RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

An efficient method to synthesize functionalized tetraarylphosphonium salts is described. The nickel-catalyzed coupling reaction between aryl iodides, bromides, chlorides, or triflates and triphenylphosphine generates tetraarylphosphonium salts in high yields. The coupling is wide in scope and tolerates a variety of functional groups such as alcohols, amides, ketones, aldehydes, phenols, phosphines and amines.

A general method to access phenyliodonium ylides from malonates has been developed. These ylides provide easy access to a variety of useful 1,1-cyclopropane diesters using rhodium or copper catalysis. Moreover, the iodonium ylide of dimethyl malonate was obtained in 78% yield using improved conditions that involve a simple filtration step to isolate the desired product. This ylide was shown to be a safer and convenient alternative to the corresponding diazo compound and a very efficient way to 1,1-cyclopropane diesters when used with a catalytic amount of Rh(2)(esp)(2).

An efficient method to synthesize functionalized tetraarylphosphonium salts is described. This palladium-catalyzed coupling reaction between aryl iodides, bromides, or triflates and triphenylphosphine generates phosphonium salts in high yields. The coupling is compatible with a variety of functional groups such as alcohols, ketones, aldehydes, phenols, and amides.

A highly stereoselective (up to 98% ee and 99:1 dr) Rh(II)-catalyzed formation of nitrile-substituted cyclopropanes is described. Alpha-cyano diazoacetamide reagents react with a variety of mono- and disubstituted olefins in good yields and excellent enantio- and diastereocontrol. Less reactive substrates, such as aliphatic olefins, also undergo the reaction. This new methodology features the unprecedented use of an achiral hydrogen-bond donor additive to enhance the selectivity and exploits the powerful trans-directing ability of amides solving the diastereocontrol issue of the formation of substituted 1-cyanocyclopropane-1-carboxy derivatives.

Highly stereoselective: A highly enantioselective (up to 97 % ee) and diastereoselective (>30:1 d.r.) RhII‐catalyzed cyclopropanation of alkenes using a diazo reagent bearing two carboxy groups is described. This new methodology exploits the powerful trans‐directing ability of amides to improve enantiocontrol. Mono‐ and disubstituted olefins are cyclopropanated in good yields. nttl=N‐1,8‐naphthoyl‐tert‐leucine.

Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.

In this article, we describe our efforts toward the enantioselective formation of 1,1-cyclopropane diesters via the metal-catalyzed cyclopropanation of olefins. The strategies envisioned to achieve such a goal are discussed as well as the results that led us to the discovery of the powerful trans-directing ability of the amide group in Rh(II)-catalyzed cyclopropanation reactions. We show how this feature enables a solution for the stereoselective synthesis of 1,1-dicarboxy cyclopropane derivatives. The scope and limitations are discussed as well as the demonstration that these newly formed cyclopropanes display reactivity similar to that of 1,1-cyclopropane diesters. Conversely, 1,1-cyclopropane diesters could be accessed in two steps from commercially available alkenes. The potential utility of this methodology is illustrated by several functional group transformations and its use in the expedient stereoselective formal synthesis of (S)-(+)-curcumene, (S)-(+)-nuciferal, (S)-(+)-nuciferol, (+)-erogorgiaene, (+/-)-xanthorrhizol, and (+/-)-2-hydroxycalamenene.