A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC₅₀ values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC₅₀ value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.

设计了一系列3-（咪唑并[1,2 - a ]吡嗪-3-基乙炔基）-2-甲基苯甲酰胺，并利用结构指导的优化策略合成了它们作为新的原肌球蛋白受体激酶（Trks）抑制剂。最有效的化合物之一9o抑制了TrkA / B / C，IC ₅₀值分别为2.65、10.47和2.95 nM。该化合物剂量依赖性抑制脑源性神经营养因子（BDNF）介导的TrkB活化，并抑制表达高水平TrkB的SH-SY5Y-TrkB神经母细胞瘤细胞的迁移和侵袭。抑制剂9o还抑制SH-SY5Y-TrkB细胞的增殖，IC ₅₀值为58 nM，与美国FDA最近批准的药物LOXO-101相当。化合物9o可以作为新的先导化合物用于进一步的抗癌药物发现。