To discover an alternative heterocyclic scaffold to the thiazole series of FBPase inhibitors such as thiazole 1, oxazoles were investigated to see if replacing the sulfur of the thiazole scaffold with an oxygen is tolerated. To expand the SAR of the thiazole series of FBPase inhibitors, various oxazole phosphonic acids were also explored as potential FBPase inhibitors. Establishment of oxazoles as FBPase inhibitors will not only expand intellectual property coverage but also provide an alternative scaffold to the thiazoles and enable fine-tuning of pharmacokinetic properties and solubility due to potential differences in polarity and metabolic stability between oxazoles and thiazoles. Numerous oxazoles with a phosphonic group linked by both 2,5-furandiyl and –COOCH2– groups were prepared. Several oxazoles were discovered to have similar potency as thiazole 1; for example, oxazole 3.10 has an IC50 of 70 nM and lowered blood glucose in normal fasted rats by 61%, and oxazole 3.18 exhibited biological activities comparable to thiazole 1. Herein we report the synthesis and the SAR of oxazole phosphonic acids as FBPase inhibitors.