The discovery of clinical candidates is a daunting task. Investigating novel or underexplored functional groups can support medicinal chemists in finding innovative small molecules and optimizing their properties. For example, very recently sulfoximines, sulfonimidamides, and phosphine oxides have been highlighted as valuable additions to the medicinal chemist′s toolbox. By way of contrast N–trifluoromethyl amines and azoles are very rarely used in medicinal chemistry, likely due to their historically challenging syntheses and questions over their chemical stability. However, in recent years four reports were published describing mild, one pot trifluoromethylations of amines. Inspired by these publications, we decided to systematically investigate the aqueous stability and key in vitro properties of N–trifluoromethyl amines and azoles with a view to making sound recommendations for using N–trifluoromethyl amines and azoles in drug design. We show that N–trifluoromethyl amines are prone to hydrolysis, whereas N–trifluoromethyl azoles have excellent aqueous stability. Compared to their N–methyl analogues, N–trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, N–trifluoromethyl azoles can serve as bioisosteres of N–iso–propyl and N–tert–butyl azoles. Consequently, we suggest that N–trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry. We further highlight the need to develop new synthetic approaches to these compounds avoiding the use of environmentally damaging and highly toxic reagents.

N–Trifluoromethyl amines and azoles: An underexplored functional group in the medicinal chemist′s toolbox

ACS Spring Meeting 2021

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