In 2018, Sébastien Degorce and co-workers embarked on a campaign to optimize the biophysical properties of IRAK4 inhibitors, with the goal of identifying potent and orally bioavailable inhibitors as potential treatments for diffuse large B-cell lymphoma. As a part of this effort, scaffold hopping between different pyrrolopyrimidine and pyrrolotriazine cores was investigated, with the goal of increasing lipophilicity and lowering the hydrogen-bond basicity of the scaffold. The authors found that moving from the original pyrrolopyrimidine scaffold (exemplified by A.14) to an isomeric pyrrolopyrimidine (A.17) decreased permeability and lipophilicity, despite removing one hydrogen-bond donor (Figure ).