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

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 SNAr 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 SNAr 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.