3-D building blocks: a modular synthetic platform for elaborating fragments to 3-D lead compounds Andres R. Gomez-Angel 1 , William T. Butler 1 , James R. Donald 1 , Hanna F. Klein 1 , Stephen Y. Yao 1 ,James D. Firth 1 , Lucia Fusani 2 , Simon C. C. Lucas 2 and Peter O’Brien 1 . 1 Department of Chemistry, University of York, UK, 2 Hit Discovery, The Discovery Centre, Cambridge, UK With the advent of Fragment Based Drug Discovery (FBDD) for the efficient sampling of chemical space, the overall rate of discovery of potential drug candidates starting from fragments has increased. 1 However, this increase has highlighted the need to further develop synthetic chemistry to support FBDD. 2 One of these needs is increasing the 3-D shape of potential drug candidates 3 and interest in 3-D shaped fragments has emerged. 4 Nonetheless, as current libraries possess many compounds with low 3-D shapes 5 and elaborating such compounds is challenging, we now present a new, modular approach for the conversion of 2-D fragments into 3-D lead-like compounds with potential for automation. Our technology platform enables the rapid elaboration of 2-D fragments in three-dimensions. A series of bifunctional 3-D building blocks with defined elaboration vectors has been designed and synthesised ( A , available from Key Organics). Utilising the cyclopropyl MIDA boronate handle, elaboration with medicinally relevant aryl bromides via Suzuki-Miyaura cross-coupling can be achieved. Additionally, a variety of N -functionalisation reactions are demonstrated to give access to a series of lead-like compounds by the use of precedented pharmacophores ( B ) 6,7 – this provides access to a wide range of 3-D vector space ( B ). The utility of our modular synthetic platform is further highlighted by the design and synthesis of selective JAK3 inhibitors utilising two of the designed 3-D building blocks ( C ). Finally, a new generation of 3-D building blocks comprising a cyclobutyl alcohol or BF 3 K is showcased. Using Pd-catalysed sp 3 -sp 2 Suzuki-Miyaura cross-coupling or a novel application of MacMillan’s Ir/Ni-catalysed deoxygenative photoredox cross-coupling 8 allows access to new areas of chemical space not covered by the cyclopropyl building blocks ( D ). Full details will be presented.
References 1. D. A. Erlanson, S. W. Fesik, R. E. Hubbard, W. Jahnke, H. Jhoti, Nat. Rev. Drug Discov . 2016 , 15, 605–619. 2. C. W. Murray, D. C. Rees, Angew. Chemie - Int. Ed. 2016 , 55, 488–492. 3. Lovering, F.; Bikker, J.; Humblet, C., J. Med. Chem . 2009 , 52, 6752-6756. 4. Kidd, S. L.; Osberger, T. J.; Mateu, N.; Sore, H. F.; Spring, D. R., Front. Chem . 2018 , 6, 460. 5. Fuller, N.; Spadola, L.; Cowen, S.; Patel, J.; Schönherr, H.; et al ., Drug. Discov. Today . 2016 , 21, 1272-1283. 6. M. R. Harris, Q. Li, Y. Lian, J. Xiao, A. T. Londregan, Org. Lett . 2017 , 19, 2450–2453. 7. M. R. Harris, H. M. Wisniewska, W. Jiao, X. Wang, J. N. Bradow, Org. Lett . 2018 , 20, 2867–2871. 8. Dong, Z., MacMillan, D.W.C., Nature 2021 ,598, 451–456.
P13
© The Author(s), 2023
Made with FlippingBook Learn more on our blog