Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ

Btk inhibitors and PI3K delta inhibitors play crucial roles in the treatment of leukemia, and studies confirmed that the synergetic inhibition against Btk and PI3K delta could gain an optimal response. Herein, a series of novel benzofuro [3,2-b]pyridin-2(1H)-one derivatives were designed and synthesized as dual Btk/PI3K delta kinases inhibitors for the treatment of leukemia. Studies indicated that most compounds could suppress the proliferation of multiple leukemia or lymphoma cells (Raji, HL60 and K562 cells) at low micromolar concentrations in vitro. Further kinase assays identified several compounds could simultaneously inhibit Btk kinase and PI3K delta kinase. Thereinto, compound 16b exhibited the best inhibitory activity (Btk: IC50 = 139 nM; PI3K delta: IC50 = 275 nM) and showed some selectivity against PI3K delta compared to PI3K beta/gamma. Finally, the SAR of target compounds was preliminarily discussed combined with docking results. In brief, 16b possessed of the potency for the further optimization as anti-leukemia drugs by inhibiting simultaneously Btk kinase and PI3K delta kinase.