Design and synthesis of a 3-D fragment library

This thesis describes the design and synthesis of a library of novel 3-D fragments for use in drug discovery. Chapter 1 explains the process of fragment based drug discovery in detail, as well as why the synthesis of novel 3-D fragments is needed and the previous work carried out in the group to design and select 33 initial 3-D fragments. These fragments were designed to fit industry-recommended guidelines on physicochemical properties and their 3- D shape was analysed using principal moments of inertia (PMI) plots to demonstrate that they occupied under-explored areas of 3-D space. Chapter 2 describes synthetic efforts towards four of these fragments. Chapter 3 details a new approach that was devised in order to synthesise 3-D fragments that contained greater functional group variation. This route focussed on the triflation, Suzuki- Miyaura cross-coupling, hydrogenation and derivatisation of β-ketoesters to give 3-D fragments. Using this route, 24 novel 3-D fragments were synthesised. Finally, Chapter 4 contains an analysis of both the physicochemical properties and the 3-D shapes of the 1st and 2nd generation 3-D fragments. These properties are compared to both industry-recommended guidelines and commercially available fragment libraries.