Claims for Patent: 6,391,874

Summary for Patent: 6,391,874

Title:	Fused heterocyclic compounds as protein tyrosine kinase inhibitors
Abstract:	Substituted heteroaromatic compounds of formula (I) and in particular substituted quinolines and quinazolines, are protein tyrosine kinase inhibitors. The compounds are described as are methods for their preparation, pharmaceutical compositions including such compounds and their use in medicine, for example in the treatment of cancer and psoriasis, or a salt or solvate thereof; wherein X is N or CH; Y is a group W(CH2), (CH2)W, or W, in which W is O, S(O)m wherein m is 0, 1 or 2, or NRa wherein Ra is hydrogen or a C1-8 alkyl group; R1 represents a phenyl group or a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S(O)m, wherein m is as defined above, with the provisos that the ring does not contain two adjacent O or S(O)m atoms and that where the ring contains only N as heteroatom(s) the ring is C-linked to the quinazoline or quinoline ring, R1 being optionally substituted by one or more R3;groups; P=0 to 3; U, R2, R3 are as defined in the application.
Inventor(s):	George Stuart Cockerill, Malcolm Clive Carter, Stephen Barry Guntrip, Kathryn Jane Smith
Assignee:	Novartis AG, GlaxoSmithKline Research and Development Ltd
Application Number:	US09/214,267
Patent Claims:	1. A compound of formula (I): or a salt or solvate thereof; wherein X is N or CH; Y is a group W(CH2), (CH2)W, or W, in which W is O, S(O)m wherein m is 0, 1 or 2, or NRa wherein Ra is hydrogen or a C1-8 alkyl group; R1 represents a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S(O)m, wherein m is as defined above, with the provisos that the ring does not have two adjacent O or S(O)m atoms and that where the ring has only N as heteroatom(s) the ring is C-linked to the quinazoline or quinoline ring, R1 is optionally substituted by one or more R3 groups; each R3 is independently selected from the group consisting of amino, hydrogen, halogen, hydroxy, nitro, carboxy, formyl, cyano, trifluoromethyl, trifluoromethoxy, carbamoyl, ureido, guanidino, C1-8 alkyl, C1-8 alkoxy, C3-8 cycloalkoxyl, C4-8 alkylcycloalkoxy, C1-8 alkylcarbonyl, C1-8 alkoxycarbonyl, N-C1-4 alkylcarbamoyl, N,N-di-(C1-4 alkyl)carbamoyl, hydroxyamino, C1-4 alkoxyamino, C2-4 alkanoyloxyamino, C1-4 alkylamino, di(C1-4 alkyl)amino, di-(C1-4 alkyl)amino-C1-4 alkylene-(C1-4 alkyl)amino, C1-4 alkylamino-C1-4 alkylene-(C1-4 alkyl)amino, hydroxy-C1-4 alkylene-(C1-4 alkyl)amino, phenyl, phenoxy, 4-pyridon-1-yl, pyrrolidin-1-yl, imidazol-1-yl, piperidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, piperazin-1-yl, 4-C1-4 alkylpiperazin-1-yl, dioxolanyl, C1-8 alkylthio, arylthio, C1-4 alkylsulphinyl, C1-4 alkylsulphonyl, arylsulphonyl, arylsulphinyl, halogeno-C1-4 alkyl, hydroxy-C1-4 alkyl, C2-4 alkanoyloxy-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, carboxy-C1-4 alkyl, formyl-C1-4 alkyl, C1-4 alkoxycarbonyl-C1-4-alkyl, carbamoyl-C1-4 alkyl, N-C1-4 alkylcarbamoyl-C1-4alkyl, N,N-di-(C1-4 alkyl)carbamoyl-C1-4alkyl, amino-C1-4 alkyl, C1-4 alkylamino-C1-4 alkyl, di-(C1-4 alkyl)amino-C1-4 alkyl, phenyl-C1-4 alkyl, 4-pyridon-1-yl-C1-4 alkyl, pyrrolidin-1-yl-C1-4 alkyl, imidazol-1-yl-C1-4 alkyl, piperidino-C1-4 alkyl, morpholino-C1-4 alkyl, thiomorpholino-C1-4 alkyl, thiomorpholino-1-oxide-C1-4alkyl, thiomorpholino-1,1-dioxide-C1-4alkyl, piperazin-1-yl-C1-4alkyl, 4-C1-4 alkylpiperazin-1-yl-C1-4 alkyl, hydroxy-C2-4 alkoxy-C1-4 alkyl, C1-4 alkoxy-C2-4 alkoxy-C1-4 alkyl, hydroxy-C2-4 alkylamino-C1-4 alkyl, C1-4 alkoxy-C2-4 alkylamino-C1-4 alkyl, C1-4 alkylthio-C1-4 alkyl, C1-4 alkylsulphinyl-C1-4 alkyl, C1-4 