Cyclic urea HIV protease inhibitors containing alkynyl- and alkenyl-tethered heterocycles in the P2 region

A series of cyclic urea HIV protease inhibitors containing alkynyl-and alkenyl-tethered heterocycles in the P2 region were synthesized. The alkynyl compounds exhibited poor activity against the HIV protease enzyme. However, reduction of the triple bond afforded trans-alkenyl derivatives (XU348 and XU430) which displayed superb potency (sub-nanomolar Ki).