Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.