alkylsulphonyl-C1-4 alkyl, hydroxy-C2-4 alkylthio-C1-4 alkyl, C1-4 alkoxy-C2-4 alkylthio-C1-4 alkyl, phenoxy-C1-4 alkyl, anilino-C1-4 alkyl, phenylthio-C1-4 alkyl, cyano-C1-4 alkyl, halogeno-C2-4 alkoxy, hydroxy-C2-4 alkoxy, C2-4 alkanoyloxy-C2-4 alkoxy, C1-4 alkoxy-C2-4 alkoxy, carboxy-C1-4 alkoxy, formyl-C1-4 alkoxy, C1-4 alkoxycarbonyl-C1-4 alkoxy, carbamoyl-C1-4 alkoxy, N-C1-4 alkylcarbamoyl-C1-4 alkoxy, N,N-di-(C1-4 alkyl)carbamoyl-C1-4 alkoxy, amino-C2-4 alkoxy, C1-4 alkylamino-C2-4 alkoxy, di-(C1-4 alkyl)amino-C2-4 alkoxy, di-(C1-4 alkyl-C2-4 alkoxy)amino-C2-4 alkoxy, C2-4 alkanoyloxy, hydroxy-C2-4 alkanoyloxy, C1-4alkoxy-C2-4 alkanoyloxy, phenyl-C1-4 alkoxy, phenoxy-C2-4 alkoxy, anilino-C2-4 alkoxy, phenylthio-C2-4 alkoxy, 4-pyridon-1-yl-C2-4 alkoxy, piperidino-C2-4 alkoxy, morpholino-C2-4 alkoxy, thiomorpholino-C2-4 alkoxy, thiomorpholino-1-oxide-C2-4 alkoxy, thiomorpholino-1,1-dioxide-C2-4 alkoxy, piperazin-1-yl-C2-4 alkoxy, 4-C1-4 alkylpiperazin-1-yl-C2-4 alkoxy, pyrrolidin-1-yl-C2-4 alkoxy, imidazol-1-yl-C2-4 alkoxy, halogeno-C2-4 alkylamino, hydroxy-C2-4 alkylamino, C2-4 alkanoyloxy-C2-4 alkylamino, C1-4 alkoxy-C2-4 alkylamino, carboxy-C1-4 alkylamino, C1-4 alkoxycarbonyl-C1-4 alkylamino, carbamoyl-C1-4 alkylamino, N-C1-4 alkylcarbamoyl-C1-4 alkylamino, N,N-di-(C1-4 alkyl)carbamoyl-C1-4 alkylamino, amino-C2-4 alkylamino, C1-4 alkylamino-C2-4 alkylamino, di-(C1-4alkyl)amino-C2-4 alkylamino, phenyl-C1-4 alkylamino, phenoxy-C2-4 alkylamino, anilino-C2-4 alkylamino, 4-pyridon-1-yl-C2-4 alkylamino, pyrrolidin-1-yl-C2-4 alkylamino, imidazol-1-yl-C2-4 alkylamino, piperidino-C2-4 alkylamino, morpholino-C2-4 alkylamino, thiomorpholino-C2-4 alkylamino, thiomorpholino-1-oxide-C2-4 alkylamino, thiomorpholino-1,1-dioxide-C2-4 alkylamino, piperazin-1-yl-C2-4alkylamino, 4-(C1-4alkyl)piperazin-1-yl-C2-4alkylamino, phenylthio-C2-4 alkylamino, C2-4 alkanoylamino, C1-4 alkoxycarbonylamino, C1-4 alkylsulphonylamino, C1-4 alkylsulphinylamino, benzamido, benzenesulphonamido, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halogeno-C2-4 alkanoylamino, hydroxy-C2-4 alkanoylamino, hydroxy-C2-4 alkanoyl-(C1-4 alkyl)-amino, C1-4 alkoxy-C2-4 alkanoylamino, carboxy-C2-4 alkanoylamino, C1-4 alkoxycarbonyl-C2-4 alkanoylamino, carbamoyl-C2-4 alkanoylamino, N-C1-4 alkylcarbamoyl-C2-4 alkanoylamino, N,N-di-(C1-4 alkyl)carbamoyl-C2-4 alkanoylamino, amino-C2-4 alkanoylamino, C1-4 alkylamino-C2-4 alkanoylamino or di-(C1-4 alkyl)amino-C2-4 alkanoylamino; and wherein said benzamido or benzenesulphonamido substitutent or any anilino, phenoxy or phenyl group on a R3 substituent may optionally have one or two halogeno, C1-4 alkyl or C1-4 alkoxy substituents; and wherein any substituent having a heterocyclic ring may optionally have one or two halogeno, C1-4 alkyl or C1-4 alkoxy substituents on said ring; and wherein any substituent having a heterocyclic ring may optionally have one or two oxo or thioxo substituents on said ring; or R3 represents a group selected from M1—M2—M3—M4, M1—M5 or M1—M2—M3′—M6 wherein M1 represents a C1-4 alkyl group, wherein optionally a CH2 group is replaced by a CO group; M2represents NR12 or CR12R13, in which R12 and R13 each independently represent H or C1-4 alkyl; M3 represents a C1-4 alkyl group; M3′ represents a C1-4 alkyl group or is absent; M4 represents CN, NR12S(O)mR13, S(O)mNR14R15, CONR14R15, S(O)mR13 or CO2R13, in which R12, R13 and m are as above defined and R14 and R15 each independently represent H or C1-4 alkyl, or R14 and R15 together with the nitrogen atom to which they are attached form a 5- or 6-membered ring optionally containing 1 or 2 additional heteroatoms