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

项目总结/摘要 有机化合物制备和使用新方法的发现和发展， 这对药物的发现和合成产生了巨大的影响。本申请的一个总体目标是 是催化C-H键活化和碳-碳键形成的收敛 84%的小分子药物中含有含胺化合物。的方法 强调了存在于59%的药物中的氮杂环子集的制备。高效合成 将通过C-H官能化方法来实现这些化合物类别的合成。一个例子是 立体选择性催化二组分和三组分C-H键加成至C=O/C=N键，以提供不同的 胺和醇产物，其可以原位转化为更复杂的、与药物相关的杂环。 将开发和研究用于这些转化的新的地球丰富的Co（III）催化剂。另一 实例是各种哌啶的有效合成， 通过高度取代的1，2-二氢吡啶的区域和立体选择性制备在药物中的存在 通过一步C-H键官能化/电环化级联原位生成。新方法也将 实现了制备桥连和稠合的双环和多环哌啶，包括药剂。 创新的新型反应性将在C-H键官能化和随后的 转变这些重要的研究将使药物发现中类似物的制备更加快速 由于以下原因，药物生产中的努力和降低的成本和浪费;（1）C-H键的普遍存在， 有机化合物，（2）所用Rh和Co催化剂的非常高的官能团相容性，和（3） 编写复合类的重要性。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酶抑制剂。口头 cruzain是引起南美锥虫病的寄生虫的必需蛋白酶， 开发了基于近红外淬灭活性的组织蛋白酶S抑制剂，用于体内成像。第一 纹状体富集磷酸酶（STEP）的抑制剂，一种涉及蛋白酪氨酸磷酸酶（PTP）的抑制剂， 许多神经退行性疾病，包括阿尔茨海默病（AD），将进一步发展。结构- 将使用STEP抑制剂络合物的第一X射线结构进行基于的优化。可逆 为了概括已知的PTP调节的生理手段而开发的共价抑制剂也将被 先进这种创新的PTP抑制平台已经产生了逆转认知的化合物， AD小鼠模型中的功能障碍。基质片段方法也将应用于越来越多的 蛋白质翻译后修饰酶的突出类别，蛋白质精氨酸脱亚胺酶（PAD），用于 到目前为止已经进行了很少的抑制剂开发。这一创新的新方法已经 导致PAD 3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.