oxy]ethyl}acetamide
The procedure described in Example 3 was repeated using 4-(chlorornethyll,3-
miazole and 2-hydroxy-N-[2-({4-[(4-hydroxy-3-memylphenyl)amino]quinazolin-5-
yl}oxy)ethyl]acetamide (obtained as described in Example 79, preparation of starting
materials) to give the title compound as a yellow solid in 21% yield; NMR spectrum QDMSOd6)
2.20 (s, 3H), 3.71 (q, 2H), 3.77 (d, 2H), 4.38 (t, 2H), 5.23 (s, 2H), 5.49 (t, IH), 7.08 (d,
IH), 7.J3 (d, IH), 7.32 (d, IH), 7.44 (d, IH), 7.57 (dd, IH), 7.69 (t, IH), 7.77 (d, IH), 8.17 (t,
IH), 8.42 (s, IH), 9.14 (d, IH), 9.77 (s, IH); Mass spectrum MlT 466.
Example 81
Af-{2-[(4-{[3hkro(pyridiD-2-ylmethoxy)phenyl]ainino}quinazolin-5-yI)oxy]-l,l"
dimethylethyI}-2-hydroxyacetainkie
The procedure described in Example 3 was repealed using 2-(chloromethyl)pyridine
and 2ydroxy2{4-[(4ydroxy3-riirylphenyloJ qninazo]ro-5-yl}oxy)-Udiniethyletfay]]
acetaniide to give the title compound as a white solid in 16% yield; NMR
spectrum (DMSO16) 1.46 (s, 6H), 3.72 (d, 2BX 4.42 (s, 2H), 5.27 (s, 2H), 534 (t, IH), 7.16
(d, IH), 7.24 (d, IH), 737 (m, 2H), 7.50 (m, 2H), 738 (d, IH), 7.73 (t, IH), 7.87 (td, IH),
8.06 (d, IH), 8.50 (s, IH), 8.59 (d, IH), 9.83 (s, IH); Mass spectrum MH+ 508.
The 2-hydroxy-JV-[2{4-[(4-hydroxy-3-roethyhnyl)amino]quinazolin-5-yl }oxy-
l,l-dimethylethyl]acetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using 2-amino-2-methylpropan-l-ol and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol
(obtained as described in Example 3, preparation of starting materials) to give 4-{ [5-(2-
arruno-2-methylpropoxy)quinazoun-4-yl]arnino}-2-methylphenol as a white solid in 78%
yield; NMR spectrum (DMSO-d6) 1.34 (s, 6H), 4.23 (s, 2H), 6.97 (d, IH), 7.18 (d, IH), 7.35
(d, IH), 7.52 (dd, IH), 7.73 (t, IH), 7.96 (d, IH), 8.46 (s, IH), 10.50 (s, IH); Mass spectrum
MH+360.
The procedure described in Example 3 (preparation of starting materials) was repeated
using glycolic acid and 4-{[5-(2-amino-2-methylpropoxy)quinazoHn-4-yl]amino}-2-
methylphenol to give 2-hydroxy-N-[2-({4-[(4-hydroxy-3-memylphenyl) amino]quinazolin-5-
yl)oxy,l-dimethylethyl]acetamide as a light brown solid in 53% yield; NMR spectrum
(DMSO-d6) 1.47 (s, 6H), 3.69 (d, 2H), 4.47 (s, 2H), 7.04 (d, 1H), 7.38 (m, 3H), 7.78 (d, 1H),
7.% (t, 1H), 8.18 (t, 1H), 8.80 (s, 1H), 10.40 (s, 1H), 10.67 (s, 1HV. Mass spectrum MH 417.
Example 82
2-Hydroxy-A-{(2K)-2-[(4-{[3-methyI-4-(pyridin-2-yImethoxy)phenyl]ainiiio}quinazolin-
5-yDoxy]propyl}acetamide
The procedure described in Example 3 was repeated using 2-(chlorcanediyl)pyridine
and 2-hydroxy-N-[(2)-2-((4-[(4-hydroxy-3-methyrphenyi) arnino)qumazolin-5-
yloxy)propyl]cetaimde to give the tide compound at a white solid in 29% yield; MMR
spectrum (DMSOd6) 1.40 (d, 3HX 2.27 (s. 3HX 3.43 (dt, 1H), 3.72 (dt. 1H), 3.80 (4 2HX
4.94 (m. 1H), 5.20 (s, 2H), 5.46 (t, 1H), 7.00 (d, 1H), 7.21 (d, 1H), 7.30 (d, 1HX 734 (dd,
1H), 7.56 (m, 3HX 7.68 (U1HX 7.85 (td, IHX 8.16 (t, 1HX 8-43 (s, IB), 8.58 (d, 1H), 9.94 (s,
1H); Mass spectrum MH** 474.
Tie2-hydxy--[(2l2K{4-[(4-hydoxy-3nethylrAenyl)arnino]qlrin
yl}oxy)propyl]acetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using (/0-(-l-anrino-propan-2-ol and 4-[(5-fluoroquinazolin^yl)arnino]-2-rnethylphenol
(obtained as described in Example 3, preparation of starting materials) to give 4-({5-[(LR)-2-
amino-l-methylethoxy]quinazolin-4-yl}amino)-2-mcthylphenol as a brown solid in 65%
yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.16 (s, 3H), 2,96 (m, 2H), 3.30 (s, 2H), 4.96
(m, 1H), 6.77 (d, 1H), 7.14 (d, 1H), 7.25 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 7.67 (t, 1H),
8.39 (s, 1H), 9.16 (s, 1H), 10.50 (s, 1H: Mass spectrum MH" 325.
The procedure described in Example 3 (preparation of starting materials) was repeated
using glycolic acid and4{5-[(l/0-2-armno-l-rnethytemoxy]qutnazoUnyl}amino2-
methylphenol to give 2-hydroxy-JV-[(2R)-2-({4-[(4-hydroxy-3-
methylphenyl)ainino]quinazohn-5-yl}oxy)propyl]acetamide as a dark brown solid in 59%
yield; NMR spectrum (DMSQ-d6) 1.41 (d, 3H), 2.17 (s, 3H), 3.43 (dt, 1H), 3.75 (dt, 1H),
3.78 (s, 2H), 5.01 (m, 1H), 6.84 (d, 1H), 7.30 (d, 1H), 7.32 (dd, 1H), 7.39 (d, 1H), 7.46 (d,
1H), 7.95 (t, 1H), 8.22 (t, 1H), 8.75 (s, 1H), 9.54 (d, 1H), 10.78 (s, 1H); Mass spectrum MH
383.
Example 83
2-Hydroxy-N-{(2fi)-2-[(4-{[3-metbyl-4-(lr3-thiazol-4-ylmethoxy)phenyl]amino}
quinazolin-5-yI)oxy)prxpyl}acetainide
The procedure described in Example 3 was repeated using 4-(chloromethyl13-
thiazote and 24draxy-(2f2{4-[(4-hydroxy qirinazoKn-5-
yloxy)propyf)acctamide (obtained as described in Example 82, preparation of starting
materials) to give the title compound as a white solid in 13% yield;
d6) 139 (d, 3H), 2.21 (s, 3H), 3.42 (dt, 1H), 3.71 (dt, 1H), 3.79 (d, 2H), 4.95 (m, 1H), 5.24 (s,
2H), 5.48 (t, 1H), 7.09 (d, 1H), 7.23 (d, 1H), 729 (d, 1H), 7.54 (d, 1H), 7.62 (dd, 1H), 7.68 (t,
1H), 7.77 (d, 1H), 8.16 (t, 1H), 8.44 (s, 1H), 9.14 (d, 1H), 9.95 (s, 1H); Mass spectrum MH
480.
Example 84
Af(2)-2-{[4-({4-[(3-Fluorobenzyl)oxy]-3-methylphenyl}ainino)quinazolin-5-
yi]oxy}propyl)2hydroxyacetamkle
The procedure described in Example 3 was repeated using l-(chloromethyl3-
fluorobenzene and 2-hydroxy-A-[(2)-2-({4-[(4-hydroxy-3-rnethylphenyl)amino] quinazolin-
5-yl}oxy)propyl]acetamide (obtained as described in Example 82, preparation of starting
materials) to give the title compound as a light yellow solid in 25% yield; NMR spectrum
(DMSO-d6) 139 (d, 3H), 2.25 (s, 3H), 3.42 (dt, IH), 3.72 (dt, IH), 3.81 (d, 2H), 4.94 (m,
IH), 5.17 (s, 2H), 5.47 (t, IH), 6.99 (d, IH), 7.16 (td, IH), 7.22 (d, IH), 7.30 (m, 3H), 7.43
(m, IH), 7.56 (d, IH), 7.61 (dd, IH), 7.68 (t, IH), 8.16 (t, IH), 8.43 (s, IH), 9.94 (s, IH);
Mass spectrum MH 491.
Example 85
2-Hydroxy-N-{(2)-2-[(4-{[3-inethyl(13-thiazol-2-ylimth)xy)phenyl]amino}
quinazolin-5-yl)oxy]propyl}acetaniide
The procedure described in Example 3 was repeated using 2-(chloromcthyl)-13-
thiazole and 2ydroxy- [(2K}-2"{4-[(4 quinazolin-5-
yl}oxy)ptopyi)acetaimde (obtained as described in Example 82, preparation of starting
materials) to give flic title compound as a light brown solid in 31% yield; NMBjg^ttym
(DMSO-d6) 139 (d, 3H), 2.25 (s, 3H), 3.42 (dt, IH), 3.73 (m, IH), 3.79 (d, 2H), 4.94 (m,
IH), 5.44 (s, 2H), 5.47 (t, IH), 7.09 (d, IH), 7.23 (d, IH), 730 (d, IH), 7.58 (d, IH), 7.63 (dd,
IH), 7.69 (t, IH), 7.77 (d, IH), 7.84 (d, IH), 8.16 (t, IH), 8.43 (s, IH), 9.96 (s, IH); Mass
spectrum MH 480.
Example 86
{(22-[(
yl)oxy]propyl}acetandde
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine
and AK(2/?)-2-({4-[(4-hydroxy-3-methylphenyl)aminoJ quinazolin-5-
yl oxy)propyl]acetamide to give the title compound as a white solid in 43% yield; NMR
spectrum (DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.27 (s, 3H), 3.41 (dt, IH), 3.58 (dt, IH),
4.87 (m, IH), 5.20 (s, 2H), 7.01 (d, IH), 7.22 (d, IH), 7.29 (d, IH), 7.35 (dd, IH), 7.55 (m,
2H), 7.58 (dd, IH), 7.69 (t, IH), 7.85 (td, IH), 8.23 (t, IH), 8.45 (s, IH), 8.58 (d, IH), 9.97 (s,
IH); Mass spectrum NOT 458.
The-[(2R-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazoIin-5-
yloxy)propyl]acetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using acetic acid and 4-({5-[(l)-2-amino-l-methylethoxy]quinazolin-4-yl}amino)-2-
methylphenol (obtained as described in Example 82, preparation of starting materials) to give
Af-[(2{4-[(4ydroxy-3-niethylphenyl)amino] quinazolin-5-yl)oxy)propyI]acetamide as
a ginger solid in 90% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.76 (s, 3H), 2.17 (g,
3H), 3.41 (d^ IHX 3.62 (dt, IH), 4.96 (m, IH), 6.85 (d, IH), 731 (d, IH), 7.36 (m, 2H), 7.49
(d, IH), 7.96 (t, IH), 8.24 (t, IH), 8.77 (s, IH), 9.57 (s, IH), 10.77 (s, IH); Mass spectrum
MH+367.
Examples?
2-[(4-{[3-Methyllthiarolylnt
yl)oxy]propyl}acetaniide
N
The procedure described in Example 3 was repeated using 4-(chloromethyl)-l,3-
thiazole and -[(2)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-
yl }oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting
materials) to give the title compound as a white solid in 20% yield; NMR spectrum (DMSOd6)
1.41 (d, 3H), 1.78 (s, 3H), 2.23 (s, 3H), 3.41 (dt, IH), 3.58 (dt, IH), 4.87 (m, IH), 5.25 (s,
2H), 7.H (d, 1H), 7.21 (d, IH), 7.29 (d, IH), 7.53 (d, IH), 7.63 (dd, IH), 7.69 (t, IH), 7.76 (d,
IH), 8.23 (t, IH), 8.44 (s, IH), 9.14 (d, IH), 9.% (s, IH); Mass spectrum MH 464.
Example 88
Af-((2V2-{[4-{4-[(3-Fhiorobenzyl)oxy]-3-methylphenyl}amino)quinazolin-5-
yl]oxy}propyl)acetamide
The procedure described in Example 3 was repeated using l-(chloromethyl)-3-
fluocobenzene and N-[(2JO-2K{4-[(4-hydroxy-3-inetbyhph
yl}oxy)ptopyacetatmde (obtained at described m Example 86t preparation of starting
tnatmrirt to give the tide compounds white solid in 46% viekL NMR spectrum
d6) 1.41 (d, 3HX 1.77 (s, 3H), 236 (s, 3H), 3.41 (dt, IHX 3.58 (dt. IHX 4.86 (m, IH), 5.18 (s,
2H), 7.01 (d, IH), 7.16 (Id, IHX 7.22 (d, IHX 730 (m, 3HX 7.42 (m, IHX 754 (d, IHX 7.62
(dd, IH), 7.68 (t, IH), 8.22 (t, IH), 8.43 (s, IH), 9.95 (s, IH); Mass spectrum MH* 475.
Example 89
AH(2£V2(4-{[3-MethyIwHltfaiaz
yl)oxy]propyl}acetainide
The procedure described in Example 3 was repeated using 2-(chloromethyl)-l,3-
thiazole and V-[(2R)-2-{4-[(4-hydroxy-3-memylphenyl)amino]quinazolin-5-
yl}oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting
materials) to give the title compound as a fight brown solid in 25% yield;
(DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.25 (s, 3H), 3.42 (dt, IH), 3.60 (dt, IH), 4.88 (m,
IH), 5.45 (s, 2H), 7.11 (d, IH), 7.22 (d, IH), 7.31 (d, IH), 7.56 (d, IH), 7.63 (dd, IH), 7.68 (t,
IH), 7.76 (d, IH), 7.83 (d, IH), 8.23 (t, IH), 8.43 (s, IH), 9.97 (s, IH); Mass spectrum MIT
464.
Example 90
2-Hydroxy-N-methyl-A-{(2)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyI]
amino}quinazoKn-5-yl)oxy]propyl}acetamide
The procedure described in Example 3 was repealed using 2-(chloromethyl)pyridine
and 2-hiroxy--[(2)-2-({4-[(4-hydToxy-3-roethylphenyI) amhx]quinazolin-5-
yl )oxy)prDpyi]-^methylacetamide to give the title compound as a light yellow solid in 17%
yield; NMR spectrum (DMSCM6 373K) 1.43 (d, 3H), 2.29 (s, 3H), 2^7 (s, 3H), 3.58 (m,
IH), 4.08 (m, 3H), 5.11 (m, IH), 5.19 (s, 2H), 7.01 (d, IH), 7.21 (d, IH), 732 (m, 2H), 7.57
(m, 3H), 7.67 (t, IH), 8.83 (td, IH), 8.41 (s, IH), 8.57 (d, IH), 9.81 (s, IH); Mass spectrum
MH488.
The2-hydroxy-7V-[(2)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-
yl}oxy)propyl]-methylacetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using (2)-l-[allyl(methyl)amino]propan-2-oI (obtained as described in Example 2.3,
preparation of starting materials) and 4-[(5-fluoroquinazolin-4-yl) amino]-2-methylphenol
(obtained as described in Example 3, preparation of starting materials) to give 4-[(5-{ (l/?)-2-
[allyl(rnethyl)amino]-l-methylethoxy}quinazoIin-4-yl)amino]-2-methylphenol as a brown oil
in 86% yield; NMR spectrum (DMSO-d6) 1.43 (d, 3H), 2.15 (s, 3H), 2.18 (s, 3H), 2.54 (dd,
IH), 2.88 (dd, IH), 3.00 (m, 2H), 4.92 (m, IH), 5.01 (d, IH), 5.11 (d, IH), 5.62 (m, IH), 6.77
(d, IH), 7.16 (d, IH), 7.26 (d, IH), 7.35 (s, IH), 7.38 (d, IH), 7.66 (t, IH), 8.37 (s, IH), 9.17
fs, IH), 10.16 (s. IH): Mass spectrum MH 379.
The procedure described in Example 2.3 (preparation of starting materials) was
repeated using chlorotris(triphenylphosphine)rhodium 00 and 4-[(5-{(l)-2-
[a)lyl(methyl)amino]-l-methylethoxy}quinazolin-4-yl)amino]-2-methylphenol to give 2-
methyl({5-[(l/fl-methyl-2Kniethylamino)ethoxy]quinazolin-4-yl}ainino)-phenol as a
brown foam in 56% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 2.15 (s, 3H), 2.33 (s,
3H), 2.87 (m, 2H), 4.85 (m, IH), 6.77 (d, IH), 7.14 (d, IH), 7.25 (d, IH), 7.43 (s, IH), 7.46
(d, IH), 7.64 (t, IH), 8.38 (s, IH), 9.14 (s, IH), 10.35 (s, IH); Mass spectrum MH 339.
The procedure described in Example 3 (preparation of starting materials) was repeated
using glycolic acid and 2-mediyl-4-({5-[(l/l-meftyl-2-(methylamino) ethoxy]quinazolin-4-
yl}anrino)phenol to give 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-
methylphenyl)amino]quinazolin-5-yl}oxy)propyI]-N-methylacetarnide as an orange solid in
81% yield; NMR spectrum (DMSO-d6) 138 (d, 3H), 2.15 (s, 3H), 2.96 (s, 3H), 3.35 (dd, IH),
4.02 (s, 2H), 4.21 (m, 2H), 5.18 (m, IH), 6.83 (d, IH), 7.27 (m, IH), 7.38 (s, IH), 7.46 (d,
IH), 7.92 (t, IH), 8.70 (s, IH), 9.52 (s, IH), 10.68 (s, IH): Mass spectrum MH* 397.
Example 91
The procedure described in Example 3 was repeated using 4-(chloromethyll,3-
thiazole and 2-hydroxy-W-[(2)-2-({4-[(4-hydroxy-3-methylphenyl)arnino] quinazolin-5-
yl}oxy)propyl]-Af-methylacetarnide (obtained as described in Example 90, preparation of
starting materials) to give the title compound as a white solid in 41% yield; NMR spectrum
(DMSO-d6 373K) 1.43 (d, 3H), 2.24 (s, 3H), 2.97 (s, 3H), 3.57 (m, IH), 4.07 (m, 3H), 5.13
(m, IH), 5.25 (s, 2H), 7.09 (d, IH), 7.11 (d, IH), 7.34 (d, IH), 7.57 (m, 2H), 7.69 (m, 2H), 494.
Example 92
2-Hydroxy-A-methyl-Ar-((2R)-2-{[4-({3-methyI-4-[(5-methylisoxa2oI-3-
y))methoxy]plieny)}ainino)quinazoJin-5-yl]oxy}propyI)acetamide
The procedure described in Example 3 was repeated using 3-(chloromethyl}-5-
methylisoxazole and 2-hydroxy-A?-[(2)-2{4-[(4-hydroxy-3-methylphenyl)amino]
quinazolin-5-yl}oxy)propyl]-N-mediylacetaraide (obtained as described in Example 90,
preparation of starting materials) to give the title compound as a white solid in 7% yield;
NMR spectrum (DMSCM6 373K) 1.44 (d, 3H), 2.22 (s, 3H), 2.42 (s, 3H), 2.98 (s, 3H), 3.58
(m, IH), 4.17 (m, 3HX 5.11 (m, IH), 5.15 (s, 2HX 629 (s, IH), 7.07 (d, IH), 7.11 (d, IH),
733 (d, IH), 7SJ (m, 2H), 7.69 (t, IH), 8.44 (s, 1HX 9.83 (s, IH); Mass spectrum MH492.
Example 93
amino}quinazolin-5-yl)oxy]etbyl}acetainide
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine
andJV-[(l/?)-2-({4-[(4-hydroxy-3-nwthylphenyI)arnino]quinazoh"n-5-yl}oxy)-l-methylethyl]-
TV-methylacetamide to give the title compound as a tight beige solid in 43% yield; NMR
spectrum (DMSO-d6 373K) 1.21 (d, 3H), 1.85 (s, 3H), 2.27 (s, 3H), 2.84 (s, 3H), 4.34 (m,
IH), 4.40 (t, IH), 5.07 (m, IH), 5.20 (s, 2H), 7.01 (d, IH), 7.17 (d, IH), 7.33 (m, 2H), 7.42 (d,
IH), 7.47 (dd, IH), 7.55 (d, IH), 7.67 (t, IH), 7.82 (td, IH), 8.41 (s, IH), 8.57 (d, IH), 9.50
(s, IH); Mass spectrum MH472.
The/V-[(l/?)-2-({4-[(4-hydroxy-3-methylphenyl)ainino]quinazolin-5-yl}oxy)-lmethylethyl]-
