Increasing complexity: A practical synthetic approach to three dimensional, cyclic sulfoximines and first insights into their in vitro properties

Despite their interesting properties, sulfoximines (2), the mono-aza analogues of sulfones (1), have received little interest in drug discovery for a long time. Nevertheless, four sulfoximine compounds (roniciclib, atuveciclib, BAY 1251152, AZD6738) have entered clinical evaluation of late and their promising physicochemical and DMPK properties were important triggers for their selection as clinical candidates.

However, only limited literature on the synthesis of cyclic sulfoximines (3) and their properties is currently available. This presentation highlights a practical, safe approach for the synthesis of five- to seven-membered cyclic sulfoximines (3), which are currently underrepresented in drug discovery.

To gain further knowledge of the medicinal chemistry properties of cyclic sulfoximines (3), the behavior of fragment-like reaction products 3 was evaluated in selected in vitro assays (aqueous solubility, metabolic stability, Caco2 permeability, logD) and compared to acyclic analogues (2). In order to overcome the limitations of analyzing such small and fragment-like compounds we also compared the in vitro properties of pan-CDK inhibitor roniciclib and its cyclic analogue.