Synthesis and Vectorial Functionalisation of N-Heterocycles for Fragment-based Drug Discovery

Abstract

Fragment-based drug discovery (FBDD) is a well established method of finding and developing biologically active molecules. Nitrogen heterocycles are a common motif found in many commercial drug compounds and are therefore valuable inputs for FBDD. However, the range of nitrogen heterocycles in common usage remains limited and novel scaffolds offer a much needed source of molecular diversity. This project advances two complementary areas of FBDD - exploring key heterocyclic cores representing unexplored region of chemical space and developing new synthetic methodology to support fragment elaboration.
The first heterocyclic cores of interest were the 5-halo-1H-pyrazolo[3,4-c]pyridines (77 and 185), accessed in two steps from the corresponding 6-halo-5-methylpyridin-3-amine. Complimentary methods of late-stage functionalisation enabled elaboration along the major growth-vectors. N-alkylation and nitrogen protection strategies decorated N-1 and N-2 on the pyrazole ring, while the C-3 vector was accessed by a tandem C-H borylation and Suzuki-Miyaura cross-coupling, the C-5 vector was accessed by Buchwald-Hartwig amination, and the C-7 vector was accessed by a turbo-Grignard metalation strategy. These methods can be used individually or in sequences to generate an elaborated library of compounds. Biological characterisation of this library sort to exemplify the pharmaceutical value of the pyrazolo[3,4-c]pyridine core. Unfortunately, both crystal soaking and thermal shift assays were challenged by the limited aqueous solubility of the heterocycles, so were unable to verify results of the virtual screening.
The second heterocyclic cores of interest, the semi-saturated azabenzolactams (241, 242, 243, and 244), were designed to incorporate more sp3 character to improve aqueous solubility. A multi-step synthetic route was established to afford four analogues starting from the respective halo-cyanopyridine. The saturated part of these ring systems opens new possibilities for functionalisation, with a particular site of interest being C-α to the amine nitrogen. This led to an in-depth study developing methodology for the α-functionalisation of cyclic amines.
This methodology study established a route of C-H activation by electrochemical oxidation followed by reaction with phenylzinc. By first performing a boron-to-zinc transmetalation of commercial aryl boronic acids, the scope of this transformation was extended to include substitution by other aryl groups. Variation in ring size, protecting group, morpholines, and benzo-fused systems were all tolerated, while future work will see the application of this methodology to more drug-like cores, including the azabenzolactams.