US20090060872A1

US20090060872A1 - Phosphadiazine hcv polymerase inhibitors v

Info

Publication number: US20090060872A1
Application number: US12/198,900
Authority: US
Inventors: Cyril Dousson; Dominique Surleraux; Jean-Laurent Paparin
Original assignee: Idenix Pharmaceuticals LLC
Current assignee: Idenix Pharmaceuticals LLC
Priority date: 2007-08-31
Filing date: 2008-08-27
Publication date: 2009-03-05
Also published as: RU2483073C2; HK1137028A1; EP2183260A1; MX2010002296A; US20090081158A1; US7932240B2; AU2008296997B2; US20090060867A1; JP2010537986A; US20090060866A1; WO2009032176A1; AU2008296997A1; TW200927143A; KR20100072002A; BRPI0815920A2; ES2367550T3; WO2009032180A1; WO2009032177A1; RU2010112408A; UA95715C2

Abstract

Provided herein are phosphadiazine polymerase inhibitor, for example, of any of Formulas V, V′, I″, II″, or Va, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 60/967,237, filed Aug. 31, 2007, the content of which is incorporated herein by reference in its entirety.

FIELD

Provided herein are phosphadiazine polymerase inhibitor compounds, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.

BACKGROUND

Hepatitis C virus (HCV) is known to cause at least 80% of posttransfusion hepatitis and a substantial proportion of sporadic acute hepatitis (Houghton et al., Science 1989, 244, 362-364; Thomas, Curr. Top. Microbiol. Immunol. 2000, 25-41). Preliminary evidence also implicates HCV in many cases of “idiopathic” chronic hepatitis, “cryptogenic” cirrhosis, and probably hepatocellular carcinoma unrelated to other hepatitis viruses, such as hepatitis B virus (Di Besceglie et al., Scientific American, October, 1999, 80-85; Boyer et al., J. Hepatol. 2000, 32, 98-112).
HCV is an enveloped virus containing a positive-sense single-stranded RNA genome of approximately 9.4 kb (Kato et al., Proc. Natl. Acad. Sci. USA 1990, 87, 9524-9528; Kato, Acta Medica Okayama, 2001, 55, 133-159). The viral genome consists of a 5′ untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of approximately 3011 amino acids, and a short 3′ UTR. The 5′ UTR is the most highly conserved part of the HCV genome and is important for the initiation and control of polyprotein translation. Translation of the HCV genome is initiated by a cap-independent mechanism known as internal ribosome entry. This mechanism involves the binding of ribosomes to an RNA sequence known as the internal ribosome entry site (IRES). An RNA pseudoknot structure has recently been determined to be an essential structural element of the HCV IRES. Viral structural proteins include a nucleocapsid core protein (C) and two envelope glycoproteins, E1 and E2. HCV also encodes two proteinases, a zinc-dependent metalloproteinase encoded by the NS2-NS3 region and a serine proteinase encoded in the NS3 region. These proteinases are required for cleavage of specific regions of the precursor polyprotein into mature peptides. The carboxyl half of nonstructural protein 5, NS5B, contains the RNA-dependent RNA polymerase. The function of the remaining nonstructural proteins, NS4A and NS4B, and that of NS5A (the amino-terminal half of nonstructural protein 5) remain unknown.
Presently, the most effective HCV therapy employs a combination of alpha-interferon and ribavirin, leading to sustained efficacy in about 40% of patients (Poynard et al., Lancet 1998, 352, 1426-1432). Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy. However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load (Manns et al, Lancet 2001, 358, 958-965; Fried et al., N. Engl. J. Med. 2002, 347, 975-982; Hadziyannis et al., Ann. Intern. Med. 2004, 140, 346-355). Furthermore, research shows that using pegylated interferon and ribavirin to treat patients with HCV can cause significant side effects, such as alopecia, anorexia, depression, fatigue, myalgia, nausea and prunitus (Ward et al., American Family Physician. 2005, Vol. 72, No. 4; Al-Huthail, The Saudi Journal of Gastroenterology. 2006, Vol. 12, No. 2, 59-67). Severe weight loss is also reported as a side effect in the interferon-based therapy in combination with ribavirin (Bani-Sadr et al., Journal of Viral Hepatitis. 2008, 15(4): 255-260). Thus, there is a clear and unmet need to develop effective therapeutics for treatment of HCV infection.

