Quinazolinone and isoindolinone analogs were designed and prepared as Hh pathway inhibitors. Several analogs exhibited potent inhibitory activity up to nanomolar IC50. New quinazolinone derivatives suppressed Hh signaling by blocking Smo and Gli translocation into cilia. The representative quinazolinone derivatives preserved the inhibitory activity to vismodegib-resistant Smo mutants. Novel quinazolinone scaffolds can be a useful platform for the development of Hh pathway inhibitors.