Selective Metalation of Functionalized Quinazolines to Enable Discovery and Advancement of Covalent KRAS Inhibitors

The quinazoline compound ARS-1620 is a recently discovered, mutant-specific covalent inhibitor of KRASG12C. Route scouting in support of multigram ARS-1620 batches led to a new synthetic approach that relies on metalation of substituted quinazolines at C7. The exquisite selectivity seen in this metalation formed the basis for a scalable route to kilogram quantities of compounds in this family. It also accelerated medicinal chemistry efforts as critical intermediates became readily available in large quantities.