Title of Invention	"A QUINAZOLINE COMPOUND AND A PROCESS FOR PREPARING THE SAME THEREOF"
Abstract	A quinazoline compound of the formula (I) wherein: R1, R2, R3, R3a, R4, R5, R5a R6, R7, a, m and p are as defined in the description. Also claimed are pharmaceutical compositions containing the quinazoline compound, the use of the quinazoline compound as medicaments and processes for the preparation of the quinazoline compound. The quinazoline compound of formula (I), are useful in the treatment of hyperproliferative disorders such as a cancer.

Title of Invention

"A QUINAZOLINE COMPOUND AND A PROCESS FOR PREPARING THE SAME THEREOF"

Abstract

A quinazoline compound of the formula (I) wherein: R1, R2, R3, R3a, R4, R5, R5a R6, R7, a, m and p are as defined in the description. Also claimed are pharmaceutical compositions containing the quinazoline compound, the use of the quinazoline compound as medicaments and processes for the preparation of the quinazoline compound. The quinazoline compound of formula (I), are useful in the treatment of hyperproliferative disorders such as a cancer.

Full Text	FIELD OF THE INVENTION The 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 compounds, 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 signaling 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 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 receptor tyrosine kinase. STATEMENT OF THE INVENTION Accordingly the present invention relates to a quinazoline derivative of the formula I: (Formula Removed) wherein: p is 1 or 2; each R1, which may be the same or different, is selected from hydrogen, hydroxy, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula : -X1-wherein X1 is a direct bond or is O, and Q1 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R8), CO, CH(OR8), CON(R8), N(R8)CO, SO2N(R8), N(R8)S02, CH=CH and OC wherein R8 is hydrogen or(l-6C)alkyl, and wherein any CH2=CH- or HOC- group within a R1 substituent optionally bears at the germinal CH2= or HOs position a substituent selected from halogeno, carboxy, carbamoyl, 1 (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula (Formula Removed) wherein X2 is a direct bond or is selected from CO and N(R9)CO, wherein R9 is hydrogen or (l-6C)alkyl, and Q2 is heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent, 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, oxo, thioxo, formyl, (l-6C)alkoxy, (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, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(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 from a group of the formula: -X3Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R10), CO, CH(OR10), CON(R10), N(R10)CO, S02N(R10), N(R10)SO2, C(R10)2O, C(R10)2S and C(R10)2N(R10), wherein R10 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 or heterocyclyl-(l-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears one or more R11 substituents, which may be the same or different, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents; a is 1, 2, 3,4 or 5; each R2, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifiuoromethyl, trifluoromethoxy, (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, (2- 6C)alkanoyloxy, (2-6C)alkanoylamino, N-( 1 -6C)alkyl-(2-6C)alkanoylamino, N-(l-6C)alkylsulfamoyl, N,N-di-[(l-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(l-6C)alkyl-(l-6C)alkanesulfonylamino and a group of the formula : -X4-R12 wherein X4 is a direct bond or is selected from O and N(R13), wherein R13 is hydrogen or (1-SQalkyl, and R12 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-( 1 -6C)alkyl or (1 -6C)alkoxycarbonylamino-( 1 -6C)alky 1; m is 1 or 2; each of R3 and R3a, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, or R3 and R3a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, and wherein any R3 or R3a optionally bears on carbon one or more (for example 1, 2 or 3) R14 substituents, which may be the same or different; R4 is selected from is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, carbamoyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (l-6C)alkoxycarbonyl and (l-6C)alkylsulfonyl, and wherein a R4 substituent optionally bears on carbon one or more (for example 1, 2 or 3) R15 substituents, which may be the same or different; R5 and R5a, which may be the same or different, is selected from hydrogen, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-4C)alkyl, heterocyclyl and heterocyclyl-(l-4C)alkyl, and wherein and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R5 or R5a substituent optionally bears on each said CH2 or CH3 one or more R16 substituents, which may be the same or different, and wherein any heterocyclyl group within a substituent on R5 or R5a optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different, selected from halogeno, (l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-4C)alkoxy-(2-4C)alkanoyl and (l-4C)alkylsulfonyl, and wherein any heterocyclyl group within a R5 or R5a substituent optionally bears 1 or 2 oxo or thioxo substituents, or R5 and R5a together with the nitrogen atom to which they are attached form a heterocyclyl group, which group optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, (l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-4C)alkoxy-(2-4C)alkanoyl and (l-4C)alkylsulfonyl, and wherein any heterocyclyl group formed by R5 and R5a together with the nitrogen atom to which they are attached, optionally bears 1 or 2 oxo or thioxo substituents; Z is O or S; q is 1 or 2; each R6, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, and (2-6C)alkynyl, and wherein R6 optionally bears on carbon one or more (for example 1, 2 or 3) R17 substituents, which may be the same or different; each R7, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, provided that when R7 is heterocyclyl or heteroaryl and q is 1, R7 is linked to the carbon carrying R6 and the R5aR5NC(Z) group by a ring carbon, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R7 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, S02, N(R18), CO, CH(OR18), CON(R18), N(R18)CO, SO2N(R18), N(R18)S02, CH=CH and OC wherein R18 is hydrogen or (l-6C)alkyl, and wherein any CH2=CH- or HC=C- group within a R7 substituent optionally bears at the terminal CH2= or HCH position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (1-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula : Q4X5- wherein X5 is a direct bond or is selected from CO and N(R19)CO, wherein R19 is hydrogen or (1-6C)alkyl, and Q4 is aryl, aryl-( 1-6C)alkyl, heteroaryl, heteroaryl-( 1-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -6C)alkyl, and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R7 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, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, formyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, NR32R33, (l-6C)alkoxycarbonyl, C(0)NR34R35, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(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 from a group of the formula : -X6-Q5 wherein X6 is a direct bond or is selected from O, S, SO, S02, N(R20), CO, CH(OR20), CON(R20), N(R20)CO, S02N(R20), N(R20)SO2, C(R20)2O, C(R20)2S and N(R20)C(R20)2, wherein R20 is hydrogen or (l-6C)alkyl, and Q5 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l -6C)alkyl, wherein each of R , R , R34 and R , which may be the same or different, is selected from .hydrogen (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein any of R32, R33, R34 and R35 optionally bears on carbon one or more R36 substituents, which may be the same or different, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R7 optionally bears one or more R21 substituents, which may be the same or different, and wherein any heterocyclyl group within a R7 substituent optionally bears 1 or 2 oxo or thioxo substituents; or R6 and R7 together with the carbon atom to which they are attached form a (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R22 substituents, which may be the same or different, and wherein any heterocyclyl group formed by R6 and R7 together with the carbon atom to which they are attached, optionally bears 1 or 2 oxo or thioxo substituents; or R7 and the group R5aR5NC(Z) together with the carbon atom to which they are attached form a heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R23 substituents, which may be the same or different, or R4 and the group R5aR5NC(Z) together with the atoms to which they are attached form a heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R24 substituents, which may be the same or different; each Ru, R21, R22, R23 and R24, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (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-[( 1 -6C)alkyl]amino, (1 -6C)alkoxycarbony 1, N-( 1 -6C)alkylcarbamoy 1, N,N-di-[( 1 -6C)alkyl]carbamoyl, N-( 1 -6C)alkylsulfamoyl, N,N-di-[( 1 -6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino, N-( 1 -6C)alkylsulfamoyl, N,N-di-[(l -6C)alkyl]sulfamoyl, (1 -6C)alkanesulfonylamino, N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, a group of the formula: -X7-R25 wherein X7 is a direct bond or is selected from O, N(R26) and C(O), wherein R26 is hydrogen or (l-6C)alkyl, and R25 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, (l-6C)alkylamino-(l-6C)alkyl, di-[( 1 -6C)alkyl]amino-( 1 -6C)alkyl, (2-6C)alkanoylamino-( 1 -6C)alkyl, N-( 1 -6C)alkyl-(2-6C)alkanoylamino-( 1 -6C)alkyl, (1 -6C)alkoxycarbonylamino-( 1 -6C)alkyl, carbamoyl-( 1 -6C)alkyl, N-( 1 -6C)alkylcarbamoyl-( 1 -6C)alkyl, N,N-di-[( 1 -6C)alkyl]carbamoyl-( 1 -6C)alkyl, (2-6C)alkanoyl-( 1 -6C)alkyl, (2-6C)alkanoyloxy-( 1 -6C)alky 1 or (1 -6C)alkoxycarbonyl-( 1 -6C)alkyl, and from a group of the formula: (Formula Removed) wherein X8 is a direct bond or is selected from O, S02, N(R31) and CO, wherein R31 is "hydrogen or (l-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, which optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different selected from halogeno, hydroxy, (l-4C)alkyl and (l-4C)alkoxy, and wherein R11, R21, R22, R23 and R24 optionally bears on carbon one or more (for example 1, 2 or 3) R29 substituents, which may be the same or different; each of R14, R15, R16 and R17, which may be the same or different, is selected from halogeno, hydroxy, cyano, (l-6C)alkoxy and NR27R28, wherein R27 and R28, which may be the same or different, are selected from hydrogen, formyl, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (2-4C)alkanoyl, and wherein any of R14, R15, R16 and R17 optionally bears on carbon one or more (for example 1,2 or 3) R30 substituents, which may be the same or different; R29, R30 and R36, which may be the same or different, are