There are currently eight small-molecule kinase inhibitors approved as cancer treatments, and a significantly larger number of compounds are in the earlier stages of clinical development. Although kinase inhibitors are most commonly developed in a cancer setting, other disease areas have been targeted. The vast majority of reported kinase small-molecule inhibitors contain functionalities that interact with the adenosine triphosphate (ATP) binding site of the kinase. The 4-anilinoquinazolines have previously been reported as potent epidermal growth factor receptor (EGFR) inhibitors, binding at the 'hinge' region of the ATP site. Subsequently, this chemical series has been optimized against a number of different kinases including Src and Aurora B. Here, we detail the computational enumeration of ring systems that have the ability to make comparable interactions to the 4-anilinoquinazoline core. These were prioritized by computational, medicinal, and synthetic chemistry input, and a number of libraries were subsequently synthesized.