A series of novel indazole-based diarylurea derivatives targeting c-kit were designed by structure-based drug design. The derivatives were prepared, and their antiproliferative activities were evaluated against human colon cancer HCT-116 cell line and hepatocellular carcinoma PLC/PRF/5 cell line. The antiproliferative activities demonstrated that six of nine compounds exhibited comparable activities with sorafenib against HCT-116. The structure-activity relationship (SAR) analysis indicated that the indazole ring part tolerated different kinds of substituents, and the N position of the central pyridine ring played key roles in antiproliferative activity. The SAR and interaction mechanisms were further explored using molecular docking method. Compound 1i with N-(2-(pyrrolidin-1-yl)ethyl)-carboxamide possessed improved solubility, 596.1 ng/ml and best activities, IC at 1.0 μm against HCT-116, and 3.48 μm against PLC/PRF/5. It is a promising anticancer agent for further development.

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