W-rnethylacetamide used as starting material was prepared as follows:
The procedure described in Example 3 (preparation of starting materials) was repeated
using (2tf)-2-(:nrethylammo)propan-l-ol (obtained as described in Becker et al., J. Chem. Soc.
1957, 858) and 4-[(5-fluoroqiMna2oHn-4-yl)amino]-2-methylphenol (obtained as described hi
Example 3, preparation of starting materials) to give 2-methyl-4-[(5-{ [(2K)-2-
(methy]ammo)propyl]oxy }quinazoKn-4-yl)amino]phenol as a brown solid in 80% yield;
NMR spectrum (DMSO-d6) 1.16 (d, 3H), 2.14 (s, 3H), 2.34 (s, 3H), 3.04 (m, IH), 3.24 (bs,
IH), 4.08 (dd, IH), 4.25 (dd, IH), 6.76 (d, IH), 7.06 (d, IH), 7.26 (d, IH), 7.47 (d, IH), 7.53
(dd, IH), 7.65 (t, IH), 8.39 (s, IH), 9.17 (s, IH), 10.37 (s, IH); Mass spectrum MH 339.
To a mixture of triethylamine (420 |il) and 2-methyl-4-[(5-{[(2-2-
(methylamino)propyl)oxy }qoinazc4in-4-yl)amino]phenol (450 mg) in DCM (5 ml) was added
acetyi chloride (190 jil). The reaction was stirred for 30 minutes and then quenched with
water and extracted with DCM (x2 The residue was dissolved in 7N MeOH/NH3 and stirred
at loom temperature for 30 infantes. Solvent was removed mwcuo and water was added. The
mixture was extracted with DCM (x2), filtered and men
methylacetamide as a pink foam (365 mg, 72%); NMR spectrum (DMSO-d6 373K) 1.41 (d,
3H), 1.86 (s, 3H), 2.17 (s, 3H), 2.83 (s, 3H), 4.36 (m, 2H), 5.04 (m, IH), 6.77 (d, IH), 7.16 (d,
IH), 7.29 (m, 3H), 7.67 (t, IH), 838 (s, IH), 8.78 (s, IH), 9.43 (s, IH): Mass spectrum MH
381.
Example 94
N-Methyt-]V.{(ll.methyl.2-[(4.{[3-methyl.4.(l,3-thiazol.4-
ylmethoxy)phenyllamino}quinazoHn-5-yl)oxy]ethyl}acetamlde
The procedure described in Example 3 was repeated using 4-(chloromethyl13-
thiazole and N-[(LR-2K{4-[(4-hydroxy-3-memylphenyl)aniino]quinazolin-5-yl}oxy)-lmethylethyl]-
Af-methylacetamide (obtained as described in Example 93, preparation of
starting materials) to give the title compound as a white solid in 13% yield; NMR spectrum
(DMSO-d6 373K) 1.22 (d, 3H), 1.86 (s, 3H), 2.24 (s, 3H), 2.85 (s, 3H), 4.33 (m, IH), 4.42 (t,
IH), 5.09 (m, IH), 5.25 (s, 2H), 7.09 (d, IH), 7.18 (d, IH), 7.34 (d, IH), 7.39 (s, IH), 7.50 (d,
IH), 7.70 (m, 2H), 8.41 (s, IH), 9.08 (s, IH), 9.51 (s, IH); Mass spectrum MH 478.
Example 95
N-{(l)-2-[(4-{[3-ChJoro(lthia2olyImethoxy)phenyl]amino}quinazolin-5-yl)oxy]-
l-methylethy)}-2-hydroxy-AT.meihylacetamide
-S
The procedure described in Example 3 was repeated using4-(cbloromethyl)-13-
tbiazote and A4(l2{4(3-cMoro-4
nKthytethyI]-2ydfoxyTynethy)acetainide (obtained as described in Example 54,
preparation of starting materials) to give the title compound as a white solid in 64% yield;
NMR spectrum (DMSCM6 373K) 1.25 (d, 3H), 2.83 (s, 3H), 3.98 (s, 2H), 4.34 (m, IH), 4.47
(t, IH), 4.98 (m, IH), 5.34 (s, 2H), 7.19 (d, IH), 7.37 (d, 2H), 7.51 (dd, IH), 7.70 (t, IH), 7.74
(d, IH), 7.93 (d, IH), 8.46 (s, IH), 9.08 (s, IH), 9.57 (s, IH); Mass spectrum MH+ 514.
Example 96
ybnetboxy)phenyl]amino}quinazolin-5-yI)oxy]ethy]}acetainide
The procedure described in Example 3 was repeated using 2-(chIoromethyl)pyridine
2-h) droxy -N- [(lK)-2({ K(4-hydroxy-3-methylphenyl) amino]quinazolin-5-yl}oxy)-lmethylethyl]-
JV-methylacetamide to give the title compound as a white solid in 15% yield;
NMR spectrum (DMSO-d6 373K) 1.25 (d, 3H), 2.28 (s, 3H), 2.83 (s, 3H), 3.96 (s, 2H), 4.35
(ro, IH), 4.46 (t, IH), 4.97 (m, 1H), 5.19 (s, 2H), 7.01 (d, 1H), 7.18 (d, 2H), 7.33 (m, 2H),
7.44 (m, 1H), 7.56 (d, IH), 7.68 (t, 1H), 7.83 (td, 1H), 8.40 (s, IH), 8.58 (d, 1H), 9.48 (s, 1H);
Mass spectrum MH 488.
The2-hydroxy-[(l/0-2{4-[(4ydroxy-3-methylphenyl)amino]quinazolin-5-
yl}oxyl-methylethyl]-N-methylacetanude used as starting material was prepared as follows:
The procedure described in Example 94 (preparation of starting materials) was
repeated using acetoxyacetyl chloride and 2-methyl-4-[(5-{ [(2/0-2-
(methylamino)propyl]oxy }quinazolin-4-yl)aniino]phenol (obtained as described in Example
93, preparation of starting materials) to give 2-hydroxy-N-[(17)-2-({4-[(4-hydroxy-3- ,
memylphenyl)ainrao]quiiiazoliiH5-y as an orange
foam in 75% yield; NMR spectrum (DMSOd6 373K) 1.25 (d, 3H)y 2.17 (s, 3H), 2.83 (s, 3H),
3.97 (s, 2H), 433 (dd, 1H), 4.45 (t, 1HX 4.95 (m, IH), 6.77 (d, IH), 7.17 (d, 1H), 7.30 (m,
3H), 7.(7 (t, 1H), 8.37 (s, 1H), 8.79 (s, 1HX 9.43 (s, 1H); Massspeclmm
Example 97
The procedure described in Example 3 was repeated using 4-(chloromethyl)-l,3-
thiazole and 24iydtoxy-N-[(l-2K{4-[(4-hydroxy-3-methylphenyl)amino] quinazolin-5-
yl}oxy)-l-methylethyl]-JV-metiiylacetamide (obtained as described in Example 96,
preparation of starting materials) to give the title compound as a foam in 29% yield; NMR
spectrum (DMSO-d6 373K) 1.26 (d, 3H), 2.24 (s, 3H), 2.83 (s, 3H), 3.97 (s, 2H), 4.35 (m,
1H), 4.46 (t, 1H), 4.95 (m, IH), 5.24 (s, 2H), 7.08 (d, 1H), 7.18 (d, 2H), 7.35 (d, 1H), 7.42 ;(s,
1H), 7.46 (d, IH), 7.70 (m, IH), 8.41 (s, IH), 9.07 (s, IH), 9.50 (s, im: Mass spectrum MH"
494.
Example 98
N-{(2)-2-[(4-{[3-Chloro-4-(pyridin-2-yImethoxy)phenyl]aniino}quiDazolin-5-
yl)oxy]pit»pyl}-l-faydroxyWV-inethyIcycIopropanecarboxamide
The procedure described in Example 1 was repeated using hydroxy-1-cyclopropane
carboxylic acid andN-[3horo-4-(pyridin-2-ylmedioxy) phenyl]-5-[(LR)-l-methyl-2-
(methylairrino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation
of starting materials) to give the title compound as a foam in 19% yield: NMR spectrum
(DMSO-d6) 0.70 (s, 4H), 1.40 (d, 3H), 323 (s, 3H), 336 (m, 1H), 4.19 (m, 1H), 5.15 (m,
1H), 5.29 (s, 2H), 6.20 (s, 1H), 724 On, 2HX. 735 (m, 2H), 7.58 (m, 2H), 7.71 (t, 1H), 7.87
(dt, 1H), 8.09 (d, 1H), 8.44 (s, 1HX 8^8 (d, 1H), 9.86 (s, 1H): Mass spectrum MFT 534.
yl)oxy)propyI}-2-hydroxy-ArHi)etfaytpropaiuunkie
The procedure described hi Example 1 was repeated using L-(+)-]actic acid and N-[3-
chloiX)yridin-2-ylmethoxy)phenyl]-5(l)-l-methyl-2metliylainino)ethoxy]qm
4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the
tide compound as a white solid in 35% yield; NMR spectrum (DMSO-d6 373K) 1.07 (d, 3H),
1.45 (d, 3H), 2.98 (s, 3H), 3.22 (m, 1H), 4.19 (m, 1H), 4.43 (m, 1H), 5.15 (m, 1H), 5.27 (s,
2H), 7.22 (m, 2H), 735 (m, 2H), 7.59 (m, 2H), 7.69 (t, 1H), 7.84 (dt, 1H), 8.08.(d, 1H), 8.47
(s, 1H), 8.58 (d, 1H), 9.93 (s, 1H); Mass spectrum MH 522.
Example 100
The procedure described in Example 1 was repeated using 2-hydroxy-tso-butyric acid
(methylamino)ethoxy]qainazolin-4-anune (obtained as described in Example 2.3, preparation
of starting materials) to give the tide compound as a white solid in 28% yield; NMR spectrum
(DMSO46 373K) 1.25 (s, 3HX 1.27 (s, 3HX 1.43 (d, 3HX 3.26 (s, 3H), 3.54 (m, 1HX 4.16
(dd, IH), 5.16 (m, IH), 5.28 (s, 2H), 7.23 (m, 2HX 734 (m, 2H), 7 5B (m, 21$, 7.69 (t, 1H),
7.83 (dt, 1H), 8.07 (d, 1H), 8.46 (s, IH), 8.58 (d, 1H), 9.88 (s 1H, Mass spectrum MlT 536.
Example 101
The procedure described in Example 1 was repeated using D-(-lactic acid and N-[3nethylarr
4-amine (obtained as described in Example 23, preparation of starting materials) to give the
title compound as a white solid in 26% yield; NiyiR spectni (DMSO-d6 373K) 1.15 (d, 3H),
1.44 (d, 3H), 2.97 (s, 3H), 3.16 (m, 1H), 4.05 (dd, 1H), 4.43 (m, 1H), 5.16 (m, 1H), 5.27 (s
2H), 7.23 (m, 2H), 7.35 (m, 2H), 7.59 (m, 2H), 7.70 (t, IH), 7.84 (dt, 1H), 8.09 (d, 1H), 8.47
(s, IH), 8.59 (d, IH), 9.90 (s, IH); Mass spectrum MH 522.
Example 102
(2)-A-{(2-2-[(4-{[3-ChJoro-4-(pyridin-2-ylmethoxy)phenyl]amJno}quinazolin-5-
yl)oxy]propy]}-2-inetboxy-Ar-methyIpropanarnide
The procedure described in Example 1 was repeated using (K)-(+)-2-
methoxypropionic acid and JV-[3x;hloro-4-(pyridin-2-ylmemoxy)phenyl]-5-[(l/Z)-l-methyl-2-
(methylarnino)ethoxy]quina2olin-4-arnine (obtained as described in Example 23, preparation
of starting materials) to give die title compound as a brown gum in 44% yield; NMR spectrum
(DMSOd6 373K) 1.11 (d, 3H), 1.37 (d, 3H), 2.97 (s, 3H), 3.09 (s, 3H), 3.38 (m, IH), 4.17 (q,
IH), 4.26 (dd, IH), 5.16 (m, IH), 5.28 (s, 2H), 7.24 (m, 2H), 7.33 (d, IH), 7.37 (dd, IH), 736
(d, IH), 7.64 (dd, IH), 7.69 (t, IH), 7.86 (dt, IH), 8.13 (d, IH), 8.44 (s, IH), 859 (d, IH),
9.89 (s, IH); Mass spectrum MH" 536.
Example 103
2-Hydroxy-N-methyl-Ar.((2)-2-{[4-({3.methyl[(6-roe4hylpyridin-3-
yI)oxy]phenyI}amino)quiiiazoUn-5-yl]oxy}propyl)acetamide
The procedure described in Example 1 was repeated using glycolic acid and 5-[(l)-lrnemyl-
2-(memylamino)ethoxy]-{3-methyl[(6-methylpyridin-3-yl)oxy]
phenyl}quinazolin-4-amine to give the title compound in 86% yield; NMR spectrum (CDCH)
1.55 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.96 (s, 3H), 3.59 (dd, IH), 4.16-4.07 (m, 3H), 5.08
(m, IH), 6.92 (d, IH), 7.02 (d, IH), 7.09 (d, IH), 7.14 (d, IH), 7.50 (m, 2H), 7.65 (in, 2H),
8.28 (s, IH), 8.61 (s, IH), 9.87 (s IH); Mass spectrum: MH 488.
The5-[(1/J)-l-inethyl-2-(methylamino)ethoxy]-N-{3-inethyI-4-[(6-methylpyridin-3-
yl)oxy}phenyl }quinazolin-4-amine used as starting material was prepared as follows:
Sodium hydride (25.6 g, 60% dispersion in oil, 0.64 mol) was added portion wise to a
solution of 5-hydroxy-2-methylpyridine (70 g, 0.64 mol) in DMA (700 ml) while beeping the
temperature below 40°C. At the end of the addition, the mixture was stirred at room
temperature for 1 hour and 2-fluoro-5-mtrotoruene (91.3 g, 0.59 mol) in DMA (100 ml) was
added slowly. The mixture was stirred at 80°C for 3 hours and then cooled. The solvents were
evaporated under vacuum and the residue was partitioned between ethyl acetate and water.
The organic layer was washed with water and brine, dried over MgSO. After evaporation of
the solvents, the residue was purified by chromatography on silica gel (eluant 30% ethyl
acetate in petroleum ether) to give 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridinc (141 g,
98%) as an oil; NMR spectrum (CDCfe); 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d, 1H),
7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 832 (s, 1H).
A mixture of 2-ineAyl-5iriethvl-4Hiitn)phenoxy)pyridirie (141 g, 0.58 mol) and
10% palladium on charcoal (13 g) in ethyl acetate (200 ml) ethanol (700 ml) was stirred
under an atmosphere of hydrogen (1.2 bar) for 5 homes. After jeaction completion, the mixture
was purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to
dryness to give 3-njemyl[(6-rnethylpyridin-3-yl)oxy]amlirie (120.6 g 98%) as a white
solid; Muss spectrum MH*" 215.
3-Methyl-4-[(6-methyrpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4N hydrogen
chloride in dioxane (7.55 ml, 30 mmol) were added to a suspension of 4-chloro-5-
fluoroqumazoline (5 g, 27.5 mmol; obtained as described in PCT Int Appl. WO2001094341,
AstraZeneca) in acetonitrile (100 ml). The mixture was stirred at 80°C for 2 hours. After
cooling, the precipitate was washed with acetonitrile. This precipitate was partitioned between
DCM and 5% aqueous sodium bicarbonate and the pH was adjusted to 8. The organic layer
was washed with brine and dried over MgSO. Evaporation of the solvents gave 5-fluoro-W-
{3-memyW-[(6-memylpyridm-3-yl)oxy]phenyl}qumazolm-4-arnine (9.3 g, 94%) as a dark
gum which crystallised on standing; NMR spectrum (CDC13); 2.30 (s, 3H), 2.54 (s, 3H), 6.93
(d, 1H), 7.15-7.08 (m, 2H), 7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s,
1H), 8.37 (d, 1H), 8.71 (s, 1H).
Sodium hydride (960 rhg, 60% dispersion in oil, 20 mmol) was added portion wise to
an ice-cooled solution of (2 -[allyl(methyl)amino]propan-2-ol (3.87 g, 30 mmol, obtained
as described in Example 23, preparation of starting materials) and 5-fluoro-/V-{3-methyl-4-
[(6-rnethylpyridin-3-yl)oxy]phenyl}quina2»lin-4-aniinc (3.6 g, 10 mmol) in THF (25 ml). The
mixture was heated at 65°C for 24 hours. After cooling, the solvents were evaporated under
vacuum. The mixture was diluted with DCM, and washed with water and brine. The organic
layer was dried over MgSO4. After evaporation of the solvents, the residue was purified by
chrornatography on silica gel (eluant: 2 to 4% methanol in DCM) to give 5-{(lJ?)-2-
[allyl(mehyl)amino]-l-methylethoxy}-{3-methyl-4-[(6-methylpyridin-3- 470.
A mixture of 5-{(l2-[aUyl(methyl)amino]-l-methyleraoxy}-Ar-{3-memyl-4-[(6-
methylpyridin-3-yl)oxy]phenyl}quinazolin-4-aniine (2.25 g, 4.8 mmol) and
chlorotris(triphenylphospnine)rhodium(I) (463 mg, 0.48 ml) in acetonitrile - water (17 ml : 3
ml) was heated at reflux for 3 hours. After cooling, the solvents were evaporated under
vacuum. The residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol
in DCM) to give 5-[(U -mediyl-2-(inethyfamino)cthoxy] -AT-{3-mcthyl-4-[(6-
methyh?yridm-3-y])oxy]phenyl} quraazoiro-4-amine (1,70 g. 83 %); Mass spectrum: MET
E mple 104
Acetyl chloride (24 uj, 0.33 mmol) was added drop wise to a solution of 5-[(lJ?)-lmethyl-
2-(methylamino)ethoxy]-{3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}quinazolin-4-amine (129 mg, 030 mmol, obtained as described in Example
103, preparation of starting materials) and DIPEA (105 ul, 0.6 mmol) in DCM (5 ml). The
mixture was stirred at room temperature for 2 hours and diluted with DCM. The solution wa
washed with water and brine, and dried over MgSO. After evaporation of the solvents, the
residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to
give the tide compound (84 mg, 60%) as a pale solid; NMR spectrum (CDC13) 1.55 (d, 3H),
2.08 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 3.08 (s, 3H), 3.56 (dd, 1H), 3.93 (dd, 1H), 5.09 (m,
1H)> 6.92 (d, 1H), 7.12 (m, 3H), 7.50 (m, 2H), 7.65 (m, 1H), 7.70 (s, 1H), 8.27 (s, 1H), 8.62
(s, 1H); Mass spectrum: MH 472.
Example 105
ATTrimethyl-C
yIoxy]pbenyl}anuno)quiiiazolin-5-yl]oxy}propylycinainide
Chloroacetyl chloride (33 ul, 0.42 mrool) was added drop wise to a solution of 5-
[(ll-methyl-2nM&y)ami
yl)oxy)phenyl}qumazolm-4-aQntne (172 mg, 0.40 mmoi, obtained as described in Example
1O3, preparation of starting materials)) andDIPEA (139 pi, 0.8 mmol) in DCM (2 ml). The
mixture was stirred at room temperature for 1 hour. THF (S ml) was added to the solution and
dunemyiamme was bubbled in the reaction mixture. After 30 minutes, the solvents were
evaporated under vacuum. The mixture was diluted with DCM, washed with water and brine,
and dried over MgSQ. After evaporation of the solvents, the residue was purified by
chromatography on silica gel (eluant: 2 to 4% 7N ammonia-methanol in DCM) to give die
title compound (85 mg, 41%) as a pale solid; NMR spectrum (CDC13) 1.53 (d, 3H), 2.28 (s,
