Tricyclic Sulfones As Potent, Selective And Efficacious Ror Gamma T Inverse Agonists-Exploring C6 And C8 Sar Using Late-Stage Functionalization

In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of ROR gamma t inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective ROR gamma t inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.