Stereoselective Synthesis of aza-Sulfur(VI) Motifs as Design Elements for Drug Discovery

在药物化学中引入“不寻常”的官能团，为进入生物学相关的化学和知识产权空间的新领域提供了机会。这对于可以提供改进的物理化学性质或新的取代基团的基团特别有吸引力。在这种情况下，氮杂-硫（VI）基序（含有S=N基团）已经出现，提供了一个有吸引力的平衡的性质和控制的三维框架，以及作为其他重要功能的生物电子等排体。这在阿斯利康ATR抑制剂AZD 6738（Ceralasertib）中的亚砜亚胺类药物中最为显著，用于各种晚期癌症的临床试验。该项目将开发新的立体控制方法来产生氮杂硫（VI）基序，预计将在药物化学中提供有价值的设计选择。将开发的方法，提供更容易获得这些未充分探索的图案，并控制绝对的3-D形状，使药物化学家很容易将这些纳入发现计划。新的立体控制过程将开发用于亚砜亚胺、磺酰亚胺酰胺和磺酰二亚胺基团。此外，还将开发相应氮原子的官能化，以证明整体性质的可调性以及环状衍生物的制备。该项目符合EPSRC转变医疗保健的优先事项。我们将开发用于药物和化学探针的新替代基团的简便方法，并扩大药物化学家的设计选择。该项目将采用两种方法通过S-N和S-C键形成来不对称合成目标结构，以最大限度地提高将这些衍生物纳入药物发现计划的灵活性，并直接获得硫原子上的任何一种构型。对这些过程中中间体的基础研究将提供新的机理见解。最后，我们将探索所生成的化合物的性质。

The incorporation of "unusual" functional groups in medicinal chemistry provides access to new areas of biologically relevant chemical and intellectual property space. This is particularly attractive for groups that can provide improved physicochemical properties or novel replacement groups. In this context, aza-sulfur (VI) motifs (containing an S=N group) have emerged as offering an attractive balance of properties and controlled three-dimensional frameworks, as well as acting as bioisosteres for other important functionality. This is most notable in sulfoximines, which feature in AstraZeneca's ATR inhibitor AZD6738 (Ceralasertib), in clinical trials for various advanced cancers. This project will develop new stereocontrolled methods to generate aza-sulfur (VI) motifs that are predicted to provide valuable design options in medicinal chemistry. Methods will be developed that provide more facile access to these underexplored motifs and control the absolute 3-D shape to enable medicinal chemists to readily incorporate these into discovery programmes. New stereocontrolled processes will be developed for sulfoximines, sulfonimidamides, and sulfondiimine groups. Furthermore functionalisation of the respective nitrogen atoms will be developed to demonstrate tunability of the global properties, and the preparation of cyclic derivatives. This project fits with the EPSRC priority of transforming healthcare. We will develop facile access to new replacement groups for use in drugs and chemical probes, and expand the design options for medicinal chemists. The project will take two approaches to the asymmetric synthesis of the targeted structures by S-N and S-C bond formation, to maximise flexibility to incorporate these derivatives in a drug discovery programme, and to directly access to either configuration at the sulfur atom. Fundamental studies on the intermediates in these processes will provide new mechanistic insights. Finally we will explore the properties of the generated compounds.