3,3-Difluorooxetane – A Versatile Functional Group for Bioisosteric Replacements in Drug Discovery

Functional group (FG) is one of the cornerstone concepts in organic chemistry and related areas. The wide spread of bioisosterism ideas in medicinal chemistry and beyond caused a striking rise in demand for novel FGs with a defined impact on the developed compound properties. In this work, the evaluation of the 3,3-difluorooxetane unit (3,3-diFox) as a functional group for bioisosteric replacements is disclosed. A comprehensive experimental study (including multigram building block synthesis, quantification of steric and electronic properties, measurements of pKa, LogP, chemical stability, and biological evaluation of the 3,3-diFox-derived bioisostere of a drug candidate) revealed a prominent behavior of the 3,3-diFox fragment as a versatile substituent for early drug discovery programs.