selected from N, O or S(O)m in which ring any nitrogen atom present may optionally be substituted with a C1-4 alkyl group, and which ring may optionally contained one or two oxo or thioxo substituents; M5 represents the group NR14R15, wherein R14 and R15 are as defined above, or M5 represents the group in which t represents 2 to 4 and R16 represents OH, OC1-4 alkyl or NR14R15; and M6 represents a C3-6 cycloalkyl group, the group NR14R15, wherein R14 and R15 are as defined above, or a 5- or 6-membered heterocyclic ring system containing 1 to 4 heteroatoms selected from N, O or S; and p is 0 to 3; or when p is 2 or 3, two adjacent R3 groups together form an optionally substituted methylenedioxy or ethylenedioxy group; R2 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, C1-4 alkyl and C1-4 alkoxy; U represents phenyl or a 5 to 10-membered mono or bicyclic ring system in which one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S(O)m, wherein m is 0, 1 or 2, and wherein U is substituted by at least one independently selected R6 group and U is optionally substituted by at least one independently selected R4 group; each R4 is independently hydrogen, hydroxy, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, di-[C1-4 alkyl]amino, C1-4 alkylthio, C1-4 alkylsulphinyl, C1-4 alkylsulphonyl, C1-4 alkylcarbonyl, C1-4 alkylcarbamoyl, di-[C1-4 alkyl]carbamoyl, carbamyl, C1-4 alkoxycarbonyl, cyano, nitro or trifluoromethyl; each R6 is independently a group ZR7 wherein Z is joined to R7 through a (CH2)p group in which p is 0, 1 or 2 and Z represents a group V(CH2), V(CF2), (CH2)V, (CF2)V, V(CRR′), V(CHR) or V where R and R′ are each C1-4 alkyl and in which V is a hydrocarbyl group containing 0, 1 or 2 carbon atoms, carbonyl, dicarbonyl, CH(OH), CH(CN), sulphonamide, amide, O, S(O)m or NRb where Rb is hydrogen or Rb is C1-4 alkyl; and R7 is an optionally substituted C3-6 cycloalkyl; or an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety; or R6 is a group ZR7 in which Z is NRb, and NRb and R7 together form an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety. 2. A compound as claimed in claim 1 wherein R3 is as defined in claim 1 with the exception of wherein any substituent containing a heterocyclic ring has one or two oxo or thioxo substituents on said ring, and with the exception of C1-4 alkylsulphinyl-C1-4 alkyl or C1-4 alkylsulphonyl-C1-4 alkyl; and wherein R14 and R15 are as defined in claim 1 with the exception of wherein R14 and R15 together with the nitrogen atom to which they are attached represent a 5- or 6-membered ring and said ring has one or two oxo or thioxo substituents; wherein R3 includes 4-pyridon-1-yl, 4-pyridon-1-yl-C1-4 alkyl, 4-pyridon-1-yl-C2-4 alkoxy, 4-pyridon-1-yl-C2-4 alkylamino, 2-oxopyrrolidin-1-yl or 2,5-dioxopyrrolidin-1-yl. 3. A compound as claimed in claim 1 wherein X is N. 4. A compound as claimed in claim 1 wherein Y is NRb, NRb(CH2), or (CH2)NRb. 5. A compound as claimed in claim 1 wherein R1 is a 5- or 6-membered heterocyclic ring as defined in claim 1, optionally substituted by one or more R1 groups selected from the group consisting of amino, hydrogen, halogen, hydroxy, hydroxy-C1-4 alkyl, formyl, carboxy, cyano, nitro, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, C1-8 alkylsulphinyl, C1-8 alkylsulphonyl, C1-4 alkylamino, C1-4 dialkylamino, dioxolanyl or hydroxy-C1-4 alkanoyl-(C1-4 alkyl)-amino. 6. A compound as claimed in claim 1 wherein R1 is a 5- or 6-membered heterocyclic ring substituted by one or more R3 groups selected from the group consisting of C1-4alkyl, C1-4alkylamino-C1-4alkyl, di(C1-4alkyl)amino-C1-4 alkyl, formyl, carboxy, C1-4alkoxycarbonyl, dioxolanyl and trifluoromethyl. 7. A compound as claimed in claim 1 wherein R1 is a 5- or 6-membered heterocyclic ring substituted by one or more R3 groups selected from C1-4alkylsulphinyl-C1-4alkyl or C1-4alkylsulphonyl-C1-4alkyl. 8. A compound as claimed in claim 1 wherein R1 is a 5- or 6-membered heterocyclic ring substituted with an R3 group selected from M1—M2—M3—M4, M1—M5 or M1—M2—M3′—M6 as defined in claim 1 or claim 2; and p=0. 9. A compound as claimed in claim 1 wherein R1 is a 5- or 6-membered heterocyclic ring substituted with an R3 group selected from piperidonyl-methyl, pyrrolidinonyl-methyl or dioxoimidazolidinyl-methyl. 10. A compound as claimed in claim 1 wherein M1 represents CH2, CO, CH2CH2 or CH2CO; M2 represents NR12 in which R12 is as defined in claim 1; M3 represents CH2, CH2CH2 or propyl; M3′ represents CH2, ethyl, propyl, isopropyl or is absent; M4 represents SOR13, SO2R13, NR12SO2R13, SO2NR14R15, CO2R13 or CONR14R15 in which R12 and R13 are defined in claim 1 and R14 and R15 each independently represent H or C1-4 alkyl; M5 represents a group NR14R15 in which R14 and R15 together with the nitrogen atom to which they are attached represent a 6-membered ring optionally containing an additional heteroatom selected from N or O, in which ring any nitrogen atom present may optionally be substituted with a C1-4 alkyl group; or M5 represents a group in which t represents 2 or 3 and R16 represents OH, NH2, N(C1-4 alkyl)2 or OC1-4 alkyl; or M5 represents a group NR14R15 in which R14 and R15 each independently represent hydrogen or C1-4 alkyl, and M6 represents a group NR14R15 in which R14 and R15 each independently represent C1-4 alkyl, or R14 and R15 together with the nitrogen atom to which they are attached represent a 5- or 6-membered ring optionally containing an additional heteroatom selected from N or O, in which ring any nitrogen atom present may optionally be substituted with a C1-4 alkyl group; or M6 represents a 5- or 6-membered heterocyclic ring system containing 1 or 2 heteroatoms selected from N or O. 11. A compound as claimed in claim 1 wherein M2—M3—M4 represents an α-amino carboxylic acid or a methyl ester or amide thereof; or M2—M3—M4 represents a β- or γ-amino sulphinic or sulphonic acid or a methyl ester thereof. 12. A compound as claimed in claim 1 wherein M2—M3—M4 represents a methylsulphonylethylamino, methylsulphinylethylamino, methylsulphonylethyl(methylamino), methylsulphinylethyl(methylamino), methylsulphonylpropylamino, methylsulphinylpropylamino, methylsulphonamidoethylamino, aminosulphonylethylamino, methylaminosulphonylethylamino, sarcosinamide, glycine, glycinamide, glycine methyl ester or acetylaminoethylamino group. 13. A compound as claimed in claim 1 wherein M1—M5 represents a piperazinyl-methyl, methylpiperazinyl-methyl, piperidinyl-methyl, pyridylmethyl, prolinamidomethyl, N,N-dimethylprolinamido-methyl, isopropylacetamido or N-morpholinoacetamido group. 14. A compound as claimed in claim 1 wherein M1—M5 represents a piperidonyl-methyl, pyrrolidinonyl-methyl or dioxoimidazolidinyl-methyl group. 15. A compound as claimed in claim 1 wherein M2—M3′M6 represents a pyridylamino, cyclopropylamino, N-(piperidin-4-yl)-N-methylamino, N,N-dimethylaminoprop-2-ylamino, N-(2-dimethylaminoethyl)-N-ethylamino or tetrahydrofuranomethylamino group, preferably a pyridylamino group. 16. A compound as claimed in claim 1 wherein R1 is selected from the group consisting of furan, dihydrofuran, thiophene, imidazole, tetrazole, triazole, pyridine, pyrrole, pyrimidine, isoxazole or oxadiazole. 