A Tetrazine-Based Synthesis for Accessing Underutilized Aza-Indole Analogues

Aza-indole functionalities fill an important role in drug discovery. While indoles are considered privileged scaffolds, aza-indoles allow for better pharmacological properties and on-target activities. Synthetic approaches to access aza-indoles are limited, with pyrazolopyridazines being some of the scarcest aza-indoles. To provide access to these underutilized cores, a synthetic approach utilizing a reaction cascade between a protected propargylhydrazine and dichlorotetrazine has been developed. In addition, a variety of methods were developed to access each position on the core for late-stage functionalization. This method offers an expedited synthetic route to a rare aza-indole scaffold with superior physiochemical properties when compared to indole analogues.