SUMMARY OF THE DISCLOSURE

Provided herein are phosphadiazine polymerase inhibitor compounds, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of the use of the compounds for the treatment of an HCV infection in a host in need thereof.
In one aspect, provided herein is a compound of Formula V′:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R¹is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
R⁴is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;
R^4′ is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;
R⁵is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴and R⁵together form a part of a 3-8 membered heterocycloalkyl ring;
R^5′ is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, heteroaryl, —NR⁸R¹⁰, alkenyl, or alkynyl;
R^6′ is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl; or R^5′ and R^6′ together form a part of a 3-8 membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl ring;
R¹²is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹; and
each Y is O or S,
wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
In another aspect, provided herein is a compound of Formula V:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R¹is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
R⁶is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;
R¹²is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;
each R¹⁴is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^9′, —OCHR^9′C(O)O—R⁸, —OCHR^9′C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′C(O)R⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —OCHR^9′C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^9′, —O—(C₁-C₆alkyl)-S(O)₂R^9′, —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^9′—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′C(O)R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^9′S(O)₂NR⁸R⁹, —NR^9′S(O)₂NR⁸R¹⁰, —S(O)R^9′, —S(O)₂R^9′, or —S(O)₂NR⁸R⁹;
each n is independently an integer from 1 to 4;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;
each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; and
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹,
wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
Also provided herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; in combination with one or more pharmaceutically acceptable excipients or carriers.
Also provided herein is a method for treating or preventing an HCV infection, which comprises administering to a subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Also provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection, comprising administering to a subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Also provided herein is a method for inhibiting replication of a virus in a host, which comprises contacting the host with a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Also provided herein is a method for inhibiting replication of a virus, which comprises contacting the virus with a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Also provided herein is a method for inhibiting the activity of a polymerase, which comprises contacting the polymerase with a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Provided is a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, or a pharmaceutical composition thereof, for use in therapy. Also provided is a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, or a pharmaceutical composition thereof, for use in treating or preventing an HCV infection. Also provided is a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, or a pharmaceutical composition thereof, for use in treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection. Also provided is a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, or a pharmaceutical composition thereof, for use in inhibiting replication of a virus in a host. Also provided is the use of a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, or a pharmaceutical composition thereof, for manufacture of a medcicament for treating or preventing an HCV infection. Also provided is the use of a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, or a pharmaceutical composition thereof, for manufacture of a medcicament for treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection. Also provided is the use of a compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, or a pharmaceutical composition thereof, for manufacture of a medcicament for inhibiting replication of a virus in a host.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event that there is a plurality of definitions for a term used herein, those in this section prevail unless stated otherwise.
The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
The term “host” refers to a unicellular or multicellular organism in which a virus can replicate, including, but not limited to, a cell, cell line, and animal, such as human.
The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disease; or reducing a subject's risk of acquiring a disorder, disease, or condition.
The term “therapeutically effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
The term “IC₅₀” refers an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such response.
The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004).
The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
The terms “active ingredient” and “active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder or disease. As used herein, “active ingredient” and “active substance” may be an optically active isomer of a compound described herein.
The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
The term “release controlling excipient” refers to an excipient whose primary function is to modify the duration or place of release of an active substance from a dosage form as compared with a conventional immediate release dosage form.
The term “nonrelease controlling excipient” refers to an excipient whose primary function do not include modifying the duration or place of release of an active substance from a dosage form as compared with a conventional immediate release dosage form.
The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical. The term “alkyl” also encompasses both linear and branched alkyl, unless otherwise specified. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C_1-20), 1 to 15 (C_1-15), 1 to 10 (C_1-10), or 1 to 6 (C_1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) carbon atoms. In certain embodiments, the alkyl is a linear or branched saturated monovalent hydrocarbon radical that has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. As used herein, linear C_1-6and branched C_3-6alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, C_1-6alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl may be substituted.
The term “alkylene” refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted. The term “alkylene” encompasses both linear and branched alkylene, unless otherwise specified. In certain embodiments, the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C_1-20), 1 to 15 (C_1-15), 1 to 10 (C_1-10), or 1 to 6 (C_1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) carbon atoms. In certain embodiments, the alkylene is a linear or branched saturated divalent hydrocarbon radical that has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. As used herein, linear C_1-6and branched C_3-6alkylene groups are also referred as “lower alkylene.” Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms). For example, C_2-6alkylene refers to a linear saturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more carbon-carbon double bonds. The alkenyl may be optionally substituted, e.g., as described herein. The term “alkenyl” also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations, as appreciated by those of ordinary skill in the art. As used herein, the term “alkenyl” encompasses both linear and branched alkenyl, unless otherwise specified. For example, C_2-6alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C_2-20), 2 to 15 (C_2-15), 2 to 10 (C_2-10), or 2 to 6 (C_2-6) carbon atoms or a branched monovalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl.
The term “alkenylene” refers to a linear or branched divalent hydrocarbon radical, which contains one or more carbon-carbon double bonds. The alkenylene may be optionally substituted, e.g., as described herein. Similarly, the term “alkenylene” also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations. As used herein, the term “alkenylene” encompasses both linear and branched alkenylene, unless otherwise specified. For example, C_2-6alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C_2-20), 2 to 15 (C_2-15), 2 to 10 (C_2-10), or 2 to 6 (C_2-6) carbon atoms or a branched divalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) carbon atoms. Examples of alkenylene groups include, but are not limited to, ethenylene, propenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.
The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more carbon-carbon triple bonds. The alkynyl may be optionally substituted, e.g., as described herein. The term “alkynyl” also encompasses both linear and branched alkynyl, unless otherwise specified. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C_2-20), 2 to 15 (C_2-15), 2 to 10 (C_2-10), or 2 to 6 (C_2-6) carbon atoms or a branched monovalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH) and propargyl (—CH₂C≡CH). For example, C_2-6alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
The term “alkynylene” refers to a linear or branched divalent hydrocarbon radical, which contains one or more carbon-carbon triple bonds. The alkynylene may be optionally substituted, e.g., as described herein. The term “alkynylene” also encompasses both linear and branched alkynylene, unless otherwise specified. In certain embodiments, the alkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C_2-20), 2 to 15 (C_2-15), 2 to 10 (C_2-10), or 2 to 6 (C_2-6) carbon atoms or a branched divalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) carbon atoms. Examples of alkynylene groups include, but are not limited to, ethynylene (—C≡C—) and propargylene (—CH₂C≡C—). For example, C_2-6alkynyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
The term “cycloalkyl” refers to a cyclic saturated bridged or non-bridged monovalent hydrocarbon radical, which may be optionally substituted, e.g., as described herein. In certain embodiments, the cycloalkyl has from 3 to 20 (C_3-20), from 3 to 15 (C_3-15), from 3 to 10 (C_3-10), or from 3 to 7 (C_3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl.
The term “cycloalkylene” refers to a cyclic saturated bridged or non-bridged divalent hydrocarbon radical, which may be optionally substituted, e.g., as described herein. In certain embodiments, the cycloalkylene has from 3 to 20 (C_3-20), from 3 to 15 (C_3-15), from 3 to 10 (C_3-10), or from 3 to 7 (C_3-7) carbon atoms. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, decalinylene, and adamantylene.
The term “aryl” refers to a monocyclic or multicyclic monovalent aromatic group. In certain embodiments, the aryl has from 6 to 20 (C_6-20), from 6 to 15 (C_6-15), or from 6 to 10 (C_6-10) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). All such aryl groups may also be optionally substituted, e.g., as described herein.
The term “arylene” refers to a monocyclic or multicyclic divalent aromatic group. In certain embodiments, the arylene has from 6 to 20 (C_6-20), from 6 to 15 (C_6-15), or from 6 to 10 (C_6-10) ring atoms. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, fluorenylene, azulenylene, anthrylene, phenanthrylene, pyrenylene, biphenylene, and terphenylene. Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene, indenylene, indanylene, or tetrahydro-naphthylene(tetralinyl). All such aryl groups may also be optionally substituted, e.g., as described herein.
The term “heteroaryl” refers to a monocyclic or multicyclic aromatic group, wherein at least one ring contains one or more heteroatoms independently selected from O, S, and N. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. All such heteroaryl groups may also be optionally substituted, e.g., as described herein.
The term “heterocyclyl” or “heterocyclic” refers to a monocyclic or multicyclic non-aromatic ring system, wherein one or more of the ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, and thiomorpholinyl. All such heterocyclic groups may also be optionally substituted, e.g., as described herein.
The term “alkoxy” refers to an —OR radical, wherein R is, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-propoxy, 2-propoxy, n-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzoxy, and 2-naphthyloxy.
The term “acyl” refers to a —C(O)R radical, wherein R is, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each as defined herein. Examples of acyl groups include, but are not limited to, acetyl, propionyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, docosanoyl, myristoleoyl, palmitoleoyl, oleoyl, linoleoyl, arachidonoyl, benzoyl, pyridinylcarbonyl, and furoyl.
The term “halogen”, “halide” or “halo” refers to fluorine, chlorine, bromine, or iodine.
The term “arylalkyl” refers to an aryl group appended to an alkyl radical, such as aryl-(CH₂)—, aryl-CH₂—CH₂—, and aryl-CH₂—CH₂—CH₂—.
The term “heteroarylalkyl” refers to an heteroaryl group appended to an alkyl radical, such as heteroaryl-(CH₂)—, heteroaryl-CH₂—CH₂—, and heteroaryl-CH₂—CH₂—CH₂—.
The term “optionally substituted” is intended to mean that a group, such as an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxyl, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, or heterocyclyl group, may be substituted with one or more substituents independently selected from, e.g., halo, cyano (—CN), nitro (—NO₂), —SR^a, —S(O)R^a, —S(O)₂R^a, —R^a, —C(O)R^a, —C(O)OR^a, —C(O)NR^bR^c, —OCH₂C(O)NR^bR^c, —C(NR^a)NR^bR^c, —OR^a, —OC(O)R^a, —OC(O)OR^a, OC(O)NR^bR^c, —OC(═NR^a)NR^bR^c, —OS(O)R^a, —OS(O)₂R^a, —OS(O)NR^bR^c, —OS(O)₂NR^bR^c, —NR^bR^c, —NR^aC(O)R^b, —NR^aC(O)OR^b, —NR^aC(O)NR^bR^c, —NR^aC(═NR^d)NR^bR^c, —NR^aS(O)R^b, —NR^aS(O)₂R^b, —NR^aS(O)R^bR^c, —NR^aS(O)₂R^bR^c, or —OSi—R^aR^bR^c; wherein R^a, R^b, R^c, and R^dare each independently, e.g., hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted, e.g., as described herein; or R^band R^ctogether with the N atom to which they are attached form heterocyclyl or heteroaryl, each optionally substituted, e.g., as described herein. The group can be substituted with any described moiety, including, but not limited to, one or more moieties selected from the group consisting of halogen (fluoro, chloro, bromo, or iodo), hydroxyl, amino, alkylamino (e.g., monoalkylamino, dialkylamino, or trialkylamino), arylamino (e.g., monoarylamino, diarylamino, or triarylamino), alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. As used herein, all groups that can be substituted in one embodiment are “optionally substituted,” unless otherwise specified.
In certain embodiments, “optically active” and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, or no less than about 94% no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, or no less than about 99.5%, no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The (+) and (−) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (−) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (−), is not related to the absolute configuration of the molecule, R and S.
The term “solvate” refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

