Pyrrolo[2,1-f][1,2,4]triazines: From C-nucleosides to kinases and back again, the remarkable journey of a versatile nitrogen heterocycle.

Pyrrolo[2,1-f][1,2,4]triazine, a unique NN bond-containing heterocycle with a bridgehead nitrogen, was first synthesized in the late 1970s but did not find utility until more than a decade later in the early 1990s when it was incorporated into C-nucleosides as a novel purine-like mimetic. This heterocycle remained at the fringes of medicinal chemistry until a confluence of events spurred by the explosion of the kinase inhibitor field in the early 2000s and the pressing need for novel, druggable scaffolds to occupy that exciting space led to numerous applications against diverse therapeutic targets. This digest will explore the history of this scaffold and the importance of chemistry in propelling drug discovery. The varied uses of this scaffold will be detailed as it progressed from C-nucleosides, to kinase inhibitors, to recognition as a "privileged" template, and finally reemergence in the C-nucleoside field.