Our route scouting efforts toward finding the most efficient construction of PF-07265807 (ARRY-067) in readiness for process development prior to commercial manufacture are described. ARRY-067 contains the azaindazole (1H-pyrazolo [3,4-b]pyridine) building block that is common to many pharmaceuticals and bioactive agents. Herein, our novel approach to this challenging structural motif is described where an oxazoline ring-opening cyclization cascade triggered by the addition of hydrazine reveals the target 3-alaninol-substituted azaindazole in one step. An improved synthesis of the uracil carboxylic acid coupling partner is also described. Overall, the new route is six steps shorter than the enabling route, minimizes protecting group manipulations, and avoids the use of transition metal catalysis.

中文翻译：

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PF-07265807（一种 AXL-MER 肿瘤学候选抑制剂）的商业路线开发

描述了我们为寻找 PF-07265807 (ARRY-067) 最有效的结构而为商业制造之前的工艺开发做好准备的路线探索工作。 ARRY-067 含有氮杂吲唑（1 H -吡唑并[3,4- b ]吡啶）结构单元，这是许多药物和生物活性剂所常见的结构单元。在此，我们描述了解决这一具有挑战性的结构基序的新方法，其中通过添加肼触发的恶唑啉开环环化级联一步揭示了目标3-丙氨醇取代的氮杂吲唑。还描述了尿嘧啶羧酸偶联配偶体的改进合成。总体而言，新路线比现有路线短了六步，最大限度地减少了保护基团操作，并避免了过渡金属催化的使用。