6H), 2.30 (s, 3H), 2.53 (s, 3H), 3.15-3.05 (m, 5H), 3.54 (dd, 1H), 3.95 (dd, 1H), 5.10 (m, 1H),
6.91 (d, 1H), 7.12 (m, 3H), 7.46 (d, 1H), 7.55 (d, 1H), 7.64 (m, 1H), 7.72 (s, 1H), 8.27 (s,
1H), 8.62 (s, 1H); Mass spectrum: MET 515.
Example 106
AT-Methyl-V-((21)-2-{[4-«3-methyI-4-[(6-methylpyridin-3-
yl)oxy]phenyI}aimno)qiihiazDlin-5-yl]oxy}pr(pyl-2-pyiToHdin-l-yIacetamide
The procedure described in Example 105 was repeated using pyrrolidine (4
equivalents) instead of dimethylamine to give the title compound in 57% yield; NMR
spectrum (CDCfe) 1.53 (d, 3H), 1.75 (m, 4H), 2.30 (s, 3H), 2.55 (m, 7H), 3.13 (s, 3H), 327
(d, IH), 332 (d, IH), 3 SJ (dd, IH), 3.92 (dd, IH), 5.11 (m, IH), 631 (d, IH), 7.12 (m, 3H),
7.46 (d, IH), 7.54 (d, IH), 7.64 (m, IH), 7.72 (s, IH), 827 (s, IH), 8.62 (s, IH); Mass
spectrum: MH 541.
Example 17
yl)oxy]phenyl}amiiio)qiiina
The procedure described in Example 105 was repeated using morpholine (4
equivalents) instead of diiricthylamine to give the title compound in 63% yield; NMR
spectrum (CDC13) 1.53 (d, 3H), 2.30 (s, 3H), 2.48 (m, 4H), 2.53 (s, 3H), 3.15 (m, 5H), 3.53
(dd, IH), 3.65 (m, 4H), 3.97 (dd, IH), 5.11 (m, IH), 6.92 (d, IH), 7.14-7.07 (m, 3H), 7.46 (d,
IH), 7.54 (d, IH), 7.63 (m, IH), 7.72 (s, IH), 8.27 (s, IH), 8.62 (s, IH), 9.93 (s, IH); Mass
spectrum: MH 557.
Example 108
A-MethyI-Ar-((2)-2-{[4-{3-methyl-4-[(6-melhylpyridin-3-
y)oxy]phenyI}amino)quinazolin-5-yl]oxy}propyl)-2-(4-iTiethylpiperazin-l-yl)acetaraide
The procedure described in Example 105 was repeated using N-methylpiperazine (4
equivalents) instead of dimethylamuie to give die title compound in 68% yield; NMR
spectrum (CDC13) 1.53 (d, 3H), 2.25 (s 3H), 2.30 (s, 3H), 25-23 (m, 8H), 253 (s, 3H), 3.15
(m, 5HX 354 (dd, IH), 354 (dd, IH), 5.11 (m, IH), 6.92 (d, IH), 7.14-7ff7 (m, 3H), 7.45 (d,
IH), 7.54 (d, IH), 7.64 (m, IH), 7.72 (s, IH), 8.27 (s, IH), 8.62 (s, IH); Mass spectrum: MH
Example 109
The procedure described in Example 1 was repeated using glycolic acid and 5-[(lS)-lmethyl-
2-(meoiylamino)emoxy]-N-{3-memyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}quinazoUn-4-amine to give the title compound in 46% yield; NMR spectrum
(CDC13) 1.55 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.96 (s, 3H), 359 (dd, IH), 4.164.07 (m,
3H), 5.08 (m, IH), 6.92 (d, IH), 7.02 (d, IH), 7.09 (d, IH), 7.14 (d, IH), 7.50 (m, 2H), 7.65
(m, 2H), 8.28 (s, IH), 8.61 (s, IH), 9.87 (s IH); Mass spectrum: MH 488.
The5-[(15)-l-methyl-2^methylamino)ethoxy]-N-{3-methyl-4-[(6-inethylpyridin-3-
yl)oxyJphcnyl}quinazolin-4-amine used as starting material was prepared as follows:
The procedure described in Example 103, preparation of starting materials, was
repeated using (25)-l-[allyl(methyl)amino]propan-2-ol (obtained as described for the Rantipode
in Example 2.3, preparation of starting materials) and 5-fluoro-.N-{3-methyl-4-[(6-
methy)pyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103,
preparation of starting materials) to give 5-{(15)-2-[allyl(methyl)amino]-l-methy]ethoxy}-A
{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazoh"n-4-amine in 92% yield as a gum;
M««s spectrum: MH 470.
The procedure described in Example 103, preparation of starting materials, was
repeated using 5-{(lS-2-[aUvl(inethyl)arm
methylpyridin-3-yl)oxy]phenyl}qiiiriazolin-4-amine to give 5-[(lS)-l-methyl-2-
(inemylamino)ethoxy]-AH3~inemyl-
aminein 56% viekk Mass spectrum: MET 430.
Example lit
The procedure described in Example 104 was repeated using 5-[(lS)-l-methyl-2-
(methylamino)ethoxy]-Ar- {3-meuiyl-4-[(6-methylpyridin-3-yl)oxy]phenyl }quinazolin-4-
amine (obtained as described in Example 109, preparation of starting materials) and acetic
anhydride to give the title compound in 64% yield; NMR spectrum (CDC13) 1.55 (d, 3H),
2.08 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 3.08 (s, 3H), 3.56 (dd, IH), 3.93 (dd, IH), 5.09 (m,
IH), 6.92 (d, IH), 7.12 (m, 3H), 7.50 (m, 2H), 7.65 (m, IH), 7.70 (s, IH), 8.27 (s, IH), 8.62
(s, IH); Mass spectrum: MH 472.
Example 111
Methyl-((2S2.{[4-({3-methy]-4.[(6-methylpyridin-3-
y)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)-2-pyTroIkliii-l-ylacetamlde
The procedure described in Example 105 was repeated using 5-[(15l-methyl-2-
o)ethoxy-{3-inetty
amine (obtained as described in Example 109, preparation of starting materials) and
pyrrolidrne (4 equivalents) instead of dimethylainine to give the title compound in 51% yield;
NMR spectrum fCDCM 153(d,3H), 175 $aa,4H), 230 (s,3H), 235 (jni.7H), 3.13 (s,3HX
3.27 (d, 1HX 332 (d, IH), 357 (dd, IH), 352 (dd, IH), 5.11 (m, IH), 651 (d, IH), 7.12 (m,
3H), 7.46 (d, IH), 754 (d, 1HX 7.64 On, IH), 7.72 (s, IH), 8.27 (s, IH), 8.62 (s, IH); Mats
AAur 541.
Example 112
oxy]phenyl)quinmoh5-yl]oxy}prtpyl)butanainid
The procedure described in Example 63 was repeated using 5-[(lK2-amino-lmethylethoxy]-
3-rnethyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}qumazoUnamine and
(S)-a-hydroxybutyrolactone to give the title compound in 53% yield as a solid; NMR
Spectrum: (CDC13) 1.55 (d, 3H), 1.79 (m, IH), 2.05 (m, IH), 2.26 (s, 3H), 2.49 (s, 3H), 3.90-
3.65 (m, 4H), 4.21 (dd, IH), 4.94 (m, IH), 6.96 (m, 2H), 7.11 (d, IH), 7.23 (dd, IH), 7.39 (d,
IH), 7.43 (m, IH), 7.60-752 (m, 2H), 7.69 (s, IH), 8.00 (s, IH), 8.55 (s, IH); Mass spectrum:
MET 518.
The 5-l(l/?)-2-anMno-l-methylethoxy]-AH 3-methyl-4-[(6-methylpyridin-3-
ylX)xy]phenyIJquinazolin-4-amine used as starting material was prepared as follows:
The procedure described in Example 103 (preparation of starting materials) was
repeated using 5-fluoro-7Vr-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl }quinazolin-4-
amine (obtained as described in Example 103, preparation of starting materials) and (2R)-laminopropan-
2-ol to give 5-[(lJ?)-2-amino-l-methylethoxy]-A/r-{3-niethyl-4-[(6-
methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 77% yield; Mass spectrum: MH416
Example 113
(2SBronx)-2-hydroxy-/V-((2R)-2-{[4-({3-methyl-4-[(6-raethylpyridin-3-
yl)oxy]phenyl}amino)quiiia3»lin-5-yI]oxy}propyl)b«tanamide
solution of (2S):2y4-dihvdroxv(2)-2-{
yl)oxy]phenyl}aniino)quinazolin-5-yl]oxy }piopyl)butanainib (856 mg. 1.65 mmol, obtained
as described in Example 1 12) and carbon tetrabronride (658 mg, 2 mmol) in DCM (10 ml).
The mixture was stirred overnight at room temperature. After evaporation of the solvents, the
residue was purified by chromatography on silica gel (eluant: 2% to 5% 7N ammoniamethanol
in DCM) to give the title compound (712 mg, 74%) as a solid; NMR Spectrum:
(CDC13) 1.53 (d, 3H), 2.07 (m, 1H), 2.28 (s, 3H), 2.38 (m, 1H), 2.52 (s, 3H), 3.51 (t, 2H),
3.80-3.65 (m, 2H), 4.34 (dd, 1H), 4.95 (m, 1H), 6.90 (m, 2H), 7.09 (d, 1H), 7.14 (dd, 1H),
7.28 (m, 1H), 7.50 (m, 3H), 7.63 (s, 1H), 8.23 (s, 1H), 8.44 (s, 1H); Mass spectrum: MlT 580,
582.
Example 114
-(2-Chlorothyl)-A""-((2R2-{[4-{3-inethyl-4-[(6-methylpyridin-3-
yl)oxy]pheny1}aniinoqui]MaoIin-5-yI]oxy}propyI)urea
Cbloroethylisocyanate (116 ul, 1.36 mmol) was added drop wise to an ice-cooled
solution of 5-[(lR2-arnino-l-niemyleuK)xy]-W-{3-melhyl-[(6-methylpyridin-3-
yl)oxy]phenyl}quinazolin-4-amine (516 mg, 1.24 mmol, obtained as described in Example
112, pieparation of starting materials) in DCM (10 ml). The mixture was stirred at 0°C for 30
minutes and at room temperature for 1 hour. After evaporation of die solvents, the residue was
purified by cfaromatography on stfica gel (ehianf 3% to 5% 7N ammonia-memanol in DCM)
to give me tide compound (S84 mg. 74%fc NMR Spectrum: (CDCfe)
3H), 232 (s, 3HX 3.46 (m, IHX 3.57 (m, 4H), 4.00 (m, 1H), 4.76 (m, IHX 640 (m, IHX 6.62
(m, IHX 6.67 (d, 1H), 6.91 (d, IHX 7.08 (d, 1H), 7.12 (dd, 1H), 7.18 (d, 1H), 734 (t, 1H),
7.53 (dd, IH), 7.67 (, 1H), 8.27 (, 1H), 834 (, 1H), 9.82 (s, 1H); Mass spectrum: MET 521.
Example 115
2-Hydroxy-N-iMthyl-N(l)-
y)oxy]phenyl}amino)quinaa»Bn-5-yroxy}ethyI)acetanilde
Acetoxyacetyl chloride (70 ul, 0.64 mmol) was added drop wise to an ice-cooled
solution of 5-{ [(2/2)-2inethylarruno)prc^yl]oxy}-N-{3-memyl[(6-methylpyridin-3-
yl)oxy]phenyl}quinazolin-4-amine (250 mg, 0.58 mmol), triethylamine (97 ul, 0.70 mmol) in
DCM (7 ml). The mixture was wanned to room temperature and stirred for 2 hours. After
evaporation of die solvents under vacuum, the residue was diluted with pyrrolidine (0.50 ml,
6 mmol) and the mixture was stirred at 65°C for 2 hours. After evaporation of the mixture to
dryness, the residue was injected on an HPLC column (CIS, 5 microns, 19 mm diameter, 100
mm length) of a preparative HPLC-MS system eluting with a mixture of water (containing
5% raethanol and 1% acetic acid) and acetonitrile (gradient). After evaporation of the
solvents, the solid was diluted in DCM The solution was washed with aqueous sodium
bicarbonate and dried over magnesium sulfate to give the title compound (140 mg, 49%);
NMR Spectrum: (CDCI3) 1.34 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.79 (s, 3H), 3.12 (m, 1H),
3.95 (dd, 1H), 4.09 (dd, 1H), 4.30-4.15 (m, 2H), 5.40 (m, 1H), 6.91 (m, 2H), 7.09 (d, 1H),
7.17 (dd, 1H), 7.38 (m, 1H), 7.46 (s, 1H), 7.50 (d, 1H), 7.64 (t, 1H), 8.30 (d, 1H), 8.58 (s,
1H), 9.36 (s, 1H); Mass spectrum: MH488.
The5-{[(2/0-2-(methylainino)propyl]oxy}-7l/-{3--rnethyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}quinazolin-4-aminc used as starting material was prepared as follows:
The procedure described in Example 103, preparation of starting materials, was
repeated using 5-fluoro-{3-memyl-4-[(6-methyl
amine (obtained as described in Example 103, preparation of starting materials) and (2/0-2-
(methylammo)propan-l-ol (obtained as described in Becker et aL, J. Chem. Soc. 1957,858)
to give 5-{[(2/0-2KmcylanriiK
yl)oxy]pheny] }qtraazohn-4-amme in 75% yield; NMR Spectrum: (CDQ3) 1.30 (d, 3H), 2.28
(s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.20 (m, 1H), 4.09 (m, 1H), 4.21 (m, 1H), 6.89 (m, 2H).
7.14-7.07 (m, 2H), 7.45 (d, 1H), 7.63 (m, 2H), 8.26 (s, 1H), 8.63 (s, 1BD, 103 (bs, 1H); Mass
spectrum: MET 430.
Example
N-Methyl-Ar.((y) 2-{[4-({3-methyl-4-[(6-methylPyridin-3-
yl)oxy]phenyl}arohio)quina2olin-5-yl]oxy}ethyl)acetamide
Acetic anhydride (66 pj, 0.7O mmol) was added drop wise to a solution of 5-{[(2R)-2-
(methylarnino)propyl]oxy}-A-{3-memyM-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-
amine (250 mg, 0.58 mmol, obtained as described in Example 115, preparation of starting
materials) and potassium carbonate (161 mg, 1.16 mmol) in acetone (10 ml). The mixture was
stirred at room temperature for 2 hours. After evaporation of the solvents, the residue was
diluted in DCM The solution was washed with aqueous sodium bicarbonate and dried over
magnesium sulfate. After evaporation of the solvents, the residue was purified by
chromatography on silica gel (eluant: 2 to 5% 7N ammonia-methanol in DCM) to give the
title compound (230 mg, 84%); NMR Spectrum: (CDC13) 1.28 (d, 3H), 1.94 (s, 3H), 2.30 (s,
3H), 2.53 (s, 3H), 2.90 (s, 3H), 4.30-4.10 (m, 2H), 5.38 (m, IH), 6.92 (m, 2H), 7.08 (d, IH),
7.14 (dd, IH), 7.48 (d, 2H), 7.53 (s, IH), 7.64 (t, IH), 8.27 (d, IH), 8.60 (s, IH), 9.51 (s, IH);
Mass spectrum: MH 472.
Example 117
2-Hydroxy-N-roethyl-AfK(lS)-l-methyl-2^[4-({3-methyl^[(6-methyIpyridin-3-
fl)oxy]pbenyl}aniino)quiDazolm-5-yl}oxy}ethvl)acetaniide
Hie procedure described in Example 115 was repeated using 5-{[(252-
amine to give the title compound in 72% yield; FMft TO-" (CDC13) 1.34 (d, 3H), 2.30
(s, 3H), 2.53 (s, 3H), 2.79 (s, 3H), 3.12 (m, IH), 3.95 (dd, IH), 4.09 (dd, IH), 4.30-4.15 (m,
2H), 5.40 (m, IH), 6.91 (m, 2H), 7.09 (d, IH), 7.17 (dd, IH), 7.38 (m, IH), 7.46 (s, IH), 7.50
(d, IH), 7.64 (t, IH), 8.30 (d, IH), 8.58 (s, IH), 9.36 (s, IH); Mass spectrum: MH 488.
The 5-{[(2S)-2-(memylanaiio)pK
yl)oxy]phenyl}quinazolin-4-anrine used as starting material was prepared as follows:
The procedure described in Example 103, preparation of starting materials, was
repeated using 5-fluoro-AT-{3-niemyl[(6-niemylpyridn-3-yl)oxy]phenyl}quma2Un
amine (obtained as described in Example 103, preparation of starting materials) and (2S)-2-
(mcthylamino)propan-l-ol (obtained as described in Chacchio et al., Tetrahedron, 1995, 51,
5689) to give 5-{[(22-(metihylaimno)propyl]oxy}-{3-methyW-K6-memylpyridin-3-
yl)oxy]phenyl}quinazolin-4-armne in 71% yield; NMR Spectrum: (CDC13) 1.30 (d, 3H), 2.28
(s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.20 (m, IH), 4.09 (m, IH), 4.21 (m, IH), 6.89 (m, 2H),
7.14-7.07 (m, 2H), 7.45 (d, IH), 7.63 (m, 2H), 8.26 (s, IH), 8.63 (s, IH); Mass spectrum:
MH+430.
Example 118
N-Methyl-N-((15l-methyl-2-{[4-({3-nM}thyI-4-[(6-methyIpyridin-3-
yl)oxy]phenyl}amino)quina2olin-5-yI]oxy}ethyl)acetamide
The procedure described in Example 116 was repeated using 5-{ [(252-
(methylamino)propyl]oxy}-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}qiima
amine (obtained as described in Example 117, preparation of starting materials) and acetic
anhydride to give the title compound in 88% yield; NMR Spectrum: (CDC13) 1.28 (d, 3H),
1.94 (s, 3H), 2.30 (s, 3HX 253 (s, 3H), 2.90 (s, 3H), 430-4.10 (m, 2H), 538 (m, 1H), 6.92
(m, 2H), 7.08 (d, lH)t 7.14 (dd, 1HX 7.48 (d, 2H), 753 (s, 1H), 7.64 (t, 1H), 8.27 (41H),
8.60 (s, 1H), 9.51 (s, 1H); Mass spectrum: MET 472.
Example 119
Methyl {2-[(4[3-cWoroHpyridto.2-ylMedioxy)phenyl)amii}qurn
yl)oxy]ethyl}methykarlMunate
N-[3-chloro-4-(pyridin-2-ylrnethoxy)phcnyl]-5-[2-(meliiylanuno)emoxy]quinazoUn
amine (obtained as described in Example 1, preparation of starting materials, 217 mg) and
DIPEA (0.2 ml) were stirred in DCM (20 ml). Methyl chloroformate (0.043 ml) was added
slowly and the resulting solution was stirred for 18 hours. The solution was evaporated and
the residue purified by chromatography, eluting with increasing concentrations of methanol in
ethyl acetate (5-10%). The appropriate fractions were evaporated to give an oil, which was
triturated with acetonitrile to give the title compound as a solid (43 mg, 17%); NMR spectrum
(DMSO-d6 @ 373K) 2.88 (s, 3H), 3.30 (s, 3H), 3.75-3.85 (t, 2H), 4.35-4.55 (bs, 2H), 5.30 (s,
2H), 7.10-7.30 (m, 2H), 7.30-7.40 (m, 2H), 7.50-7.60 (m, 2H), 7.70-7.78 (t, 1H), 7.80-7.95
(m, 2H), 8.43 (bs, 1H), 8.75-8.80 (d, 1H), 9.60-9.80 (bs, 1H); Mass spectrum MBT 494.0.
Example 120
N42-[(4-{[3-CWoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolui-5-yI)oxylethyl}-
AgV-dimethylurea
Methyl isocyanate (0.035 ml) was added slowly to a stirred solution of AT-[3-chloro-4-