Compounds

Provided herein are compounds which are useful for the treatment of HCV infection, which, in one embodiment, can have activity as HCV polymerase inhibitors. Also provided herein are pharmaceutical compositions that comprise the compounds, methods of manufacture of the compounds, and methods of use of the compounds for the treatment of HCV infection in a host in need of treatment.
In one aspect, provided herein is a compound of Formula V′:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R¹is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
R⁴is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;
R^4′ is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;
R⁵is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴and R⁵together form a part of a 3-8 membered heterocycloalkyl ring;
R^5′ is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, heteroaryl, —NR⁸R¹⁰, alkenyl, or alkynyl;
R^6′ is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R^5′ and R^6′ together form a part of a 3-8 membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring;
R¹²is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl; and
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹,
wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
In certain embodiments, each pair of R^5′ and R^6′ together independently form a part of a 3-8 membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring. In some embodiments, R^5′ and R^6′ together independently form a part of a ring having formula O or P:
where
each * is a bond;
each R¹⁴is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^9′, —OCHR^9′C(O)O—R⁸, —OCHR^9′C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′C(O)R⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —OCHR^9′C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^9′, —O—(C₁-C₆alkyl)-S(O)₂R^9′, —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^9′—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′C(O)R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^9′S(O)₂NR⁸R⁹, —NR^9′S(O)₂NR⁸R¹⁰, —S(O)R^9′, —S(O)₂R^9′, or —S(O)₂NR⁸R⁹;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;
each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl;
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹;
each n is independently an integer from 0 to 1, from 0 to 2, from 0 to 3, or from 0 to 4;
each m is independently an integer from 0 to 1, from 0 to 2, or from 0 to 3;
each A is independently CR¹⁵R¹⁶or NR¹⁷;
each A′ is independently CR¹⁵R¹⁶, NR¹⁷, N, CR¹⁵, N-oxide, N—OR⁸—, S or O;
each R¹⁵is independently a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;
R¹⁶is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkyl)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkyl)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkyl)-NR^9′S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;
R¹⁷is a bond, H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl; and
R¹⁸is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl,
wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
In certain embodiments, each pair of R^5′ and R^6′ together independently forms a part of a 3-8 membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring. In certain embodiments, each pair of R^5′ and R^6′ together independently forms a benzo ring having formula (A):
where
each * is a bond;
each R¹⁴is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^9′, —OCHR^9′C(O)O—R⁸, —OCHR^9′C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′C(O)R⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —OCHR^9′C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^9′, —O—(C₁-C₆alkyl)-S(O)₂R^9′, —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^9′—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′C(O)R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^9′S(O)₂NR⁸R⁹, —NR^9′S(O)₂NR⁸R¹⁰, —S(O)R^9′, —S(O)₂R^9′, or —S(O)₂NR⁸R⁹;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;
each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl;
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹; and
n is an integer from 1 to 4,
wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
In some embodiments, each pair of R^5′ and R^6′ together independently form a part of a ring having one of formulae C-L:
where
each * is a bond;
each R¹⁴is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^9′, —OCHR^9′C(O)O—R⁸, —OCHR^9′C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′C(O)R⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —OCHR^9′C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^9′, —O—(C₁-C₆alkyl)-S(O)₂R⁹, —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^9′—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′C(O)R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^9′S(O)₂NR⁸R⁹, —NR^9′S(O)₂NR⁸R¹⁰, —S(O)R^9′, —S(O)₂R^9′, or —S(O)₂NR⁸R⁹;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;
each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl;
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹;
each n is an integer from 1 to 3; and
each X is independently S, O, NH, or N(C₁-C₆alkyl)
wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
In certain embodiments, each n is independently an integer from 1 to 2. In certain embodiments, each n is 1.
In other embodiments, the compound of Formula V′ has the following formula I″ or II″:
where compounds of formula I″ can exist in the following resonance structures I″-a, or I″-b:
and compounds of formula II″ can exist in the following resonance structures II″-a, II″-b, or II″-c:
where
each Y is O or S;
each A is independently CR¹⁸or N;
each A′ is independently CR¹⁵R¹⁶, NR¹⁷, N, CR¹⁵, N-oxide, N—OR⁸—, S or O;
each R¹²is independently F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;
each R¹⁴is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^9′, —OCHR⁹C(O)O—R⁸, —OCHR^9′C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′C(O)R⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —OCHR^9′C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^9′, —O—(C₁-C₆alkyl)-S(O)₂R^9′, —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^9′—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′C(O)R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^9′S(O)₂NR⁸R⁹, —NR^9′S(O)₂NR⁸R¹⁰, —S(O)R^9′, —S(O)₂R^9′, or —S(O)₂NR⁸R⁹; each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;
each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl;
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹;
each R¹⁵is independently a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;
R¹⁶is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkyl)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkyl)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkyl)-NR^9′S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;
R¹⁷is a bond, H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;
R¹⁸is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkylene)-NR^9′SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;
m is independently an integer from 1 to 3; and
Z has the following structure:
where
R¹is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
R⁴is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl; and
R⁵is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴and R⁵together form a part of a 3-8 membered heterocycloalkyl ring, wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
In certain embodiments, each n is independently an integer from 1 to 3. In certain embodiments, each n is independently an integer from 1 to 2. In certain embodiments, each n is 1.
Each compound of Formula V′ may exist in various tautomeric forms. Accordingly, provided herein are tautomeric forms of compounds of Formula V′, for example, when R⁴is H, when R^4′ is H, or when R⁴and R^4′ are H. For example, compounds having formula V′ where R⁴and R^4′ are H may exist in, but not limited to, the following tautomeric forms V′_a, V′_bor V′_c:
wherein
each R¹is independently H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
each R⁵is independently H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴and R⁵together form a part of a 3-8 membered heterocycloalkyl ring;
each R^5′ is independently H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, heteroaryl, —NR⁸R¹⁰, alkenyl, or alkynyl;
each R^6′ is independently H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R^5′ and R^6′ together independently form a part of a 3-8 membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring;
each R¹²is independently F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl; and
each Y is independently O or S.
In one aspect, provided herein is a compound of Formula V:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein
R¹is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
R⁶is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;
