-Trifluoromethyl Amines and Azoles: An Underexplored Functional Group in the Medicinal Chemist's Toolbox.

Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, -trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of -trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties. We show that -trifluoromethyl amines are prone to hydrolysis, whereas -trifluoromethyl azoles have excellent aqueous stability. Compared to their -methyl analogues, -trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, -trifluoromethyl azoles can serve as bioisosteres of --propyl and --butyl azoles. Consequently, we suggest that -trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry.