Triazolopyridine derivatives as modulators of TNF activity
A series of substituted [1,2,4]triazolo[4,3-a]pyridine derivatives, being potent modulators of human TNF 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 as represented by formula (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof,
wherein
V represents C—R 22 or N;
R 21 represents hydroxy(C 1-6 )alkyl; or R 21 represents (C 3-7 )cycloalkyl or (C 3-7 )heterocycloalkyl, either of which groups is optionally substituted by one, two, or three substituents independently selected from halogen, halo(C 1-6 )alkyl, cyano, cyano-(C 1-6 )alkyl, nitro, nitro(C 1-6 )alkyl, C 1-6 alkyl, trifluoro-methyl, trifluoroethyl, C 2-6 alkenyl, hydroxy, hydroxy-(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoro-methoxy, trifluoroethoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, C 1-6 alkylsulphonyl, (C 1-6 )alkylsulphonyl(C 1-6 )alkyl, oxo, amino, C 1-6 alkyl-amino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, C 2-6 alkoxycarbonyl-amino, C 1-6 alkylsulphonylamino, (C 1-6 )alkylsulphonyl-amino(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, morpholinyl-(C 1-6 )alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, C 2-6 alkoxycarbonylmethylidenyl, tetrazolyl(C 1-6 )alkyl, amino-carbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylamino-carbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl, di(C 1-6 )alkylaminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl, (C 1-6 )alkylsulphonylaminocarbonyl, (C 2-6 )alkylcarbonylamino-sulphonyl, (C 1-6 )alkoxyaminocarbonyl, tetrazolyl and hydroxyoxadiazolyl;
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 ;
R 12 represents hydrogen or halogen;
R 15 represents hydrogen, halogen, C 1-6 alkyl, trifluoromethyl, 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), (IIE), (IIF), (IIG), (IIH) or (IIJ) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate 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 hydrogen, cyano(C 1-6 )alkyl, C 1-6 alkyl, trifluoromethyl, trifluoroethyl, C 1-6 alkylsulphonyl, (C 1-6 )alkylsulphonyl(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, tetrazolyl-(C 1-6 )alkyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl or di(C 1-6 )alkylaminosulphonyl;
R 32 represents hydrogen, halogen, cyano, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, aminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl, (C 1-6 )alkylsulphonylaminocarbonyl, (C 2 )alkylcarbonylaminosulphonyl, (C 1-6 )alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazoly;
R 33 represents hydrogen, halogen, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy-(C 1-6 )alkyl, C 1-6 alkoxy, amino or carboxy;
R 34 represents hydrogen, halogen, halo(C 1-6 )alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkyl-amino, (C 2-6 )alkylcarbonylamino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, (C 1-6 )alkylsulphonylamino or (C 1-6 )alkylsulphonylamino(C 1-6 )alkyl;
E represents —CH 2 ;
R 12 represents hydrogen or halogen;
R 15 represents hydrogen, halogen, C 1-6 alkyl, trifluoromethyl, C 1-6 alkoxy, difluoromethoxy, or trifluoromethoxy; and
R 16 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, difluoromethoxy or amino.
3. The compound as claimed in claim 1 wherein R 15 represents difluoromethoxy.
4. A compound that is
4-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)-pyrimidin-2-yl]morpholine,
1-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)-pyrimidin-2-yl]piperidine-4-carboxylic acid,
4-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}[1,2,4]triazolo[4,3-a]pyridin-6-yl)-pyrimidin-2-yl]piperazin-2-one, or
3-{[2-(Difluoromethoxy)phenyl]methyl}-6-{2-[4-(methylsulfonyl)piperazin-1-yl)]-pyrimidin-5-yl}[1,2,4]triazolo[4,3-a]pyridine.
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, in association with a pharmaceutically acceptable carrier.
6. The pharmaceutical composition as claimed in claim 5 further comprising an additional pharmaceutically active ingredient.
7. A method for the treatment of rheumatoid arthritis, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (JIB) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof.