title: Synthesis of spiropiperidine lactam acetyl-CoA carboxylase inhibitors.
abstract: The synthesis of 4',6'-dihydrospiro[piperidine-4,5'-pyrazolo[3,4-c]pyridin]-7'(2'H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-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 tert-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.
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Huard
authors.forename: Scott W
authors.initials: SW
authors.lastname: Bagley
authors.forename: Elnaz
authors.initials: E
authors.lastname: Menhaji-Klotz
authors.forename: Cathy
authors.initials: C
authors.lastname: Préville
authors.forename: James A
authors.initials: JA
authors.lastname: Southers
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Smith
authors.forename: David J
authors.initials: DJ
authors.lastname: Edmonds
authors.forename: John C
authors.initials: JC
authors.lastname: Lucas
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Dunn
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Allanson
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blaney
authors.forename: Carmen N
authors.initials: CN
authors.lastname: Garcia-Irizarry
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kohrt
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dow
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000478:Alkylation; D003500:Cyclization; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: C580830:4',6'-dihydrospiro(piperidine-4,5'-pyrazolo(3,4-c)pyridin)-7'(2'H)-one; D007769:Lactams; D010880:Piperidines; D011720:Pyrazoles; D011728:Pyridones; C520862:ethyl 3-amino-1H-pyrazole-4-carboxylate; D000103:Acetyl-CoA Carboxylase