R¹²is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;
each R¹⁴is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^9′, —OCHR^9′C(O)O—R⁸, —OCHR^9′C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′C(O)R⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —OCHR^9′C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^9′, —O—(C₁-C₆alkyl)-S(O)₂R^9′, —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^9′—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′C(O)R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^9′S(O)₂NR⁸R⁹, —NR^9′S(O)₂NR⁸R¹⁰, —S(O)R^9′, —S(O)₂R^9′, or —S(O)₂NR⁸R⁹;
each n is independently an integer from 1 to 4;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;
each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; and
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹,
wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
In some embodiments, provided herein is a compound according to any of Formulas V, V′, I″, II″, or Va as described herein, or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In one aspect, provided herein is a compound of Formula Va:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein
R¹is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
R⁶is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;
R¹²is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;
each R¹⁴is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^9′, —OCHR^9′C(O)O—R⁸, —OCHR^9′C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′C(O)R⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —OCHR^9′C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^9′, —O—(C₁-C₆alkyl)-S(O)₂R^9′, —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂R^9′, —O—(C₁-C₆alkylene)-S(O)₂R^9′—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′C(O)R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^9′S(O)₂NR⁸R⁹, —NR^9′S(O)₂NR⁸R¹⁰, —S(O)R^9′, —S(O)₂R^9′, or —S(O)₂NR⁸R⁹;
each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;
each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;
each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; and
each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹,
wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
In certain embodiments according to Formula V, V′, I″, II″, or Va, each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl, arylalkyl, or heteroarylalkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is C_1-6alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 2-cyclopropylethyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 3,3-dimethylbutyl. In further embodiments, R¹has one of the following structures:
In certain embodiments according to Formula V or Va, R⁶is H, halo, —OR⁸, —NR⁸R⁹, —C(O)R⁸, alkyl, arylakyl, aryl, or heteroaryl. In other embodiments according to Formula V or Va, R⁶is hydrogen or halogen. In some embodiments according to Formula V or Va, R⁶is H, I, Cl, F, methyl, isobutyl, t-butyl, phenyl or benzyl. In certain embodiments according to Formula IV or IVa, R⁶is (S)-tert-butyl. In other embodiments according to Formula V or Va, R⁶is F. In certain embodiments according to Formula V or Va, R⁶is heteroaryl. In further embodiments, R⁶is heteroaryl having one of the following structures:
In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹²is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹²is C_1-6alkoxy. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹²is methoxy. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹²is ethoxy. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹²is OH. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹²is NH₂. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹²is —CH2-cyclopropyl, isopropyl, —CH₂CH₂CH₂—C(O)NHCH₃, —CH₂CH₂CH₂—C(O)NH₂, or —CH₂CH₂OCH₃.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹⁴is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl where R⁸, R⁹and R¹⁰are as defined herein. In other embodiments according to Formula V, V′, I″, II″, or Va, R¹⁴is hydrogen. In some embodiments according to Formula V, V′, I″, II″, or Va, R¹⁴is —NR¹⁰SO₂R⁸where R⁸is methyl and R¹⁰is H or alkyl such as methyl or ethyl. In some embodiments according to Formula V, V′, I″, II″, or Va, R¹⁴is OCH₂C(O)NR⁸R⁹where each of R⁸and R⁹is independently H or alkyl.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁸is C_1-6alkyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, or C_1-6alkyl-C_3-7cycloalkylene, each optionally substituted as described herein. In certain embodiments, R⁸is C_1-6alkyl, optionally substituted as described herein. In certain embodiments, R⁸is C_3-7cycloalkyl, optionally substituted as described herein. In certain embodiments, R⁸is cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R⁸is C_6-14aryl, optionally substituted as described herein. In certain embodiments, R⁸is heteroaryl, optionally substituted as described herein. In certain embodiments, R⁸is heterocyclyl, optionally substituted as described herein.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁸is C_1-6alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁸is methyl.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁹is hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁸and R⁹together with the N atom to which they are attached form heterocyclyl.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl; R⁶is H, alkyl or halogen; R¹²is —OR⁸; R¹⁴is H or —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl; R⁶is halogen; R¹²is —OR⁸; R¹⁴is H or —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl; R⁶is F; R¹²is —OR⁸; R¹⁴is H or —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl; R⁶is F; R¹²is —OR⁸; R¹⁴is H or —NHSO₂Me; and R⁸is H, methyl or ethyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is C_1-6alkyl; R⁶is C_1-6alkyl; R¹²is —OR⁸; R¹⁴is —NHSO₂R⁸; and each R⁸is independently methyl or ethyl. In certain embodiments according to this paragraph, each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 2-cyclopropylethyl; R⁶is H, alkyl or halogen; R¹²is —OR⁸; R¹⁴is H or —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 2-cyclopropylethyl; R⁶is halogen; R¹²is —OR⁸; R¹⁴is H or —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 2-cyclopropylethyl; R⁶is F; R¹²is —OR⁸; R¹⁴is H or —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 2-cyclopropylethyl; R⁶is F; R¹²is —OR⁸; R¹⁴is H or —NHSO₂Me; and R⁸is H, methyl or ethyl. In certain embodiments according to this paragraph, each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl; R⁶is H, alkyl or halogen; R¹²is —OR⁸; R¹⁴is H; and R⁸is H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl; R⁶is halogen; R¹²is —OR⁸; R¹⁴is H; and R⁸is H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl; R⁶is F; R¹²is —OR⁸; R¹⁴is H; and R⁸is H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is alkyl; R⁶is F; R¹²is —OR⁸; R¹⁴is H; and R⁸is H, methyl or ethyl. In certain embodiments according to this paragraph, each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 3,3-dimethylbutyl; R⁶is H, alkyl or halogen; R¹²is —OR⁸; R¹⁴is —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 3,3-dimethylbutyl; R⁶is halogen; R¹²is —OR⁸; R¹⁴is —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 3,3-dimethylbutyl; R⁶is F; R¹²is —OR⁸; R¹⁴is —NHSO₂R⁸; and each R⁸is independently H or alkyl. In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹is 3,3-dimethylbutyl; R⁶is F; R¹²is —OR⁸; R¹⁴is —NHSO₂Me; and R⁸is H, methyl or ethyl. In certain embodiments according to this paragraph, each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
In certain embodiments, provided herein are the following compounds according to formulae V-1 to V-4:
The compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified. Where the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers. Where structural isomers are interconvertible via a low energy barrier, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of an enantiomeric pair, a racemic mixture, or a diastereomeric mixture. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
When the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of Pharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).
Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-ammo-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.
Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.
The compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula V, V′, I″, II″, or Va and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in “Design of Biopharmaceutical Properties through Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drug in Drug Design, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asgharncjad in “Transport Processes in Pharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Methods of Synthesis

