The insulin-like growth factor receptor (IGF-1R) is a transmembrane tyrosine kinase which has been implicated as a key driver in certain forms of cancers. Receptor over-expression and/or over-stimulation through either of its cognate ligands, IGF-I or IGF-II, leads to signal transduction processes which synergize to promote cellular proliferation, inhibit apoptosis, and increase cell survival. The validated role of IGF-1R in tumors such as colorectal, NSCLC and ovarian, has made it an attractive candidate for molecular targeted therapy. Here we present our efforts which led to the identification of the clinical candidate, cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol (OSI-906) as a potent, selective and orally bioavailable IGF-1R inhibitor. Initial efforts focused on optimizing substituents at the C1 position of the imidazo[1,5-a]pyrazine core and establishing SAR around a benzyloxyphenyl moiety. Through structure based design efforts utilizing IGF-1R and IR co-crystal structures, the benzyloxyphenyl substituent was replaced with a bioactive, conformationally constrained 2-phenylquinolinyl moiety which resulted in a 10x boost in cellular potency. The progression towards OSI-906 continued with optimization of the partially solvent exposed C3 imidazopyrazine substitutent, optimizing for favorable DMPK properties (i.e. blocking key sites of metabolism and incorporating functionality to improve solubility). Upon optimization of both the C1 and C3 imidazopyrazine substituents for IGF-1R potency and ideal DMPK and physiochemical properties, efforts shifted to exploring a novel imidazo[5,1-f][1,2,4]triazine core, as a potential bioiostere to the imidazo[1,5-a]pyrazine series. In summary, the general SAR around the benzyloxyphenyl substituent, progression to the quinolinyl series, optimization of the C3 substituent, and comparison of the two cores will be presented.