Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing

3,3-Disubstituted
oxetanes have been utilized as bioisosteres for
gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane
indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once
every 3 weeks) oral and parenteral dosing. A diamide class of IDO
inhibitors was discovered through an automated ligand identification
system (ALIS). Installation of an oxetane and fluorophenyl dramatically
improved the potency. Identification of a biaryl moiety as an unconventional
amide isostere addressed the metabolic liability of amide hydrolysis.
Metabolism identification (Met-ID)-guided target design and the introduction
of polarity resulted in the discovery of potent IDO inhibitors with
excellent pharmacokinetic (PK) profiles in multiple species. To enable
rapid synthesis of the key oxetane intermediate, a novel oxetane ring
cyclization was also developed, as well as optimization of a literature
route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept
testing for the IDO1 inhibition mechanism for oncology.