Synthesis, Evaluation, and Context for Applications of SF5-Containing [1.1.1]Bicyclopentane and [ <i>2</i> ]Staffane “Hybrid Bioisosteres”

Abstract Bioisosteric replacements are conventionally applied as single-variable changes to a parent molecule during drug discovery campaigns. Herein, we evaluate hybrid bioisosteric replacements as strategic combinations of multiple substitutions that counterbalance the physicochemical consequences of incorporating single bioisosteres individually. In this context, we validate SF5-substituted [1.1.1]bicyclopentanes (SF5-BCPs) and SF5-[2]staffanes (SF5-BCP-BCPs) as hybrid bioisostere motifs that have not been field-tested due to lack of access to versatile building blocks. We address a key synthetic limitation by developing scalable routes to carboxylic acid-containing intermediates that facilitate incorporation of these motifs into drug-like molecules via carbonyl group manipulations. These advances enable (1) crystallographic studies that contextualize structural features of these motifs, (2) syntheses of structurally diverse pharmaceutical and agrochemical derivatives, and (3) systematic evaluation of single (SF5-Ph → SF5-BCP) and multicomponent “hybrid” bioisosteric replacements (CF3-Ph → SF5-BCP and CF3-Ph-Ph → SF5-BCP-BCP) through in vitro ADME profiling. Finally, we investigate the chemical stability profile of these novel SF5-[2]staffanes, establish an extensive suite of building blocks, and demonstrate their compatibility with reactions frequently used in medicinal chemistry. Together, the results of this extensive study position SF5-BCPs and SF5-[2]staffanes as practical hybrid bioisosteres for tuning molecular properties in drug discovery.