Fused pentacyclic imidazole derivatives as modulators of TNF activity
Disclosed herein are compounds of formula (I) and pharmaceutically acceptable salt thereof, wherein variables X, R 1 , R 2 , and R 3 are defined herein. These compounds are potent modulators of human TNFα activity and, 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;
R 2 represents hydrogen, methyl or trifluoromethyl; and
R 3 represents hydrogen, cyano, or hydroxymethyl.
2. The compound as claimed in claim 1 represented by formula (IIA), or a pharmaceutically acceptable salt thereof:
wherein X, R 1 , R 2 and R 3 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, R 1 , R 2 and R 3 are as defined in claim 1 .
4. A compound selected from the following:
cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-1-methyl-cyclobutanecarbonitrile;
cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-1-methyl-cyclobutanecarbonitrile;
cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]-3-fluoropyridin-2-yl}-1-methylcyclobutanecarbonitrile;
cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]-3-fluoropyridin-2-yl}-1-methylcyclobutanecarbonitrile;
(7R,14R)-11-{6-[(1S,2R)-1-amino-2-methylcyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;
(7R,14R)-11-{6-[(1R,2S)-1-amino-2-methylcyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one;
(7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;
(7R,14R)-11-[6-(cis-1-amino-3-hydroxy-3-methylcyclobutyl)-5-fluoropyridin-3-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one;
(7R,14R)-11-[6-(cis-1-amino-3-hydroxy-3-methylcyclobutyl)-5-fluoropyridin-3-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;
(7R,14R)-11-{2-[cis-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one;
(7R,14R)-11-(6-[cis-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one;
(7R,14R)-11-(6-[cis-1-amino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one;
(7R,14R)-11-{2-[cis-1-amino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one;
(7R,14R)-11-(6-[cis-1-amino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one;
(7R,14R)-11-(2-{cis-1-amino-3-[hydroxy(dideutero)methyl]-3-methylcyclobutyl}-pyrimidin-5-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one;
(7R,14R)-11-{2-[cis-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; and
(7R,14R)-11-(6-{cis-1-amino-3-[hydroxy(dideutero)methyl]-3-methylcyclobutyl}-5-fluoropyridin-3-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b]-[2,5]benzodiazocin-5(14H)-one.
5. 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.
6. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 4 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.