Design and Discovery of N-(2-Methyl-5′-morpholino-6′-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers

RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRASmutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small moleculeapproaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [Aversa, Biaryl amide compounds as kinase inhibitors and their preparation. WO 2014151616, 2014], a selective B/ C RAFinhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistrycampaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRASmutant tumor cell lines. We investigated the small moleculecrystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improv...