Bicyclic heteroaromatic compounds as kinase inhibitors
View Patent ↗A series of 5-6 fused ring bicyclic heteroaromatic derivatives, based in particular on the 5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine ring system, being inhibitors of p38 kinase, are accordingly of use in medicine, for example in the treatment and/or prevention of immune or inflammatory disorders.
1. A compound of formula (1):
wherein:
the dashed line joining A and C(R a ) is present and represents a bond and A is a —C(R b )═ group;
R a and R b are each hydrogen;
X is a —CH═ group;
Y is a —C(R e )═ group;
R e is hydrogen, —CN, —COR 1 , —CO 2 R 1 , —CONR 1a R 2a , —S(O) 2 NR 1a R 2a , —CONR 1a OR 2a or —C(O)N(R 3a )NR 1a R 2a ;
R 1 is methyl, ethyl or trifluoromethyl
R 1a and R 2a are, independently, a hydrogen atom or methyl group, or together with the nitrogen atom to which they are attached, represent —(CH 2 ) 4 — or —CH(CH 2 OH)(CH 2 ) 3 —;
R 3a is a hydrogen atom or C 1-6 alkyl group;
L is a —CH 2 —, —CH(CH 3 )—, —C(O)— or —CH 2 CH 2 — group;
n is zero;
Alk 1 is an optionally substituted aliphatic or heteroaliphatic chain;
L 1 is a covalent bond;
Cy 1 is phenyl, methylphenyl, methoxyphenyl, thienyl or indolyl; and
Ar represents phenyl, pyridinyl, thienyl or benzothienyl, any of which groups may be optionally substituted by one or two substituents selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy and nitro;
or a pharmaceutically acceptable salt or N-oxide thereof.
2. A compound as claimed in claim 1 wherein Ar is a phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichiorophenyl, (chloro)(fluoro)phenyl, cyanophenyl, methylphenyl, (fluoro)(methyl)phenyl, methoxyphenyl, nitrophenyl, pyridinyl, chlorothienyl or benzothienyl group.
3. A compound as claimed in claim 1 which is
1-Benzyl -4-phenyl- 1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3-Chlorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(4-Fluorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(2,6-Dichlorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3-Methoxybenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-Benzyl-4-(4-methoxyphenyl)-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-Benzoyl--4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
4-[(5-Oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl]benzonitrile;
3-[5-Oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl]benzonitrile;
1-(2-Methylbenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3-Methylbenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(4-Methylbenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(4-Chlorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3,4-Dichlorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(2,5-Dichlorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3,4-Difluorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(2,4-Difluorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3-Chloro-4-fluorobenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
4-Phenyl-1-(pyridin-4-ylmethyl)-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
4-Phenyl-1-(pyridin-3-ylmethyl)-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
4-Phenyl-1-(1-phenylethyl)-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3-Chlorobenzyl)-4-phenyl-2-(pyrrolidin-1-ylsulfonyl)-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
Ethyl 1-benzyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;
Ethyl 1-(3-chloro-4-fluorobenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;
Ethyl 1-(3-methylbenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;
Ethyl 1-(3-chlorobenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;
1-(3-Chloro-4-fluorobenzyl)-N-methoxy-N-methyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
N-Methoxy-N-methyl-1-(3-methylbenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
1-(3-Chlorobenzyl)-N-methoxy-N-methyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
1-(3-Chloro-4-fluorobenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
1-(3-Methylbenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
1-(3-Chlorobenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
4-Phenyl-1-(2-phenylethyl)- 1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3-Chlorobenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carbonitrile;
1-(3-Chlorobenzyl)-N,N-dimethyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
1-(3-Chlorobenzyl)-N-methyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
1-(3-Chlorobenzyl)-4-phenyl-2-(pyrrolidin-1-ylcarbonyl)- 1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-(3-Chlorobenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carbohydrazide;
Ethyl 1-(3-chlorobenzyl)-4-( 1H-indol-5-yl)-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;
Ethyl 1-(3-chlorobenzyl)-5-oxo-4-(3-thienyl)-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;
1-(3-Chlorobenzyl)-4-( 1H-indol-5-yl)-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
Ethyl 1-(4-fluoro-3-methylbenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;
1-(3-Chlorobenzyl)-4-(3-thienyl)- 1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
Ethyl 1-(3-chlorobenzyl)-4-(4-methylphenyl)-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;.
1-(2-Cyanobenzyl)-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
1-(4-Fluoro-3-methylbenzyl)-5-oxo-4-phenyl-4,5-dihydro-1 H-pyrrolo[3,2-b]pyridine-2- carboxamide;
1-(3-Chlorobenzyl)-4-(4-methylphenyl)-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxamide;
1-(3-Chlorobenzyl)-4-(4-methylphenyl)-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2- carbohydrazide;
Ethyl 1-(3-chlorobenzyl)-4-(2-nitrophenyl)-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate;
1-(1,3 -Benzothiazol-2-ylmethyl)-4-phenyl- 1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1 [(5-Chloro-2-thienyl)methyl]-4-phenyl- 1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one;
1-Benzyl-4-phenyl-3-(trifluoroacetyl)- 1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one; or
2-{[(2S)-2-(Hydroxymethyl)pyrrolidin- l-yl]carbonyl}-1-(3-methylbenzyl)-4-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-5-one.
4. A pharmaceutical composition comprising a compound as claimed in claim 1 , or a pharmaceutically acceptable salt, or N-oxide thereof, in association with a pharmaceutically acceptable carrier.