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 KRAS(G12C). 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.

Automated summary

ARS-1620, a quinazoline compound, is a mutant-specific covalent inhibitor of KRAS(G12C) that has recently been discovered. A novel synthetic approach involving metalation at C7 position of substituted quinazolines has been developed for the multigram production of ARS-1620. The metalation process has shown excellent selectivity, enabling the scalable synthesis of kilogram quantities of compounds in this family and accelerating medicinal chemistry efforts.