A Practical Synthetic Route to Cinnolines: Application to the Design and Synthesis of RSV NNI Inhibitor JNJ-8003...

The manuscript describes the development of an efficient synthetic route to cinnolines, facilitating faster access to JNJ-8003 related Respiratory Syncytial Virus (RSV) non-nucleoside (NNI) inhibitors. Starting from correctly functionalized aryl halides, a Sonogashira reaction followed by S_NAr reaction with hydrazine 1,2-dicabroxylate reagents provided dihydrocinnolines directly via in situ 6-endo-dig cyclization. The dihydrocinnolines were conveniently transformed to corresponding cinnolines in one step. Notably, this three-step route to cinnolines is more practical and safer than traditional methods that involve hazardous diazo intermediates. The methodology demonstrated a broad substrate scope. Strategic selection of a readily available aryl halide enabled the synthesis of diverse cinnolines that served as JNJ-8003 analogues through late-stage functionalization. Furthermore, by capitalizing the inherent reactivity of aryl halides toward S_NAr reactions, we explored the synthesis of various heteroaromatic cinnolines. Given the extensive biological properties exhibited by cinnolines, our approach is poised to inspire further investigations in this field.