As third-generation cyclin-dependent kinase inhibitors, CDK4/6 inhibitors have become pivotal therapeutic agents in the treatment of breast cancer, lung cancer, and other malignancies due to their favorable safety profile and high in vivo efficacy. This review provides a systematic examination of the synthetic routes of eight representative compounds—palbociclib and dalpiciclib, ribociclib and volbociclib, abemaciclib and tericiclib, as well as trilaciclib and lerociclib—selected based on their time of market authorization and structural homology. Special emphasis is placed on the role of novel reaction systems and advanced synthetic strategies in enhancing process efficiency. These agents predominantly share an N-(pyridin-2-yl)-pyri- midin-2-amine core scaffold, with their synthesis primarily dependent on metal-catalyzed cross-coupling reactions for C—N bond formation and condensation reactions for pyrimidine ring construction. Key challenges remain, including difficulties in regioselectivity control, significant reliance on precious metal catalysts, and limited scalability of current processes. Consequently, the development of greener, more cost-effective, and efficient synthetic methodologies represents a critical direction for future optimization in this domain.

Key words: CDK4/6 inhibitors, anticancer drugs, polycyclic structures, green chemistry