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

  • Bioorg Med Chem Lett. 2022 May 1;63:128646. doi: 10.1016/j.bmcl.2022.128646.
Yiqing Fan  1 ,  Yongjie Zhang  1 ,  Yan Liu  1 ,  Hongyu Jiang  1 ,  Ying Zhou  1 ,  Chunlei Tang  2 ,  Weizheng Fan  3
Affiliations
  • 1. School of Pharmaceutical Science, Jiangnan University, Wuxi, China.
  • 2. School of Pharmaceutical Science, Jiangnan University, Wuxi, China. Electronic address: [email protected].
  • 3. School of Pharmaceutical Science, Jiangnan University, Wuxi, China. Electronic address: [email protected].
PMID: 35231576 DOI: 10.1016/j.bmcl.2022.128646
Abstract

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.

Keywords
Antitumor; Design and synthesis; High selectivity; The next-generation Trk inhibitor; Tropomyosin receptor kinase.
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