Identification of novel 3-aryl-1-aminoisoquinolines-based KRAS^G12C inhibitors: Rational drug design and expedient construction by CH functionalization/annulation

Developing a synthetic methodology to expediently construct a specific drug scaffold with the desired biological activity remains challenging. Herein, we describe a work on rational application of a synthetic methodology in the synthesis of KRAS^G12C inhibitors. Novel KRAS^G12C inhibitors were initially designed with 1-amino-3-aryl isoquinoline scaffold using structure-based drug design strategy. A ruthenium-catalyzed direct monoCH functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was then developed with high versatility of substrates and good tolerance for polar functional groups. By using this reaction, the target compounds 1-amino-3-aryl isoquinolines were facilely prepared. Further in vitro tests led to identification of two novel lead compounds with KRAS^G12C inhibitory activity.