selected from halogeno, hydroxy, cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, vinyl, allyl and ethynyl; or a pharmaceutically acceptable salt thereof Further, the present invention relates to a process for the preparation of a quinazoline derivative of the formula I as defined in claim 1 which process comprises: preparing quinazolines of formula I in which Z is O, the coupling of a compound of the formula V, or a reactive derivative thereof: (Formula Removed) wherein R1, R2, R3, R3a, R4, R6' R7, a, m and p are as defined in claim 1, except that any functional group is protected if necessary, with an amine of the formula VI, or salt thereof: (Formula Removed) Wherein R5 and R5a are as hereinbefore defined, except that any functional group is protected if necessary. SUMMARY OF THE INVENTION 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 EGFR tyrosine kinase over that of the erbB2 tyrosine kinase. Accordingly, it may be possible to administer a compound according to the present invention at a dose that is sufficient to inhibit EGFR tyrosine kinase whilst having no significant effect upon erbB2 (or other) tyrosine kinases. The selective inhibition provided by the compounds according to the present invention may provide treatments for conditions mediated by EGFR tyrosine kinase, whilst reducing undesirable side effects that may be associated with the inhibition of other tyrosine kinases. DETAILED DESCRIPTION According to a first aspect of the invention there is provided a quinazoline derivative of the formula I: (Formula Removed) wherein: p is 1 or 2; each R1, which may be the same or different, is selected from hydrogen, hydroxyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula: We Claim: 1. A quinazoline compound of the formula I: (Formula Removed) wherein: p is 1 or 2; each R1, which may be the same or different, is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula : (Formula Removed) wherein X1 is a direct bond or is O, and Q1 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-( 1 -6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-( 1 -6C)alkyl, heterocyclyl as herein described or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R8), CO, CH(OR8), CON(R8), N(R8)CO, SO2N(R8), N(R8)SO2, CH=CH and C≡C wherein R8 is hydrogen or (1-6C)alkyl, and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogcno as herein described, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula : (Formula Removed) wherein X2 is a direct bond or is selected from CO and N(R9)CO, wherein R9 is hydrogen or (1-6C)alkyl, and Q2 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, ibrmyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsu!finyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-( 1 -6C)alkyl-(2-6C)alkanoylamino, N-( 1 -6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: (Formula Removed) wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R10), CO, CH(OR10), CON(R10), N(R10)CO, SO2N(R10), N(Rl0)SO2, C(Rl0)20, C(R10)2S and C(R10)2N(R10), wherein R10 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 or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears one or more R11 substituents, which may be the same or different, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents; a is 1, 2, 3, 4 or 5; each R2, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyioxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfmyl. (1-6C)alkylsulfonyI, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula : -X4-R12 wherein X4 is a direct bond or is selected from O and N(R13), wherein R11 is hydrogen or (1-6C)alkyl, and R12 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1- 6C)alkoxycarbonylamino-( 1 -6C)alkyl; m is 1 or 2; each of R and R3a, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, or R3 and R3a together with the carbon atom to which they are attached form a (3- 7C)cycloalkyl ring, and wherein any R3 or R3a optionally bears on carbon one or more (for example 1, 2 or 3) R substituents, which may be the same or different; R4 is selected from is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, carbamoyl, N-(1-6C)alky[carbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2- 6C)alkanoyl, (1-6C)alkoxycarbonyl and (1-6C)alkylsulfonyl, and wherein a R substituent optionally bears on carbon one or more (for example 1, 2 or 3) R13 substituents, which may be the same or different; R5 and R5a, which may be the same or different, is selected from hydrogen, (1- 4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l- 4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-4C)alkyl. heterocyclyl and heterocyclyl-(l-4C)alkyl, and wherein and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R5 or R5a substituent optionally bears on each said CH2 or CH3 one or more R16 substituents, which may be the same or different, and wherein any heterocyclyl group within a substituent on R5 or R5a optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different, selected from halogeno, (l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (1- 4C)alkoxy-(2-4C)a)kanoyl and (l-4C)alkylsulfonyl, and wherein any heterocyclyl group within a R5 or R5a substituent optionally bears 1 or 2 oxo or thioxo substituents, or R5 and R5a together with the nitrogen atom to which they are attached form a heterocyclyl group, which group optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, (1 - 4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-4C)alkoxy-(2-4C)alkanoyl and (l-4C)alkylsulfonyl, and wherein any heterocyclyl group formed by R3 and R5a together with the nitrogen atom to which they are attached, optionally bears 1 or 2 oxo or thioxo substituents; Z is O or S; q is 1 or 2; each R6, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, and (2-6C)alkynyl, and wherein R6 optionally bears on carbon one or more (for example 1, 2 or 3) R17 substituents, which may be the same or different; each R7, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3- 7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl, provided that when R7 is heterocyclyl or heteroaryl and q is 1, R7 is linked to the carbon carrying R6 and the R5aR5NC(Z) group by a ring carbon, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R18), CO, CH(OR18), CON(R18), N(R18)CO, SO2N(Rl8). N(R18)SO2, CH=CH and C≡C wherein R18 is hydrogen or (1-6C)alkyl, and wherein any CH2=CH- or HC≡C- group within a R7 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogcno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(l-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula : (Formula Removed) wherein X5 is a direct bond or is selected from CO and N(Rl9)CO, wherein R19 is hydrogen or (1-6C)alkyl, and Q4 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R7 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, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, formyl, (1-6C)alkoxy. (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, NR32R33, (1-6C)alkoxycarbonyl, C(O)NR34R35, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2- 6C)alkanoylamino, N-( 1 -6C)alkyl-(2-6C)alkanoylamino, N-( 1 -6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(l-6C)alkanesulfonylamino, or from a group of the formula : (Formula Removed) wherein X6 is a direct bond or is selected from O, S, SO, SO2, N(R20), CO, CH(OR20), CON(R20), N(R20)CO, SO2N(R20), N(R20)SO2, C(R20)2O, C(R20)2S and N(R20)C(R20)2, wherein R20 is hydrogen or (1-6C)alkyl, and Q5 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkcnyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -6C)alky 1, wherein each of R32, R33, R34 and R35, which may be the same or different, is selected from hydrogen (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein any of R32 R33 , R34 and R35 optionally bears on carbon one or more R36 substituents, which may be the same or different, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R7 optionally bears one or more R21 substituents, which may be the same or different, and wherein any heterocyclyl group within a R7 substituent optionally bears 1 or 2 oxo or thioxo substituents; or R6 and R7 together with the carbon atom to which they arc attached form a (3-7C)cycloalkyl, (3-7C)cycloaikenyl or heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R22 substituents, which may be the same or different, and wherein any heterocyclyl group formed by R6 and R together with the carbon atom to which they are attached, optionally bears 1 or 2 oxo or thioxo substituents; or R7 and the group R5aR5NC(Z) together with the carbon atom to which they arc attached form a heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R" substituents, which may be the same or different, or R4and the group R5aR5NC(Z) together with the atoms to which they are attached form a heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R24 substituents, which may be the same or different; each R11, R21, R22, R23, and R24, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy. (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl,N-(1-6C)alkylsulfamoyl, N,N-di-[( 1 -6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[( 1 -6C)alkyl]sulfamoyl, (1 -6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, a group of the formula: -X7-R25 wherein X7 is a direct bond or is selected from O, N(R26) and C(O), wherein R26 is hydrogen or (1-6C)alkyl, and R25 is halo geno-( 1 -6C)alkyl, hydroxy-( 1 -6C)alkyl, carboxy-( 1 -6C)alkyl, (1 -6C)alkoxy-( 1 -6C)alky 1, cyano-( 1 -6C)alkyl, amino-( 1 -6C)alkyl, (1 -6C)alkylamino-(1-6C)alkyl, di-[( 1 -6C)alkyl]amino-( 1 -6C)alkyl, (2-6C)alkanoylamino-( 1 -6C)alkyl, N-( 1 -6C)alkyl-(2-6C)alkanoylamino-( 1 -6C)alkyl, (1 -6C)alkoxycarbonylamino-( 1 -6C)alkyl, carbamoyl-( 1 -6C)alky 1, N-(1 -6C)alkylcarbamoyl-( 1 -6C)alkyl, N,N-di-[( 1 -6C)alkyl]carbamoyl-( 1 -6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl, (2-6C)alkanoyloxy-(1-6C)alkyl or (1 -6C)alkoxycarbony l-( 1 -6C)alky 1, and from a group of the formula: (Formula Removed) wherein X8 is a direct bond or is selected from O, SO2, N(R31 ) and CO, wherein R31 is hydrogen or (1-6C)alkyl, and Q is (3-7C)cycloalkyl, (3-7C)cycloalkyl-( 1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, which optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different selected from halogeno, hydroxy, (l-4C)alkyl and (l-4C)alkoxy, and wherein R11, R21, R22, R23 and R24 optionally bears on carbon one or more (for example 1, 2 or 3) R29 substituents, which may be the same or different; each of R14, R15, R16 and R17, which may be the same or different, is selected from halogeno, hydroxy, cyano, (1-6C)alkoxy and NR27R28, wherein R27 and R28, which may be the same or different, are selected from hydrogen, formyl, (l-4C)alkyl, (2- 4C)alkenyl, (2-4C)alkynyl and (2-4C)alkanoyl, and wherein any of R14, R15, R16 and R17 optionally bears on carbon one or more (for example 1, 2 or 3) R30 substituents, which may be the same or different; R29, R30 and R36 , which may be the same or different, are selected from halogeno, hydroxy, cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, vinyl, allyl and ethynyl; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim lor a pharmaceutically acceptable salt thereof wherein: q is 1; R5a is hydrogen; and R5 is selected from hydrogen, (l-4C)alkyl, (2-4C)alkenyl, and (2-4C)alkynyl. and wherein R5 optionally bears on carbon one or more R16 substitucnts, which may be the same or different, wherein R1 is as defined in claim 1. 