Modular Synthetic Platform for Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery

Fragment-based drug discovery (FBDD) is a key strategy employed in the hit-to-lead phase of pharmaceu-tical development. The rate limiting step of this process is often identifying and optimising synthetic chem-istry suitable for fragment elaboration, especially in 3-dimensions (3-D). To address this limitation, we herein present a modular platform for the systematic and programmable elaboration of 2-dimensional (2-D) fragment hits into lead-like 3-D compounds, utilising nine bifunctional building blocks (commercially available from Key Organics) that explore a range of vectors in 3-D. The building blocks comprise: (i) rig-id sp3-rich bicyclic cyclopropane-based structures to fix the vectors, and (ii) two synthetic handles – a pro-tected cyclic amine and a cyclopropyl N-methyliminodiacetic acid (MIDA) boronate. To validate our ap-proach, we present: (i) multi-gram scale synthesis of each 3-D building block; (ii) Suzuki-Miyaura cross-coupling reactions of the cyclopropyl BMIDA functionality with aryl bromides; (iii) N-functionalisation (via commonplace medicinal chemistry toolkit reactions) of arylated products to deliver 3-D lead-like com-pounds. Each building block accesses a distinct 3-D exit vector, as shown by analysis of the lowest energy conformations of lead-like molecules using RDKit, and by X-ray crystallography of pyrimidine me-thanesulfonamide derivatives. Since the synthetic methodology is established in advance of fragment screening and utilises robust chemistry, the elaboration of fragment hits in 3-D for biochemical screening can be achieved rapidly. To provide proof-of-concept, starting from the drug Ritlecitinib, the development of inhibitors of Janus kinase 3 (JAK3) around a putative pyrrolopyrimidine 2-D fragment hit was ex-plored, streamlining the discovery of a novel and selective 69 nM inhibitor.