Quinoline derivatives as kinase inhibitors
View Patent ↗A series of quinoline derivatives, substituted by an optionally substituted bicyclic heteroaryl moiety consisting of two fused six-membered aromatic rings attached via an alkylene chain optionally linked to a heteroatom, being selective inhibitors of PI3 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 (IIA) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
wherein E represents (methyl)methylene;
Q represents N—R 4 ;
M represents the residue of a piperazin-1-yl moiety, optionally substituted by one or more substituents independently selected from heteroaryl, hydroxy, hydroxy(C 1-6 )alkyl, oxo, C 2-6 alkylcarbonyl, hydroxy(C 1-6 )alkylcarbonyl, di(C 1-6 )alkylamino(C 1 - 6 )alkylcarbonyl, (C 3-7 )cycloalkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, hydroxy(C 1-6 )alkylcarbonylamino, (C 3-7 )cycloalkylcarbonylamino, aminocarbonyl, aminocarbonyl(C 1-6 )alkyl, C 1-6 alkylaminocarbonyl and (C 1-6 )alkylaminocarbonyl(C 1-6 )alkyl;
R 1 and R 2 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, aryl(C 1-6 )-alkyl, heteroaryl(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 )alkylamino, 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;
X represents N or CH; and
R 16 and R 17 independently represent hydrogen, C 1-6 alkyl, amino, C 1-6 alkylamino or di(C 1-6 )alkylamino.
2. 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 4 ;
M represents the residue of a piperazin-1-yl moiety, optionally substituted by one or more substituents independently selected from heteroaryl, hydroxy, hydroxy(C 1-6 )alkyl, oxo, C 2-6 alkylcarbonyl, hydroxy(C 1-6 )alkylcarbonyl, di(C 1-6 )alkylamino(C 1-6 )alkylcarbonyl, (C 3-7 )cycloalkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, hydroxy(C 1-6 )alkylcarbonylamino, (C 3-7 )cycloalkylcarbonylamino, aminocarbonyl, aminocarbonyl(C 1-6 )alkyl, C 1-6 alkylaminocarbonyl and (C 1-6 )alkylaminocarbonl(C 1-6 )alkyl,
R 1 and R 2 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, aryl(C 1-6 )-alkyl, heteroaryl(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 )alkylamino, 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
X represents N or CH; and
R 16 and R 17 independently represent hydrogen, C 1-6 alkyl, amino, C 1-6 alkylamino or di(C 1-6 )alkylamino.
3. A compound as claimed in claim 1 wherein the moiety of which M is the residue is selected from 4-(pyridin-2-yl)piperazin-1-yl, 4-(pyrazin-2-yl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 3-oxopiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-(ethylcarbonyl)piperazin-1-yl, 4-(tert-butylcarbonyl)piperazin-1-yl, 4-(hydroxyacetyl)piperazin-1-yl, 4-(dimethylaminoacetyl)piperazin-1-yl, 4-(cyclopropylcarbonyl)piperazin-1-yl, 4-(carboxymethyl)piperazin-1-yl, 4-(methoxycarbonyl)piperazin-1-yl, 4-(aminocarbonyl)piperazin-1-yl, 4-(aminocarbonylmethyl)piperazin-1-yl and 4-(methylaminocarbonylmethyl)piperazin-1-yl.
4. A compound as claimed in claim 1 wherein R 1 represents hydrogen, halogen or C 1-6 alkyl.
5. A compound as claimed in claim 1 wherein R 2 represents hydrogen or halogen.
6. A compound selected from the group consisting of
(S)-4-{8-chloro-3-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;
(S)-2-(4-{8-chloro-3-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanol;
S)-4-{7-fluoro-8-methyl-3-[1-(pyrido[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;
(S)-4-{7-fluoro-8-methyl-3-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-2-one;
(S)-1-(4-{7-fluoro-8-methyl-3-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone;
(S)-1-(4-{7-fluoro-8-methyl-3-[1-(1,5-naphthyridin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone;
(S)-N-(1-{7-fluoro-8-methyl-2-[4-(pyridin-2-yl)piperazin-1-yl]quinolin-3-yl}ethyl)pyrido[3,2-d]pyrimidin-4-amine;
(S)-N-(1-{7-fluoro-8-methyl-2-[4-(pyrazin-2-yl)piperazin-1-yl]quinolin-3-yl}ethyl)pyrido[3,2-d]pyrimidin-4-amine;
(S)-1-(4-{7-fluoro-8-methyl-3-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)propan-1-one;
S)-1-(4-{7-fluoro-8-methyl-3-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-2,2-dimethylpropan-1-one;
(S)-methyl 4-{7-fluoro-8-methyl-3-[1-(pyrido[2,3-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazine-1-carboxylate;
(S)-2-(4-{8-chloro-3-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl)}piperazin-1-yl)acetic acid;
1-(4-{8-chloro-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone;
4-{7-fluoro-8-methyl-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazine-1-carboxamide;
(cyclopropyl)(4-{7-fluoro-8-methyl-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]-quinolin-2-yl}piperazin-1-yl)methanone;
(4-{7-fluoro-8-methyl-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)acetic acid;
1-(4-{8-chloro-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-2-hydroxyethanone;
1-(4-{8-chloro-3-[(1S)-1-(pyrido[3,2-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-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone formic acid salt;
1-(4-{8-chloro-3-[(1S)-1-(pyrido[3,4-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-(pyrido[3,4-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)ethanone;
(4-{7-fluoro-8-methyl-3-[(1S)-1-(pyrido[3,4-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)acetic acid;
2-(4-{8-chloro-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)acetamide;
2-(4-{7-fluoro-8-methyl-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-N-methylacetamide;
2-(4-{8-chloro-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)-N-methylacetamide; and
2-(4-{7-Fluoro-8-methyl-3-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]quinolin-2-yl}piperazin-1-yl)acetamide;
and a pharmaceutically acceptable salt or N-oxide of any of the foregoing.
7. 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.
8. A compound as claimed in claim 2 wherein the moiety of which M is the residue is selected from 4-(pyridin-2-yl)piperazin-1-yl, 4-(pyrazin-2-yl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 3-oxopiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-(ethylcarbonyl)piperazin-1-yl, 4-(tert-butylcarbonyl)piperazin-1-yl, 4-(hydroxyacetyl)piperazin-1-yl, 4-(dimethylaminoacetyl)-piperazin-1-yl, 4-(cyclopropylcarbonyl)piperazin-1-yl, 4-(carboxymethyl)piperazin-1-yl, 4-(methoxycarbonyl)piperazin-1-yl, 4-(aminocarbonyl)piperazin-1-yl, 4-(aminocarbonylmethyl)piperazin-1-yl and 4-(methylaminocarbonylmethyl)piperazin-1-yl.
9. A compound as claimed in claim 2 wherein R 1 represents hydrogen, halogen or C 1-6 alkyl.
10. A compound as claimed in claim 2 wherein R 2 represents hydrogen or halogen.
11. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 2 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.