Modular Synthetic Platform for the 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 pharmaceutical development. The rate-limiting step of this process is often identifying and optimizing synthetic chemistry suitable for fragment elaboration, especially in three dimensions (3-D). To address this limitation, we herein present a modular platform for the systematic and programmable elaboration of two-dimensional (2-D) fragment hits into lead-like 3-D compounds, utilizing nine bifunctional building blocks that explore a range of vectors in 3-D. The building blocks comprise (i) rigid sp³-rich bicyclic cyclopropane-based structures to fix the vectors and (ii) two synthetic handles─a protected cyclic amine and a cyclopropyl N-methyliminodiacetic acid (MIDA) boronate. To validate our approach, we present (i) multigram-scale synthesis of each 3-D building block; (ii) Suzuki-Miyaura cross-coupling reactions of the cyclopropyl BMIDA functionality with aryl bromides; and (iii) N-functionalization (via commonplace medicinal chemistry toolkit reactions) of arylated products to deliver 3-D lead-like compounds. 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 methanesulfonamide derivatives. Since the synthetic methodology is established in advance of fragment screening and utilizes 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 explored, streamlining the discovery of a novel and selective JAK3 inhibitor with IC₅₀ = 69 nM.