Details for Patent: 6,828,320

Title:	Heterocyclic compounds
Abstract:	Substituted heteroaromatic compounds, 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.
Inventor(s):	Cockerill; George Stuart (Bedford, GB), Carter; Malcolm Clive (Ware, GB), Guntrip; Stephen Barry (Hertford, GB), Smith; Kathryn Jane (Bishop's Stortford, GB)
Assignee:	SmithKline Beecham Corporation (Philadelphia, PA)
Filing Date:	Jan 31, 2002
Application Number:	10/062,647
Claims:	1. A method of treating a susceptible cancer in a human or animal subject in need thereof, comprising administering to said subject an effective amount of a compound of formula (I): ##STR19## or a salt or solvate thereof; wherein X is N or CH; Y is a group W(CH.sub.2), (CH.sub.2)W, or W, in which W is O, S(O).sub.m wherein m is 0, 1 or 2, or NR.sup.a wherein R.sup.a is hydrogen or a C.sub.1-8 alkyl group; R.sup.1 is a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group N, O or S(O).sub.m, wherein m is as defined above, with the provisos that the ring does not have two adjacent O or S(O).sub.m atoms and that where the ring has only N as heteroatom(s) the ring is C-linked to the quinazoline or quinoline ring, R.sup.1 being optionally substituted by one or more R.sup.3 groups; each R.sup.3 is independently selected from the group consisting of amino, hydrogen, halogen, hydroxy, nitro, carboxy, formyl, cyano, trifluoromethyl, tritluoromethoxy, carbamoyl, ureido, guanidino, C.sub.1-8 alkyl, C.sub.1-8 alkoxy, C.sub.3-8 cycloalkoxyl, C.sub.4-8 alkylcycloalkoxy, C.sub.1-8 alkylcarbonyl, C.sub.1-8 alkoxycarbonyl, N-C.sub.1-4 alkylcarbamoyl, N,N-di-[C.sub.1-4 alkyl]carbamoyl, hydroxyamino, C.sub.1-4 alkoxyamino, C.sub.2-4 alkanoyloxyamino, C.sub.1-4 alkylamino, di[C.sub.1-4 alkyl]amino, di-[C.sub.1-4 alkyl]amino-C.sub.1-4 alkylene-(C.sub.1-4 alkyl)amino, C.sub.1-4 alkylamino-C.sub.1-4 alkylene-(C.sub.1-4 alkyl)amino, hydroxy-C.sub.1-4 alkylene-(C.sub.1-4 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-C.sub.1-4 alkylpiperazin-1-yl, dioxolanyl, C.sub.1-8 alkylthio, arylthio, C.sub.1-4 alkylsulphinyl, C.sub.1-4 alkylsulphonyl, arylsulphonyl, arylsulphonyl, halogen O-C.sub.1-4 alkyl, hydroxy-C.sub.1-4 alkyl, C.sub.2-4 alkanoyloxy-C.sub.1-4 alkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, carboxy-C.sub.1-4 alkyl, formyl-C.sub.1-4 alkyl, C.sub.1-4 alkoxycarbonyl-C.sub.1-4 -alkyl, carbamoyl-C.sub.1-4 alkyl, N-C.sub.1-4 alkylcarbamoyl-C.sub.1-4 alkyl, N,N-di-[C.sub.1-4 alkyl]carbamoyl-C.sub.1-4 alkyl, amino-C.sub.1-4 alkyl, C.sub.1-4 alkylamino-C.sub.1-4 alkyl, di-[C.sub.1-4 alkyl]amino-C.sub.1-4 alkyl, phenyl-C.sub.1-4 alkyl, 4-pyridon-1-yl-C.sub.1-4 alkyl, pyrrolidin-1-yl-C.sub.1-4 alkyl, imidazol-1-yl-C.sub.1-4 alkyl, piperidino-C.sub.1-4 alkyl, morpholino-C.sub.1-4 alkyl, thiomorpholino-C.sub.1-4 alkyl, thiomorpholino-1-oxide-C.sub.1-4 alkyl, thiomorpholino-1,1-dioxide-C.sub.1-4 alkyl, piperazin-1-yl-C.sub.1-4 alkyl, 4-C.sub.1-4 alkylpiperazin-1-yl-C.sub.1-4 alkyl, hydroxy-C.sub.2-4 alkoxy-C.sub.1-4 alkyl, C.sub.1-4 alkoxy-C.sub.2-4 alkoxy-C.sub.1-4 alkyl, hydroxy-C.sub.2-4 alkylamino-C.sub.1-4 alkyl, C.sub.1-4 alkoxy-C.sub.2-4 alkylamino-C.sub.1-4 alkyl, C.sub.1-4 