Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors

The synthesis of 4′,6′-dihydrospiro­[piperidine-4,5′-pyrazolo­[3,4-<i>c</i>]­pyridin]-7′(2′<i>H</i>)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 <i>tert</i>-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1<i>H</i>-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 <i>tert</i>-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues