title: Synthesis of 7-oxo-dihydrospiro[indazole-5,4'-piperidine] acetyl-CoA carboxylase inhibitors.
abstract: Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, USA. Scott.W.Bagley@Pfizer.com
authors.forename: Scott W
authors.initials: SW
authors.lastname: Bagley
authors.forename: James A
authors.initials: JA
authors.lastname: Southers
authors.forename: Shawn
authors.initials: S
authors.lastname: Cabral
authors.forename: Colin R
authors.initials: CR
authors.lastname: Rose
authors.forename: David J
authors.initials: DJ
authors.lastname: Bernhardson
authors.forename: David J
authors.initials: DJ
authors.lastname: Edmonds
authors.forename: Jana
authors.initials: J
authors.lastname: Polivkova
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kung
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bader
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000475:Alkenes / Q000737:chemistry; D000478:Alkylation; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007659:Ketones / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D000475:Alkenes; D004791:Enzyme Inhibitors; D007191:Indazoles; D007659:Ketones; D010880:Piperidines; D011720:Pyrazoles; C031280:pyrazole; C032727:piperidine; D000103:Acetyl-CoA Carboxylase