AB680 is a highly potent small-molecule CD73 inhibitor discovered and developed by Arcus Biosciences, currently in clinical trials for the treatment of pancreatic cancer. Herein, we report a concise synthesis of 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine 3, which is the central azaindazole core of AB680. The process consists of four synthetic operations and three isolations, including a PMB-protected pyrazole formation, a telescoped two-step cyclization and aromatization sequence, and finally a one-pot PMB deprotection and chlorination to furnish 3. This chemistry was successfully scaled up to provide >200 g of 3 in 44% overall yield and 97.6% HPLC purity. Overall, the route developed toward 3 represents an efficient construction of an azaindazole core, which is a synthetically challenging yet prevalent structural motif.

中文翻译：

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开发用于合成 CD73 抑制剂 AB680 的氮杂吲唑核心的简明工艺

AB680是Arcus Biosciences发现和开发的一种高效小分子CD73抑制剂，目前正处于治疗胰腺癌的临床试验阶段。在此，我们报告了 4,6-二氯-1H-吡唑并 [3,4- b ] 吡啶3的简明合成，它是 AB680 的中心氮杂吲唑核心。该过程包括四个合成操作和三个分离，包括 PMB 保护的吡唑形成、伸缩的两步环化和芳构化序列，以及最后的一锅 PMB 脱保护和氯化以提供3。该化学反应成功放大，可提供 >200 g 的3，总收率为 44%，HPLC 纯度为 97.6%。总体而言，路线向3代表了氮杂吲唑核的有效构建，这是一种具有综合挑战性但普遍存在的结构基序。