The transmembrane protein butyrophilin functions as an intracellular receptor and when ligand-bound it stimulates an immune system response to bacterial infections. Because the most potent natural ligand, (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate is too unstable metabolically for potential clinical use, we have explored the preparation and biological activity of aryl phosphonamidate derivatives of the natural ligand analog, C-HMBP. Testing of these new compounds has revealed that this strategy can provide compounds with sub-nanomolar potency and extended plasma stability.