Development of a Robust and Scalable Synthetic Route for a Potent and Selective Isoindolinone PI3K gamma Inhibitor

We recently described the structure-guided optimization of a series of pyrazolopyrimidine isoindolinone PI3K gamma inhibitors, which resulted in the identification of an advanced lead compound specialIntscript with favorable potency, selectivity, and drug-like properties. To support preclinical characterization of 1, a robust and scalable synthesis was required. Herein, we report the development of an optimized synthesis of 1, which features a scalable difluoromethylation protocol and a one-pot borylation/ Suzuki-Miyaura cross-coupling reaction to access the biaryl core of the molecule. A method was developed for the efficient removal of residual palladium following Pd-catalyzed cross-coupling, which provided access to 1 in high purity without the use of any chromatographic purifications. A comprehensive investigation of solid-state polymorphism identified a thermodynamically stable crystalline form of 1, greater than 200 g of which were prepared using our optimized synthesis.