(pyridii-2-yliriethoxy)phenyl]-5-[2-(meth (obtained as
described in Example 1, preparation of starting material, 217 mg) in PCM (10 ml). The
resulting solution was stored for 2 hours and then evapootod The res&ue was triturated with
acetomtnfe and the resulting solid WM washed with ether to give the title compound as a solid
(205 mg. 83% ); NMR spectrum fDMSCMtt & 373K) 2.85 (s, 3H), 2.95 (s, 3H), 3.75-3.85 (t,
2H), 43S4.45 (t, 2H), 55 (s, 2H), 550-6.00 (bs, 1H), 7.10-7.15 (d, 1H), 7.15-7.25 (d, 1H),
7.30-7.37 (t, 2H), 7J2-7.60 (m, 2H), 7.65-7.73 (t, 1H), 7.80-7.86 (m, 1H), 7.94- 759 (d, 1H),
8.44 (s, Ifl), 8.55-8.60 (d, IH), 9.80 (s, 1H); Mass spectmm 1493.4.
Example 121
N"-(2-Chloroethyl{2-[(4-{[3-chIoro-4-(pyridin-2-
ylmethoxy)phenyl]amino}quina2olin-5-yl)oxy]ethyl}-A-methylurea
The procedure described in Example 120 was repeated using 2-chloroethyl isocyanate
amine (obtained as described in Example 1, preparation of starting materials) to give the tide
compound as a solid in 80% yield; NMR spectrum fDMSO-d6 @ 373K) 2.90 (s, 3H), 3.15-
3.25 (q, 2H), 3.43-3.50 (t, 2H), 3.75-3.85 (t, 2H)T 4.35-4,45 (t, 2H), 5.25,6.35 (bs, IH), 7.08-
7.13 (d,lH), 7.13- 730 (ra, IH), 7.35-7.40 (m, 2H), 7.5O-7.65 (m, 2H), 7.65-7.80 (m, IH),
7.80-7.90 (t, IH), 7.95 (d, IH), 8.50 (s, IH), 8.55-8.60 (d, IH), 9.80 (s, IH); Mass spectrum
MH 541.3.
Example 122
A-{(2)-2-[(4-{[3-Chlon)-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
ylxyJpropyl-methylurea
The procedure described in Example 120 was repeated using methyl isocyanate and 5-
[(lXV2-aimno-l-methyled)oxy;
anrine (obtained as described in Bcample 65, preparation of starting materials) to give the title
compound as a solid hi 43% yield; NMR spectrum (DMSO-d6 @ 373K) 1.40-1.45 (d, 3H),
2.50-2.55 (d, 3H), 3.38-3.48 (m, IH), 330-3.60 (m, IH), 4.83-4.92 (m, IH), 5.28 (s, 2H),
5.55-5.65 (bs, IH), 6.00-6.10 (bs, IH), 7.19-7.24 (dd, 2H), 7.31-737 (m, 2H), 7.56-7.62 (m,
2H), 7.66-7.73 (t, IH), 7.81-7.88 (dt, IH), 8.06-8.08 (d, IH), 8.48 (s, IH), 8.55-8.60 (d, IH),
9.95-10.05 (bs, IH); Mass spectrum MH* 493.4.
Example 123
2-{4-[3-Chloro-4-(pyridfai-2-ylmethoxy)pnylano]quina2»lin-5-
yloxy}propylcarbamoyl)methyl]methylcarbamk acid terj-butyl ester
5-[( -2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-
ylmethoxy^)henyl]quinazo]in-4-amine (obtained as described in Example 65, preparation of
slatting materials, 868 mg) was stirred in DCM (40 ml) with DIPEA (1 ml). JV-(tertbutoxycarbonyl)
sarcosine (400 mg) and HATU (800 mg) were added and mixture was stirred
for 18 hours. Volatile material was removed by evaporation and the residue was purified by
chromatography, eluting with increasing concentrations of methanol in ethyl acetate (0-10%).
Evaporation of the appropriate fractions gave the tide compound as a froth (0.50 g); NMR
S2ecttunL(DMSO-d6 @ 373k) 1.10 (s,6H), 1.20 (s, 3H), 1.40-1.42 (d, 3), 2.72 (s, 3H), 3.40-
3.60 (d, IH, (masked by H2O), 3.60-3.75 (q, 2H), 3.75-3.8O (d, IH), 4.90-5.00 (bs, IH), 5.30
(s, 2H), 7.28-7.34 (q, 2H), 734-7.40 (m, IH), 7.42-7.46 (d, IH), 7.50-7.62 (m, 2H), 7.85-7.91
(dt, IH), 7.91-7.99 (m, 2H), 8.24-8.34 (bs, IH), 8.57-8.62 (d, IH), 8.75 (s, IH), 10.60-10.70
(bs, IH); Mass spectrum MH607.
Example 124
yloxy}propylcarbanioyl)niethyl]niemylc»rbamic acid fat-butyl ester (obtained as described in
Example 123,0.50 g) was stirred in trifluoroacetic acid (5 ml) for 20 hours. Volatile material
was removed by evaporation and the residue was purified by chromatography, eluting with
aqueous ammonia (0.880), methanol, DCM (1:10:90). Evaporation of the appropriate
fractions gave the title compound as a solid (60 mg, 15%); (DMSO~d6 @ 373k) 1.47-1.50 (d,
3H), 2.20 (s, 3H), 3.10 (s, 2H), 3.45-3.55 (q, IH), 3.55-3.65 (q, IH), 4.85-5.00 (m, IH), 5.25
(s, 2H),"7.15-7.25 (q, 2H), 7.25-7.30 (m, 2H), 7.55-7.65(t, IH), 7.70-7.80 (m, 2H), 8.20 (s,
IH), 8.50 (s, IH), 8.55-8.60 (d, IH), 9.85-9.95 (bs, Iffi: Mass spectrum MH 507.
Example 125
2-Hydroxy-N-methyl-2-{[4-{3-meihyl-4-[(6-methylpyridin-3-
yi)oxy]pbenyl}amino)quinazolin-5-yl]oxy}ethy])acetamide
5-[2-(MethylamiiK))ethoxy]-]V-{3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}quinazolin-4-amine (32 mg, 0.077 mmol) and glycolic acid (6 mg, 0.085
mmol) were dissolved in DMA (10 ml). HATU (32 mg, 0.085 mmol) was added, and the
mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated in
vacua, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in
HO containing 0.2% TFA. The appropriate fraction was evaporated, and the residue
dissolved m methanoVDCM (1:1,25 ml). The mixture was neutralised by stirring overnight
wimtetnKilkylaninxmii)mcarbone,polyiner bound The mixture was filtered, and die
filtrate was evaporated. Crystallisation from ethyl acetate/iso-hexane gave 2-hydroxy-tfinethyl-
AH2-{[4K{3-memyl-(6
yl]oxy}ethyl)acetamide as a white crystalline solid (22 mg, 60%); NMR Spectrum (DMSOd6,400
MHz, 373K) 2.26 (s, 3H), 2.48 (s, 3H), 3.02 (s, 3H), 3.95 (t, 2H), 4.02-4.11 (m-3H),
4.55 (t, 2H), 6.96 (d, 1H), 7.20 (d, 1H), 7.23 (m, 2H), 7.38 (d, 1H), 7.65 (dd, 1H), 7.70 (d,
1H), 7.73 (dd, 1H), 8.20 (m, 1H), 8.49 (s, 1H), 9.77 (s, 1H); Mass spectrum MH 473.9
The5-[2memylamino)emoxy]-{3-methyl-[(6-rnemylpyridin-3-
yl)oxy]phenyl}quinazolin-4-amine used as starting material was prepared as follows:
Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.69 mmol) was suspended in
DMA (10 ml) and N-methylethanolamine (56 pi, 0.69 mmol) was added under an atmosphere
of nitrogen. The mixture was stirred for 20 minutes at ambient temperature, and 5-fluoro-N-
{3-methyl-4-[(6-mcthylpyridin-3-yl)oxy]phenyl}quinazolm-4-amine (obtained as described in
Example 103, preparation of starting materials, 100 mg, 0.28 mmol) was added. The mixture
was heated under an atmosphere of nitrogen at 110°C for 1 hour, then at 125°C for 14 hours.
The mixture was cooled to ambient temperature, and acidified with TFA. The mixture was
concentrated in vacua, and the residue purified by reverse-phase HPLC, eluting with 5 to 50%
acetonitrile in HaO. The appropriate fractions were evaporated to a volume such that all of
the acetonitrile had been removed. The resulting aqueous solution was basified with
concentrated aqueous ammonia, and extracted with DCM (4 x 20 ml). The combined extracts
were filtered through a silicone-treated filter paper, and concentrated in -vacua to give 5-[2-
(memylarnino)ethoxy]-JV- {3-methyl-4-[(6-methylpyridin-3-yl)oxy]pheriyl }quinazolin-4-
amine as a yellow solid (40 rag, 34%); NMR Spectrum (CDC13,400 MHz) 2.20 (s, 3H), 2.44
(s, 3H), 2.49 (s, 3H), 3.12 (t, 2H), 4.25 (t, 2H), 6.80 (d, 1H), 6.83 (d, 1H), 7.00 (d, 1H), 7.04
(dd, 1H), 7.39 (d, IH), 7.55 (dd, IH), 7.61 (dd, 1H), 7.68 (d, 1H), 8.19 (d, 1H), 8.56 (s, IH),
10.26 (s, IH); Mass spectrum MH 416.0
Example 126
Methyl-tf-(2[4K{3-methy
yl]oxy}ethyl)acetaink)e
(38 mg, 0.136 mmol)
and 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (obtained as described in Example 103,
preparation of staring materials, 32 mg, 0.150 mmol) were dissolved in wo-propanol, and the
mixture heated to reflux for 1 hour. The mixture was concentrated in vacua, and the residue
purified by cinematography, during with 0 to 5.5% (10:1 methanol cone. NH3 (»q)) in ethyl
acetate. Evaporation of the appropriate fractions gave AMnethyWv~-(2-{ [4-({3-methyl-4-[(6-
mernylpyridm-3-yl)oxy]phenyl}aim^)quina^ as a dry film (24
mg, 39%); NMR Spectrum (DMSO-d6.400 MHz), 373K 1.96 (s, 3H), 2.24 (s, 3H), 2.46 (s,
3H), 2.94 (s, 3H), 3.90 (t, 2H), 4.50 (t, 3H), 6.94 (d, 1H), 7.18 (d, 1H), 7.21 (m, 2H), 7.36
(d,lH), 7.63 (dd, 1H), 7.68 (d, 1H), 7.71 (dd, 1H), 8.17 (dd, 1H), 8.47 (s, 1H), 9.76 (s, 1H);
Mass spectrum MH1" 458.4.
The JV-{2-[(4^hloroqmnazoUn-5-yl)oxy]emyl}-N-memylacetairiide used as starting
material was prepared as follows:
Sodium hydride (60% dispersion in mineral oil, 732 mg, 18.3 rnrnol) was suspended in
DMA (50 ml) and N-methylethanolamine (734 jil, 9.15 mmol) was added under an
atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature, and
5-fluoroquinazolin-4(3None (1.0 g, 6.10 mmol) was added. The mixture was heated under
an atmosphere of nitrogen at 8S°C for 90 minutes. The mixture was cooled to ambient
temperature, and the resulting slurry poured into methanol (100 ml). Dowex resin (50WX4-
400,25g) was added, and the mixture stirred for 1 hour at ambient temperature. The resin
was collected by filtration, and washed with methanol (100 ml). The resin was suspended in a
solution of ammonia in methanol (2.3 N, 150 ml), and the mixture stirred for 30 minutes. The
mixture was filtered and the residue was washed with ammonia in methanol (2.3 N, 100 ml).
The combined filtrates were concentrated in vacuo, and dried in vacua (1 mbar, 60°C) for 16
hours to give 5-[2methylamino)ethoxy]quinazohrn-4(3Jy)-one as an off white solid (1.09 g,
82%); NMR Spectrum fDMSO-d6.400 MHz) 2.36 (s, 3H), 2.85 (t, 2H), 5.11 (t, 2H), 6.97
(d, 1H), 7.14 (d, 1H), 7.61 (dd, 1H), 7.97 (s, 1H); Mass spectrum MH+ 220.
5-[2-(Mcthylammo)etrioxy]quinazolin-43/f)-one (823 mg, 3.76 mmol) was dissolved
in pyridine (25 ml), and the solution cooled to 0°C. Acetic anhydride (1.20 ml, 12.70 mmol)
was added drop wise; the solution was wanned to ambient temperature aixl stirred for 90
minutes. The mixture was concentrated mvociw, and the resadne purified by
cnromatography, eluting with 4% to 7% (10:1 methanol / cone. NH3 in DCM.
Evaporation of the appropriate fractions gave ATHaaemyl-N-{2-[(4xo-3,4-dihydxoqumazouii-
5-yl)oxy]ethyl Jacetamide as a white foam (970 mg, 99%); NMR Spectrum (DMSO-d6.400
MHz, 373K) 2.05 (bs, 3H), 2.92 (s, 3H), 3.71 (bt, 2H), 4.20 (bt, 2H), 7.01 (d, 1H), 7.19 (d,
1H), 7.63 (dd, 1H), 7.89 (s, 1H); Mass spectrum M+NH/ 284.0 (ES-) M-H+ 260.0.
N-Memyl-{2-[(4xc-3,4Hlihydroquinazoh"n-5-yl)oxyethyl Jacetamide (261 mg,
1.00 mmol) and diwo-propylethylamine (522 (il, 3.00 mmol) were dissolved in DCM (25 ml),
and the mixture cooled to 0°C. Phosphorus oxychloride (930 ill, 10 mmol) was added drop
wise; the solution was wanned to ambient temperature and stirred for 2 hours. The mixture
was cooled to 0°C, and saturated sodium hydrogen carbonate solution (30 ml) was added with
vigorous stirring. The stirred mixture was allowed to warm to ambient temperature over 20
minutes. The DCM layer was separated, washed with saturated sodium hydrogen carbonate
solution (30 ml), water (30 ml) and brine (30 ml), filtered through a silicone-treated filter
paper, and evaporated to give N-{2-[(4hloroquinazoh"n-5-yl)oxy]ethyl}-JV;-methylacetamide
as an orange solid (90 mg, 32%); NMR Spectrum (DMSO-d6.400MHz, CDC13) 2.05 (s, 3H),
3.17 (s, 3H), 3.85 (t, 2H), 4.28 (t, 2H), 6.99 (d, 1H), 7.58 (d, 1H), 7.76 (dd, 1H), 8.87 (s, 1H);
Mass spectrum 276.4 MR (4-OMe derivative - product quenched with MeOH in instrument).
Example 127
{2-[(4-{[3-Chloro(l-methyl-lyrWtiv2-yIethoxy)phenyllamiDo quinazoUn-5-
yi)oxy]ethy]}-tf-inethylacetainide
The procedure described in Example 126 was repeated using /Sf-{2-[(4-
chlwtxjuinazolin-5-ylxy)ethyl}-VHnaethylacetamide (obtained as described in Example 126,
preparation of starting materials, 47 nag, 0.170 mmol) and 3-chloro-4-(l-methyl-l-pyridin-2-
ylethoxy)aniline (49 mg, 0.187 mmol) to give the title compound in 31% yield; NMR
Spectrum (DMSCXd6.400 MHz, 373K) 1,75 (s, 6H), 1.92 (s, 3HX194 (s, 3H), 3.88 (t, 2H),
4.47 (t, 2H), 6.62 (d. 1H), 7.16 (d, IB), 731 (ddd, 1H), 735 (d, 1H), 739 (dd, 1H), 7.70 (dd,
1H), 7.75 (dd, 1H), 7.83 (ddd, 1HX 759 (d, 1H), 8.46 (s, 1H), 858 (dd, 1HX 9.70 (s, 1H);
Mass spectrum MH 506.0.
The 3-Aloro-41-niethyl-lyridin-2-yletboxy)anilroe used as starting material was
prepared as follows:
Sodium hydride (60% dispersion in mineral oil, 220 mg, 5.50 mmol) was suspended in
DMA (30 ml) and 2-pyridin-2-ylpropan-2-ol (obtained as described in Organometallics, 1997,
16,3303,754 mg, 5.50 mmol) was added under an atmosphere of nitrogen. The mix.ture was
stirred for 30 minutes at ambient temperature, then cooled to 0°C. 3-Chloro-4-
fluoronitrobenzene (878 mg, 5.00 mmol) was added as a solution in DMA (15 ml); the
mixture was wanned to room temperature, and was stirred for 2 hours. The mixture -was
concentrated in vacuo, and the residue partitioned between ethyl acetate (75 ml) and -water (75
ml). The aqueous layer was extracted with ethyl acetate (75 ml), and the extractions
combined with the organic layer. The combined organics were dried over MgSO4 and
concentrated in vacuo. The residue was purified by chromatography, eluting with 0 to 20%
ethyl acetate in wo-hexane, giving 2-[l2hloro-4-nitrophenoxy)-l-methylethyl]pyridine as
a pale yellow solid (810 mg, 55%); NMR Spectrum (DMSQ-d6.400 MHz, CDCb) 1.91 (s,
6H), 6.40 (d, 1H), 7.25 (ddd, 1H), 7.50 (d, 1H), 7.70 (ddd, 1H), 7.82 (dd, 1H), 8.30 (d, 1H),
8.65 (d, 1H); Mass spectrum MH 293.0.295.0.
2-[l-(2-Chloro-4-nitrophenoxy)-l methylethyljpyridine (800 rag, 2.74 mmol) was
dissolved in ethyl acetate (50 ml). The mixture was purged with nitrogen, and platinum on
activated carbon (10%, 100 mg) was added. The mixture was hydrogenated for 6 hours using
a burette filled with hydrogen. The system was degassed and purged with nitrogen, and the
catalyst removed by filtration. The filtrate was concentrated in vacua, and the residue
purified by chromatography, eluting with 20% to 30% ethyl acetate in iso-hexane. The
appropriate fractions were evaporated to give 3-chloro-4-(l-methyl-l-pyridin-2-
ylethoxy)aniline as a straw-coloured oil (452 mg, 63%); NMR Spectrum (DMSO-d6, 400
MHz, CDC13) 1.63 (s, 6H), 3.41 (bs, 2H), 6.25 (dd, 1H), 6.35 (d, 1H), 6.65 (d, 1H), 7.11
(ddd, 1H), 7.63 (ddd, 1H), 7.77 (d, 1H), 8.50 (d, 1H).
Example 128
Pharmaceutical compositions ,
The following illustrates representative frtiannaceirticaldcwagefoansof tbeinveatioa as
defined tetem (fee arive ingredient be for therapeutic or prophylactic use in humans:
(a) Tablet I nag/tablet
Compound X. 100
Lactose Ph.Eur. „ 182.75
Croscarmellose sodium 12.0
Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0
(b) Injection I (50 mg/ml)
Compound X 5.0% w/v
1M Sodium hydroxide solution 15.0% v/v
0.1M Hydrochloric acid (to adjust pH to 7.6)
Polyethylene glycol 400 4.5% w/v
Water for injection to 100%.
The above compositions may be prepared by conventional procedures well known in
the pharmaceutical art. For example, Tablet I may be prepared by blending the components
together and compressing the mixture into a tablet.

