Quinoline derivatives as kinase inhibitors
View Patent ↗A series of quinoline and quinoxaline derivatives, substituted by a fused bicyclic pyridine or pyrimidine moiety attached via an alkylene chain optionally linked to a heteroatom, being selective inhibitors of P13 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
1. A compound represented by formula (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
wherein E represents (methyl)methylene;
Q represents N—R 8 ;
M represents the residue of piperazin-1-yl, optionally substituted by one or more substituents independently selected from oxo, C 2-6 alkylcarbonyl, hydroxy(C 1-6 )alkylcarbonyl, di(C 1-6 )alkylamino(C 1-6 )alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, hydroxy(C 1-6 )alkylcarbonylamino, (C 3-7 )cycloalkylcarbonylamino, aminocarbonyl and C 1-6 alkylaminocarbonyl;
R 1 and R 2 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, aryl(C 1-6 )alkyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkyl-amino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl or di(C 1-6 )alkylaminosulfonyl; and
R 5 and R 6 independently represent C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or hydrogen, halogen, trifluoromethyl, —OR a , —SR a , —SOR a , —SO 2 R a , —NR b R c , —NR c COR d , —NR c CO 2 R d , —NR c SO 2 R e , —COR d , —CO 2 R d , —CONR b R c or —SO 2 NR b R c ; or
R 5 and R 6 , when taken together with the carbon atoms to which they are attached, represent optionally substituted C 5-7 cycloalkenyl;
R a represents C 1-6 alkyl, difluoromethyl or trifluoromethyl;
R b represents hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl-(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
R c represents hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl;
R d represents hydrogen or C 1-6 alkyl; and
R e represents C 1-6 alkyl.
2. A compound as claimed in claim 1 wherein the moiety of which M is the residue is selected from 3-oxopiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-(hydroxyacetyl)piperazin-1-yl, 4-(dimethylaminoacetyl)piperazin-1-yl, 4-(carboxymethyl)piperazin-1-yl, 4-(methoxycarbonyl)piperazin-1-yl and 4-(methylaminocarbonyl)piperazin-1-yl.
3. A compound as claimed in claim 1 wherein R 1 represents hydrogen, halogen or C 1-6 alkyl.
4. A compound as claimed in claim 1 wherein R 2 represents hydrogen or halogen.
5. A compound as claimed in claim 1 wherein R 5 represents hydrogen or C 1-6 alkyl.
6. A compound as claimed in claim 1 wherein R 6 represents hydrogen or C 1-6 alkyl.
7. A compound selected from the group consisting of
(S)-4-{8-chloro-3-[1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;
(S)-4-{8-chloro-3-[1-(6-methylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;
(S)-1-(4-{3-[1-(2,3-dihydro-1H-8-thia-5,7-diazacyclopenta[a]inden-4-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-1-yl)ethanone;
(4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)acetic acid;
1-(4-{8-chloro-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-2-hydroxyethanone;
1-(4-{8-chloro-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-2-(dimethylamino)ethanone;
2-(dimethylamino)-1-(4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone;
methyl 4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}piperazine-1-carboxylate;
4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}-N-methylpiperazine-1-carboxamide;
4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;
1-(4-{7-fluoro-8-methyl-3-[(1S)-1-(6-methylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}piperazin-1-yl)ethanone;
1-(4-{7-fluoro-8-methyl-3-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone;
1-(4-{3-[(1S)-1-(5,6-dimethylthieno[2,3-d]pyrimidin-4-ylamino)ethyl]-7-fluoro-8-methylquinolin-2-yl}piperazin-1-yl)ethanone;
and a pharmaceutically acceptable salt or N-oxide of any of the foregoing.
8. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.