17. A compound as claimed in claim 1 wherein R1 is an oxadiazolidinone ring. 18. A compound as claimed in claim 16 wherein R1 is selected from the group consisting of furan, imidazole, oxadiazole and triazole. 19. A compound as claimed in claim 1 wherein R6 is benzyl, fluorobenzyl, difluorobenzyl, benzyloxy, fluorobenzyloxy, pyridylmethyl, phenyl, benzenesulphonyl, phenoxy or fluorophenoxy. 20. A compound as claimed in claim 1 wherein U represents an phenyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group. 21. A compound as claimed in claim 20 wherein U represents a phenyl or 1H-indazolyl group. 22. A compound as claimed in claim 1 wherein the optional substituents for the carbocyclic or heterocyclic moiety and also for other optionally substituted groups are selected from the group consisting of hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkyl carbonyl, carboxylate and C1-4 alkoxy carboxyl. 23. A compound of formula (I) or a salt thereof as claimed in claim 1 wherein X represents N; Y represents NRa, wherein Ra is hydrogen or C1-4 alkyl; R1 represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, oxazole, isoxazole, oxadiazole, tetrazole, triazole, dioxolane or a partially or fully hydrogenated derivative of any of these groups, optionally substituted by one or more R3 groups selected from halo, trifluoromethyl, C1-4 alkyl, carboxy, C1-4-alkoxycarbonyl, formyl, hydroxy-C1-4 alkyl, 1,3-dioxolan-2-yl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy-C1-4alkanoyl-(C1-4alkyl)-amino, C1-4 alkylamino-C1-4 alkyl or di(C1-4 alkyl)amino-C1-4 alkyl; p is 0; R2 represents hydrogen; R4 represents hydrogen, halo or methyl; U represents phenyl, indolyl, benzimidazolyl or indazolyl; and R6 represents phenyl, benzyl, α-methylbenzyl, fluorobenzyl, difluorobenzyl, pyridylmethyl, benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy. 24. A compound of formula (I) or a salt thereof as claimed in claim 1 wherein X represents N; Y represents NRa, wherein Ra is hydrogen or C1-4 alkyl; R1 represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, oxazole, isoxazole, oxadiazole, tetrazole, triazole, dioxolane or a partially or fully hydrogenated derivative of any of these groups, optionally substituted with an R3 group selected from methylsulphonylethylaminomethyl, methylsulphonylethylamino-carbonyl, methylsulphinylethylamino-methyl, methylsulphinylethylamino-carbonyl, methylsulphonylpropylamino-methyl, methylsulphinylpropylamino-methyl, methylsulphonylpropyamino-carbonyl, methylsulphinylpropylamino-carbonyl, methylsulphonylethyl-(methylamino)-methyl, methylsulphonylethyl-(methylamino)-carbonyl, methylsulphinylethyl-(methylamino)-methyl, methylsulphinylethyl-(methylamino)-carbonyl, methylsulphonylpropyl-(methylamino)-methyl, methylsulphinylpropyl-(methylamino)-methyl, methylsulphonylpropyl-(methylamino)-carbonyl, methylsulphinylpropyl-(methylamino)-carbonyl, methylsulphonamidoethylamino-methyl, methylsulphonamidopropylamino-methyl, aminosulphonylethylaminomethyl, methylaminosulphonylethylaminomethyl, sarcosinamidomethyl, glycinylmethyl, glycinamidomethyl, glycinylmethyl methyl ester acetylaminoethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl, piperidinylmethyl, pyridylmethyl, N-(prolinamido)methyl, (N,N-dimethyl-prolinamido)methyl, pyridylaminomethyl, cyclopropylaminomethyl, N-(piperidin-4-yl)-N-methylaminomethyl, N,N-dimethylaminoprop-2-ylaminomethyl, N-(2-dimethylaminoethyl)-N-ethylaminomethyl, isopropylacetamido, N-morpholinylacetamido or tetrahydrofuranomethylaminomethyl and optionally further substituted by one or more C1-4 alkyl groups; p is 0; R2 represents hydrogen; R4 represents hydrogen, halo