A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized <i>via</i> the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC<sub>50</sub> values against PI3Kδ, along with low micromolar to submicromolar GI<sub>50</sub> values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC<sub>50</sub> = 6.3 nM) and anti-proliferative activity (GI<sub>50</sub> = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, <i>in vitro</i> metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.