Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo3,4-cpyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo3,4-cpyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50=11nM; PC-3 antiproliferative IC50=36nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50=10nM; A2780 antiproliferative IC50=7nM) in complex with the NAMPT protein was also determined.