3. A compound as claimed in claim 1 or claim 2 or a pharmaceutically acceptable salt thereof wherein Z is O. 4. A compound as claimed in any one of the preceding claims or a pharmaceutically acceptable salt thereof wherein R4 is (l-4C)alkyl and wherein R optionally bears on carbon one or more R15 substituents, which may be the same or different, wherein R15 is selected from halogeno, hydroxy, cyano, (l-3C)alkoxy. 5. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein m is 1; R3a is hydrogen and R3 is hydrogen or (1-4C)alkyl. 6. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein m is 1; q is 1; Z is O; R3a is hydrogen; and R15 is selected from hydrogen, (l-4C)alkyl, (2-4C)alkenyl, and (2-4C)alkynyl, and wherein R optionally bears on carbon one or more substituents, which may be the same or different, selected from hydroxy and (l-3C)alkoxy. 7. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein one of R6 and R7 is not hydrogen. 8. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein R is selected from (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, provided that when R7 is heterocyclyl and q is 1, R7 is linked to the carbon carrying R6 and the R5aR5NC(Z) group by a ring carbon, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R7 substituent are optionally separated by the insertion into the chain of a group selected from O, S, N(R18), CON(R18), N(Rl8)CO, CH=CH and C≡C wherein R18 is hydrogen or(1-6C)alkyl, and wherein any CH2=CH- or HC≡C- group within a R7 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl\|carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula : (Formula Removed) wherein X is a direct bond or is selected from CO and N(R19)CO, wherein R19 is hydrogen or (1-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R7 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, cyano, amino, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of the formula : (Formula Removed) wherein X6 is a direct bond or is selected from O, S, N(R20), CON(R20), N(R20)CO and C(R20)2O, wherein R20 is hydrogen or (1-6C)alkyl, and Q5 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R7 optionally bears one or more (for example 1, 2 or 3) R21 substituents, which may be the same or different, as defined in claim 1, and wherein any heterocyclyl group within a R7 substituent optionally bears 1 or 2 oxo or thioxo substituents; or R6 and R7 together with the carbon atom to which they are attached form a (3-7C)cycloalky(, (3-7C)cycloalkeny( or heterocyclyl group, which group optionally bears one or more R22 substituents, which may be the same or different, as defined in claim 1, and wherein any heterocyclyl group formed by R and R together with the carbon atom to which they are attached, optionally bears 1 or 2 oxo substituents; or R7 and the group R5aR5NC(Z) together with the carbon atom to which they are attached form a heterocyclyl group, which group optionally bears one or more R23 substituents, which may be the same or different, as defined in claim 1. 9. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein R7 is selected from methyl, ethyl, isopropyl. hydroxymethyl, methoxymethyl, isopropyloxymethyl, 2-hydroxyethyl. 2-methoxyethyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-(methylamino)ethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, pyrrolidin-3-yl and l-methylpyrrolidin-3-yl, or R and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-3-en-l-yl, azetidin-3-yl, piperidin-3-yl, piperidin-4-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, which group optionally bears 1 or 2 substituents, which may be the same or different, selected from (l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-3C)alkoxy-(l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-3C)alkoxy-(2-4C)alkanoyl, (1-4C)alkylsulfonyl, carbamoyl-(l-4C)alkyl, N-(l-4C)alkylcarbamoyl-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]carbamoyl-(l-4C)alkyl, or R7 and the group R5aR5NC(Z) together with the carbon atom to which they are attached form a heterocyclyl group selected from a group of the formula: (Formula Removed) wherein R6 is hydrogen, and R5a is selected from hydrogen, methyl and ethyl; n is 0, 1 or 2; and each R23, which may be the same or different, is methyl. 10. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein R6 is hydrogen. 11. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein a is 1, 2 or 3 and each R2, which may be the same or different, is selected from halogeno and (2-4C)alkynyl. 12. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein p is 1, R1 is located at the 7-position and R1 is selected from (l-3C)alkoxy, hydroxy-(2-3C)alkoxy and (l-3C)alkoxy-(2-3C)alkoxy. 13. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein the anilino group at the 4-position on the quinazoline ring in formula (I) is selected from 3-chloro-2-fluoroanilino, 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2,4-difluoroanilino, 3-chloro-2,6-difluoroanilino and 3-chloro-5-fluoroanilino. 14. A compound as claimed in claim 1: (Formula Removed) wherein: R1 is selected from (l-3C)alkoxy, hydroxy-(2-3C)alkoxy and (l-3C)alkoxy-(2- 3C)alkoxy; R2a is selected from fluoro, chloro and bromo; one of R2band R2c is selected from fluoro, chloro and bromo, and the other of R2b and R2c is hydrogen; R3a is hydrogen; R3 is selected from hydrogen and (l-3C)alkyl; R4is(l-3C)alkyl; R5 is selected from hydrogen and (l-3C)alkyl; R6 is selected from hydrogen and (l-3c)alkyl; R7 is selected from methyl, ethyl, isopropyl, hydroxymethyl, methoxymethyl. isopropyloxymethyl, 2-hydroxyethyl, 2-methoxyethyl, aminomcthyl, 2-aminoethyl, methylaminomethyl, 2-(methylamino)ethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, pyrrolidin-3-yl and l-methylpyrrolidin-3-yl, or R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-3-en-l-yl, azetidin-3-yl, piperidin-3-yl, piperidin-4-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, which group optionally bears 1 or 2 substituents, which may be the same or different, selected from (l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-3C)a!koxy-(l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-3C)alkoxy-(2-4C)alkanoyl, (1-4C)alkylsulfonyl, carbamoyl-(1-4C)alkyl, N-(l-4C)alkylcarbamoyl-(l-4C)alkyl and N,N-di-[( 1 -4C)alkyl]carbamoyl-( 1 -4C)alkyl, or R7 and the group R5NHC(O) together with the carbon atom to which they arc-attached form a heterocyclyl group selected from a group of the formula: (Formula Removed) wherein R6 is hydrogen; n is 0, 1 or 2 and each R23, which may be the same or different, is methyl (particularly n is 0); or a pharmaceutically acceptable salt thereof. 15. A compound as claimed in claim 1 selected from: N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2- methylglycinamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-methyl-D-alaninamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-methyl-L-alaninamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-methyl-L-serinamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-D-alaninamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)glycinamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-L-serinamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-D-serinamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-L-homoserinamide; N2-({4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-L-serinamide; N2-({4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-methyl-D-alaninamide; 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl) amino]-1 -isopropylazetidine-3-carboxamide; 3-f({4-[(3-chloro-2-fluorophenyl)aminol-7-methoxyquinazolin-6-yl}methyl)(methyl) amino] -l-methylazetidine-3-carboxamide; ]-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopropanecarboxamide; 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-l-methylpiperidine-3-carboxamide; l-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopent-3-ene-l-carboxamide; 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6- yl}methyl)(methyl)amino]-N,l-dimethylpiperidine-4-carboxamide; 4-[({4-[(3-chloro-2-fluorophenyl)arnino]-7-methoxyquinazolin-6- yl}methyl)(methyl)amino]-l-methylpiperidine-4-carboxamide; N2-{[4-[(3-chloro-2-fluorophenyl)amino]-7-(2-methoxyethoxy)quinazolin-6- yl]methyl}-N2-rnethyl-D-alaninamide; 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6- yl}methyl)(methyl)amino]-l-(2-methoxyethyl)azetidine-3-carboxamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl} methyl)- N2- ethyl-D-alaninamide; oro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino\|-2-(l- methylpyrrolidin-3-yljacetamide; N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-Nl,N2- dimethyl-D-alaninamide; l-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6- yl}methyl)(ethyl)amino]cyclopropanecarboxamide; and N2-(l-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethyl)-N2- methyl-D-alaninamide; or a pharmaceutically acceptable salt thereof. 16. A pharmaceutical composition comprising a quinazoline compound of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 or claim 2 alongwith a pharmaceutically-acceptable diluent or carrier. 17. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 or claim 2, for use as a medicament. 18. A process for the preparing a quinazoline compound of the formula I as claimed in claim 1 which comprises of: coupling of a compound of the formula V, or a reactive derivative thereof: (Formula Removed) wherein R1, R2, R3, R3a, R4, R6, R7, a, m and p are as defined in claim 1 and Z is O, except that any functional group is protected if necessary, with an amine of the formula VI, or salt thereof: (Formula Removed) wherein R3 and R5a are as hereinbefore defined, except that any functional group is protected if necessary. 19. A quinazoline compound of the formula (I), process for preparing and a pharmaceutical composition comprising a compound of the formula (1) substantially as herein described with reference to the foregoing examples.