alkylthio-C.sub.1-4 alkyl, C.sub.1-4 alkylsulphinyl-C.sub.1-4 alkyl, C.sub.1-4 alkylsulphonyl-C.sub.1-4 alkyl, hydroxy-C.sub.2-4 alkylthio-C.sub.1-4 alkyl, C.sub.1-4 alkoxy-C.sub.2-4 alkylthio-C.sub.1-4 alkyl, phenoxy-C.sub.1-4 alkyl, anilino-C.sub.1-4 alkyl, phenylthio-C.sub.1-4 alkyl, cyano-C.sub.1-4 alkyl, halogen O-C.sub.2-4 alkoxy, hydroxy-C.sub.2-4 alkoxy, C.sub.2-4 alkanoyloxy-C.sub.2-4 alkoxy, C.sub.1-4 alkoxy-C.sub.2-4 alkoxy, carboxy-C.sub.1-4 alkoxy, formyl-C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl-C.sub.1-4 alkoxy, carbamoyl-C.sub.1-4 alkoxy, N-C.sub.1-4 alkylcarbamoyl-C.sub.1-4 alkoxy, N,N-di-[C.sub.1-4 alkyl]carbamoyl-C.sub.1-4 alkoxy, amino-C.sub.2-4 alkoxy, C.sub.1-4 alkylamino-C.sub.2-4 alkoxy, di-[C.sub.1-4 alkyl]amino-C.sub.2-4 alkoxy, di-[C.sub.1-4 alkyl-C.sub.2-4 alkoxy]amino-C.sub.2-4 alkoxy, C.sub.2-4 alkanoyloxy, hydroxy-C.sub.2-4 alkanoyloxy, C.sub.1-4 alkoxy-C.sub.2-4 alkanoyloxy, phenyl-C.sub.1-4 alkoxy, phenoxy-C.sub.2-4 alkoxy, anilino-C.sub.2-4 alkoxy, phenylthio-C.sub.2-4 alkoxy, 4-pyridin-1-yl-C.sub.2-4 alkoxy, piperidino-C.sub.2-4 alkoxy, morpholino-C.sub.2-4 alkoxy, thiomorpholino-C.sub.2-4 alkoxy, thiomorpholino-1-oxide-C.sub.2-4 alkoxy, thiomorpholino-1,1-dioxide-C.sub.2-4 alkoxy, piperazin-1-yl-C.sub.2-4 alkoxy, 4-C.sub.1-4 alkylpiperazin-1-yl-C.sub.2-4 alkoxy, pyrrolidin-1-yl-C.sub.2-4 alkoxy, imidazol-1-yl-C.sub.2-4 alkoxy, halogeno-C.sub.2-4 alkylamino, hydroxy-C.sub.2-4 alkylamino, C.sub.2-4 alkanoyloxy-C.sub.2-4 alkylamino, C.sub.1-4 alkoxy-C.sub.2-4 alkylamino, carboxy-C.sub.1-4 alkylamino, C.sub.1-4 alkoxycarbonyl-C.sub.1-4 alkylamino, carbamoyl-C.sub.1-4 alkylamino, N-C.sub.1-4 alkylcarbamoyl-C.sub.1-4 alkylamino, N,N-di-[C.sub.1-4 alkyl]carbamoyl-C.sub.1-4 alkylamino, amino-C.sub.2-4 alkylamino, C.sub.1-4 alkylamino-C.sub.2-4 alkylamino, di-[C.sub.1-4 alkyl]amino-C.sub.2-4 alkylamino, phenyl-C.sub.1-4 alkylamino, phenoxy-C.sub.2-4 alkylamino, anilino-C.sub.2-4 alkylamino, 4-pyridon-1-yl-C.sub.2-4 alkylamino, pyrrolidin-1-yl-C.sub.2-4 alkylamino, imidazol-1-yl-C.sub.2-4 alkylamino, piperidino-C.sub.2-4 alkylamino, morpholino-C.sub.2-4 alkylamino, thiomorpholino-C.sub.2-4 alkylamino, thiomorpholino-1-oxide-C.sub.2-4 alkylamino, thiomorpholino-1,1-dioxide-C.sub.2-4 alkylamino, piperazin-1-yl-C.sub.2-4 alkylamino, 4-(C.sub.1-4 alkyl)piperazin-1-yl-C.sub.2-4 alkylamino, phenylthio-C.sub.2-4 alkylamino, C.sub.2-4 alkanoylamino, C.sub.1-4 alkoxycarbonylamino, C.sub.1-4 alkylsulphonylamino, C.sub.1-4 alkylsulphinylamino, benzamido, benzenesulphonamido, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halogeno-C.sub.2-4 alkanoylamino, hydroxy-C.sub.2-4 alkanoylamino, hydroxy-C.sub.2-4 alkanoyl-(C.sub.1-4 alkyl)-amino, C.sub.1-4 alkoxy-C.sub.2-4 alkanoylamino, carboxy-C.sub.2-4 alkanoylamino, C.sub.1-4 alkoxycarbonyl-C.sub.2-4 alkanoylamino, carbamoyl-C.sub.2-4 alkanoylamino, N-C.sub.1-4 alkylcarbamoyl-C.sub.2-4 alkanoylamino, N,N-di-[C.sub.1-4 alkyl]carbamoyl-C.sub.2-4 alkanoylamino, amino-C.sub.2-4 alkanoylamino, C.sub.1-4 alkylamino-C.sub.2-4 alkanoylamino and di-[C.sub.1-4 alkyl]amino-C.sub.2-4 alkanoylamino; and wherein said benzamido or benzenesulphonamido