Discovery of\nPotent Azetidine-Benzoxazole MerTK Inhibitors\nwith <i>In Vivo</i> Target Engagement

Inhibition of the receptor tyrosine kinase MerTK by small\nmolecules\nhas the potential to augment the immune response to tumors. Potent,\nselective inhibitors with high levels of <i>in vivo</i> target\nengagement are needed to fully evaluate the potential use of MerTK\ninhibitors as cancer therapeutics. We report the discovery and optimization\nof a series of pyrazinamide-based type 1.5 MerTK inhibitors bearing\nan azetidine-benzoxazole substituent. Compound <b>31</b> potently\nengages the target <i>in vivo</i> and demonstrates single\nagent activity in the immune-driven MC-38 murine syngeneic tumor model.