Discovery of 2H-Pyrrolo[3,4- <i>c</i> ]pyridin-3-one Derivatives as Type-III c-MET Inhibitors Enabled by Free-Energy Perturbation Calculations

The clinical emergence of diverse c-MET mutations with resistance to approved inhibitors has created an urgent demand for next-generation inhibitors with efficacy against c-MET-resistant mutations while maintaining c-MET wild-type (WT) potency, selectivity over other kinases, and brain penetration. Here, we report a novel chemical series discovered through iterative core enumeration and decoration guided by free energy perturbation calculations. Type-III inhibitor 20 demonstrated potent activity against both WT and c-MET with the D1228V resistance mutation with promising physicochemical properties, laying the foundation for the development of brain-penetrant therapies targeting c-MET–driven cancers.