Pyrizolo[1,5-a]pyrimidine derivatives of the second-generation TRK inhibitor: Design, synthesis and biological evaluation

• DOI: 10.1016/j.bmcl.2022.128646
• Publication Date: 2022-02-26T16:06:02Z
• Authors: Yiqing Fan; Yongjie Zhang; Yan Liu; Hongyu Jiang; Ying Zhou; Chunlei Tang; Weizheng Fan
• Keywords: 0301 basic medicine; 03 medical and health sciences; Pyrimidines; Neoplasms; Humans; Receptor, trkA; Protein Kinase Inhibitors; 3. Good health

As a receptor tyrosine kinase (RTK), tropomyosin receptor kinase (Trk) is a key drug target in solid tumors. However, the use of the First-generation Trk inhibitors was greatly restricted due to mutant drug resistance. Fortunately, the emergence of the Second-generation of Trk inhibitors has brought an effective solution to this mutant resistance, such as TPX-0005 (Repotrectinib). Here, we reported a series of pyrizolo[1,5-a]pyrimidine derivatives as the second-generation Trk inhibitors, and carried out the subsequent biological activity evaluation. Among them, the best compound 14h (IC50 = 1.40, 1.80 nM, against TrkA, TrkAG595R, respectively) and 14j (IC50 = 0.86, 6.92 nM, against TrkA, TrkAG595R, respectively) has a kinase activity comparable to TPX-0005, and 14j (IC50 = 350 nM against ALK) has a higher selectivity of Trk inhibition than TPX-0005, which may be of great significance for reducing toxicity.