Substituted Diaryl Ether Compounds As Retinoic Acid-Related Orphan Receptor-Gamma T (Ror Gamma T) Agonists

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor gamma t (ROR gamma t) agonists is described. Compound 1 was identified from deck mining as a ROR gamma t agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. (C) 2020 Elsevier Science Ltd. All rights reserved.