To homeostasis and beyond! Recent advances in the medicinal chemistry of heterobifunctional derivatives.

The field of induced proximity therapeutics has expanded dramatically over the past 3 years, and heterobifunctional derivatives continue to form a significant component of the activities in this field. Here, we review recent advances in the field from the perspective of the medicinal chemist, with a particular focus upon informative case studies, alongside a review of emerging topics such as Direct-To-Biology (D2B) methodology and utilities for heterobifunctional compounds beyond E3 ligase mediated degradation. We also include a critical evaluation of the latest thinking around the optimisation of physicochemical and pharmacokinetic attributes of these beyond Role of Five molecules, to deliver appropriate therapeutic exposure in vivo.

Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist.

The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushing's syndrome.

1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as potent GR antagonists with reduced hERG inhibition and an improved pharmacokinetic profile.

We report the further optimization of our series 1H-pyrazolo[3,4-g]hexahydro-isoquinoline sulfonamides as GR antagonists. By incorporating a heteroaryl ketone group at the ring junction, we have obtained compounds with excellent functional GR antagonism. Optimization of the sulfonamide substituent has provided compounds with a very desirable overall profile, including minimal hERG activity, good bioavailability and in vivo efficacy.

Rhodium-catalyzed annulation of ynamides with bifunctional arylboron reagents.

Annulation of ynamides with arylboronic acids or esters containing an electrophilic functional group at the ortho-position proceeds under the action of rhodium catalysis to generate 2-amidoindenols or 2-amidoindenes, usually with good regioselectivity.

Preparation of multisubstituted enamides via rhodium-catalyzed carbozincation and hydrozincation of ynamides.

Rhodium-catalyzed carbozincation of ynamides using diorganozinc reagents or functionalized organozinc halides is described. Using a tri(2-furyl)phosphine-modified rhodium catalyst, the reaction course is altered to hydrozincation when diethylzinc is employed as the organozinc reagent. Trapping of the alkenylzinc intermediates produced in these reactions in further functionalization reactions is possible.

Stereoselective synthesis of multisubstituted enamides via rhodium-catalyzed carbozincation of ynamides.

A new rhodium-catalyzed carbozincation of ynamides has been developed, using diorganozinc reagents or functionalized alkylzinc halides. The reactions are highly regio- and stereoselective, allowing access to a wide range of multisubstituted enamides, which are increasingly important building blocks for organic synthesis. Utilization of the alkenylzinc intermediates in further carbon-carbon bond-forming reactions to form trisubstituted enamides is also possible.