Discovery of new thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives as orally active phosphoinositide 3-kinase inhibitors.

Abstract As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp 3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity and drug-like properties than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.