The compound provided herein can be prepared, isolated, or obtained by any method known to one of skill in the art. For an example, a compound of Formula V can be prepared as shown in Scheme 1.
In certain embodiments, substituted aldehyde 1A can be reacted with substituted hydrazine hydrochloride in the presence of, for example, diethyl ether and triethylamine to form compound 1B. Compound 1B can be coupled with ethyl acetate in the presence of, for example, pyridine, to form compound 1C. Compound 1C can be reacted with, for example, acetic acid, tetrahydrofuran, and sodium cyanohydridoborate to form compound 1D. Compound 1D can be coupled with cyanoacetic acid in the presence of, for example, a coupling agent, to form compound 1E. Compound 1E can be cyclized by potassium tert-butoxide in the presence of tert-butanol to form cyclic compound 1F. Cyclic compound 1F can be coupled with compound 1J in the presence of, for example, trimethylaluminum (AlMe₃), dioxane, and dimethylacetamide (DMA) at 160° C., to form compound 1G. The ethyl group can be removed from the phosphadiazine group of compound 1G to yield hydroxyphosphadiazine compound 1H. Hydroxyphosphadiazine compound 1H can be coupled with a variety R_Dcompounds to form further phosphadiazine derivatives 1I, such as aminophosphadiazine compounds. Protecting groups can be used where suitable according to the judgment of one of skill in the art.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a compound provided herein as an active ingredient, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof; in combination with one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical composition comprises at least one release controlling excipient or carrier. In certain embodiments, the pharmaceutical composition comprises at least one nonrelease controlling excipient or carrier. In certain embodiments, the pharmaceutical composition comprises at least one release controlling and at least one nonrelease controlling excipients or carriers.
The compound provided herein may be administered alone, or in combination with one or more other compounds provided herein, one or more other active ingredients. The pharmaceutical compositions that comprise a compound provided herein may be formulated in various dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2003; Vol. 126).
In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers.
In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers.
In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers.
The pharmaceutical compositions provided herein may be provided in unit-dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.
The pharmaceutical compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein may be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also include buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co. of Boston, Mass.); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc. Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
The pharmaceutical compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
The tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
The pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
The pharmaceutical compositions provided herein for oral administration may be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
The pharmaceutical compositions provided herein may be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
Coloring and flavoring agents can be used in all of the above dosage forms.
The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
The pharmaceutical compositions provided herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action, such as drotrecogin-, and hydrocortisone.

B. Parenteral Administration

The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
The pharmaceutical compositions provided herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).
The pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.
Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).
The pharmaceutical compositions provided herein may be formulated for single or multiple dosage administration. The single dosage formulations are packaged in an ampoule, a vial, or a syringe. The multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
In one embodiment, the pharmaceutical compositions are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
The pharmaceutical compositions may be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
Suitable inner matrixes include polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein may be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
The pharmaceutical compositions provided herein may be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, dermal patches. The topical formulation of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
The pharmaceutical compositions may also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, Oreg.).
The pharmaceutical compositions provided herein may be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including such as lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient but generally require addition of antioxidants and preservatives.
Suitable cream base can be oil-in-water or water-in-oil. Cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
The pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of the various vehicles may be used. Rectal and vaginal suppositories may be prepared by the compressed method or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
The pharmaceutical compositions provided herein may be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
The pharmaceutical compositions provided herein may be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions may also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.
Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein, a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
The pharmaceutical compositions provided herein may be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes may be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration may further comprise a suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.
The pharmaceutical compositions provided herein for topical administration may be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein may be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
Examples of modified release include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified release dosage form may be fabricated using a matrix controlled release device known to those skilled in the art (see, Takada et al in “Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).
In one embodiment, the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water-swellable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.
In further embodiments, the pharmaceutical compositions are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device included, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, and; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate, and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
The pharmaceutical compositions provided herein in a modified release dosage form may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified release dosage form may be fabricated using an osmotic controlled release device, including one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) the core which contains the active ingredient(s); and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels,” including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol, organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.
Osmotic agents of different dissolution rates may be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM™ EZ (SPI Pharma, Lewes, Del.) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
The core may also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
Semipermeable membrane may also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
The delivery port(s) on the semipermeable membrane may be formed post-coating by mechanical or laser drilling. Delivery port(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports may be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
The pharmaceutical compositions in an osmotic controlled-release dosage form may further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).
In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified release dosage form may be fabricated a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm in diameter. Such multiparticulates may be made by the processes know to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.
Other excipients or carriers as described herein may be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting particles may themselves constitute the multiparticulate device or may be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

Provided herein are methods for treating or preventing a hepatitis C viral infection in a subject, which comprises administering to a subject a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.
Additionally, provided herein is a method for inhibiting replication of a virus in a host, which comprises contacting the host with a therapeutically effective amount of the compound of Formula V, V′, I″, II″, or Va, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one embodiment, the host is a cell. In another embodiment, the host is a human cell. In yet another embodiment, the host is a mammal. In still another embodiment, the host is human.
In certain embodiments, administration of a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, results in a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more reduction in the replication of the virus relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after the administration by a method known in the art, e.g., determination of viral titer.
In certain embodiments, administration of a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, results in a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of the virus relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after the administration by a method known in the art.
In certain embodiments, administration of a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, results in a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more reduction in the viral titer relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after the administration by a method known in the art.
In certain embodiments, administration of a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, results in a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 or more fold reduction in the viral titer relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after the administration by a method known in the art.
Further provided herein is a method for inhibiting the replication of an HCV virus, which comprises contacting the virus with a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In certain embodiments, the contacting of the virus with a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, results in a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more reduction in the virus titer relative to the virus without such contact, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after the initial contact, by a method known in the art.
In certain embodiments, the contacting of the virus with a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, results in a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the virus titer relative to the virus without such contact, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after the initial contact, by a method known in the art.
In certain embodiments, the contacting of the virus with a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, results in a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more reduction in the viral titer relative to the virus without such contact, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after the initial contact by a method known in the art.
In certain embodiments, the contacting of the virus with a therapeutically effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, results in a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 or more fold reduction in the viral titer relative to the virus without such contact, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after the initial contact, by a method known in the art.
Also provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection, comprising administering to a subject a therapeutically effective amount of the compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Non-limiting examples of diseases associated with HCV infection include chronic hepatitis, cirrhosis, hepatocarcinoma, or extra hepatic manifestation.
Provided herein is a method for inhibiting the activity of a polymerase, which comprises contacting the polymerase with an effective amount of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one embodiment, the polymerase is hepatitis C NS5B polymerase.
Depending on the condition, disorder, or disease, to be treated and the subject's condition, a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration, and may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
The dose may be in the form of one, two, three, four, five, six, or more sub-doses that are administered at appropriate intervals per day. The dose or sub-doses can be administered in the form of dosage units containing from about 0.1 to about 1000 milligram, from about 0.1 to about 500 milligrams, or from 0.5 about to about 100 milligram active ingredient(s) per dosage unit, and if the condition of the patient requires, the dose can, by way of alternative, be administered as a continuous infusion.
In certain embodiments, an appropriate dosage level is about 0.01 to about 100 mg per kg patient body weight per day (mg/kg per day), about 0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, or about 0.05 to about 10 mg/kg per day, which may be administered in single or multiple doses. A suitable dosage level may be about 0.01 to about 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about 0.1 to about 10 mg/kg per day. Within this range the dosage may be about 0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg per day.