Full Text

FIELD OF THE INVENTION
The 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 compounds, 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 signaling 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

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 receptor tyrosine kinase.
STATEMENT OF THE INVENTION
Accordingly the present invention relates to a quinazoline derivative of the formula I:
(Formula Removed)
wherein:
p is 1 or 2;
each R1, which may be the same or different, is selected from hydrogen, hydroxy, (l-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula :
-X1-wherein X1 is a direct bond or is O, and Q1 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R8), CO, CH(OR8), CON(R8), N(R8)CO, SO2N(R8), N(R8)S02, CH=CH and OC wherein R8 is hydrogen or(l-6C)alkyl,

and wherein any CH2=CH- or HOC- group within a R1 substituent optionally bears at the
germinal CH2= or HOs position a substituent selected from halogeno, carboxy, carbamoyl,
1
(l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl,
(l-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula
(Formula Removed)
wherein X2 is a direct bond or is selected from CO and N(R9)CO, wherein R9 is hydrogen or (l-6C)alkyl, and Q2 is heterocyclyl or heterocyclyl-(l-6C)alkyl,
and wherein any CH2 or CH3 group within a R1 substituent, 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, oxo, thioxo, formyl, (l-6C)alkoxy, (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, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(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 from a group of the formula:
-X3Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R10), CO, CH(OR10), CON(R10), N(R10)CO, S02N(R10), N(R10)SO2, C(R10)2O, C(R10)2S and C(R10)2N(R10), wherein R10 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 or heterocyclyl-(l-6C)alkyl,
and wherein any heterocyclyl group within a substituent on R1 optionally bears one or more R11 substituents, which may be the same or different,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents;
a is 1, 2, 3,4 or 5;
each R2, which may be the same or different, is selected from halogeno, cyano, nitro,
hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifiuoromethyl, trifluoromethoxy, (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, (2-
6C)alkanoyloxy, (2-6C)alkanoylamino, N-( 1 -6C)alkyl-(2-6C)alkanoylamino,
N-(l-6C)alkylsulfamoyl, N,N-di-[(l-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(l-6C)alkyl-(l-6C)alkanesulfonylamino and a group of the formula :
-X4-R12

wherein X4 is a direct bond or is selected from O and N(R13), wherein R13 is hydrogen or (1-SQalkyl, and R12 is halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, (2-6C)alkanoylamino-( 1 -6C)alkyl or (1 -6C)alkoxycarbonylamino-( 1 -6C)alky 1;
m is 1 or 2;
each of R3 and R3a, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, or
R3 and R3a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring,
and wherein any R3 or R3a optionally bears on carbon one or more (for example 1, 2 or 3) R14 substituents, which may be the same or different;
R4 is selected from is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, carbamoyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (l-6C)alkoxycarbonyl and (l-6C)alkylsulfonyl,
and wherein a R4 substituent optionally bears on carbon one or more (for example 1, 2 or 3) R15 substituents, which may be the same or different;
R5 and R5a, which may be the same or different, is selected from hydrogen, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-4C)alkyl, heterocyclyl and heterocyclyl-(l-4C)alkyl,
and wherein and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R5 or R5a substituent optionally bears on each said CH2 or CH3 one or more R16 substituents, which may be the same or different,
and wherein any heterocyclyl group within a substituent on R5 or R5a optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different, selected from halogeno, (l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-4C)alkoxy-(2-4C)alkanoyl and (l-4C)alkylsulfonyl,
and wherein any heterocyclyl group within a R5 or R5a substituent optionally bears 1 or 2 oxo or thioxo substituents,
or R5 and R5a together with the nitrogen atom to which they are attached form a heterocyclyl group, which group optionally bears one or more substituents (for example 1, 2 or 3), which may be the same or different, selected from halogeno, (l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-4C)alkoxy-(2-4C)alkanoyl and (l-4C)alkylsulfonyl,
and wherein any heterocyclyl group formed by R5 and R5a together with the nitrogen atom to which they are attached, optionally bears 1 or 2 oxo or thioxo substituents;
Z is O or S;
q is 1 or 2;

each R6, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, and (2-6C)alkynyl,
and wherein R6 optionally bears on carbon one or more (for example 1, 2 or 3) R17 substituents, which may be the same or different;
each R7, which may be the same or different, is selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl and heterocyclyl-(l-6C)alkyl, provided that when R7 is heterocyclyl or heteroaryl and q is 1, R7 is linked to the carbon carrying R6 and the R5aR5NC(Z) group by a ring carbon,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R7 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, S02, N(R18), CO, CH(OR18), CON(R18), N(R18)CO, SO2N(R18), N(R18)S02, CH=CH and OC wherein R18 is hydrogen or (l-6C)alkyl,
and wherein any CH2=CH- or HC=C- group within a R7 substituent optionally bears at the terminal CH2= or HCH position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(l-6C)alkyl, (1-6C)alkylamino-(l-6C)alkyl and di-[(l-6C)alkyl]amino-(l-6C)alkyl or from a group of the formula : Q4X5-
wherein X5 is a direct bond or is selected from CO and N(R19)CO, wherein R19 is hydrogen or (1-6C)alkyl, and Q4 is aryl, aryl-( 1-6C)alkyl, heteroaryl, heteroaryl-( 1-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -6C)alkyl,
and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R7 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, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, formyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulfinyl, (l-6C)alkylsulfonyl, NR32R33, (l-6C)alkoxycarbonyl, C(0)NR34R35, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(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 from a group of the formula :
-X6-Q5 wherein X6 is a direct bond or is selected from O, S, SO, S02, N(R20), CO, CH(OR20), CON(R20), N(R20)CO, S02N(R20), N(R20)SO2, C(R20)2O, C(R20)2S and N(R20)C(R20)2, wherein R20 is hydrogen or (l-6C)alkyl, and Q5 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l -6C)alkyl,

wherein each of R , R , R34 and R , which may be the same or different, is selected from .hydrogen (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein any of R32, R33, R34 and R35 optionally bears on carbon one or more R36 substituents, which may be the same or different,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R7 optionally bears one or more R21 substituents, which may be the same or different,
and wherein any heterocyclyl group within a R7 substituent optionally bears 1 or 2 oxo or thioxo substituents;
or R6 and R7 together with the carbon atom to which they are attached form a (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R22 substituents, which may be the same or different,
and wherein any heterocyclyl group formed by R6 and R7 together with the carbon atom to which they are attached, optionally bears 1 or 2 oxo or thioxo substituents;
or R7 and the group R5aR5NC(Z) together with the carbon atom to which they are attached form a heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R23 substituents, which may be the same or different,
or R4 and the group R5aR5NC(Z) together with the atoms to which they are attached form a heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R24 substituents, which may be the same or different;
each Ru, R21, R22, R23 and R24, which may be the same or different, is selected from
halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto,
sulfamoyl, (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-[( 1 -6C)alkyl]amino, (1 -6C)alkoxycarbony 1, N-( 1 -6C)alkylcarbamoy 1,
N,N-di-[( 1 -6C)alkyl]carbamoyl, N-( 1 -6C)alkylsulfamoyl, N,N-di-[( 1 -6C)alkyl]sulfamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l-6C)alkyl-(2-6C)alkanoylamino,
N-( 1 -6C)alkylsulfamoyl, N,N-di-[(l -6C)alkyl]sulfamoyl, (1 -6C)alkanesulfonylamino,
N-(l-6C)alkyl-(l-6C)alkanesulfonylamino, a group of the formula:
-X7-R25
wherein X7 is a direct bond or is selected from O, N(R26) and C(O), wherein R26 is hydrogen or
(l-6C)alkyl, and R25 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, (l-6C)alkylamino-(l-6C)alkyl,
di-[( 1 -6C)alkyl]amino-( 1 -6C)alkyl, (2-6C)alkanoylamino-( 1 -6C)alkyl,
N-( 1 -6C)alkyl-(2-6C)alkanoylamino-( 1 -6C)alkyl, (1 -6C)alkoxycarbonylamino-( 1 -6C)alkyl,
carbamoyl-( 1 -6C)alkyl, N-( 1 -6C)alkylcarbamoyl-( 1 -6C)alkyl,
N,N-di-[( 1 -6C)alkyl]carbamoyl-( 1 -6C)alkyl, (2-6C)alkanoyl-( 1 -6C)alkyl,
(2-6C)alkanoyloxy-( 1 -6C)alky 1 or (1 -6C)alkoxycarbonyl-( 1 -6C)alkyl, and from a group of the formula:

(Formula Removed)
wherein X8 is a direct bond or is selected from O, S02, N(R31) and CO, wherein R31 is "hydrogen or (l-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, which optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different selected from halogeno, hydroxy, (l-4C)alkyl and (l-4C)alkoxy,
and wherein R11, R21, R22, R23 and R24 optionally bears on carbon one or more (for example 1, 2 or 3) R29 substituents, which may be the same or different;
each of R14, R15, R16 and R17, which may be the same or different, is selected from halogeno, hydroxy, cyano, (l-6C)alkoxy and NR27R28, wherein R27 and R28, which may be the same or different, are selected from hydrogen, formyl, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (2-4C)alkanoyl,
and wherein any of R14, R15, R16 and R17 optionally bears on carbon one or more (for example 1,2 or 3) R30 substituents, which may be the same or different;
R29, R30 and R36, which may be the same or different, are selected from halogeno, hydroxy, cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, vinyl, allyl and ethynyl; or a pharmaceutically acceptable salt thereof
Further, the present invention relates to a process for the preparation of a quinazoline derivative of the formula I as defined in claim 1 which process comprises:
preparing quinazolines of formula I in which Z is O, the coupling of a compound of the formula V, or a reactive derivative thereof:
(Formula Removed)

wherein R1, R2, R3, R3a, R4, R6' R7, a, m and p are as defined in claim 1, except that any functional group is protected if necessary, with an amine of the formula VI, or salt thereof:
(Formula Removed)