CLAIMS
1. A quinazoline derivative of the formula I
(Formula Removed)

wherein:
m isO;
R1 is selected from hydroxy, (l-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(l-6C)alkoxy,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (1 -6C)alkyl substituents, or a substituent selected from hydroxy and (l-6C)alkoxy,
R2 is hydrogen or (l-4C)alkyl;
n is 1;
R3 is selected from halogeno and (l-4C)aIkyl;
X1 is selected from O, S, SO, SO2, N(R7), OC(R7)2, SC(R7)2, CO and N(R7)C(R7)2, wherein each R7, which may be the same or different, is hydrogen or (l-6C)alkyl;
Q1 is aryl, or a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1, 2 or 3 heteroaioms independently selected from oxygen, nitrogen and sulfur,
and wherein Ql optionally bears one or more substituents, which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (1 -6C)alkyI, (2-8C)alkenyl, (2-8C)alkynyl, (I-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl,

[2-6C)alkanoyl, (3-6C)alkenoyl, (3-6C)aIkynoyI, (2-6C)alkanoyloxy, 2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, (3-6C)aIkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylauuno,(3-6C)aIkynoylamino,N-(l-6C)alkyl-(3-6C)alkynoylamino N-(l-6C)aIkylsulfamoyl,N,N-di-[(l-6C)alkyl]sulfamoyl, (l-6C)alkanesulfonyIamino N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, and a group of the formula:
(Formula Removed)
wherein X2 is a direct bond or is selected from O, CO and N(R9), wherein R9 is hydrogen or (l-6C)alkyl, and R8 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, N- (l-6C)alkylamino-(l-6C)alkyl, N,N-di-[( 1-6C)alkyl]amino-( 1-6C)alkyl, (2-6C)alkanoyIamino-(l-6C)alkyl, N-( 1 -6C)alkyl-(2-6C)alkanoylamino-( 1 -6C)alky 1, (1 -6C)alkoxycarbonylamino-( 1 -6C)alkyl, carbamoyl-( 1 -6C)alkyl, N-( 1 -6C)alkylcarbamoyl-(l -6C)aikyl, N,N-di-[( 1 -6C)alkyl]carbamoyl-( 1 -6C)alkyl, (1 -6C)alkylthio-( 1 -6C)alky 1, (1 -6C)alkylsulfinyl-( 1 -6C)alkyl, (1 -6C)alkylsulfonyl-( 1 -6C)alkyl sulfamoyl(l-6C)alkyl, N-(l-6C)alkylsulfamoyl(l-6C)alkyl, N3N-di-(l-6C)alkylsulfamoyl(l-6C)alkyl,(2-6C)alkanoyl-(l-6C)alkyl,(2-6C)alkanoyloxy-(l-6C)aIkyl or (l-6C)alkoxycarbonyl-(l-6C)alkyl,
and wherein any CH2 or CH3 group within -X1-Q1 optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyI substituents or a substituent selected from hydroxy, cyano, amino, (l-4C)alkoxy, (l-4C)aIkylamino and di-[(l-4C)alkylamino];
R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (l-6C)alkyl,
and wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy, cyano, (l-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-[(l-6C)alkylamino];
R6 is selected from hydrogen, (l-3C)alkyl, (2-3C)aIkenyl, (2-3C)alkynyl, (3-5C)cycloalkyl, (3-5C)cycloalkyl-(l-3C)alkyI, heterocyclyl and heterocyclyl-(l-3C)alkyl,
wherein any heterocyclyl group within R6 is a 4, 5, 6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2

heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclyl group is linked to the group to which it is attached by a ring carbon atom,
and wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyI, (l-6C)aIkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
(Formula Removed)
wherein X3 is a direct bond or is selected from O and N(R11), wherein Ru is hydrogen or (l-4C)alkyl, and R10 is halogeno-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, cyano-(l-4C)alkyl, amino-(l-4C)alkyl, N-(l-4C)alkylamino-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]amino-(l-4C)alkyl,
and wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents;
and wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino;
A is selected from a group of the formula Z-(CRI2R13)P- and R14,
wherein p is 1, 2 or 3,
each R12 and R13, which may be the same or different, is selected from hydrogen and (l-6C)alkyl,
and wherein any CH2 or CH3 group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy and (l-6C)alkoxy,
Z is selected from hydrogen, OR15, NR,6R17 and (l-6C)alkylsulfonyl, wherein each of R15, R16 and R17, which may be the same or different, is selected from hydrogen and (l-6C)alkyI,
RM is selected from OR19 and NR16R17, wherein R19 is selected from (1-6C)alkyl and wherein R16and R17 are as defined above,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl or heterocyclyl,

and wherein any heterocyclyl group within a Z or R substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy, (l-6C)alkyl and (l-6C)alkoxy,
and wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy and (l-6C)alkoxy; or a pharmaceutically acceptable salt thereof.
2. A quinazoline derivative as claimed in claim 1, wherein R2 is hydrogen.
3. A quinazoline derivative as claimed in any one of the preceding claims, wherein n is 1 and R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I.
4. A quinazoline derivative as claimed in any one of the preceding claims, wherein R3 is chloro.
5. A quinazoline derivative as claimed in any one of claims 1 to 3, wherein R3 is methyl.
6. A quinazoline derivative as claimed in any one of the preceding claims, wherein X1 is selected from O, S and OC(R7)2 wherein each R7 is, independently, hydrogen or (l-4C)alkyl.
7. A quinazoline derivative as claimed in any one of the preceding claims, wherein X1 is OCH2.
8. A quinazoline derivative as claimed in any one of the preceding claims, wherein Q1 is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl, IH-imidazolyl, lH-pyrazolyl, 1,3-oxazolyl and isoxazolyl.
9. A quinazoline derivative as claimed in anyone of the preceding claims, wherein R6 is (l-3C)alkyl,

