Enabling Process Development of Tetracyclic Quinolines for Brain-Penetrating KRAS G12C Inhibitors

To enable the discovery of brain-penetrating KRAS G12C inhibitors, three scalable routes to key tetracyclic quinoline cores were developed. These methods mitigate process safety risks associated with high temperature nitration by utilizing either a continuous flow process or alternative functional group strategies. Furthermore, optimized S N Ar cyclizations to forge the tetracyclic framework while suppressing hydrolysis and an improved atroposelective end-game sequence drastically increased overall synthetic efficiency, delivering potential drug candidates in good yields and high diastereomeric purity. These enabling processes supported early toxicological studies and provided a robust foundation for the development of clinical candidates.