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

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, TrkA^G595R, respectively) and 14j (IC₅₀ = 0.86, 6.92 nM, against TrkA, TrkA^G595R, 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.