Imidazopyridazine derivatives as modulators of TNF activity
A series of substituted imidazo[1,2-b]pyridazine derivatives of formula (I), being potent modulators of human TNFa 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:
wherein
V represents C—R 22 or N; R 12 represents hydrogen, fluoro, chloro, trifluoromethyl, methyl or ethoxycarbonylethyl;
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, arylamino, C 2-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 heterocycloalkylcarbonyl, 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;
R 21 represents hydroxy(C 1-6 )alkyl; or R 21 represents (C 3-7 )heterocycloalkyl, or (C 4-9 )heterobicycloalkyl, either of which groups may be optionally substituted by one, two or three substituents independently selected from trifluoromethyl, hydroxy, C 1-6 alkylsulphonyl, oxo, carboxy and C 2-6 alkoxycarbonyl;
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 —O—, —CH 2 — or —C(O)—;
Q represents —CH 2 —;
Z represents hydrogen or methyl;
R 4 and R 5 independently represent hydrogen or C 1-6 alkyl.
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 (IIC), (IIE), or (IIL) 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 );
-M- represents —CH 2 — or —CH 2 CH 2 —;
R 31 represents C 1-6 alkylsulphonyl;
R 32 represents hydrogen, hydroxy, C 1-6 alkylsulphonyl, carboxy, or C 2-6 alkoxycarbonyl;
R 33 represents hydrogen;
E represents —O—, —CH 2 — or —C(O)—;
Q represents —CH 2 —;
Z represents hydrogen or methyl;
R 4 and R 5 independently represent hydrogen or C 1-6 alkyl;
R 12 represents represents hydrogen, fluoro, chloro, trifluoromethyl, methyl or ethoxycarbonylethyl;
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.
4. The compound as claimed in claim 1 wherein E represents —CH 2 —.
5. A compound as claimed in claim 1 wherein R 15 represents difluoromethoxy.
6. A compound which is any one of
3-[2-(Difluoromethoxy)benzyl]-2-methyl-6-[2-(morpholin-4-yl)pyrimidin-5-yl]-imidazo[1,2-b]pyridazine;
1-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)piperidine-4-carboxylic acid;
4-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)piperazin-2-one;
3-[2-(Difluoromethoxy)benzyl]-2-methyl-6-{2-[4-(methylsulfonyl)piperazin-1-yl]-pyrimidin-5-yl}imidazo[1,2-b]pyridazine;
Methyl (1R,5S)-3-[5-(3-{[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-b]-pyridazin-6-yl)pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylate;
(1R,5S)-3-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylic acid;
2-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)propan-2-ol; or
1-[5-(2-methyl-3-phenoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidin-2-yl]-3-(trifluoro-methyl)azetidin-3-ol.
7. 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.
8. The pharmaceutical composition as claimed in claim 7 further comprising an additional anti-inflammatory agent.