Yale University

Glaxosmithkline Intellectual Property Development Limited

The University of Edinburgh

Cambridge Enterprise Limited University of Cambridge

Julien Michel

Craig M Crews

Joelle Le

John David Harling

William L Jorgensen

Denton Wade Hoyer

Sebastien Andre Campos

Ian Edward David Smith

Afjal Hussain Miah

Peter C Gareiss

Alison Hulme

Alessio Ciulli

Charis Georgiou

Jordi Juarez-Jimenez

Dennis Buckley

Charalampos Ioannidis

Alessio De Simone

Arun Gupta

Malcolm Walkinshaw

Inge Van Molle

Dahlia Doughty Shenton

Jeffrey Gustafson

Hyun-Seop Tae

Anke G Roth

The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof useful as inhibitors of Cyclophilins and modulators of cyclophilin-like proteins. The invention also relates to uses of said compounds in the treatment of various disorders. Formula (I), wherein: Rand Rare each independently is selected from the group consisting of &#x2014;R, -haloalkyl, -hydroxyalkyl, &#x2014;OR, &#x2014;C(O)R, &#x2014;CO2R, &#x2014;C(O)N(R)2, &#x2014;NRC(O)R, and &#x2014;N(R)2; wherein Rcould also be a sulphide; each R is independently hydrogen, Caliphatic, Caryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulphur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms selected from nitrogen, oxygen, or sulphur; Ris Formula (Ia) selected from the group consisting of &#x2014;OEt, and wherein Rand Rare independently selected from the group consisting of H, halide, methoxy, thiomethyl, morpholine and trifluoromethyl; Ris selected from the group consisting of C-alkyl-, and R&#x2014;CH&#x2014; wherein, Ris C-cycloalkyl-, a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulphur; optionally substituted with one Rwherein, Ris selected from &#x2014;H, C-alkyl, optionally substituted with one substituent selected from HN(O)C&#x2014; or EtO(O)C&#x2014;; X is carbon or nitrogen; A is selected from the group consisting of 6 membered unsaturated ring, with 1-3 nitrogen atoms, which is optionally substituted by &#x2014;NH, and Formula (Ib), wherein ring B is a fused 5-10 membered saturated or partially unsaturated heterocyclic mono-bicyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen or sulphur, which is optionally substituted by &#x2014;OH; and m is 1 or 2; and n is 1 or 2.

Compounds for the modulation of cyclophilins function

The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds of the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand that binds to the ubiquitin ligase and on the other end a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds of the present invention, consistent with the degradation/inhibition of targeted polypeptides.

Compounds and methods for the enhanced degradation of targeted proteins and other polypeptides by an E3 ubiquitin ligase

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Edinburgh, United Kingdom

Julien Michel