A recently disclosed series of pyrazolo[1,5-a]pyridine inhibitors of herpes virus replication has been closely examined herein for effects of the C3 substituent on antiviral activity. Significant changes in activity are observed by alterations of the heteroatom basicity and orientation of the group at C3. These results in combination with previous studies have served to further elaborate the minimal pharmacophore required for potency of this novel series of antiviral agents. During the course of these studies, several novel synthetic approaches were developed and are described.