Fused bicyclic heteroaromatic derivatives as modulators of TNF activity
A series of substituted heteroaromatic compounds containing two fused six-membered rings, tivity, 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 a pharmaceutically acceptable salt 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, which group is optionally substituted by one, two, or three substituents independently selected from halogen, halo(C 1-6 )alkyl, cyano, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, 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 )alkylamino, C 2-6 alkylcarbonylamino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, (C 2-6 )alkoxycarbonylamino-(C 1-6 )alkyl, C 1-6 alkyl sulphonylamino, (C 1-6 )alkyl-sulphonylamino(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, aminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl, (C 1-6 )alkylsulphonylaminocarbonyl, (C 2-6 )alkylcarbonyl-aminosulphonyl, (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;
q is zero or 1;
A represents C—R 2 or N;
G represents the residue of a six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;
E represents —O—, —CH 2 —, or —CH(CH 3 );
Q represents —CH 2 — or —CH 2 O;
Z represents hydrogen or methyl;
R 2 represents hydrogen or halogen;
R 15 represents hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or difluoromethoxy; and
R 16 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, difluoromethoxy or amino.
2. The compound as claimed in claim 1 wherein R 21 represents hydroxy(C 1-6 )alkyl.
3. The compound as claimed in claim 1 represented by formula (IIF), (IIG), (IIH), or (IIJ), or a pharmaceutically acceptable salt thereof:
wherein
W represents C(R 32 )(R 33 );
R 32 represents hydrogen, halogen, cyano, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, formyl, 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 2-6 )alkylcarbonyl-aminosulphonyl, (C 1-6 )alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl;
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 )alkyl-sulphonylamino or (C 1-6 )alkylsulphonylamino(C 1-6 )alkyl;
q is zero or 1.
4. The compound as claimed in claim 3 wherein R 34 represents hydrogen, fluoro or hydroxy.
5. The compound as claimed in claim 1 wherein R 15 represents difluoromethoxy.
6. A compound that is
2-{5-[3-Methyl-4-(1-phenylethyl)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol,
2-(5-{4-[2-(Difluoromethoxy)benzyl]-3-methylcinnolin-6-yl}pyrimidin-2-yl)propan-2-ol, or
2-{5-[3-Methyl-4-(2-methylphenoxy)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol.
7. A pharmaceutical composition comprising a compound of formula (IIB) as defined in claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
8. The pharmaceutical composition as claimed in claim 7 further comprising an additional pharmaceutically active ingredient.