Wherein R5 and R5a are as hereinbefore defined, except that any functional group is protected if necessary.
SUMMARY OF THE INVENTION
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 EGFR tyrosine kinase over that of the erbB2 tyrosine kinase. Accordingly, it may be possible to administer a compound according to the present invention at a dose that is sufficient to inhibit EGFR tyrosine kinase whilst having no significant effect upon erbB2 (or other) tyrosine kinases. The selective inhibition provided by the compounds according to the present invention may provide treatments for conditions mediated by EGFR tyrosine kinase, whilst reducing undesirable side effects that may be associated with the inhibition of other tyrosine kinases.
DETAILED DESCRIPTION
According to a first aspect of the invention there is provided a quinazoline derivative of the formula I:
(Formula Removed)

wherein:
p is 1 or 2;
each R1, which may be the same or different, is selected from hydrogen, hydroxyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula:

We Claim:
1. A quinazoline compound of the formula I:
(Formula Removed)
wherein: p is 1 or 2;
each R1, which may be the same or different, is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula :

(Formula Removed)
wherein X1 is a direct bond or is O, and Q1 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-( 1 -6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-( 1 -6C)alkyl, heterocyclyl as herein described or heterocyclyl-(1-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R8), CO, CH(OR8), CON(R8), N(R8)CO, SO2N(R8), N(R8)SO2, CH=CH and C≡C wherein R8 is hydrogen or (1-6C)alkyl,
and wherein any CH2=CH- or HC≡C- group within a R1 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogcno as herein described, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula :

(Formula Removed)
wherein X2 is a direct bond or is selected from CO and N(R9)CO, wherein R9 is hydrogen or (1-6C)alkyl, and Q2 is heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2or CH3 group one
or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, ibrmyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsu!finyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-( 1 -6C)alkyl-(2-6C)alkanoylamino, N-( 1 -6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula:

(Formula Removed)

wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R10), CO, CH(OR10), CON(R10), N(R10)CO, SO2N(R10), N(Rl0)SO2, C(Rl0)20, C(R10)2S and C(R10)2N(R10), wherein R10 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 or heterocyclyl-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on R1 optionally bears one or more R11 substituents, which may be the same or different,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents;
a is 1, 2, 3, 4 or 5;
each R2, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyioxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfmyl. (1-6C)alkylsulfonyI, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula :
-X4-R12 wherein X4 is a direct bond or is selected from O and N(R13), wherein R11 is hydrogen or (1-6C)alkyl, and R12 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,
di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1-
6C)alkoxycarbonylamino-( 1 -6C)alkyl;
m is 1 or 2;
each of R and R3a, which may be the same or different, is selected from hydrogen
and (1-6C)alkyl, or
R3 and R3a together with the carbon atom to which they are attached form a (3-
7C)cycloalkyl ring,
and wherein any R3 or R3a optionally bears on carbon one or more (for example 1, 2 or
3) R substituents, which may be the same or different;
R4 is selected from is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-
6C)alkynyl, carbamoyl, N-(1-6C)alky[carbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-
6C)alkanoyl, (1-6C)alkoxycarbonyl and (1-6C)alkylsulfonyl,
and wherein a R substituent optionally bears on carbon one or more (for example 1, 2
or 3) R13 substituents, which may be the same or different;
R5 and R5a, which may be the same or different, is selected from hydrogen, (1-
4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(l-
4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(l-4C)alkyl. heterocyclyl and
heterocyclyl-(l-4C)alkyl,
and wherein and wherein any CH2 or CH3, other than a CH2 group within a
heterocyclyl ring, within a R5 or R5a substituent optionally bears on each said CH2 or
CH3 one or more R16 substituents, which may be the same or different,
and wherein any heterocyclyl group within a substituent on R5 or R5a optionally bears
one or more (for example 1, 2 or 3) substituents, which may be the same or different,
selected from halogeno, (l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (1-
4C)alkoxy-(2-4C)a)kanoyl and (l-4C)alkylsulfonyl,
and wherein any heterocyclyl group within a R5 or R5a substituent optionally bears 1
or 2 oxo or thioxo substituents,
or R5 and R5a together with the nitrogen atom to which they are attached form a
heterocyclyl group, which group optionally bears one or more substituents (for
example 1, 2 or 3), which may be the same or different, selected from halogeno, (1 -
4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-4C)alkoxy-(2-4C)alkanoyl and
(l-4C)alkylsulfonyl,
and wherein any heterocyclyl group formed by R3 and R5a together with the nitrogen
atom to which they are attached, optionally bears 1 or 2 oxo or thioxo substituents;
Z is O or S;
q is 1 or 2;
each R6, which may be the same or different, is selected from hydrogen, (1-6C)alkyl,
(2-6C)alkenyl, and (2-6C)alkynyl,
and wherein R6 optionally bears on carbon one or more (for example 1, 2 or 3) R17
substituents, which may be the same or different;
each R7, which may be the same or different, is selected from hydrogen, (1-6C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl, aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-
7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl,
provided that when R7 is heterocyclyl or heteroaryl and q is 1, R7 is linked to the
carbon carrying R6 and the R5aR5NC(Z) group by a ring carbon,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R18), CO, CH(OR18), CON(R18), N(R18)CO, SO2N(Rl8). N(R18)SO2, CH=CH and C≡C wherein R18 is hydrogen or (1-6C)alkyl,
and wherein any CH2=CH- or HC≡C- group within a R7 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from halogcno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(l-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula :

(Formula Removed)
wherein X5 is a direct bond or is selected from CO and N(Rl9)CO, wherein R19 is hydrogen or (1-6C)alkyl, and Q4 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R7 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, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, formyl, (1-6C)alkoxy. (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, NR32R33, (1-6C)alkoxycarbonyl, C(O)NR34R35, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-
6C)alkanoylamino, N-( 1 -6C)alkyl-(2-6C)alkanoylamino, N-( 1 -6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(l-6C)alkanesulfonylamino, or from a group of the formula :

(Formula Removed)

wherein X6 is a direct bond or is selected from O, S, SO, SO2, N(R20), CO, CH(OR20), CON(R20), N(R20)CO, SO2N(R20), N(R20)SO2, C(R20)2O, C(R20)2S and N(R20)C(R20)2, wherein R20 is hydrogen or (1-6C)alkyl, and Q5 is aryl, aryl-(l-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkcnyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-( 1 -6C)alky 1,
wherein each of R32, R33, R34 and R35, which may be the same or different, is selected from hydrogen (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein any of R32 R33 , R34 and R35 optionally bears on carbon one or more R36 substituents, which may be the same or different,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R7 optionally bears one or more R21 substituents, which may be the same or different, and wherein any heterocyclyl group within a R7 substituent optionally bears 1 or 2 oxo or thioxo substituents;
or R6 and R7 together with the carbon atom to which they arc attached form a (3-7C)cycloalkyl, (3-7C)cycloaikenyl or heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R22 substituents, which may be the same or different,
and wherein any heterocyclyl group formed by R6 and R together with the carbon atom to which they are attached, optionally bears 1 or 2 oxo or thioxo substituents; or R7 and the group R5aR5NC(Z) together with the carbon atom to which they arc attached form a heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R" substituents, which may be the same or different, or R4and the group R5aR5NC(Z) together with the atoms to which they are attached form a heterocyclyl group, which group optionally bears one or more (for example 1, 2 or 3) R24 substituents, which may be the same or different;
each R11, R21, R22, R23, and R24, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy.
(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl,N-(1-6C)alkylsulfamoyl, N,N-di-[( 1 -6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[( 1 -6C)alkyl]sulfamoyl, (1 -6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, a group of the formula:
-X7-R25 wherein X7 is a direct bond or is selected from O, N(R26) and C(O), wherein R26 is hydrogen or (1-6C)alkyl, and R25 is halo geno-( 1 -6C)alkyl, hydroxy-( 1 -6C)alkyl, carboxy-( 1 -6C)alkyl, (1 -6C)alkoxy-( 1 -6C)alky 1, cyano-( 1 -6C)alkyl, amino-( 1 -6C)alkyl, (1 -6C)alkylamino-(1-6C)alkyl, di-[( 1 -6C)alkyl]amino-( 1 -6C)alkyl, (2-6C)alkanoylamino-( 1 -6C)alkyl, N-( 1 -6C)alkyl-(2-6C)alkanoylamino-( 1 -6C)alkyl, (1 -6C)alkoxycarbonylamino-( 1 -6C)alkyl, carbamoyl-( 1 -6C)alky 1, N-(1 -6C)alkylcarbamoyl-( 1 -6C)alkyl, N,N-di-[( 1 -6C)alkyl]carbamoyl-( 1 -6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl, (2-6C)alkanoyloxy-(1-6C)alkyl or (1 -6C)alkoxycarbony l-( 1 -6C)alky 1, and from a group of the formula:
(Formula Removed)
wherein X8 is a direct bond or is selected from O, SO2, N(R31 ) and CO, wherein R31 is hydrogen or (1-6C)alkyl, and Q is (3-7C)cycloalkyl, (3-7C)cycloalkyl-( 1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, which optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different selected from halogeno, hydroxy, (l-4C)alkyl and (l-4C)alkoxy, and wherein R11, R21, R22, R23 and R24 optionally bears on carbon one or more (for
example 1, 2 or 3) R29 substituents, which may be the same or different;
each of R14, R15, R16 and R17, which may be the same or different, is selected from
halogeno, hydroxy, cyano, (1-6C)alkoxy and NR27R28, wherein R27 and R28, which
may be the same or different, are selected from hydrogen, formyl, (l-4C)alkyl, (2-
4C)alkenyl, (2-4C)alkynyl and (2-4C)alkanoyl,
and wherein any of R14, R15, R16 and R17 optionally bears on carbon one or more (for
example 1, 2 or 3) R30 substituents, which may be the same or different;
R29, R30 and R36 , which may be the same or different, are selected from halogeno, hydroxy, cyano, amino, methylamino, dimethylamino, methoxy, ethoxy, vinyl, allyl and ethynyl; or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim lor a pharmaceutically acceptable salt thereof
wherein:
q is 1;
R5a is hydrogen; and
R5 is selected from hydrogen, (l-4C)alkyl, (2-4C)alkenyl, and (2-4C)alkynyl.
and wherein R5 optionally bears on carbon one or more R16 substitucnts, which may
be the same or different, wherein R1 is as defined in claim 1.
3. A compound as claimed in claim 1 or claim 2 or a pharmaceutically acceptable salt thereof wherein Z is O.
4. A compound as claimed in any one of the preceding claims or a pharmaceutically acceptable salt thereof wherein R4 is (l-4C)alkyl and wherein R optionally bears on carbon one or more R15 substituents, which may be the same or different, wherein R15 is selected from halogeno, hydroxy, cyano, (l-3C)alkoxy.
5. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein m is 1; R3a is hydrogen and R3 is hydrogen or (1-4C)alkyl.
6. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein m is 1; q is 1; Z is O; R3a is hydrogen; and R15 is selected from hydrogen, (l-4C)alkyl, (2-4C)alkenyl, and (2-4C)alkynyl,
and wherein R optionally bears on carbon one or more substituents, which may be the same or different, selected from hydroxy and (l-3C)alkoxy.
7. A compound as claimed in any one of the preceding claims, or a pharmaceutically
acceptable salt thereof wherein one of R6 and R7 is not hydrogen.
8. A compound as claimed in any one of the preceding claims, or a pharmaceutically
acceptable salt thereof wherein R is
selected from (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, provided that when R7 is heterocyclyl and q is 1, R7 is linked to the carbon carrying R6 and the R5aR5NC(Z) group by a ring carbon,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R7 substituent are optionally separated by the insertion into the chain of a group selected from O, S, N(R18), CON(R18), N(Rl8)CO, CH=CH and C≡C wherein R18 is hydrogen or(1-6C)alkyl,
and wherein any CH2=CH- or HC≡C- group within a R7 substituent optionally bears at the terminal CH2= or HC≡ position a substituent selected from carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl|carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula :
(Formula Removed)
wherein X is a direct bond or is selected from CO and N(R19)CO, wherein R19 is hydrogen or (1-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH2 or CH3, other than a CH2 group within a heterocyclyl ring, within a R7 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, cyano, amino, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of the formula :
(Formula Removed)
wherein X6 is a direct bond or is selected from O, S, N(R20), CON(R20), N(R20)CO and C(R20)2O, wherein R20 is hydrogen or (1-6C)alkyl, and Q5 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on R7 optionally bears one
or more (for example 1, 2 or 3) R21 substituents, which may be the same or different, as defined in claim 1,
and wherein any heterocyclyl group within a R7 substituent optionally bears 1 or 2 oxo or thioxo substituents;
or R6 and R7 together with the carbon atom to which they are attached form a (3-7C)cycloalky(, (3-7C)cycloalkeny( or heterocyclyl group, which group optionally bears one or more R22 substituents, which may be the same or different, as defined in claim 1,
and wherein any heterocyclyl group formed by R and R together with the carbon atom to which they are attached, optionally bears 1 or 2 oxo substituents; or R7 and the group R5aR5NC(Z) together with the carbon atom to which they are attached form a heterocyclyl group, which group optionally bears one or more R23 substituents, which may be the same or different, as defined in claim 1.
9. A compound as claimed in any one of the preceding claims, or a pharmaceutically
acceptable salt thereof wherein R7 is selected from methyl, ethyl, isopropyl. hydroxymethyl, methoxymethyl, isopropyloxymethyl, 2-hydroxyethyl. 2-methoxyethyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-(methylamino)ethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, pyrrolidin-3-yl and l-methylpyrrolidin-3-yl,
or R and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-3-en-l-yl, azetidin-3-yl, piperidin-3-yl, piperidin-4-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, which group optionally bears 1 or 2 substituents, which may be the same or different, selected from (l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-3C)alkoxy-(l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-3C)alkoxy-(2-4C)alkanoyl, (1-4C)alkylsulfonyl, carbamoyl-(l-4C)alkyl, N-(l-4C)alkylcarbamoyl-(l-4C)alkyl and N,N-di-[(l-4C)alkyl]carbamoyl-(l-4C)alkyl,
or R7 and the group R5aR5NC(Z) together with the carbon atom to which they are attached form a heterocyclyl group selected from a group of the formula:
(Formula Removed)
wherein R6 is hydrogen, and R5a is selected from hydrogen, methyl and ethyl; n is 0, 1 or 2; and each R23, which may be the same or different, is methyl.
10. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein R6 is hydrogen.
11. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein a is 1, 2 or 3 and each R2, which may be the same or different, is selected from halogeno and (2-4C)alkynyl.
12. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein p is 1, R1 is located at the 7-position and R1 is selected from (l-3C)alkoxy, hydroxy-(2-3C)alkoxy and (l-3C)alkoxy-(2-3C)alkoxy.
13. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof wherein the anilino group at the 4-position on the quinazoline ring in formula (I) is selected from 3-chloro-2-fluoroanilino, 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2,4-difluoroanilino, 3-chloro-2,6-difluoroanilino and 3-chloro-5-fluoroanilino.
14. A compound as claimed in claim 1:
(Formula Removed)
wherein:
R1 is selected from (l-3C)alkoxy, hydroxy-(2-3C)alkoxy and (l-3C)alkoxy-(2-
3C)alkoxy;
R2a is selected from fluoro, chloro and bromo;
one of R2band R2c is selected from fluoro, chloro and bromo, and the other of R2b and R2c is hydrogen; R3a is hydrogen;
R3 is selected from hydrogen and (l-3C)alkyl; R4is(l-3C)alkyl;
R5 is selected from hydrogen and (l-3C)alkyl; R6 is selected from hydrogen and (l-3c)alkyl;
R7 is selected from methyl, ethyl, isopropyl, hydroxymethyl, methoxymethyl. isopropyloxymethyl, 2-hydroxyethyl, 2-methoxyethyl, aminomcthyl, 2-aminoethyl, methylaminomethyl, 2-(methylamino)ethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, pyrrolidin-3-yl and l-methylpyrrolidin-3-yl,
or R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopent-3-en-l-yl, azetidin-3-yl, piperidin-3-yl, piperidin-4-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, which group optionally bears 1 or 2 substituents, which may be the same or different, selected from (l-4C)alkyl, hydroxy-(l-4C)alkyl, (l-3C)a!koxy-(l-4C)alkyl, (2-4C)alkanoyl, hydroxy-(2-4C)alkanoyl, (l-3C)alkoxy-(2-4C)alkanoyl, (1-4C)alkylsulfonyl, carbamoyl-(1-4C)alkyl, N-(l-4C)alkylcarbamoyl-(l-4C)alkyl and N,N-di-[( 1 -4C)alkyl]carbamoyl-( 1 -4C)alkyl,
or R7 and the group R5NHC(O) together with the carbon atom to which they arc-attached form a heterocyclyl group selected from a group of the formula:
(Formula Removed)
wherein R6 is hydrogen;
n is 0, 1 or 2 and each R23, which may be the same or different, is methyl (particularly n is 0); or a pharmaceutically acceptable salt thereof.
15. A compound as claimed in claim 1 selected from:
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-
methylglycinamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-methyl-D-alaninamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-methyl-L-alaninamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-methyl-L-serinamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-D-alaninamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)glycinamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-L-serinamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-D-serinamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-L-homoserinamide;
N2-({4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-L-serinamide;
N2-({4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2-methyl-D-alaninamide;
3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl) amino]-1 -isopropylazetidine-3-carboxamide;
3-f({4-[(3-chloro-2-fluorophenyl)aminol-7-methoxyquinazolin-6-yl}methyl)(methyl) amino] -l-methylazetidine-3-carboxamide; ]-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopropanecarboxamide; 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-l-methylpiperidine-3-carboxamide; l-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopent-3-ene-l-carboxamide;
4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-
yl}methyl)(methyl)amino]-N,l-dimethylpiperidine-4-carboxamide;
4-[({4-[(3-chloro-2-fluorophenyl)arnino]-7-methoxyquinazolin-6-
yl}methyl)(methyl)amino]-l-methylpiperidine-4-carboxamide;
N2-{[4-[(3-chloro-2-fluorophenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-
yl]methyl}-N2-rnethyl-D-alaninamide;
3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-
yl}methyl)(methyl)amino]-l-(2-methoxyethyl)azetidine-3-carboxamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl} methyl)- N2-
ethyl-D-alaninamide;
oro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino|-2-(l-
methylpyrrolidin-3-yljacetamide;
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-Nl,N2-
dimethyl-D-alaninamide;
l-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-
yl}methyl)(ethyl)amino]cyclopropanecarboxamide; and
N2-(l-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethyl)-N2-
methyl-D-alaninamide;
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising a quinazoline compound of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 or claim 2 alongwith a pharmaceutically-acceptable diluent or carrier.
17. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 or claim 2, for use as a medicament.
18. A process for the preparing a quinazoline compound of the formula I as claimed in claim 1 which comprises of:
coupling of a compound of the formula V, or a reactive derivative thereof:
(Formula Removed)
wherein R1, R2, R3, R3a, R4, R6, R7, a, m and p are as defined in claim 1 and Z is O, except that any functional group is protected if necessary,
with an amine of the formula VI, or salt thereof:
(Formula Removed)
wherein R3 and R5a are as hereinbefore defined, except that any functional group is protected if necessary.
19. A quinazoline compound of the formula (I), process for preparing and a
pharmaceutical composition comprising a compound of the formula (1) substantially as herein described with reference to the foregoing examples.

