Design, Synthesis and Applications of Three-Dimensional Building Blocks for Fragment-Based Drug Discovery

This thesis presents a novel approach for the elaboration of fragments, focusing
specifically on doing so in three dimensions through the use of specially designed
building blocks. Thus, to relieve some of the synthetic bottleneck associated with
fragment elaboration, it is proposed to establish the elaboration methodology prior to the
identification of any fragment hits.
Chapter 1 provides an overview of fragment-based drug discovery and its role in the
development and discovery of pharmaceutical agents. In Chapter 2, the design and
synthesis of an initial set of 3-D cyclopropyl building blocks A–C are described. Key
features include the addition of a cyclopropane, a BMIDA group and a Boc-protected
amine moiety, with the overall structure of building blocks following Astex’s ‘rule of
two’. Next, Chapter 3 details the application of the 3-D cyclopropyl building blocks by
demonstrating the scope of the Suzuki-Miyaura cross-coupling reaction to medicinally
relevant fragment-like aryl or heteroaryl bromides. The functionalisation at the amine
moiety is carried out in the synthesis of methanesulfonamides, such that the elaboration
vectors of 3-D cyclopropyl building blocks could be determined using X-ray
crystallography. Chapter 4 investigates the design and attempted synthesis of a second
generation cyclobutyl 3-D building block D.
The next part of the thesis details the potential use of 3-D cyclopropyl building blocks in
the generation of covalent fragments. A summary of covalent groups in drug development
is provided in Chapter 5. This chapter also includes the preliminary studies for generating
a library of covalent fragments using 3-D cyclopropyl building blocks. Finally in
Chapter 6, the synthesis of JAK3 inhibitors via scaffold hopping using 3-D cyclopropyl
building blocks is presented. The results from this chapter were formulated from a
collaborative effort between researchers at AstraZeneca and the O’Brien group. Overall,
compound E was designed and synthesised; compound E had nanomolar potency which
rivals that of a licenced drug (Litfulo™).