substituent or any anilino, phenoxy or phenyl group on a R.sup.3 substituent optionally has one or two halogeno, C.sub.1-4 alkyl or C.sub.1-4 alkoxy substituents; and wherein any substituent having a heterocyclic ring optionally has one or two halogeno, C.sub.1-4 alkyl or C.sub.1-4 alkoxy substituents on said ring; and wherein any substituent having a heterocyclic ring optionally has one or two oxo or thioxo substituents on said ring; or R.sup.3 is selected from the group consisting of M.sup.1 -M.sup.2 -M.sup.3 -M.sup.4, M.sup.1 -M.sup.5 and M.sup.1 -M.sup.2 -M.sup.3' -M.sup.6 wherein M.sup.1 is a C.sub.1-4 alkyl group, wherein optionally a CH.sub.2 group is replaced by a CO group; M.sup.2 is NR.sup.12 or CR.sup.12 R.sup.13, in which R.sup.12 and R.sup.13 each independently are H or C.sub.1-4 alkyl; M.sup.3 is a C.sub.1-4 alkyl group; M.sup.3' is a C.sub.1-4 alkyl group or is absent; M.sup.4 is selected from the group consisting of CN, NR.sup.12 S(O).sub.m R.sup.13, S(O).sub.m NR.sup.14 R.sup.15, CONR.sup.14 R.sup.15, S(O).sub.m R.sup.13 and CO.sub.2 R.sup.13, in which R.sup.12, R.sup.13 and m are as defined above and R.sup.14 and R.sup.15 each independently are H or C.sub.1-4 alkyl, or R.sup.14 and R.sup.15 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).sub.m in which ring any nitrogen atom present is optionally substituted with a C.sub.1-4 alkyl group, and which ring optionally has one or two oxo or thioxo substituents; M.sup.5 is the group NR.sup.14 R.sup.15, wherein R.sup.14 and R.sup.15 are as defined above, or M.sup.5 is the group ##STR20## in which t is 2 to 4 and R.sup.16 is OH, OC.sub.1-4 alkyl or NR.sup.14 R.sup.15 ; and M.sup.6 is selected from the group consisting of a C.sub.3-6 cycloalkyl group, the group NR.sup.14 R.sup.15, wherein R.sup.14 and R.sup.15 are as defined above, and 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 R.sup.3 groups together form an optionally substituted methylenedioxy or ethylenedioxy group; R.sup.2 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; U is 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).sub.m, wherein m is 0,1 or 2, and wherein U is substituted by at least one independently selected R.sup.6 group and U is optionally substituted by at least one independently selected R.sup.4 group; each R.sup.4 is independently selected from the group consisting of hydrogen, hydroxy, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylamino, di-[C.sub.1-4 alkyl]amino, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulphinyl, C.sub.1-4 alkylsulphonyl, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkylcarbamoyl, di-[C.sub.1-4 alkyl]carbamoyl, carbamyl, C.sub.1-4 alkocycarbonyl, cyano, nitro and trifluoromethyl; each R.sup.6 is independently a group ZR.sup.7 wherein Z is joined to R.sup.7 through a (CH.sub.2) p group in which p is 0, 1 or 2 and Z is selected from a group consisting of V(CH.sub.2), V(CF.sub.2), (CH.sub.2)V, (CF.sub.2)V, V(CRR'), V(CHR) and V where R and R' are each C.sub.1-4 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 C O).sub.m or NR.sup.b where R.sup.b is hydrogen or R.sup.b is C.sub.1-4 alkyl; and R.sup.7 is an optionally substituted C.sub.3-6 cycloalkyl; or an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety; or R.sup.6 is a group ZR.sup.7 in which Z is NR.sup.b, and NR.sup.b and R.sup.7 together form an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclic moiety. 2. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible breast cancer. 3. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible non-small cell lung cancer. 4. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible ovarian cancer. 5. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible stomach cancer. 6. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible pancreatic cancer. 7. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible head and neck cancer. 8. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible cancer in which there is expression or over-expression of EGFR. 9. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible cancer in which there is expression or over-expression of erbB-2. 10. The method as claimed in claim 1, wherein the susceptible cancer is a susceptible cancer in which there is expression or over-expression of EGFR and erbB-2. 11. The method as claimed in claim 1, wherein X is N. 12. The method as claimed in claim 1, wherein Y is NR.sup.b, NR.sup.b (CH.sub.2), or (CH.sub.2)NR.sup.b. 13. The method as claimed in claim 1, wherein R.sup.1 is a 5- or 6-membered heterocyclic ring as defined in claim 1 substituted with an R.sup.3 group selected from the group consisting of M.sup.1 -M.sup.2 -M.sup.3 -M.sup.4, M.sup.1 -M.sup.5 and M.sup.1 -M.sup.2 -M.sup.3' -M.sup.6 as defined in claim 1; and p=0. 14. The method as claimed in claim 1, wherein M.sup.1 is CH.sub.2, CO, CH.sub.2 CH.sub.2 or CH.sub.2 CO; M.sup.2 is NR.sup.12 in which R.sup.12 is as defined in claim 1; M.sup.3 is CH.sub.2, CH.sub.2 CH.sub.2 or propyl; M.sup.3' is CH.sub.2, ethyl, propyl, isopropyl or is absent; M.sup.4 is SOR.sup.13, SO.sub.2 R.sup.13, NR.sup.12 SO.sub.2 R.sup.13, SO.sub.2 NR.sup.14 R.sup.15, CO.sub.2 R.sup.13 or CONR.sup.14 R.sup.15 in which R.sup.12 and R.sup.13 are defined in claim 1 and R.sup.14 and R.sup.15 each independently are H or C.sub.1-4 alkyl; M.sup.5 is a group NR.sup.14 R.sup.15 in which R.sup.14 and R.sup.15 together with the nitrogen atom to which they are attached is a 6-membered ring optionally containing an additional heteroatom selected from N or O, in which ring any nitrogen atom present is optionally substituted with a .sub.1-4 alkyl group; or M.sup.5 is a group ##STR21## in which t is 2 or 3 and R.sup.16 is OH, NH.sub.2, N(C.sub.1-4 alkyl).sub.2 or OC.sub.1-4 alkyl; or M.sup.5 is a group NR.sup.14 R.sup.15 in which R.sup.14 and R.sup.15 each independently are hydrogen or C.sub.1-4 alkyl; and M.sup.6 is a group NR.sup.14 R.sup.15 in which R.sup.14 and R.sup.15 each independently is C.sub.1-4 alkyl, or R.sup.14 and R.sup.15 together with the nitrogen atom to which they are attached is a 5- or 6-membered ring optionally containing an additional heteroatom selected from N or O, in which ring any nitrogen atom present is optionally substituted with a C.sub.1-4 alkyl group; or M.sup.6 is a 5- or 6-membered heterocyclic ring