New synthetic routes to triazolo-Benzodiazepine analogues: expanding the scope of the bump-And-Hole approach for selective bromo and extra-Terminal (bet) bromodomain inhibition.
We describe new synthetic routes developed toward a range of substituted
analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1
based on the triazolo-benzodiazepine scaffold. These new routes allow for the
derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the
diazepine ternary center and the side chain methylene moiety. Substitution at
the level of the side chain methylene afforded compounds targeting specifically
and potently engineered BET bromodomains designed as part of a bump and hole
approach. We further demonstrate that marked selectivity for the second over the
first bromodomain can be achieved with an indole derivative that exploits
differential interaction with an aspartate/histidine conservative substitution
on the BC loop of BET bromodomains.
