Fragment-Based Discovery of New Highly Substituted 1<i>H</i>‑Pyrrolo[2,3‑<i>b</i>]- and 3<i>H</i>‑Imidazolo[4,5‑<i>b</i>]‑Pyridines as Focal Adhesion Kinase Inhibitors

Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1<i>H</i>-pyrazolo­[3,4-<i>d</i>]­pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1<i>H</i>-pyrrolo­[2,3-<i>b</i>]­pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo­[2,3-<i>b</i>]­pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications of the 7-azaindole core