Discovery And Process Development Of Class I Pi3k And Class I Pi3k/Mtor Inhibitors Gdc-0941 And Gdc-0980

The PI3K signaling pathway has attracted significant attention in drug development due to its role in tumorigenesis. Two orally available clinical compounds which have been developed include GDC-0941 (pictilisib), a selective Class I PI3K inhibitor, and GDC-0980 (apitolisib), a selective Class I PI3K/mTOR inhibitor. Chemical process development has been conducted to support both compounds, which share a common thienopyrimidine core, from the pre-clinical development stage to the clinical study. An enabling process (the first-generation route) was employed to produce multikilogram of API for the GLP and initial GMP production while an improved process (the second-generation route) was developed as the projects were advanced to late stage development. The development of a practical and protecting-group-free synthesis for GDC-0980 and an efficient synthesis of a key intermediate for GDC-0941 through aminoalkylation is discussed in detail in this chapter.