and wherein anyCH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (l-6C)alkyl substituents or a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino.
10. A quinazoline compound as claimed in claim 1 is selected from one
or more of the following:
N-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-
methoxy-N-methylacetamide;
N-{2-[(4-{3-chloro-4-(pyridm-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-
(dimethylamino)-N-methylacetamide;
N-{(2R)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-
yl)oxy]propyl}-2-methoxy-N-methylacetamide);
2-hydroxy-N-methyl-N-{2-[(4-{3-methyl-4-(pyrazin-2-ylmethoxy)anilino}quinazolin-
5-yl)oxy]ethyl}acetamide;
2-hydroxy-N-methyI-N-{2-[(4-{3-methyl-4-(l,3-thiazol-4-
ylmethoxy)anilino} quinazolin-5-yl)oxy]ethyl }acetamide;
2-hydroxy-N-methyl-N-2-{[4-(3-methyl-4-[(5-methylisoxazol-3-
yl)methoxy]anilino)quinazolin-5-yl]oxy}ethyl)acetamide;
N- {(2R)-2-[(4- {3 -chloro-4-(pyridin-2-ylmethoxy)anilino} quinazolin-5-
yl)oxy]propyl} -2-methoxyacetamide;
N-(2-{[4-(3-chloro-4-[(6-methylpyridin-2-yl)methoxy]anilino)quinazolin-5-
yl]oxy}emyl)-2-hydroxy-N-methylacetamide;
N-((2R)-2- {[4-(3 -chloro-4-[(6-methylpyridin-2-yl)methoxy]anilino)quinazolin-5-
yl]oxy}propyl)-2-hydroxy-Ar-methylacetamide;
N-2-{t4-(3-chloro-4-[(6-methyIpyridin-2-yl)methoxy]anilino)quinazolin-5-
yl]oxy}ethyl)-Ar-rnethylacetamide;
N-(2-{[4-(3-chIoro-4-[(2-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}ethyl)-N-
methylacetamide;
N-(2-{[4-(3-chloro-4-[(3-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy}ethyl)-N-
methylacetamide;
N- {2-[(4- {3-chloro-4-( 1,3 -thiazol-4-ylmethoxy)anilino} quinazolin-5 -yl)oxy] ethyl} -
N-methylacetamide;
N- {2-[(4- {3-chloro-4-(pyrazin-2-ylmethoxy)anilino} quinazolin-5-yl)oxy]ethyl} -N-
methylacetamide;

N-{(2R)-2-[(4-{3-chIoro-4-(pyridin-2-'ylmethoxy)anilino}quinazolin-5-
yl)oxy]propyl} -2-hydroxyacetamide;
N-{2-[(4- {3-chloro-4-(pyridin-2-ylmethoxy)anilino} qumazolin-5-yl)oxy]ethyl} -N-
methylacetamide;
2-hydroxy-N-rnethyl-N- {2-[(4-{ 3-methyl-4-(pyridin-2-ylmethoxy)anilino} quinazolin-
5-yl)oxy]ethyl}acetamide;
N-{(lR)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l-
methy lethy 1} acetamide;
N-{(lR)-2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]-l-
methylethyl} -2-hydroxyacetamide;
N-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-N-methylacetamide;
N-(2-{[4-(3-criloro-4-[(3-fluorobenzyl)oxy]aniIino)quinazolin-5-yl]oxy}ethyl)-2-
hydroxy-iV-methylacetamide;
N-{2-[(4-{3-chloro-4-(l,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-N-methylacetamide;
N-{2-[(4-{3-chloro-4-(pyrazin-2-yImethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-
hydroxy-N-methylacetamide;
N-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)antlino}quinazolin-5-
yI)oxy]ethyl} acetamide;
N- {(2R)-2-[(4- {3 -chloro-4-(pyridin-2-ylmethoxy)anilino} quinazolin-5-
yl)oxy]propyl} acetamide;
N-{(2R)-2-[(4-{3-chloro-4-(pyridin-2-yImethoxy)anilino}quinazolin-5-
yl)oxy]propyl} -2-hydroxy-N-methylacetamide;
N- {(2R)-2- [(4- {3 -chloro-4-(pyrazin-2-ylmethoxy)anilino} quinazolin-5-
yl)oxy]propyl} -2-hydroxy-N-methylacetamide;
N-((2R)-2-{ [4-(3 -chloro-4-[(3-fluorobenzyl)oxy]anilino)quinazolin-5-yl]oxy} propyl)-
2-hydroxy-iV-methylacetamide;
N-{(2R)-2-[(4- {3 -chIoro-4-( 1,3-thiazol-4-ylmethoxy)anilino} quinazolin-5-
yl)oxy]propyl} -2-hydroxy-JV-methylacetamide;
N-{(2R)-2-[(4-{3-chloro-4-(pyridiii-2-ylmethoxy)anilino}quinazolin-5-
yI)oxy]propyl} -N-methylacetamide;
N- {2-[(4- {[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino} quinazolin-5-
yl)oxy]ethyl} -N-ethylacetamide;

N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-lyl)oxy]ethyl}-N-ethyl-2-hydroxyacetamide;
N-{2-[(4-{[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIin-5-yl)oxy]ethyll}-N-propylacetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} -2-hydroxy-N-propylacetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] ethyl} -N-isopropylacetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2-hydroxy-N-isopropylacetamide;
N-allyl-N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetamide;
N-aIlyl-N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quiiiazolin-5-yI)oxy]ethyI} -2-hydroxyacetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-.N-cyclopropylacetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-yIraethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N-cyclopropyl-2-hydroxyacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] ethyl} -N-(cyclopropylmethyl)acetamide;
N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl}-N-(cyclopropylmethyl)-2-hydroxyacetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyI}-N-cyclobutylacetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIiii-5-yl)oxy] ethyl} -N-cyclobutyl-2-hydroxyacetamide; N{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] ethyl} -N-( 1 -methyl piperidin-4-yl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} -N-(tetrahydro-2H-pyran-4-yl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] ethyl} -2-hydroxy-N-(tetrahydro-2H-pyran-4-yl)acetamide; N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl} -N-(2-hydroxyethyl)acetamide;

N- {2-[(4- {[3 -chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-
yl)oxy]ethyl}-2-hydroxy-N-(2-hydroxyethyl)acetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl} -N-(2-methoxyethyl)acetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy] ethyl} -2-hydroxy-N-(2-methoxyethyl)acetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
y l)oxy] ethyl} -N-prop-2-yn-1 -yl acetamide;
N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-
yI)oxy] ethyl} -2 -hydroxy -N-prop-2-yn-1 -ylacetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIin-5-
yl)oxy]ethyl} -2-hydroxy-N-methylpropanamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyI} -N-methyl-tetrahydrofuranyl-2-carboxamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl} -N, 1 -dimethylprolinamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]emyl}-2-hydroxy-N,2-dimethylpropanamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl} -1 -hydroxy-N-methylcyclopropanecarboxamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazoIin-5-
yl)oxy]ethyl}N1-N2-dimethylglycinamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl}-3-hydroxy-N,2,2-trimethylpropanamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]ethyl} -3-hydroxy-N-methylpropanamide;
N-{(2S)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl}acetamide;
N- {(2S)-2- [(4- {[3 -chloro-4-(pyridin-2-y lmethoxy)phenyl] amino} quinazolin-5-
yl)oxy]propyl} -2-hydroxyacetamide;
N1-{(2S)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yI)oxy]propyl}-N1-N2-dimethylgIycinamide;
N- {(2S)-2- [(4- {[3 -chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-
yl)oxy]propyl}-2-methoxyacetamide;

N-{(2S)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5- yl)oxy]propyl} -2-(methylsulfonyl)acetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl} -2-hydroxyacetamide;
N'-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]ethyl}-N1-N2-dimethylglycinamide;
N- {2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl} -2-methoxyacetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yI)oxy]ethyl}-2-(methylsulfonyl)acetamide;
N-{(25)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]propyl}-N-methylacetamide;
N-{(25)-2-[(4-{[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI} -2-hydroxy-.N-methylacetamide;
Nl- {(25)-2-[(4- {[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]propyl} -N1-N2,N2trimethylglycinamide;
N-{(25)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl}-2-methoxy-N-rnethylacetarnide;
N- {(25)-2- [(4- {[3 -chloro-4-(pyridin-2-ylmethoxy)pheny IJamino} qui nazolin-5-yl)oxy]propyl}-N-methyl-2-(methylsulfonyl)acetaniide; N-{(2R)-2-[(4-{[3-chloro-4-(pyrazin-2-yImethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI}-N-methylacetamide;
N- {(2R)-2-[(4-{ [3-chloro-4-(l ,3 -thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxylpropyll-N-methylacetamide;
N-((2R)-2-{[4-({3-chloro-4-[(3-fluoroben2yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)-N-methylacetamide;
N-((2R)-2-{[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)-N-methylacetamide;
N- {(1 R)-2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy] -1 -methy lethyl} -2 -hydroxy -N-methylacetamide; N-{(lR)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] -1 -methylethyl} -N-methylacetamide;
N- {(1S)-2-[(4-{ [3 -chloro-4-(pyridin-2-ylmethoxy)phenyl]amino }quinazolin-5-yl)oxy]-1 -methylethyl} -2-hydroxy-N-methylacetamide;