Combination Therapy

The compounds provided herein may also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of an HCV infection.
As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.
As used herein, the term “synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to treat, prevent, or manage a disease or disorder, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention or treatment of a disorder). In addition, a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.
The compound provided herein can be administered in combination or alternation with another therapeutic agent, such as an anti-HCV agent. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially. The dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
It has been recognized that drug-resistant variants of HCV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs due to the mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against the viral infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution or other parameters of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
In certain embodiments, the compound provided herein is combined with one or more agents selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a nucleoside analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.
In certain embodiments, the compound provided herein is combined with a HCV protease inhibitor, including, but not limited to, Medivir HCV protease inhibitor (Medivir/Tobotec); ITMN-191 (InterMune), SCH 503034 (Schering), VX950 (Vertex); substrate-based NS3 protease inhibitors as disclosed in WO 98/22496; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; DE 19914474; WO 98/17679; WO 99/07734; non-substrate-based NS3 protease inhibitors, such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo et al., Biochem. Biophys. Res. Commun. 1997, 238, 643-647), RD3-4082, RD3-4078, SCH 68631, and a phenanthrenequinone (Chu et al., Tetrahedron Letters 1996, 37, 7229-7232); SCH 351633 (Chu et al., Bioorganic and Medicinal Chemistry Letters 1999, 9, 1949-1952); Eglin c, a potent polymerase inhibitor (Qasim et al., Biochemistry 1997, 36, 1598-1607).
Other suitable protease inhibitors for the treatment of HCV include those disclosed in, for example, U.S. Pat. No. 6,004,933, which discloses a class of cysteine protease inhibitors of HCV endopeptidase 2.
Additional hepatitis C virus NS3 protease inhibitors include those disclosed in, for example, Llinàs-Brunet et al., Bioorg. Med. Chem. Lett. 1998, 8, 1713-1718; Steinkühler et al., Biochemistry 1998, 37, 8899-8905; U.S. Pat. Nos. 5,538,865; 5,990,276; 6,143,715; 6,265,380; 6,323,180; 6,329,379; 6,410,531; 6,420,380; 6,534,523; 6,642,204; 6,653,295; 6,727,366; 6,838,475; 6,846,802; 6,867,185; 6,869,964; 6,872,805; 6,878,722; 6,908,901; 6,911,428; 6,995,174; 7,012,066; 7,041,698; 7,091,184; 7,169,760; 7,176,208; 7,208,600; U.S. Pat. App. Pub. Nos.: 2002/0016294, 2002/0016442; 2002/0037998; 2002/0032175; 2004/0229777; 2005/0090450; 2005/0153877; 2005/176648; 2006/0046956; 2007/0021330; 2007/0021351; 2007/0049536; 2007/0054842; 2007/0060510; 2007/0060565; 2007/0072809; 2007/0078081; 2007/0078122; 2007/0093414; 2007/0093430; 2007/0099825; 2007/0099929; 2007/0105781; WO 98/17679; WO 98/22496; WO 99/07734; WO 00/059929; WO 00/09543; WO 02/060926; WO 02/08187; WO 02/008251; WO 02/008256; WO 02/08198; WO 02/48116; WO 02/48157; WO 02/48172; WO 03/053349; WO 03/064416; WO 03/064456; WO 03/099274; WO 03/099316; WO 2004/032827; WO 2004/043339; WO 2005/037214; WO 2005/037860; WO 2006/000085; WO 2006/119061; WO 2006/122188; WO 2007/001406; WO 2007/014925; WO 2007/014926; and WO 2007/056120.
Other protease inhibitors include thiazolidine derivatives, such as RD-1-6250, RD4 6205, and RD4 6193, which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo et al., Antiviral Research 1996, 32, 9-18); thiazolidines and benzanilides identified in Kakiuchi et al., FEBS Lett. 1998, 421, 217-220; Takeshita et al., Analytical Biochemistry 1997, 247, 242-246.
Suitable helicase inhibitors include, but are not limited to, those disclosed in U.S. Pat. No. 5,633,358; and WO 97/36554.
Suitable nucleotide polymerase inhibitors include, but are not limited to, gliotoxin (Ferrari et al., Journal of Virology 1999, 73, 1649-1654), and the natural product cerulenin (Lohmann et al., Virology 1998, 249, 108-118).
Suitable interfering RNA (iRNA) based antivirals include, but are not limited to, short interfering RNA (siRNA) based antivirals, such as Sirna-034 and those described in WO/03/070750, WO 2005/012525, and U.S. Pat. Pub. No. 2004/0209831.
Suitable antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5′ non-coding region (NCR) of HCV virus include, but are not limited to those described in Alt et al., Hepatology 1995, 22, 707-717, and nucleotides 326-348 comprising the 3′ end of the NCR and nucleotides 371-388 located in the core coding region of HCV RNA (Alt et al., Archives of Virology 1997, 142, 589-599; Galderisi et al., Journal of Cellular Physiology 1999, 181, 251-257);
Suitable inhibitors of IRES-dependent translation include, but are not limited to, those described in Japanese Pat. Pub. Nos.: JP 08268890 and JP 10101591.
Suitable ribozymes include those disclosed in, for example, U.S. Pat. Nos. 6,043,077; 5,869,253 and 5,610,054.
Suitable nucleoside analogs include, but are not limited to, the compounds described in U.S. Pat. Nos. 6,660,721; 6,777,395; 6,784,166; 6,846,810; 6,927,291; 7,094,770; 7,105,499; 7,125,855; and 7,202,224; U.S. Pat. Pub. Nos. 2004/0121980; 2005/0009737; 2005/0038240; and 2006/0040890; WO 99/43691; WO 01/32153; WO 01/60315; WO 01/79246; WO 01/90121, WO 01/92282, WO 02/18404; WO 02/32920, WO 02/48165, WO 02/057425; WO 02/057287; WO 2004/002422, WO 2004/002999, and WO 2004/003000.
Other miscellaneous compounds that can be used as second agents include, for example, 1-amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134), alkyl lipids (U.S. Pat. No. 5,922,757), vitamin E and other antioxidants (U.S. Pat. No. 5,922,757), squalene, amantadine, bile acids (U.S. Pat. No. 5,846,964), N-(phosphonacetyl)-L-aspartic acid (U.S. Pat. No. 5,830,905), benzenedicarboxamides (U.S. Pat. No. 5,633,388), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546), 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687), benzimidazoles (U.S. Pat. No. 5,891,874), plant extracts (U.S. Pat. Nos. 5,725,859; 5,837,257; and 6,056,961), and piperidines (U.S. Pat. No. 5,830,905).
In certain embodiments, one or more compounds provided herein are administered in combination or alternation with an anti-hepatitis C virus interferon, including, but not limited to, INTRON® A (interferon alfa-2b) and PEGASYS® (Peginterferon alfa-2a); ROFERON® A (recombinant interferon alfa-2a), INFERGEN® (interferon alfacon-1), and PEG-INTRON® (pegylated interferon alfa-2b). In one embodiment, the anti-hepatitis C virus interferon is INFERGEN®, IL-29 (PEG-Interferon lambda), R7025 (Maxy-alpha), BELEROFON®, oral interferon alpha, BLX-883 (LOCTERON®), omega interferon, MULTIFERON®, medusa interferon, ALBUFERON®, or REBIF®.
In certain embodiments, one or more compounds provided herein are administered in combination or alternation with an anti-hepatitis C virus polymerase inhibitor, such as ribavirin, viramidine, NM 283 (valopicitabine), PSI-6130, R1626, HCV-796, or R7128.
In certain embodiments, the one or more compounds provided herein are administered in combination with ribavirin and an anti-hepatitis C virus interferon, such as INTRON® A (interferon alfa-2b), PEGASYS® (Peginterferon alfa-2a), ROFERON® A (recombinant interferon alfa-2a), INFERGEN® (interferon alfacon-1), and PEG-INTRON® (pegylated interferon alfa-2b),
In certain embodiments, one or more compounds provided herein are administered in combination or alternation with an anti-hepatitis C virus protease inhibitor, such as ITMN-191, SCH 503034, VX950 (telaprevir), or Medivir HCV protease inhibitor.
In certain embodiments, one or more compounds provided herein are administered in combination or alternation with an anti-hepatitis C virus vaccine, including, but not limited to, TG4040, PEVIPRO™, CGI-5005, HCV/MF59, GV1001, IC41, and INNO0101 (E1).
In certain embodiments, one or more compounds provided herein are administered in combination or alternation with an anti-hepatitis C virus monoclonal antibody, such as AB68 or XTL-6865 (formerly HepX-C); or an anti-hepatitis C virus polyclonal antibody, such as cicavir.
In certain embodiments, one or more compounds provided herein are administered in combination or alternation with an anti-hepatitis C virus immunomodulator, such as ZADAXIN® (thymalfasin), NOV-205, or oglufanide.
In certain embodiments, one or more compounds provided herein are administered in combination or alternation with NEXAVAR®, doxorubicin, PI-88, amantadine, JBK-122, VGX-410C, MS-3253 (celgosivir), SUVUS® (BIVN-401 or virostat), PF-03491390 (formerly IDN-6556), G126270, UT-231B, DEBIO-025, EMZ702, ACH-0137171, MitoQ, ANA975, AVI-4065, bavituximab (tarvacin), ALINIA® (nitrazoxanide) or PYN17.
In certain embodiments, the compounds provided herein can be combined with one or more steroidal drugs known in the art, including, but not limited to the group including, aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone.
In certain embodiments, the compounds provided herein can be combined with one or more antibacterial agents known in the art, including, but not limited to the group including amikacin, amoxicillin, ampicillin, arsphenamine, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimycin, imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin, piperacillin, platensimycin, polymyxin B, prontocil, pyrazinamide, quinupristine, rifampin, roxithromycin, spectinomycin, streptomycin, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, tetracycline, ticarcillin, tobramycin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin.
In certain embodiments, the compounds provided herein can be combined with one or more antifungal agents known in the art, including, but not limited to the group including amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, and voriconazole.
In certain embodiments, the compounds provided herein can be combined with one or more anticoagulants known in the art, including, but not limited to the group including acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximelagatran.
In certain embodiments, the compounds provided herein can be combined with one or more thrombolytics known in the art, including, but not limited to the group including anistreplase, reteplase, t-PA (alteplase activase), streptokinase, tenecteplase, and urokinase.
In certain embodiments, the compounds provided herein can be combined with one or more non-steroidal anti-inflammatory agents known in the art, including, but not limited to, aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin.
In certain embodiments, the compounds provided herein can be combined with one or more antiplatelet agents known in the art, including, but not limited to, abeiximab, cilostazol, clopidogrel, dipyridamole, ticlopidine, and tirofibin.
The compounds provided herein can also be administered in combination with other classes of compounds, including, but not limited to, endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abeiximab, eptifibatide, and tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor VIa Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, atavastatin, or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-adrenergic agents; beta-adrenergic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, and vardenafil); protein tyrosine kinase inhibitors; antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antimetabolites, such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as pacitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathioprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin.
In certain embodiments, the pharmaceutical compositions provided herein further comprise a second antiviral agent as described herein. In one embodiment, the second antiviral is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a nucleoside analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme. In another embodiment, the second antiviral agent is an interferon. In yet another embodiment, the t interferon is selected from the group consisting of pegylated interferon alpha 2a, interferon alphcon-1, natural interferon, ALBUFERON®, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma-1b.
The compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
Provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.
Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
The disclosure will be further understood by the following non-limiting examples.

