Claims for Patent: 6,828,320

Summary 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):	George Stuart Cockerill, Malcolm Clive Carter, Stephen Barry Guntrip, Kathryn Jane Smith
Assignee:	Novartis AG, SmithKline Beecham Corp
Application Number:	US10/062,647
Patent 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): 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 is a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group 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 being 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, tritluoromethoxy, 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, arylsulphonyl, halogen O-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, halogen O-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-pyridin-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,{overscore (N)}-di-[C1-4 alkyl]carbamoyl-C2-4 alkanoylamino, amino-C2-4 alkanoylamino, C1-4 alkylamino-C2-4 alkanoylamino and di-[C1-4 alkyl]amino-C2-4 alkanoylamino; and wherein said benzamido or benzenesulphonamido substituent or any anilino, phenoxy or phenyl group on a R3 substituent optionally has one or two halogeno, C1-4 alkyl or C1-4 alkoxy substituents; and wherein any substituent having a heterocyclic ring optionally has one or two halogeno, C1-4 alkyl or C1-4 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 R3 is selected from the group consisting of M1-M2-M3-M4, M1-M5 and M1-M2-M3′-M6 wherein M1 is a C1-4 alkyl group, wherein optionally a CH2 group is replaced by a CO group; M2 is NR12 or CR12R13, in which R12 and R13 each independently are H or C1-4 alkyl; M3 is a C1-4 alkyl group; M3′ is a C1-4 alkyl group or is absent; M4 is selected from the group consisting of CN, NR12S(O)mR13, S(O)mNR14R15, CONR14R15, S(O)mR13 and CO2R13, in which R12, R13 and m are as defined above and R14 and R15 each independently are 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 is optionally substituted with a C1-4 alkyl group, and which ring optionally has one or two oxo or thioxo substituents; M5 is the group NR14R15, wherein R14 and R15 are as defined above, or M5 is the group in which t is 2 to 4 and R16 is OH, OC1-4 alkyl or NR14R15; and M6 is selected from the group consisting of a C3-6 cycloalkyl group, the group NR14R15, wherein R14 and R15 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 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 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)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 selected from the group consisting of 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 alkocycarbonyl, cyano, nitro and 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 is selected from a group consisting of V(CH2), V(CF2), (CH2)V, (CF2)V, V(CRR′), V(CHR) and 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 C 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. 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 NRb, NRb(CH2), or (CH2)NRb. 13. The method as claimed in claim 1, wherein R1 is a 5- or 6-membered heterocyclic ring as defined in claim 1 substituted with an R3 group selected from the group consisting of M1-M2-M3-M4, M1-M5 and M1-M2-M3′-M6 as defined in claim 1; and p=0. 14. The method as claimed in claim 1, wherein M1 is CH2, CO, CH2CH2 or CH2CO; M2 is NR12 in which R12 is as defined in claim 1; M3 is CH2, CH2CH2 or propyl; M3′ is CH2, ethyl, propyl, isopropyl or is absent; M4 is SOR13, SO2R13, NR12SO2R13, SO2NR14R15, CO2R13 or CONR14R15 in which R12 and R13 are defined in claim 1 and R14 and R15 each independently are H or C1-4 alkyl; M5 is a group NR14R15 in which R14 and R15 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 1-4 alkyl group; or M5 is a group in which t is 2 or 3 and R16 is OH, NH2, N(C1-4 alkyl)2 or OC1-4 alkyl; or M5 is a group NR14R15 in which R14 and R15 each independently are hydrogen or C1-4 alkyl; and M6 is a group NR14R15 in which R14 and R15 each independently is C1-4 alkyl, or R14 and R15 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 C1-4 alkyl group; or M6 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 M2-M3-M4 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 R1 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 R1 is selected from the group consisting of furan, imidazole, oxadiazole and triazole. 18. The method as claimed in claim 1, wherein R6 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, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkyl carbonyl, carboxylate and C1-4 alkoxy carboxyl. 22. The method as claimed in claim 1, wherein X is N; Y is NRa, wherein Ra is hydrogen or C1-4 alkyl; R1 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 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 is hydrogen; R4 is hydrogen, halo or methyl; U is phenyl, indolyl, benzimidazolyl or indazolyl, more preferably phenyl or indazolyl; and R6 is phenyl, benzyl, α-methylbenzyl, fluorobenzyl, difluorobenzyl, pyridylmethyl, benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy. 23. The method as claimed in claim 1, wherein X is N; Y is NRa, wherein Ra is hydrogen or C1-4 alkyl; R1 is selected from the group consisting of a furan, dihydrofuran, thiophene, pyridine, pyrrole, pyrimidine, isoxazole, triazole, tetrazole, imidazole and oxadiazole ring, substituted with an R3 group selected from the group consisting of C1-4alkyl, C1-4alkylamino-C1-4-alkyl, 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-(prolinamino)methyl and (N,N-dimethyl-prolinamido)methyl p is 0; R2 is hydrogen; R4 is hydrogen or halo; U is phenyl or indazolyl; and R6 is selected from the group consisting of benzyl, fluorobenzyl, difluorobenzyl, pyridylmethyl, benzenesulphonyl, phenoxy, benzyloxy or fluorobenzyloxy.