Discovery of Benzotriazolo[4,3‑d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo­[b]­isoxazolo­[4,5-d]­azepines and benzotriazolo­[4,3-d]­[1,4]­diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.