system containing 1 or 2 heteroatoms selected from N or O. 15. The method as claimed in claim 1, wherein M.sup.2 -M.sup.3 -M.sup.4 is a methylsulphonylethylamino, methylsulphinylethylamino, methylsulphonylethyl(methylamino), methylsulphinylethyl(methylamino), methylsulphonylpropylamino, methylsulphinylpropylamino, methylsulphonamidoethylamino, aminosulphonylethylamino, methylaminosulphonylethylamino, sarcosinamide, glycine, glycinamide, glycine methyl ester or acetylaminoethylamino group. 16. The method as claimed in claim 1, wherein R.sup.1 is selected from the group consisting of comprising furan, dihydrofuran, thiophene, imidazole, tetrazole, triazole, pyridine, pyrrole, pyrimidine, isoxazole and oxadiazole. 17. The method as claimed in claim 1, wherein R.sup.1 is selected from the group consisting of furan, imidazole, oxadiazole and triazole. 18. The method as claimed in claim 1, wherein R.sup.6 is benzyl, fluorobenzyl, difluorobenzyl, benzyloxy, fluorobenzyloxy, pyridylmethyl, phenyl, benzenesulphonyl, phenoxy or fluorophenoxy. 19. The method as claimed in claim 1, wherein U is an phenyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group. 20. The method as claimed in claim 1, wherein U is a phenyl or 1H-indazolyl group. 21. The method as claimed in claim 1, wherein the optional substituents for the carbocyclic or heterocyclic moiety include hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkyl carbonyl, carboxylate and C.sub.1-4 alkoxy carboxyl. 22. The method as claimed in claim 1, wherein X is N; Y is NR.sup.a, wherein R.sup.a is hydrogen or C.sub.1-4 alkyl; R.sup.1 is 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 R.sup.3 groups selected from halo, trifluoromethyl, C.sub.1-4 alkyl, carboxy, C.sub.1-4 -alkoxycarbonyl, formyl, hydroxy-C.sub.1-4 alkyl, 1,3-dioxolan-2-yl, amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, hydroxy-C.sub.1-4 alkanoyl-(C.sub.1-4 alkyl)-amino, C.sub.1-4 alkylamino-C.sub.1-4 alkyl or di(C.sub.1-4 alkyl)amino-C.sub.1-4 alkyl; p is 0; R.sup.2 is hydrogen; R.sup.4 is hydrogen, halo or methyl; U is phenyl, indolyl, benzimidazolyl or indazolyl, more preferably phenyl or indazolyl; and R.sup.6 is phenyl, benzyl, .alpha.-methylbenzyl, fluorobenzyl, difluorobenzyl, pyridylmethyl, benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy. 23. The method as claimed in claim 1, wherein X is N; Y is NR.sup.a, wherein R.sup.a is hydrogen or C.sub.1-4 alkyl; R.sup.1 is selected from the group consisting of a furan, dihydrofuran, thiophene, pyridine, pyrrole, pyrimidine, isoxazole, triazole, tetrazole, imidazole and oxadiazole ring, substituted with an R.sup.3 group selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkylamino-C.sub.1-4 -alkyl, di(C.sub.1-4 alkyl)amino-C.sub.1-4 alkyl, formyl, carboxy, C.sub.1-4 alkoxycarbonyl, 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-(prolinamino)methyl and (N,N-dimethyl-prolinamido)methyl p is 0; R.sup.2 is hydrogen; R.sup.4 is hydrogen or halo; U is phenyl or indazolyl; and R.sup.6 is selected from the group consisting of benzyl, fluorobenzyl, difluorobenzyl, pyridylmethyl, benzenesulphonyl, phenoxy, benzyloxy or fluorobenzyloxy.