Inhibitors of hepatitis C virus polymerase
Inventors
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Assignees
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Cocrystal PharmaCocrystal Pharma is a clinical-stage biotechnology company specializing in the discovery and development of novel antiviral therapeutics for serious and chronic viral diseases such as influenza, COVID-19, hepatitis C, norovirus, and other respiratory viruses. The company leverages structure-based drug discovery technology and expertise in structural biology to design direct viral replication inhibitors with broad-spectrum activity. Its pipeline includes candidates in preclinical and clinical development, addressing unmet needs in antiviral medicine.
Cocrystal Pharma is a clinical-stage biotechnology company specializing in the discovery and development of novel antiviral therapeutics for serious and chronic viral diseases such as influenza, COVID-19, hepatitis C, norovirus, and other respiratory viruses. The company leverages structure-based drug discovery technology and expertise in structural biology to design direct viral replication inhibitors with broad-spectrum activity. Its pipeline includes candidates in preclinical and clinical development, addressing unmet needs in antiviral medicine.
Publication Number
US-10464914-B2
Publication Date
2019-11-05
Expiration Date
Abstract
The present invention provides, among other things, compounds represented by the general Formula I: (I) and pharmaceutically acceptable salts thereof, wherein L and A (and further substituents) are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.
Core Innovation
The disclosure defines a class of compounds having a specified structural scaffold in which the linker portion L is constrained by parameters x, w, y, and z, and in which substituent groups include Rd, with permitted options of hydrogen, methyl, phenyl, or forming a C3-5 cycloalkyl ring together with the attached carbon. The structural variables are limited to defined ranges for w, x, y, and z, including a conditional constraint when y is 0. The scaffold further includes substituent groups A, D, and E selected from listed functional-group options.
The core structure is further characterized by additional substituent constraints in which the groups D and E are defined by a specified selection of functional-group options, including carboxylic acid, alkyl ester, hydroxamic acid, amide, alkoxy, amino-substituted alkyl, alkylene-linked amino groups, halo, and NO2 alternatives for E. The disclosure also addresses pharmaceutically acceptable salts of the defined compounds, indicating pharmaceutical forms for the structural class.
Claims Coverage
The independent claim set identifies a constrained chemical structure defined by the linker parameter L and substituent options A, D, and E, with explicit numeric ranges and a conditional proviso relating y, x, and z. The coverage centers on one structurally defined compound genus, with dependent claims narrowing parameter values and substituent selections, and an alternative independent claim limited to compounds listed in Table 1 or Table 2.
Constrained compound structure with defined linker parameters and substituent options
A compound having the structure, or a pharmaceutically acceptable salt thereof, wherein L is —(CH2)x—[O(CH2)w]y—O—(CRd2)z with defined constraints on w, x, y, and z, including the proviso for y = 0, where each Rd is selected from hydrogen, methyl, and phenyl or both Rd together with the carbon form C3-5 cycloalkyl; where A is selected from the listed set; and where D and E are selected according to the defined options.
Refined structural constraints via dependent narrowing
Dependent claims further narrow the structural parameters by specifying particular selections for x, w, y, z and by limiting allowed options for A, D, and E.
Compound selection from Table 1 or Table 2
A compound as listed in Table 1 or Table 2.
Overall claim coverage centers on a structurally constrained genus defined by L, Rd, A, D, and E, together with dependent refinements that further restrict the permitted structural space.
Stated Advantages
Reduces hepatitis C virus (HCV) replication.
Treats or prevents hepatitis C virus infection.
Treats or prevents hepatitis C virus reactivation.
Reduces hepatitis C virus-associated diseases, including cirrhosis, hepatocellular carcinoma, fibrosis, and cryoglobulinemia.
Compounds function as HCV NS5B polymerase inhibitors through binding in an allosteric site controlling NS5B conformation and interaction with NNI IV.
Reducing hepatitis C virus polymerase activity or viral replication in a host.
Providing a composition framework with pharmaceutically acceptable excipients and pharmaceutical dosage forms.
Enabling combination/co-administration regimens for HCV therapy with potential synergy and a higher barrier to drug resistance.
Documented Applications
Inhibition of HCV NS5B polymerase activity and reduction of HCV replication.
Treatment or prevention of HCV infection or HCV reactivation in a host.
Reduction of HCV-associated diseases, including cirrhosis, hepatocellular carcinoma, fibrosis, and cryoglobulinemia.
Use of pharmaceutical compositions containing the Formula I compounds.
Combination/co-administration regimens for hepatitis C virus therapy with multiple antiviral classes including interferons, ribavirin, NS3-4A protease inhibitors, NS5A inhibitors, entry inhibitors, cyclophilin inhibitors, and NS5B polymerase inhibitors.
Reducing hepatitis C virus polymerase activity or hepatitis C virus replication in the host.
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