Pyrazolopyridine derivatives as modulators of TNF activity
A series of substituted pyrazolo[1,5-a]pyridine derivatives, being potent modulators of human TNFα activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
1. A compound represented by formula (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
wherein
V represents C—R 22 or N;
R 21 represents hydroxy(C 1-6 )alkyl; or R 21 represents (C 3-7 )heterocycloalkyl, which group may be optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl, C 1-6 alkylsulphonyl, oxo and carboxy;
R 22 represents hydrogen, halogen or C 1-6 alkyl;
R 23 represents hydrogen, C 1-6 alkyl, trifluoromethyl or C 1-6 alkoxy;
E represents —CH 2 ;
Q represents —CH 2 ;
Z represents hydrogen or methyl;
R 12 represents hydrogen, fluoro, chloro, trifluoro-methyl, methyl or ethoxycarbonylethyl;
R 15 represents hydrogen, halogen, C 1-6 alkyl, trifluoro-methyl, C 1-6 alkoxy, difluoromethoxy or trifluoromethoxy; and
R 16 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, difluoromethoxy or amino.
2. The compound as claimed in claim 1 represented by formula (IIC), or (IIE), or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
wherein
T represents —CH 2 — or —CH 2 CH 2 —;
U represents C(O) or S(O) 2 ;
W represents O, N(R 31 ) or C(R 32 )(R 33 );
R 31 represents C 1-6 alkylsulphonyl;
R 32 represents carboxy; and
R 33 represents hydrogen or C 1-6 alkyl.
3. The compound as claimed in claim 1 wherein R 15 represents difluoromethoxy.
4. A compound that is
3-[2-(Difluoromethoxy)benzyl]-2-methyl-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-pyrazolo[1,5-a]pyridine;
1-(5-{3 [2-(Difluoromethoxy)benzyl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}pyrimidin-2-yl)piperidine-4-carboxylic acid;
4-(5-{3 [2-(Difluoromethoxy)benzyl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}pyrimidin-2-yl)piperazin-2-one;
3-[2-(Difluoromethoxy)benzyl]-2-methyl-5-{2-[4-(methylsulfonyl)piperazin-1-yl]-pyrimidin-5-yl}pyrazolo[1,5-a]pyridine; or
1-(5-{3 [2-(Difluoromethoxy)benzyl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}pyrimidin-2-yl)-4-methylpiperidine-4-carboxylic acid.
5. A pharmaceutical composition comprising a compound of formula (IIB) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, in association with a pharmaceutically acceptable carrier.
6. The pharmaceutical composition as claimed in claim 5 further comprising an additional pharmaceutically active ingredient.