Parallel synthesis of diarylureas and their evaluation as inhibitors of insulin-like growth factor receptor

Diarylurea (DAU) compounds, particularly species composed of a heteroaryl ring system conjugated through a urea linkage to a substituted arene, were previously identified by the screening of a diverse chemical library to be active against the insulin growth factor receptor (IGF-1R). DAU compounds 4 {a, b} were synthesized in parallel by the coupling of aryl amines 2 {a} with aryl isocyanates 3 {b}. Preparative RPHPLC purification was found necessary to remove an impurity 5 {b}, the symmetric urea resulting from the hydrolytic degradation of aryl isocyanates. Two libraries of DAU compounds were prepared to perform preliminary optimization of the two-ring systems for inhibitory activity against IGF-1R. In the first library, we explored a series of heteroaryl ring systems and found the 4-aminoquinaldine ring system to be optimal among those evaluated. The second library fixed the 4-aminoquinaldine ring system and we evaluated a series of substituted arenes conjugated to it. Overall, eight compounds based on the 4-aminoquinaldine heteroaryl system were found to have moderate activity against IGF-1R with IC50 values better than 40 mu M.