N- {(lS)-2-[(4- {[3 -chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-lyl)oxy]-1 -methylethyl} -N-methylacetamide;
N-{(15)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] -1 -methylethyl} -2-methoxy-N-methylacetamide; N-{(lS}-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] -1 -methylethyl} -2-hydroxyacetamide;
N-{(15)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-y l)oxy] -1 -methylethyl} acetamide;
Nl-{(lS)-2-[(4-{[3 -chloro-4-(pyridin-2-yImethoxy)phenyl]amino} quinazolin-5 -yl)oxy]-1-methylethyl}-N2-N2-dimethylglycinamide;
N1-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-yImethoxy)phenyl]amino}quinazolin-5-yl)oxy] propy 1} -N2,-N2-dimethylglycinamide;
(2S)-N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} -2,4-dihydroxybutanamide;
(2R)-N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl} -2,4-dihydroxybutanamide;
(2R)-N-{(2R)-2-[(4- {[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]propyl} -2,4-dihydroxybutanamide;
(2S)-N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI} -2,4-dihydroxybutanamide;
(2R)-N- {(2S)2-[(4- {[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]propyl}-2,4-dihydroxybutanamide;
(25)-N-{(2S)-2-[(4-{[3-chIoro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propy 1} -2,4-dihydroxybutanamide;
(25)-N-{(lR)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]-l -methylethyl} -2,4-dihydroxybutanamide;
(2R)-N- {(1 R)-2-[(4-{ [3 -chloro-4-(pyridin-2-yImethoxy)phenyl]arnino }quinazolin-5-yl)oxy] -1 -methylethyl} -2,4-dihydroxybutanamide;
(2R)-N- {2-[(4- {[3-chloro-4-( 1,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl} -2,4-dihydroxybutanamide;
(2S')-n-{2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-2,4-dihydroxybutanamide;
(2R)-N- {(1 R)-2-[(4- {[3-chloro-4-( 1,3 -thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]-l-methylethyl}-2,4-dihydroxybutanamide;

(25)-N-{(lR)-2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-
yl)oxy]-1 -methylethyl} -2,4-dihydroxybutanamide;
N-methyl-N-{2-[(4-{[3-rnethyI-4-(pyridin-2-ylniethoxy)pheny]]amino}quinazolin-5-
yI)oxy] ethyl }acetamide;
N-methyl-N-{2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}
quinazolin-5-yl)oxy]ethyl}acetamide;
N-methyl-N-(2-{[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)
quinazolin-5-yl]oxy}ethyl)acetamide;
2-hydroxy-N-methyl-N-{2-[(4-{[3-methyl-4-(l,3-thiazoI-2-ylmethoxy)phenyl]
amino}quinazolin-5-yl)oxy]ethyl}acetamide;
2-hydroxy-N-{2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-
yI)oxy]ethyl} acetamide;
2-hydroxy-N- {2-[(4- {[3 -methyl-4-(l ,3-thiazoI-4-ylmethoxy)phenyl]amino}
quinazolin-5-yl)oxy]ethyl}acetamide;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phetiyl]amino}quinazolin-5-yI)oxy]-l,l-
dimethylethyl} -2-hydroxyacetamide;
2-hydroxy-N-{(2R)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyI]amino}
quinazolin-5 -yl)oxy]propyl} acetamide;
2-hydroxy-N-{(2R)-2-[(4'{[3-methyI-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}
quinazolin-5-yl)oxy]propyl}acetamide;
N-((2R)-2-{[4-({4-f(3-fluoroben2yl)oxy]-3-methylphenyl}amino)quinazoIin-5-
yl]oxy}propyl)-2-hydroxyacetamide;
2-hydroxy-N-{(2R)-2-[(4-{[3-methyl-4-( 1,3-thiazol-2-ylmethoxy)phenyl]amino}
quinazolin-5-yl)oxy]propyl}acetamide;
N-{(2R)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy] propyl} acetamide;
N-{(2R)-2-[(4- {[3-methyl-4-( 1,3 -thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-
yl)oxy]propyl} acetamide;
N-((2R)-2-{[4-({4-[(3-fluorobenzyI)oxy]-3-methylphenyl}amino)quinazolin-5-
yl]oxy}propyl)acetamide;
N-{(2R)-2-[(4-{[3-methyl-4-(l,3-thiazol-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy] propyl} acetam ide;

2-hydroxy-N-methyl-N-{(2R)-2-[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl] amino}quinazolin-5-yl)oxy]propyI}acetamide; 2-hydroxy-N-methyl-N-{(2R)-2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyI}acetamide; 2-hydroxy-N-methyI-N-((2R)-2-{[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; N-methy\-N- {(1R)-1 -methyl-2-[(4- {[3-methyl-4-(pyridin-2-ylmethoxy)phenyl] amino}quinazolin-5-yl)oxy]ethyl}acetamide; N-methyl-N-{(lR)-l-methyl-2-[(4-{[3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino} quinazolin-5-yl)oxy]ethyl} acetamide; N-{(lR)-2-[(4-{[3-chloro-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy] -1 -methylethyl} -2..........-hydroxy-N-methylacetamide; 2-hydroxy-N-methyl-N {(1 R) .. 1 -methyl-2-[(4- {[3 -methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetamide; 2-hydroxy-N-methyI-N-{(lR)-l-methyl-2-[(4-{t3-methyl-4-(l,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}acetamide; N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yI)oxy]propyl}-1 -hydroxy-N-methylcyclopropanecarboxamide; (25)-N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-N-methylpropanamide;
N-{(2R)-2-[(4-{[3-chloro-4-{pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl} -2-hydroxy-N,2-dimethylpropanamide;
(2R)-N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]propyl}-2-hydroxy-N-methylpropanamide;
(2R)-N-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]ammo}quinazolin-5-yl)oxy]propyl}-2-methoxy-A'-methylpropanamide; 2-hydroxy-N-methyl-N-((2R)-2- {[4-( {3 -methyl-4- [(6-methylpyridin-3 -yI)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide; N-methyl-N-((2R)-2-{[4-({3-methyI-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetaraide; N1-N2.N2-trimethyl-N1 -((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl} amino)quinazolin-5-yl]oxy }propyl)glycinamide; 2-hydroxy-N-methyl-N-((2S)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl} amino)quinazoIin-5-yl]oxy} propyI)acetamide;

N-methyl-N-((25)-2-{[4-({3-methyI-4-[(6-methylpyridin-3-
fl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)acetamide;
(2S)-2,4-dihydroxy-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide;
(2S)-4-bromo-2-hydroxy-N-((2R)-2-{[4-({ 3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}amino)quina2olin-5-yl]oxy}propyl)butanamide;
N-(2-chIoroethyl)-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyI}amino)quinazolin-5-yl]oxy}propyl)urea;
2-hydroxy-N-methyl-N-((lR)-l-methyl-2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl} amino)quinazolin-5-yl]oxy} ethyl)acetamide;
N-methyl-N-(( 1R)-1 -methyl-2- {[4-( {3-methyl-4-[(6-methylpyridin-3 -
yl)oxy]phenyI}amino)quinazolin-5-yl]oxy}ethyl)acetarnide;
2-hydroxy-N-methyl-N-(( 1S)-1 -methyl-2- {[4-( {3-methyl-4- [(6-methylpyridin-3-
yl)oxy]phenyl }amino)quinazoIin-5-yl]oxy} ethyl)acetamide;
N-methyl-N-((lS)-1 -methyl-2- {[4-({ 3 -methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide;
methyl-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino} quinazolin-5-
yl)oxy]ethyl }methyl carbamate;
N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyI]amino}quinazolin-5-
yl)oxy] ethyl} -N,N-dimethylurea;
N-(2-chIoroethyl)-N-{2-[(4-{[3-chloro-4-(pyridin-2-
y lmethoxy)pheny 1] amino } quinazolin-5 -yl)oxy] ethyl} -N-methy lurea;
N-{(R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl}-N-methylurea;
[((R)-2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)phenyIamino]quinazolin-5-
yloxy}propylcarbamoyl)methyl]methylcarbamic acid tert-butyl ester;
N1-{(2R)-2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-
yl)oxy]propyl} -N2-methylglycinamide;
2-hydroxy-N-methyl-N-(2- {[4-( {3-methyl-4-[(6-methylpyridin-3-
yI)oxy]phenyl}amino)quinazolin-5-yI]oxy}ethyl)acetamide;
N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-
yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide; and
N- {2- [(4- {[3 -chloro-4-( 1 -methyl-1 -pyridin-2-ylethoxy)phenyl]amino} quinazolin-5-
yl)oxy]ethyl}-N-methylacetamide;

or a pharmaceutical^ acceptable salt thereof.
11. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 as and when used as a medicament.
12. A process for the preparation of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 which comprises:
(a) the coupling, conveniently in the presence of a suitable base, of a quinazoline of the formula II:

(Formula Removed)
wherein R1, R2, R3, R4, R4a, R5, R5a, R6, X1, Q1, m, and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a carboxylic acid of the formula III, or a reactive derivative thereof:
(Formula Removed)
wherein A has any of the meanings defined in claim 1 except that any functional group is protected if necessary; or
(b) for the preparation of those compounds of the formula I wherein X1 is OC(R7)2, SC(R7)2 or N(R7)C(R7)2, the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula IV:
(Formula Removed)

wherein Xla is O, S or N(R7) and R1, R2, R3, R4, R4\ R5, R5a, R6, R7, A, m, and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the formula V or a salt thereof:
(Formula Removed)
wherein L1 is a suitable displaceable group and Q1 and R7 have any of the meanings defined in claim 1 except that any functional group is protected if necessary;
(c) for the preparation of those compounds of the formula 1 wherein A is R14 and
R14 is NHR17 (wherein R17 is as defined in claim 1), the coupling of a quinazoline of
the formula II as defined above in (a) with an isocyanate of the formula Ilia:
A-NCO Ilia wherein A is R14 as previously defined in this section except that any functional group is protected if necessary;
(d) the reaction of a quinazoline of the formula II wherein R6 is hydrogen:

(Formula Removed)
wherein R1, R2, R3, R4, R4a, R5, R5a, X1, Q1, m, and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with α-hydroxy-γ-butyrolactone wherein any functional group is protected if necessary; or

) the coupling of a quinazoline of the formula VI:

(Formula Removed)
wherein R1, R4, R4a, R5, R5 R6, A and m have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the formula IIb:
(Formula Removed)
wherein R2, R3, X1, Q* and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary;
(f) for the preparation of those compounds of the formula I wherein X1 is O and Q1 is 2-pyridyI, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyI, 2-pyrazinyl or 3-pyridazinyl, the reaction, conveniently in the presence of a suitable base and a suitable catalyst, of a quinazoline of the formula VII:
(Formula Removed)

wherein R1, R2, R3, R4, R4a, R5, R5a, R6, A, m and n have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with 2-bromopyridine, 4-bromopyridine, 2-chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or 3-chloropyridazine; or

(g) for the preparation of those compounds of the formula I wherein A is Z-CR12R13)p-, wherein Z is NRI6R17, the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula VIII:

(Formula Removed)

wherein L1 is a suitable displaceable group and R1, R2, R3, R4, R4a, R5, R5a, R6, R12, R13, X1, Q1, m, n and p have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the formula IXa, or a reactive derivative thereof:
(Formula Removed)
wherein R16 and R17 have any of the meanings defined in claim 1 except that any functional group is protected if necessary; and thereafter, if necessary:
(i) converting a quinazoline derivative of the formula I into another quinazoline derivative of the formula I; (ii) removing any protecting group that is present by conventional means;
(iii) forming a pharmaceutically acceptable salt.

Documents:

3254-DELNP-2006-Abstract-(12-12-2008).pdf

3254-delnp-2006-abstract.pdf

3254-DELNP-2006-Claims-(11-05-2009).pdf

3254-DELNP-2006-Claims-(12-12-2008).pdf

3254-delnp-2006-claims.pdf

3254-DELNP-2006-Correspondence-Others-(05-06-2009).pdf

3254-DELNP-2006-Correspondence-Others-(12-12-2008).pdf

3254-DELNP-2006-Correspondence-Others.pdf

3254-DELNP-2006-Corresponence-Others-(11-05-2009).pdf

3254-DELNP-2006-Description (Complete)-(11-05-2009).pdf

3254-DELNP-2006-Description (Complete)-(12-12-2008).pdf

3254-delnp-2006-description (complete).pdf

3254-DELNP-2006-Form-1-(12-12-2008).pdf

3254-delnp-2006-form-1.pdf

3254-delnp-2006-form-13-(12-12-2008) 2.pdf

3254-delnp-2006-form-13-(12-12-2008).pdf

3254-delnp-2006-form-18.pdf

3254-DELNP-2006-Form-2-(12-12-2008).pdf

3254-delnp-2006-form-2.pdf

3254-DELNP-2006-Form-26-(12-12-2008).pdf

3254-DELNP-2006-Form-3-(11-05-2009).pdf

3254-delnp-2006-form-3.pdf

3254-delnp-2006-form-5.pdf

3254-DELNP-2006-Others-Document-(12-12-2008).pdf

3254-delnp-2006-pct-210.pdf

3254-delnp-2006-pct-304.pdf

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Patent Number

235051

Indian Patent Application Number

3254/DELNP/2006

PG Journal Number

28/2009

Publication Date

10-Jul-2009

Grant Date

24-Jun-2009

Date of Filing

06-Jun-2006

Name of Patentee

ASTRAZENECA AB.

Applicant Address

S-151 85 SODERTALJE, SWEDEN

Inventors:

#	Inventor's Name	Inventor's Address
1	BRADBURY, ROBERT, HUGH	ASTRAZENECA R & D ALDERLEY, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK10 4TG (GREAT BRITAIN)
2	HENNEQUIN, LAURENT, FRANCOIS, ANDRE	ASTRAZENECA, Z.I. LA POMPELLE BP 1050, CEDEX 2, F-51689 REIMS, FRANCE
3	KETTLE, JASON, GRANT	ASTRAZENECA R & D ALDERLEY, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK10 4TG (GREAT BRITAIN).

PCT International Classification Number

C07D 239/94

PCT International Application Number

PCT/GB2004/004761

PCT International Filing date

2004-11-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0326459.5	2003-11-13	U.K.