Design and Characterization of 1,3-Dihydro-2H-benzo[d]azepin-2-ones as Rule-of-5 Compliant Bivalent BET Inhibitors

The 1,3-dihydro-2H-benzo[d]azepin-2-onesare potent and ligand-efficient pan-BET bromodomain inhibitors. Herewe describe the extension of this template to exploit a bivalent modeof action, binding simultaneously to both bromodomains. Initiallythe linker length and attachment vectors compatible with bivalentbinding were explored, leading to the discovery of exceptionally potentbivalent BET inhibitors within druglike rule-of-5 space.