Chemistry principles applied to the development of new catalytic C-H bond functionalization methods for amine and heterocycle preparation and to the design, synthesis and use of new enzyme inhibitors

项目摘要/摘要 有机化合物制备和使用的新方法的发现和发展 对药物的发现和合成产生了相当大的影响。此应用程序的一个总体目标 是催化C-H键活化和碳-碳键形成的发展趋同 含胺化合物的组装存在于84%的小分子药物中。的方法。 强调了59%的药物中存在的氮杂环亚群的制备。高效合成 这些复合类将通过C-H功能化方法来完成。一个例子是 立体选择性，催化C=O/C=N键的两组分和三组分的C-H键加成，提供不同的 胺和酒精产品可以在原位转化为更复杂的、与药物相关的杂环。 新的富土Co(III)催化剂将被开发和研究用于这些转化。另一个 例如，各种哌啶类化合物的有效合成，这类杂环化合物的频率最高 通过区域和立体选择性精制高度取代的1，2-二氢吡啶在药物中的出现 通过一步C-H键官能化/电环化级联原位生成。新的方法也将是 实现了制备桥联和稠合双环和多环哌啶类化合物，包括药物制剂。 创新的新型反应性将在C-H键官能化和随后的 变形。这些有意义的研究将使药物发现中更快地制备类似物 努力减少了药品生产中的成本和浪费；(1)普遍存在的C-H键 有机化合物，(2)所使用的Rh和Co催化剂的非常高的官能团相容性，以及(3) 复合课准备的重要性。第二个压倒一切的目标是发展和 使用通过基于底物的片段方法发现的有效和选择性的酶抑制剂。口服 克鲁扎因是导致恰加斯病的寄生虫的一种基本蛋白水解酶，目前可用的抑制剂是 开发了具有近红外猝灭活性的组织蛋白酶抑制剂S，用于体内成像。第一 纹状体富含磷酸酶(STEP)的抑制物，一种蛋白质酪氨酸磷酸酶(PTP)，与 一些神经退行性疾病，包括阿尔茨海默病(AD)，将被推进。结构- 将使用阶跃抑制剂络合物的第一个X射线结构进行基于优化的研究。可逆的 为概括已知的PTP调节生理手段而开发的共价抑制剂也将是 高级。这种创新的PTP抑制平台已经产生了逆转认知的化合物 阿尔茨海默病小鼠模型的功能障碍。底物碎片方法也将应用于越来越多的 一类重要的蛋白质翻译后修饰酶，蛋白质精氨酸脱亚胺酶(PADS)，用于 到目前为止，几乎没有进行过这种抑制剂的开发。这一新的创新方法已经 得到了PAD3选择性小分子抑制剂，并将应用于其他PAD同工酶。

Project Summary/Abstract The discovery and development of new methods for the preparation and use of organic compounds has considerable impact upon how drugs are discovered and synthesized. One overall objective of this application is the development of catalytic C-H bond activation and carbon-carbon bond formation for the convergent assembly of amine containing compounds present in 84% of small-molecule drugs. Methods for the preparation of the subset of nitrogen heterocycles present in 59% of drugs are emphasized. Efficient syntheses of these compound classes will be accomplished by C-H functionalization methods. One example is stereoselective, catalytic two- and three-component C-H bond additions to C=O/C=N bonds to provide diverse amine and alcohol products that in situ can be transformed into more complex, drug-relevant heterocycles. New earth abundant Co(III) catalysts will be developed and studied for these transformations. Another example is efficient syntheses of diverse piperidines, the heterocycle class with the highest frequency of occurrence in drugs, by regio- and stereoselective elaboration of highly substituted 1,2-dihydropyridines generated in situ by one step C-H bond functionalization/electrocyclization cascades. New methods will also be achieved to prepare bridged and fused bicyclic and multicyclic piperidines, including pharmaceutical agents. Innovative new types of reactivity will be explored in C-H bond functionalization and subsequent transformations. These significant studies will enable the more rapid preparation of analogs in drug discovery efforts and reduced cost and waste in drug production due to; (1) the ubiquitous presence of C-H bonds in organic compounds, (2) the very high functional group compatibility of the Rh and Co catalysts used, and (3) the importance of the compound classes prepared. The second overriding objective is the development and use of potent and selective enzyme inhibitors discovered through substrate-based fragment approaches. Orally available inhibitors of cruzain, an essential protease of the parasite responsible for Chagas disease, have been developed as have near-IR quenched activity-based inhibitors of cathepsin S for imaging in vivo. The first inhibitors of Striatal-Enriched Phosphatase (STEP), a protein tyrosine phosphatase (PTP) implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), will be advanced. Structure- based optimization will be carried out using the first x-ray structures of STEP inhibitor complexes. Reversible covalent inhibitors developed to recapitulate known physiological means of PTP regulation will also be advanced. This innovative platform for PTP inhibition has already resulted in compounds that reverse cognitive dysfunction in AD mouse models. The substrate fragment approach will also be applied to the increasingly prominent class of protein post-translational modification enzymes, the protein arginine deiminases (PADs), for which little inhibitor development has so far been carried out. This new and innovative approach has already resulted in PAD3 selective small molecule inhibitors and will be applied to the other PAD isozymes.