Fused pentacyclic imidazole derivatives as modulators of TNF activity
A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, being potent modulators of human TNF a 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 of formula (I), or a pharmaceutically acceptable salt thereof:
wherein
X represents N or C—F;
R 1 represents hydrogen or methyl or an isotopic variant thereof;
R 2 represents hydroxy or cyano;
R 3 represents hydroxy or cyano; and
R 2 is different from R 3 .
2. The compound as claimed in claim 1 represented by formula (IIA), or a pharmaceutically acceptable salt thereof:
wherein X and R 1 are as defined in claim 1 .
3. The compound as claimed in claim 1 represented by formula (IIB), or a pharmaceutically acceptable salt thereof:
wherein X and R 1 are as defined in claim 1 .
4. The compound as claimed in claim 1 represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 represents hydrogen, —CH 3 or —CD 3 .
5. The compound as claimed in claim 1 that is 3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-12-(trideuteriomethyl)-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014, 19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile;
3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19), 15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile;
3-[5-[(1R,11R)-18-(difluoromethoxy)-6-fluoro-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19), 15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile;
3-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014, 19]icosa-3,5,7,9,14(19), 15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile;
3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3,5,7,9,14(19),15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile;
1-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-3-methylcyclobutane-1-carbonitrile; or
1-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-3-methylcyclobutane-1-carbonitrile.
6. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
7. The pharmaceutical composition as claimed in claim 6 further comprising an additional pharmaceutically active ingredient.
8. A method for the treatment of Rheumatoid arthritis or Crohn's disease which comprises administering to a patient in need of such treatment an effective amount of the compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof.