Macrocyclic Aminopyrimidines as Multitarget CDK and VEGF-R Inhibitors with Potent Antiproliferative Activities

X‐ray structures from CDK2–aminopyrimidine inhibitor complexes led to the idea to stabilize the active conformation of aminopyrimidine inhibitors by incorporating the recognition site into a macrocyclic framework. A modular synthesis approach that relies on a new late‐stage macrocyclization protocol that enables fast and efficient synthesis of macrocyclic aminopyrimidines was developed. A set of structurally diverse derivatives was prepared. Macrocyclic aminopyrimidines were shown to be multitarget inhibitors of CDK1/2 and VEGF‐RTKs. In addition, potent antiproliferative activities toward various human tumor cells and a human tumor xenograft model were demonstrated. Macrocyclization in the design of novel aminopyrimidine CDK inhibitors led to a series of multitarget CDK and VEGF‐R inhibitors with potent antiproliferative activities. To explore the SAR of these macrocyclic aminopyrimidines rapidly, a modular synthesis approach was developed that relies on a new macrocyclization protocol.