Von Richter Cinnolines Synthesis Revisited—Approach to Polysubstituted Cinnoline Derivatives as Important Scaffolds for Kinase Inhibitors

ABSTRACT Herein, we report a revised von Richter reaction‐based intramolecular cyclization approach for synthesizing polysubstituted cinnolines from 2‐aminoalkyne precursors. Our methodology addresses key limitations of the former approach, most notably the pronounced hydrolytic instability of 4‐halocinnoline intermediates. By exploring the influence of various substituents and implementing strictly anhydrous cyclization conditions or incorporating a stabilizing phenyl group at position 3, we minimized hydrolysis and expanded the reaction scope to a wide range of polysubstituted cinnolines. The resulting scaffolds retain strategically positioned halogens at C‐4, enabling late‐stage functionalization, including one‐pot nucleophilic substitution and cross‐coupling strategies. We utilized this method to synthesize several complex cinnoline derivatives, among them 45 . Profiling of 45 against a kinase panel revealed selective inhibition of multiple tyrosine kinases, underscoring both the practical value of the optimized method and the potential of cinnoline as a promising scaffold in kinase inhibitor development.