Preparation of Azinones from (Cyclopropylmethoxy)azine Ethers

A general and convenient procedure for the synthesis of azinones is presented. Cyclopropylmethanol is readily introduced onto various azines where it functions as both a protecting group and surrogate for hydroxyl. After acidic deprotection, under mild reaction conditions, the corresponding azinones are formed and isolated in excellent yields. >20 examples are included along with a discussion of reaction optimization, scope, and mechanism

Diastereoselective Synthesis of β‑Heteroaryl <i>syn</i>-α-Methyl-β-Amino Acid Derivatives via a Double Chiral Auxiliary Approach

The addition of the SuperQuat enolate to five- and six-membered heterocyclic <i>tert</i>-butyl sulfinimines led to a high <i>syn</i>-selectivity of up to 99:1 in good to excellent yields. The reaction is tentatively proposed to proceed through an open-chain transition state with the presence of an α-heteroatom on the sulfinimine leading to high diastereoselectivities. The adducts were derivatized to β-amino esters and amides in a facile manner

Diastereoselective Synthesis of β‑Heteroaryl <i>syn</i>-α-Methyl-β-Amino Acid Derivatives via a Double Chiral Auxiliary Approach

The addition of the SuperQuat enolate to five- and six-membered heterocyclic <i>tert</i>-butyl sulfinimines led to a high <i>syn</i>-selectivity of up to 99:1 in good to excellent yields. The reaction is tentatively proposed to proceed through an open-chain transition state with the presence of an α-heteroatom on the sulfinimine leading to high diastereoselectivities. The adducts were derivatized to β-amino esters and amides in a facile manner

The Synthesis of Methyl-Substituted Spirocyclic Piperidine-Azetidine (2,7-Diazaspiro[3.5]nonane) and Spirocyclic Piperidine-Pyrrolidine (2,8-Diazaspiro[4.5]decane) Ring Systems

The synthesis of a series of pharmaceutically important <i>N</i>-protected methyl-substituted spirocyclic piperidine-azetidine (2,7-diazaspiro­[3.5]­nonane) and spirocyclic piperidine-pyrrolidine (2,8-diazaspiro­[4.5]­decane) ring systems was developed. These motifs contain two differentiated sites (protected secondary amines) to allow for further functionalization via reductive amination, amidation, or other chemistry. The methyl-substituted spiroazetidine ring systems were accessed using nitrile lithiation/​alkylation chemistry while the methyl-substituted spiropyrrolidines were synthesized by 1,4-addition reactions with nitroalkanes, followed by reduction and cyclization. These conditions were then scaled for the synthesis of 1-methyl spirocyclic piperidine-pyrrolidine with a classical resolution of the product using a tartaric acid derivative to isolate a single enantiomer

Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors

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 <i>O-</i>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

Discovery and Preclinical Characterization of 6‑Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]‑1<i>H</i>‑indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy

Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (<b>7</b>). Compound <b>7</b> was advanced to first-in-human trials for the treatment of diabetic nephropathy

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Indole acids <b>1</b>, <b>2</b>, and <b>3</b> are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds <b>1</b>–<b>3</b> were scaled to supply material for preclinical studies, and indole <b>3</b> was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of <b>1</b> and <b>2</b> and 2.4 kg of <b>3</b>. Multiple polymorphs of <b>3</b> were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Indole acids <b>1</b>, <b>2</b>, and <b>3</b> are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds <b>1</b>–<b>3</b> were scaled to supply material for preclinical studies, and indole <b>3</b> was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of <b>1</b> and <b>2</b> and 2.4 kg of <b>3</b>. Multiple polymorphs of <b>3</b> were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified