Chalcogen OCF₃ Isosteres Modulate Drug Properties without Introducing Inherent Liabilities

The synthesis of SCF₃ as well as SeCF₃ isosteres of two OCF₃ -containing drugs was achieved through visible light and copper-catalyzed processes. Herein, we show that chalcogen replacement modulates physicochemical and ADME properties without introducing intrinsic liabilities. The SCF₃ and SeCF₃ groups are more lipophilic than their oxygen counterpart; however, microsomal stability is unchanged, indicating that these molecular changes may be beneficial for in vivo half-life. Enabled by modern synthetic methods, we present the chalcogen-CF₃ groups as potential key players for future fluorinated pharmaceuticals.