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.