Late-Stage Functionalization for the Optimization of Reversible BTK Inhibitors

Late-stage functionalization (LSF) enables medicinal chemists to quickly explore structure-activity relationships (SAR) of novel analogues derived from a fully elaborated parent structure. Using several known C-H functionalization chemistries, we have systematically applied the LSF strategy to modify different regions of a Bruton's tyrosine kinase (BTK) reversible inhibitor lead series. This approach allowed for broad SAR exploration across several key subunits of the molecule at positions that were previously difficult to explore with traditional synthesis, providing analogues with high potency and improved pharmacokinetic properties. This case study illustrates both the promise and the challenges associated with applying LSF to complex lead molecules.

Automated summary

Late-stage functionalization (LSF) allows for rapid exploration of structure-activity relationships (SAR) and improvement of the pharmacokinetic properties of lead molecules.