Structure-directing optimization of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzamide derivatives as selective receptor tyrosine kinase-like orphan receptor 1 (ROR1) inhibitors for cancer therapy

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an attractive therapeutic target for various cancers, including leukemia and lung cancer. Although some biological agents have entered clinical trials and several small-molecule inhibitors have been developed, selective ROR1 inhibitors remain underexplored. In our previous studies, we identified LDR102, an indole derivative, as a ROR1 inhibitor with favorable binding affinity and potent antitumor efficacy. However, LDR102 exhibited moderate ROR1 inhibitory activity and “off-target” effects on other kinases, such as c-Kit and Abl^T315I, limiting its further development. To address these limitations, we optimized LDR102 and synthesized a series of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzamide derivatives as selective ROR1 inhibitors, culminating in the identification of compound 9i, which possesses favorable ROR1 inhibitory activity, good selectivity, and potent anti-tumor activity in vivo and in vitro.