Development of a Palladium-Catalyzed Direct N2-Arylation of Indazoles.

描述(由申请人提供)：在新的候选药物中，连接在N_2位上的含芳基的吲达唑已变得越来越普遍。本文提出的研究项目的主要目的是开发一种高选择性的、钯催化的无保护吲唑的氮芳基化反应。这一目标有望通过对影响这些杂环5-9已知的N1-芳基化的催化循环进行全面的实验和计算研究来实现，并将这一理解应用于操纵反应成分以实现所需的氮偶联。最后，将努力确保该方法对广泛的潜在底物的通用性。这种方法的成功开发将对这些重要的生物活性亚结构的合成简便性产生重大影响，特别是在药物化学环境中，从而能够更快地产生和筛选潜在的新药物。 与公共健康相关：在氮位带有芳基取代基的吲哚类化合物最近已成为治疗包括代谢综合征和丙型肝炎在内的多种与人类健康相关的疾病的潜在候选药物中流行的亚结构1-4。如本文所建议的，成功开发一种用于无保护的吲唑类化合物的选择性氮-芳基化反应的方案，将允许快速生成各种此类结构用于生物筛选和SAR研究，特别是在药物化学环境中。

DESCRIPTION (provided by applicant): Indazoles bearing aryl groups attached at the N2 position have become increasingly prevalent amongst novel drug candidates.1-4. The primary aim of the research project proposed here is the development of a highly selective, palladium- catalyzed N2-arylation of unprotected indazoles. This goal is expected to be achieved through a comprehensive experimental and computational study of the catalytic cycle that effects the known N1-arylation of these heterocycles,5-9 and to aply that understanding towards manipulating the reaction components to achieve the desired N2- coupling. Finally, efforts will be made to ensure the generality of the method for a wide range of potential substrates. The successful development of this method would have a significant impact on the ease of synthesis of these important biologically active substructures particularly in a medicinal chemistry setting, allowing for the more rapid generation and screening of potential novel pharmaceuticals. PUBLIC HEALTH RELEVANCE: Indazoles bearing aryl substituents at the N2 position have recently become prevalent substructures amongst potential drug candidates indicated for the treatment of a wide variety of human health-related conditions including metabolic syndrome and hepatitis C. 1-4 The successful development of a protocol for the selective N2-arylation of unprotected indazoles, as proposed here, would allow for the rapid generation of a wide variety of these structures for biological screening and SAR studies, particularly in a medicinal chemistry setting.