The insulin-like growth factor 1 receptor (IGF1R) plays an important role in cell transformation, and it has emerged as a target for anti-cancer drug design. IGF1R is activated by autophosphorylation at three sites in the enzyme activation loop. We describe here a group of 6-5 ring-fused compounds that are the first reported inhibitors selective for the unphosphorylated (0P) form of IGF1R. These compounds do not significantly inhibit the fully activated, triply phosphorylated (3P) form. IGF1R was produced from baculovirus-infected Spodoptera frugiperda (Sf9) cells, and the 0P and 3P forms were purified to homogeneity. We used a continuous spectrophotometric assay to measure inhibition of the 0P and 3P forms. Analysis by native gel electrophoresis confirmed that the step inhibited in the autoactivation process was the transition between the 0P and IP forms of IGF1R. The compounds were also active against IGF1R autophosphorylation in intact Chinese hamster ovary (CHO) cells. Most of the compounds also inhibited the closely related insulin receptor to varying degrees, although some compounds showed selectivity for IGF1R or insulin receptor. This class of compounds could form the basis of design efforts to selectively block the autoinhibited conformation of IGF1R.