EXAMPLES

As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); hr (hours); min (minutes); TLC (thin layer chromatography); HPLC (high performance liquid chromatography); SCX (strong cation exchange); MS (mass spectrometry); ESI (electrospray ionization); R_t(retention time); SiO₂(silica); THF (tetrahydrofuran); CD₃OD (deuterated methanol); CDCl₃(deuterated chloroform); DCE (dichloroethane); DCM (dichloromethane); DMF (dimethyformamide); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); CHCl₃(chloroform); DMF (N,N-dimethylformamide); DMA (N,N-dimethyacetamide); MeOH (methanol); EtOH (ethanol); HCl (hydrochloric acid); LiOH (lithium hydroxide); NaOH (sodium hydroxide); KOH (potassium hydroxide); Cs₂CO₃(cesium carbonate); DIPEA (N,N-diisopropylethylamine); TEA (trietlylamine); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene; CDI (carbonyldiimidazole); TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate); Ac (acetyl); Me (methyl); Et (ethyl); tBu (tert-butyl); Boc (tert-butoxylcarbony); Bn (benzyl); and Ts (tosylate).
For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated in Schemes 4 to 6 are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.

Intermediate 24

(2-amino-5-nitro-phenyl)-phosphonic acid diethyl ester

2-iodo-4-nitro aniline (7.57 mmol), triethyl phosphite (15.1 mmol) and palladium acetate (1.51 mmol) were mixed together in acetonitrile (36 ml), in a microwave tube. The vessel was sealed and placed in a microwave to react at 160° C., for 30 min. After cooling to room temperature, acetonitrile was removed. The residue obtained was diluted in ethyl acetate, washed with hydrochloric solution (1N) and phosphate buffer solution (pH 7). The solvent was removed and the crude material was purified by silica gel chromatography to yield intermediate 24, which was a brown solid. Intermediate 24 was characterized by the following spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm) 1.21 (t, J=7.1 Hz, 6H), 3.92 (m, 4H), 5.13 (s, NH₂), 6.50 (t, J=7.8 Hz, 1H), 6.61 (m, 2H); ³¹P NMR (DMSO-d₆, 162 MHz) δ (ppm) 21.68 (s, 1P); and MS (ESI, EI⁺) m/z=275 (MH⁺).

