Commercial Route Development Toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate

Our route scouting efforts toward finding the most efficient construction of PF-07265807 (ARRY-067) in readiness for process development prior to commercial manufacture are described. ARRY-067 contains the azaindazole (1H-pyrazolo [3,4-b]pyridine) building block that is common to many pharmaceuticals and bioactive agents. Herein, our novel approach to this challenging structural motif is described where an oxazoline ring-opening cyclization cascade triggered by the addition of hydrazine reveals the target 3-alaninol-substituted azaindazole in one step. An improved synthesis of the uracil carboxylic acid coupling partner is also described. Overall, the new route is six steps shorter than the enabling route, minimizes protecting group manipulations, and avoids the use of transition metal catalysis.