The EGFR_T790M gatekeeper mutation is a major mechanism of acquired resistance in patients treated with current EGFR TKIs for EGFR mutant NSCLC. Our recent program culminated in the nomination of PF-06459988, a selective covalent inhibitor of T790M mutant EGFR. Herein, we describe the evolution of our synthesis route to PF-06459988. Notable challenges in the synthesis included the generation of an enantiomerically pure 3,4-disubstituted pyrrolidine, a protecting group free one-pot two-step SNAr sequence on a pyrrolopyrimidine core, and the installation of a reactive acryloyl warhead moiety. The adaptation of the synthetic route to support the larger amounts of material required for clinical studies will also be addressed.

Synthesis of PF-06459988; a next generation irreversible EGFR_T790M inhibitor for resistant non-small cell lung cancer

249th National Meeting (2015)

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