derivatives that can better occupy the HFF cleft would result in compounds with higher affinity for SmBRD3 (2). Therefore, compounds 9-14 were designed, which incorporate a variety of [6.5]-fused ring systems (Figure ). The quinoline derivative 15 was designed to probe the SmBRD3 affinity of a [6.6]-fused bicycle. The synthesis of these compounds was based, in part, on the work of Gosmini et al. and Shadrick et al. with the appropriate bicyclic bromides employed in the Buchwald-Hartwig coupling. Full details are provided in the Supplementary Information. The benzothiophene-based compound 9 and its enantiomer, 10, were synthesised first. Analysis using ITC showed that compound 9 has a Kd value of 701 ± 64.9 nM, while compound 10 showed no detectable binding (Table ). This observation is in line with data obtained on human bromodomains, where the enantiomer of an I-BET726 derivative showed reduced binding to