or methyl; U represents phenyl, indolyl, benzimidazolyl or indazolyl; and R6 represents phenyl, benzyl, α-methylbenzyl, fluorobenzyl, difluorobenzyl, pyridylmethyl, benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy. 25. A compound of formula (I) or a salt thereof as claimed in claim 23 wherein X represents N; Y represents NRa, wherein Ra is hydrogen or C1-4 alkyl; R1 represents a furan, dihydrofuran, thiophene, pyridine, pyrrole, pyrimidine, isoxazole, triazole, tetrazole, imidazole or oxadiazole ring, substituted with an R3 group selected from C1-4alkyl, C1-4alkylamino-C1-4alkyl, di(C1-4alkyl)amino-C1-4 alkyl, formyl, carboxy, C1-4alkoxycarbonyl, dioxolanyl, trifluoromethyl, methylsulphonylethylaminomethyl, methylsulphonylethylamino-carbonyl, methylsulphonylethyl(methylamino)-methyl, methylsulphonamidoethylamino-methyl, aminosulphonylethylamino-methyl, methylaminosulphonylethylamino-methyl, N,N-dimethylaminoprop-2-ylaminomethyl, N-(2-dimethylaminoethyl)-N-ethylaminomethyl, pyridylaminomethyl, tetrahydrofuranomethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl, piperidinylmethyl, pyridylmethyl, N-(prolinamido)methyl or (N,N-dimethyl-prolinamido)methyl; p is 0; R2 represents hydrogen; R4 represents hydrogen or halo; U represents phenyl or indazolyl; and R6 represents benzyl, fluorobenzyl, difluorobenzyl, pyridylmethyl, benzenesulphonyl, phenoxy, benzyloxy or fluorobenzyloxy. 26. A compound as claimed in claim 1 selected from the group consisting of: (4-Benzyloxy-phenyl)-(6-furan-2-yl-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(thiophen-2-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(pyridin-2-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(pyrimidin-2-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(3-methyl-3H-imidazol-4-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(2,3-dihydrofuran-5-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(3-methyl-1,2,3-triazol-4-yl)-quinazolin-4-yl)-amine; 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde; (4-Benzyloxy-phenyl)-(6-(5-(4-methylpiperazin-1-ylmethyl)-furan-2-yl)-quinazolin-4-yl)-amine; (S)-1-(5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-pyrrolidine-2-carboxylic acid amide; N2-(5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-N1,N1-dimethyl-propane-1,2-diamine; N-(5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-N-ethyl-N′,N′-dimethyl-ethane-1,2-diamine; (4-Benzyloxy-phenyl)-(6-(5-(pyridin-3-ylaminomethyl)-furan-2-yl)quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-(((tetrahydro-furan-2-ylmethyl)-amino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3)-dioxolan-2-yl-furan-2-yl)-quinazolin-4-yl)-amine; 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carbaldehyde; (S)-1-(5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-pyrrolidine-2-carboxylic acid amide; (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; (4-Phenoxy-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)quinazolin-4-yl)-amine; (1-(2-Fluorobenzyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-(3-Fluorobenzyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-Pyridin-2-ylmethyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-(2,3-Difluorobenzyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)quinazolin-4-yl)-amine; (3-Chloro-4-(2-fluoro-benzyloxy)-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (3-Chloro-4-(3-fluoro-benzyloxy)-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (4-(2-Fluoro-benzyloxy)-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (4-(3-Fluoro-benzyloxy)-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolinyl)-amine; (4-Benzenesulphonyl-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-(3,5-Difluoro-benzyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine (4-(4-Fluoro-benzyloxy)-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (4-(2-Fluoro-benzyloxy)-phenyl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (4-(4-Fluoro-benzyloxy)-phenyl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (4-Pyridin-3-ylmethoxy)-phenyl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(3-methyl-3H-imidazol-4-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(1-methyl-1H-imidazol-2-yl)quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(1H-tetrazol-5-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl0-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-triazol-2-yl)-quinazolin-4-yl)-amine; (S)-1-(2-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-3-methyl-3H-imidazol-4-ylmethyl)-pyrrolidine-2-carboxylic acid amide; (1-Benzyl-1H-indazol-5-yl)-(6-(5-methanesulphonylmethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(1-methylpyridinium-2-yl)quinazolin-4-yl)-amine; chloride; (4-Benzyloxy-phenyl)-(6-(2,3-dimethyl-3H-imidazol-4-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(-6-(3-methylisoxazol-5-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-(((2-methanesulphonyl-ethyl)-methyl-amino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; N-(2-((5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-amino)-ethyl)-methanesulphonamide; 2-((5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-amino)-ethanesulphonic acid amide; 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carboxylic acid methyl ester; 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carboxylic acid; 5-[4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl]-furan-2-carboxylic acid (2-methanesulphonyl-ethyl)-amide; 2-((5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-amino)-ethanesulphonic acid methylamide; (1-Benzyl-1H-indazol-5-yl)-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-methyl-1,2,4-oxadiazol-3-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-(2-dimethylamino-ethyl)-1,2,4-oxadiazol-3-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-(dimethylaminomethyl)-1,2,4-oxadiazol-3-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(5-(((2-methanesulphonyl-ethyl)-amino)-methyl)-1,2,4-oxadiazol-3-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(5-methanesulphonylmethyl-1,2,4-oxadiazol-3-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(5-methyl-1,2,4-oxadiazol-3-yl)-quinazolin-4-yl0-amine; (1-Benzyl-1H-indazol-5-yl)-6-(5-(pyridin-3-ylmethyl)-1,2,4-oxadiazol-3-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(1-methylpyrrol-2-yl)-quinazolin-4-yl)-amine; 5-(4-(1-Benzyl-1H-indazol-5-yl)-quinazolin-6-yl)-1-methyl-pyrrole-2-carbaldehyde; 1-(3-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1,2,4-oxadiazol-5-ylmethyl)-piperidin-4-one; 1-(3-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1,2,4-oxadiazol-5-ylmethyl)-pyrrolidin-2-one; 1-(3-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1,2,4-oxadiazol-5-ylmethyl)-imidazolidin-2,5-dione; 