Late-stage Modification of Complex Drug: Base-controlled Pd-catalyzed Regioselective Synthesis and Bioactivity of Arylated Osimertinibs

Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed C─H arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (KCO) promoted the arylation of acrylamide terminal C(sp)-H, affording 34 derivatives. Conversely, sodium -butoxide (-BuONa) mediated the aryl C(sp)-H arylation of the indole C2 position, providing 27 derivatives. The derivative containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFR and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a "one substrate-multi reactions-multiple products" strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.