Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases
Inventors
McComas, Casey C. • Liverton, Nigel J. • Habermann, Joerg • Koch, Uwe • Narjes, Frank • Li, Peng • Peng, Xuanjia • Soll, Richard • Wu, Hao • Palani, Anandan • Dai, Xing • Liu, Hong • He, Shuwen • Dang, Qun
Assignees
Wuxi Apptec Co Ltd • MSD Italia SRL • Merck Sharp and Dohme LLC
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Publication Number
US-9573939-B2
Publication Date
2017-02-21
Expiration Date
Abstract
The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
Core Innovation
The invention relates to substituted benzofuran compounds having a defined chemical structure, including pharmaceutically acceptable salts thereof. The disclosure also describes substituted benzofuran, sulfonamide, amide, indole, fused heteroaromatic, benzofuran-3-carboxamide intermediates, and substituted benzofuran-containing indazole/benzimidazole derivatives, with compound structures shown for multiple compounds and related structural embodiments.
The compounds are stated to inhibit hepatitis C virus (HCV) NS5B polymerase activity and HCV replication, including viral production and replicon activity in cell-based systems. The disclosure identifies use as therapeutic agents for HCV and as HCV replication inhibitors, and it states that the compounds can be used to prevent, treat, or manage HCV infection.
The disclosure also describes pharmaceutical compositions and combination use. It recites a medicament comprising a pharmaceutically acceptable carrier and an effective amount of the compound or a pharmaceutically acceptable salt, and it further recites optional combination with a second therapeutic agent selected from HCV antiviral agent classes, including HCV protease inhibitors, HCV NS5A inhibitors, HCV NS5B polymerase inhibitors, immunomodulators, and anti-infective agents.
Claims Coverage
The claim coverage centers on structure-defined compounds and their pharmaceutically acceptable salts, with dependent claims extending to pharmaceutical compositions and HCV treatment methods. Across the claim sets, there are 6 inventive features focused on the defined compound structure, formulation, combination therapy, and methods of treating or preventing HCV infection.
Substituted benzofuran compound and pharmaceutically acceptable salt
A compound having the specified structure, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with carrier and effective amount
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound or a pharmaceutically acceptable salt thereof.
Combination with a second therapeutic agent selected by class
The pharmaceutical composition further comprising a second therapeutic agent selected from HCV antiviral agents, immunomodulators, and anti-infective agents.
Second therapeutic agent selected from HCV target classes
The pharmaceutical composition wherein the second therapeutic agent is selected from HCV protease inhibitors, HCV NS5A inhibitors, and HCV NS5B polymerase inhibitors.
Method of treating or preventing HCV infection
A method of treating a patient infected with HCV, comprising administering the compound or a pharmaceutically acceptable salt thereof in an amount effective to prevent and/or treat HCV infection.
Combination treatment including pegylated-interferon alpha and ribavirin
The method further comprising administering pegylated-interferon alpha and ribavirin to the patient.
Overall, the claims focus on the structurally defined compounds and salts, and extend to pharmaceutical compositions and methods of treating or preventing HCV infection. The dependent claims further add combination regimens, including specified HCV target classes and pegylated-interferon alpha with ribavirin.
Stated Advantages
Inhibits HCV replication and viral production by acting as HCV NS5B polymerase inhibitors.
Provides compounds for preventing and/or treating HCV infection.
Combination therapy with other antiviral/immunomodulatory agents.
Provides HCV replication inhibition potency assessment in an HCV replicon system, including IC50 values for HCV genotypes 1a and 1b.
Documented Applications
Use of the compounds as HCV NS5B polymerase inhibitors for inhibiting HCV replication and viral production in cell-based system/replicon activity.
Treating and/or preventing HCV infection by administering the compound or a pharmaceutically acceptable salt to a patient infected with HCV.
Use in pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of the compound or salt.
Combination use with a second therapeutic agent selected from HCV antiviral agent classes, including HCV protease inhibitors, HCV NS5A inhibitors, and HCV NS5B polymerase inhibitors.
Combination treatment including pegylated-interferon alpha and ribavirin.
Therapeutic use for treating/preventing hepatitis C virus (HCV) infection using the substituted benzofuran compounds.
Use of the compounds as HCV replication inhibitors.
Combination therapy in the context of HCV treatment with other antiviral/immunomodulatory agents, including options such as pegylated interferon alpha and ribavirin.
HCV replicon-based potency assessment using stable neomycin phosphotransferase replicon cells and cell ELISA measuring NS3/4A protein, with IC50 values reported for HCV genotypes 1a and 1b.
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