Macrocyclic inhibitors of Flaviviridae viruses
Inventors
Aciro, Caroline • Chiva, Jean Yves • Dean, David Kenneth • Highton, Adrian John • Jansa, Petr • Keats, Andrew John • Lazarides, Linos • Mackman, Richard • Poullennec, Karine G. • Schrier, Adam James • Siegel, Dustin Scott • Steadman, Victoria Alexandra • Watt, Greg
Assignees
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Publication Number
US-9642889-B2
Publication Date
2017-05-09
Expiration Date
Abstract
Provided are compounds of Formula I:and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.
Core Innovation
The invention relates to compounds of Formula I and to methods for treating a disease selected from dengue fever, yellow fever, hepatitis C virus, Japanese encephalitis, Kyasanur forest disease, Murray valley encephalitis, St. Louis encephalitis, tick-borne encephalitis or West Nile encephalitis by administering to a human patient in need thereof a therapeutically effective amount of a compound of Formula I. The administration includes a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, or tautomer thereof.
The invention further relates to providing immunomodulation to a human patient in need thereof by administering a therapeutically effective amount of a compound of Formula I. Formula I is defined by the structural variables A, A1, A2, L1, X1, and substituents including R1, R2, R3, R4a, R4b, R5a, R5b, R6a, R6b, R8, R9, n and m, with optional substitutions and spirocycle options via Formula (a).
The disclosed embodiments include Formula II, Formula III, and related compound examples, including substituted quinoline-linked compounds, quinoline–pyridazine linked compounds, and quinolinyl 1,3-dioxane carboxylic acid motifs. The provided document content reports intermediates and final compounds, including ester, acid, hydrochloride, and prodrug forms, and characterizes prepared compounds by LCMS and 1H NMR.
Claims Coverage
The consolidated claim coverage includes two independent claims: one directed to treating a specified group of diseases and one directed to providing immunomodulation, each by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, or tautomer thereof. The core inventive features are the therapeutic or immunomodulatory administration of Formula I compounds with the stated structural-variable framework.
Treatment of specified diseases with Formula I compounds
A method for treating a disease selected from dengue fever, yellow fever, hepatitis C virus, Japanese encephalitis, Kyasanur forest disease, Murray valley encephalitis, St. Louis encephalitis, tick-borne encephalitis or West Nile encephalitis by administering to a human patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, or tautomer thereof.
Providing immunomodulation with Formula I compounds
A method for providing immunomodulation to a human patient in need thereof by administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, or tautomer thereof.
Across the independent claims, coverage is directed to administering Formula I compounds in human patients for either treatment of the listed diseases or for immunomodulation, with Formula I defined by the enumerated substituent and linkage variables.
Stated Advantages
Provides a therapeutically effective method for treating specified diseases by administering Formula I compounds to a human patient.
Provides immunomodulation to a human patient by administering Formula I compounds.
Documented Applications
Treatment of dengue fever, yellow fever, hepatitis C virus, Japanese encephalitis, Kyasanur forest disease, Murray valley encephalitis, St. Louis encephalitis, tick-borne encephalitis, or West Nile encephalitis.
Immunomodulation of a human patient in need thereof.
Example compounds are evaluated for cyclophilin A (CypA) and anti-HCV activity, including PPIase inhibition assay, CypA TR-FRET competitive binding assay, and HCV replicon-based antiviral screening.
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