Documents:

4280-DELNP-2006-Abstract (13-01-2010).pdf

4280-DELNP-2006-Abstract-(08-04-2009).pdf

4280-delnp-2006-abstract.pdf

4280-DELNP-2006-Claims (13-01-2010).pdf

4280-DELNP-2006-Claims-(08-04-2009).pdf

4280-delnp-2006-claims.pdf

4280-DELNP-2006-Correspondence-Others (13-01-2010).pdf

4280-DELNP-2006-Correspondence-Others-(08-04-2009).pdf

4280-delnp-2006-correspondence-others.pdf

4280-DELNP-2006-Description (Complete) (13-01-2010).pdf

4280-DELNP-2006-Description (Complete)-(08-04-2009).pdf

4280-delnp-2006-description (complete).pdf

4280-DELNP-2006-Form-1 (13-01-2010).pdf

4280-DELNP-2006-Form-1-(08-04-2009).pdf

4280-delnp-2006-form-1.pdf

4280-delnp-2006-form-18.pdf

4280-DELNP-2006-Form-2 (13-01-2010).pdf

4280-DELNP-2006-Form-2-(08-04-2009).pdf

4280-delnp-2006-form-2.pdf

4280-DELNP-2006-Form-26-(08-04-2009).pdf

4280-delnp-2006-form-26.pdf

4280-DELNP-2006-Form-3 (13-01-2010).pdf

4280-DELNP-2006-Form-3-(08-04-2009).pdf

4280-delnp-2006-form-3.pdf

4280-delnp-2006-form-5.pdf

4280-delnp-2006-pct-210.pdf

4280-delnp-2006-pct-304.pdf

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Patent Number

266039

Indian Patent Application Number

4280/DELNP/2006

PG Journal Number

14/2015

Publication Date

03-Apr-2015

Grant Date

30-Mar-2015

Date of Filing

25-Jul-2006

Name of Patentee

ASTRAZENECA AB

Applicant Address

SE-151 85 SODERTALJE, SWEDEN

Inventors:

#	Inventor's Name	Inventor's Address
1	DELOUVRIE, BENEDICTE	ASTRAZENECA R & D REIMS, Z.I. LA POMPELLE, BOITE POSTALE 1050, CEDEX 2, F-51689 REIMS, FRANCE
2	HARRIS, CRAIG, STEVEN	ASTRAZENECA R & D REIMS, Z.I. LA POMPELLE, BOITE POSTALE 1050, CEDEX 2, F-51689 REIMS, FRANCE
3	HENNEQUIN, LAURENT, FRANCOIS, NADRE	ASTRAZENECA R & D REIMS, Z.I. LA POMPELLE, BOITE POSTALE 1050, CEDEX 2, F-51689 REIMS, FRANCE
4	HALSALL, CHRISTOPHER, THOMAS	ASTRAZENECA R & D ALDERLEY, ALDERLEY PARK, MACCLESFIELD CHESHIRE, SK10 4TG, UK
5	PEASE, JANET, ELIZABEH	ASTRAZENECA R & D ALDERLEY, ALDERLEY PARK, MACCLESFIELD CHESHIRE, SK10 4TG, UK
6	SMITH, PETER, MARK	ASTRAZENECA R & D ALDERLEY, ALDERLEY PARK, MACCLESFIELD CHESHIRE, SK10 4TG, UK

PCT International Classification Number

C07D 239/42

PCT International Application Number

PCT/GB2005/000237

PCT International Filing date

2005-01-31

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	04290274.2	2004-02-03	EUROPEAN UNION