Late-stage sulfonamidation, and sulfonimidamidation for drug discovery

该提案提供了将磺酰胺和磺酰亚胺酰胺基团安装到复杂的药物样片段和中间体中的方法。各种催化方法将药物片段与RO-NSO试剂联合收割机，这是Willis实验室以前开发的。该方法将采用容易获得的试剂并且易于执行。硫（VI）官能团，主要是磺胺类，对医学产生了巨大的影响。例如，FDA批准了72种含有磺胺的药物，约占所有批准药物的5%。尽管开发较少，但磺酰亚胺酰胺类（磺酰胺类的单氮杂类似物）最近已显示出在医药应用中的潜力（方案1）。这主要是由于它们在硫、碱性氮原子上的不对称性，允许进一步官能化和物理化学性质的有利平衡。Willis小组一直在探索这些重要官能团的新方法，重点是开发高氧化态硫关键试剂。例如，使用亚磺酰胺试剂Tr-NSO，报道了从预形成的有机金属化合物（例如格氏试剂和有机锂）开始制备磺酰亚胺酰胺的方法。下一代试剂BiPhO-NSO可用于直接合成磺酰亚胺和亚砜亚胺，同样从预形成的有机金属试剂开始。最近，t-BuO-NSO被发现在从预形成的有机金属化合物的单步转化中提供伯磺酰胺。这些试剂是与UCB合作开发的。这些转换工作得很好，并允许直接访问这些有价值的S（VI）衍生的官能团。然而，需要使用反应性有机金属试剂是一种限制，并且特别地限制了官能团相容性。该提案的重点是开发催化方法，该方法允许将诸如t-BuO-NSO和ArO-NSO的试剂与复杂的药物样片段组合使用，以在“后期”引入磺酰胺和磺酰亚胺酰胺。实施后期功能化方法，如在高通量制药环境中的这项工作中设想的方法，可能有助于更快地鉴定先导候选药物。我们最初的方法将是开发锍盐中间体。这些是有吸引力的中间体，因为它们可以使用各种方法容易地制备，并且可以类似地使用几种机械上不同的化学进一步官能化。对于该应用重要的是，锍盐已经显示出经历经典的2电子过渡金属催化的反应，例如Pd（0）/（II）循环，以及光氧化还原促进的1电子化学。总之，本项目的重点是开发新的催化方法，将药物相关的磺酰胺和磺酰亚胺酰胺基团引入药物样片段。将探索基于过渡金属催化（可能是Pd和Ni）以及光氧化还原化学的方法。将有一个强大的重点提供有价值的分子药物化学家。在这种类型的项目中也可以设想阵列化学的应用。重要的是，医学相关主题的直接相关性和针对性意味着制药行业合作伙伴（如UCB）的密切参与将极大地增加该项目的成果。该项目福尔斯属于EPSRC的“数学和物理科学发电站”和“改变健康和医疗保健”的研究领域，并将与UCB合作。

This proposal delivers methods to install sulfonamide and sulfonimidamide groups into complex drug-like fragments and intermediates. A variety of catalytic methods will combine the drug fragments with RO-NSO reagents, which have been previously developed by the Willis laboratory. The methods will employ readily available reagents and be straightforward to perform. Sulfur(VI) functional groups, principally sulfonamides, have had an enormous impact on medicine. For example, there have been 72 FDA approvals of drugs that contain a sulfonamide, making up approximately 5% of all approved medicines. Although less developed, sulfonimidamides, the mono aza-analog of sulfonamides, have recently shown potential in medicinal applications (Scheme 1). This is mainly due to their potential for asymmetry at sulfur, basic nitrogen atom allowing further functionalisation and favourable balance of physicochemical properties. The Willis group have been exploring new approaches to these important functional groups, focusing on the development of high-oxidation state sulfur-linchpin reagents. For example, using the sulfinylamine reagent Tr-NSO, an approach to sulfonimidamides starting from pre-formed organometallics, such as Grignard reagents and organolithiums was reported. The next generation reagent, BiPhO-NSO, can be used for the direct synthesis of sulfonimidamides and sulfoximines, again starting from pre-formed organometallic reagents. More recently, t-BuO-NSO was discovered to deliver primary sulfonamides in a single-step transformation from pre-formed organometallics. These reagents have been developed in collaboration with UCB. These transformations work well, and allow straightforward access to these valuable S(VI)-derived functional groups. However, the need to use reactive organometallic reagents is a limitation, and in particular restricts functional group compatibility. The focus of this proposal is to develop catalytic methods that allow reagents such as t-BuO-NSO and ArO-NSO to be used in combination with complex, drug-like fragments, to introduce sulfonamides and sulfonimidamides at a "late-stage". The implementation of late-stage-functionalisation approaches such as that envisioned in this work in a high-throughput pharmaceutical setting, may aid in the quicker identification of lead medicinal candidates. Our initial approach will be to exploit sulfonium salt intermediates. These are attractive intermediates as they can be readily prepared using a variety of methods, and can similarly be further functionalised using several mechanistically-distinct chemistries. Importantly for this application, sulfonium salts have been shown to undergo classical 2-electron transition-metal-catalysed reactions, such as Pd(0)/(II) cycles, and also photoredox promoted 1-electron chemistries. In summary, this project focuses on the development of new catalytic methods to introduce medicinally relevant sulfonamide and sulfonimidamide groups into drug-like fragments. Approaches based on both transition metal catalysis (likely Pd and Ni), as well as photoredox chemistry, will be explored. There will be a strong focus on delivering molecules of value to medicinal chemists. Application to array chemistry can also be envisioned within this type of project. Importantly, the direct relevance, and targeting of medicinally relevant motifs, means that the close involvement of a pharmaceutical industry partner, such as UCB, would add enormously to what could be achieved in this project. The project falls within the EPSRC research areas of "The mathematical and physical sciences powerhouse", and "Transforming health and healthcare" and will be in collaboration with UCB.