The synthesis and SAR of a series of triazolopyrimidines as anticancer agents are described. Treatment of 5-chloro-6-(trifluorophenyl)-N-fluoroalkyl [1,2,4]triazolo[1,5-a]pyrimidin-7-amine with an alcohol, a thiol, or an alkylamine provided the corresponding final compounds. A clear SAR requirement has been established for optimal activity. A (1S)-2,2,2-trifluoro-1-methylethylamino group or an achiral 2,2,2-trifluoroethylamino group is required at the 5-position to achieve high potency. On the phenyl ring, both fluoro atoms, at the positions ortho to the triazolopyrimidine core, are needed for optimal activity. At the position para to the triazolopyrimidine core, on the phenyl ring, the best activity is achieved with an oxygen linkage followed by a three-methylene unit, and an alkylamino or a hydroxy group. The mechanism of action for this series of triazolopyrimidines was shown to be unique in that they promoted tubulin polymerization in vitro, but did not bind competitively with paclitaxel.1 Instead, they inhibit the binding of vincas to tubulin. Selected compounds were studied further, and it was shown that these compounds were able to overcome resistance attributed to several multidrug resistance transporter proteins. Lead compounds were shown to inhibit tumor growth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orally or intravenously.

中文翻译：

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[1,2,4]三唑并[1,5-a]嘧啶类化合物的合成与合成孔径雷达，这是一类具有微管蛋白抑制作用独特机制的抗癌药。

描述了一系列三唑并嘧啶作为抗癌剂的合成和SAR。用醇，硫醇或烷基胺处理5-氯-6-（三氟苯基）-N-氟烷基[1,2,4]三唑并[1,5-a]嘧啶-7-胺，提供了相应的最终化合物。已经建立了明确的SAR要求以实现最佳活动。在5位需要一个（1S）-2,2,2,3-三氟-1-甲基乙基氨基或非手性2,2,2-三氟乙基氨基以获得高效能。在苯环上，需要三氟嘧啶核邻位的两个氟原子以实现最佳活性。在苯环上与三唑并嘧啶核相对的位置上，通过氧键接一个三亚甲基单元和一个烷基氨基或羟基，可以实现最佳的活性。该三唑并嘧啶系列的作用机理显示出独特之处，因为它们在体外促进微管蛋白聚合，但不与紫杉醇竞争性结合。1相反，它们抑制长春花与微管蛋白的结合。进一步研究了选定的化合物，结果表明这些化合物能够克服归因于多种抗药性转运蛋白的抗药性。口服或静脉内给药时，铅化合物在几种裸鼠异种移植模型中均显示出抑制肿瘤生长的潜能，且具有很高的效力。并且表明这些化合物能够克服归因于几种多药抗性转运蛋白的抗性。口服或静脉内给药时，铅化合物在几种裸鼠异种移植模型中均显示出抑制肿瘤生长的潜能，且具有很高的效力。并且表明这些化合物能够克服归因于几种多药抗性转运蛋白的抗性。口服或静脉内给药时，铅化合物在几种裸鼠异种移植模型中均显示出抑制肿瘤生长的潜能，且具有很高的效力。