Optimization of the synthesis of BET BD2 selective inhibitor XY153

Abstract

XY153 is a promising BET BD2 inhibitor with an IC50 value of 0.79 nM against BRD4 BD2. It shows 354‐fold selectivity over BRD4‐BD1 and 6‐fold selectivity over other BET BD2 domains. However, the reported synthesis route of XY153 and its derivatives are extremely poor‐yielding. After the synthesis of three key fragments, XY153 can only be obtained with a yield of 1.3% in the original four‐step reaction. In this study, we reported a three‐step alternative route in the synthesis process of XY153. The reaction conditions for this route were thoroughly investigated and optimized, resulting in a significantly improved yield of 61.5%. This efficient synthesis route establishes a robust chemical foundation for the rapid synthesis of XY153 derivatives as BET BD2 inhibitors in the near future.