3-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-4H-1,2,4-oxadiazolidin-3-one; (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesuphonyl-ethyl-amino)-methyl)-1-methyl-pyrrol-2-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(1-(3-N,N-dimethylaminopropyl)-imidazol-5-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazolyl)-(6-(1-(3-N,N-dimethylaminopropyl)-imidazol-5-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(1-(3-N,N-dimethylaminopropyl)-imidazol-2-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazolyl)-(6-(1-(3-N,N-dimethylaminopropyl)-imidazol-5-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-(2-Fluoro-benzyl)-1H-indazol-5-yl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-(4-Fluoro-benzyl)-1H-indazol-5-yl)-(6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(7-(5-methyl-[1,3,4]oxadiazol-2-yl)-quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(7-(3-methyl-3H-imidazol-4-yl)quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-[7-(furan-2-yl)-quinazolin-4-yl]-amine; (1-Benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)-furan-2-yl)quinazolin-4-yl]amine; 5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde; (1-Benzyl-1H-indazol-5-yl)-[7-{5-[(2-methanesulphonyl-ethylamino)-methyl]-furan-2-1}-quinazolin-4-yl]-amine; (S)-1-{5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-yl-methyl}-pyrrolidine-2-carboxylic acid amide; (4-Benzyloxy-phenyl)-(6-(3-methyl-[1,2]oxazol-4-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(4-(1,3-dioxolan-2-yl)-3-methyl-3H-imidazol-2-yl)-quinazolin-4-yl)-amine; 2-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-3-methyl-3H-imidazol-4-carbaldehyde; and salts thereof. 27. A compound as claimed in claim 26 selected from the group consisting of: (4-Benzyloxy-phenyl)-(6-furan-2-yl-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(3-methyl-3H-imidazol-4-yl)-quinazolin-4-yl)-amine; (4-(4-Fluoro-benzyloxy)-phenyl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)quinazolin-4-yl)-amine; (1-Benzyl-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-triazol-2-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-methyl-1,2,4-oxadiazol-3-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-(4-methylpiperazin-1-ylmethyl)-furan-2-yl)-quinazolin-4-yl)-amine; (S)-1-(5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-pyrrolidine-2-carboxylic acid amide; (S)-1-(5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-pyrrolidine-2-carboxylic acid amide; (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; (4-Benzyloxy-phenyl)-(6-(5-(((2-methanesulphonyl-ethyl)-methyl-amino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; N-(2-((5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-ylmethyl)-amino)-ethyl)-methanesulphonamide; 1-(3-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1,2,4-oxadiazol-5-ylmethyl)-piperidin-4-one; 1-(3-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1,2,4-oxadiazol-5-ylmethyl)-pyrrolidin-2-one and salts thereof. 28. A pharmaceutical formulation comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. 29. A pharmaceutical formulation as claimed in claim 28 in unit dosage form and containing from 70 to 700 mg of said compound. 30. A method of treatment of a human or animal subject suffering from a disorder mediated by aberrant protein tyrosine kinase activity which method comprises administering to the human or animal subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 31. A method of treating a disorder mediated by aberrant protein tyrosine kinase activity in a human or animal subject, wherein at least one kinase selected from the group consisting of c-erb-B2, EGFr, and c-erb-B4 exhibits aberrant activity, comprising administering to the human or animal an effective amount of a compound of formula I or a salt thereof. 32. A method of treating a disorder mediated by aberrant protein tyrosine kinase activity in a human or animal subject, wherein at least two kinases selected from the group consisting of c-erb-B2, EGFr, and c-erb-B4 exhibits aberrant activity, comprising administering to the human or animal an effective amount of a compound of formula I.