Sulfones (1) and sulfonamides (2) are important pharmacophores found in many drugs on the market. On the other hand, the corresponding aza-analoges, sulfoximines (3), sulfondiimines (4) and sulfonimidamides (5) have received little interest in drug discovery until recently. The infrequent take-up of these sulfur (VI) groups is surprising since they seem to offer very interesting properties, like high stability, favorable PhysChem properties, multiple H-bond acceptor/donor functionalities, and structural diversity. Possible reasons for the neglected use of these functional groups are the lack of commercial availability, limited synthetic methods for their preparation and an incomplete understanding of their medicinal-chemistry-relevant properties. In the identification of CDK inhibitor roniciclib we experienced that the use of the uncommon sulfoximine group can be crucial for overcoming hurdles in lead optimization. This has sparked our interest in neglected sulfur (VI) pharmacophores, which led to additional clinical candidates (atuveclib, BAY 1251152). However, in our drug discovery efforts the syntheses of sulfur (VI) key compounds have often been met with difficulties, including safety concerns. Therefore we have not only readily adopted new synthetic methods to complex drug-like molecules but have also started to develop new synthetic methods for the syntheses of sulfur (VI) groups. In this presentation we will share the key learnings of various lead optimization efforts leading to multiple sulfur (VI) clinical candidates. In this context we will also highlight the key methods for their preparations. Moreover, we will showcase our latest results for the synthesis and functionalization of =NH sulfonimidamides and the evaluation of their medicinal-chemistry-relevant in vitro properties.

Exploration of novel chemical space by the interplay of drug design and method development: Neglected sulfur (VI) pharmacophores in drug discovery

256th National Meeting (2018)

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