Intermediate 25

(2,5-diaminophenyl)-phosphonic acid diethyl ester

Intermediate 24 (3.65 mmol) was dissolved in methanol (5 ml) Pd/C was added under nitrogen. After several cycles vacuum/nitrogen, hydrogen was introduced at atmospheric pressure. The reaction mixture was stirred at room temperature, under hydrogen, overnight. The reaction mixture was then filtered through celite and concentrated to yield intermediate 25, which was a brown solid. Intermediate 25 was characterized by the following spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm) 1.20 (t, J=7.05 Hz, 6H), 3.87-4.00 (m, 4H), 4.45 (s, NH₂), 5.15 (s, NH₂), 6.50 (t, J=8 Hz, 1H), 6.58-6.60 (m, 2H); ¹P NMR (DMSO-d₆, 162 MHz) δ (ppm) 21.46 (s, 1P); and MS (ESI, EI⁺) m/z=245 (MH⁺).

Intermediate 26

(2-amino-5-methanesulfonaminylphenyl)-phosphonic acid diethyl ester

To a stirred solution of the intermediate 25 (3.52 mmol), triethylamine (4.22 mmol) in dichloromethane (7 ml) at 0° C. was added methane sulfonyl chloride (4.22 mmol) under nitrogen. The reaction mixture was stirred at room temperature, over night. The mixture was then quenched with phosphate buffer solution (pH 7). The organic layer was separated, concentrated and the crude material was purified by silica gel chromatography (dichloromethane/methanol) to yield intermediate 26, which was a beige solid. Intermediate 26 was characterized by the following spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm) 1.34 (t, J=7.07 Hz, 6H), 2.94 (s, 3H), 4.04-4.22 (m, 4H), 5.14 (s, NH₂), 6.57 (s, NH), 6.66 (t, J=7.26, 1H), 7.29 (d, J=8.79 Hz, 1H), 7.39 (d, J=14.9 Hz, 1H); ³¹P NMR (DMSO-d₆, 162 MHz) δ (ppm) 19.44 (s, 1P); and MS (ESI, EI⁺) m/z=323 (MH⁺).

Intermediate 108

N-tert-butyl-N′-(3,3-dimethyl-butylidene)-hydrazine

To the tert-butylhydrazine hydrochloride (24 mmol, Fluka) were added diethyl ether (35 ml) and triethylamine (24 mmol). After 5 minutes of stirring, 3,3-dimethylbutyraldehyde (24 mmol) and anhydrous magnesium sulfate (26.4 mmol) were added and this mixture was stirred at room temperature for 2 days. The salt was filtered on a pad of celite and rinced with ethyl acetate and the solvent was evaporated to give intermediate 108, which was a yellow pale oil. Intermediate 108 was characterized by the following spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.96 (s, 9H), 1.01 (s, 3H), 1.20 (s, 3H), 1.21 (s, 9H), 1.94 (d, J=5.24 Hz, 0.67H), 2.1 (d, J=6.10 Hz, 2H), 6.63 (t, J=5.24 Hz, 0.33H), 7.24 (t, J=6.10 Hz, 1H) (mixture of isomers).

Intermediate 109

N-tert-butyl-N′-(3,3-dimethyl-butylidene)-hydrazinecarboxylic acid ethyl ester

The intermediate 108 (24 mmol) was dissolved in ethyl acetate (36 ml) (previously dried over MgSO₄) and the pyridine (33.6 mmol) was added. Then, the mixture was cooled down to 0° C. and ethyl chloroformate (33.6 mmol) was added. This mixture was stirred at 30° C. overnight. Then, the salts were filtered on autocup, rinced with ethyl acetate and the solvent was evaporated to give an orange oil. This oil was purified by chromatography to give intermediate 109. Intermediate 109 was characterized by the following spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 1.03 (s, 9H), 1.24 (t, J=7.12 Hz, 3H), 1.39 (s, 9H), 2.27 (d, J=6.33 Hz, 2H), 4.12 (q, J=7.12 Hz, 2H), 7.74 (t, J=6.33 Hz, 1H).

Intermediate 110

N-tert-butyl-N′-(3,3-dimethyl-butyl)-hydrazinecarboxylic acid ethyl ester

To a solution of intermediate 109 (24 mmol) in tetrahydrofurane (70 ml) were added under nitrogen the sodium cyanoborohydride (60 mmol) and then, acid acetic (120 mmol). This reaction mixture was stirred at room temperature for 40 hours. The reaction was diluted with ethyl acetate and extracted with a saturated solution of NaHCO₃. The aqueous layers were washed with ethyl acetate and the gathered organic layers were dried and concentrated under vacuo to give an oil. This oil was dissolved in methanol (40 ml) and a solution 1N of sodium hydroxide (40.8 mmol) was added at room temperature. This mixture was stirred at room temperature for 4 hours. Then, the methanol was removed by evaporation under vacuo, ethyl acetate was added and this mixture was washed. After concentration, the residue was purified by chromatography to give intermediate 110. Intermediate 110 was characterized by the following spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.91 (s, 9H), 1.26-1.31 (m, 1H), 1.29 (t, J=7.14 Hz, 3H), 1.37 (s, 9H), 1.42-1.46 (m, 1H), 2.77 (brs, 2H), 3.8 (brs, 1H), 4.16 (q, J=7.14 Hz, 2H).

Intermediate 111

N-tert-butyl-N′-(2-cyano-acetyl)-N′-(3,3-dimethyl-butyl)-hydrazinecarboxylic acid ethyl ester

A solution of intermediate 110 (4.1 mmol) and cyanoacetic acid (4.1 mmol) in anhydrous dimethylformamide (18 ml) was treated with dicyclohexylcarbodiimide (4.1 mmol). After stirring at room temperature overnight, the reaction mixture was filtered over celite and the filtrate was poured into water and an extraction was realized with ethyl acetate. After the aqueous layers were extracted with ethyl acetate, the combined organic layers were dried and concentrated under vacuo. The residue was purified by chromatography to give intermediate 111, which was an Oil. Intermediate 111 was characterized by the following spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.93 (s, 9H), 1.3 (t, J=7.12 Hz, 3H), 1.47 (s, 9H), 1.54-1.64 (m, 2H), 3.26-3.34 (m, 1H), 3.5 (s, 2H), 3.70-3.78 (m, 1H), 4.21 (q, J=7.12 Hz, 2H).

Intermediate 112

1-tert-butyl-2-(3,3-dimethyl-butyl)-5-hydroxy-3-oxo-2,3-dihydropyrrole-4-carbonitrile

A solution of intermediate 111 (0.739 mmol) in anhydrous tert butanol (24 ml) was treated with potassium tert-butoxide (1.85 mmol). After stirring 5 minutes at 140° C. and 5 minutes at 150° C., the reaction mixture was quenched with HCl 2N, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo to give intermediate 112, which was a yellow oil. Intermediate 112 was characterized by the following spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.91-0.93 (m, 9H), 1.37-1.42 (m, 1H), 1.47-1.50 (m, 9H), 1.56-1.63 (m, 1H), 3.70-3.77 (m, 2H), 6.98 (brs, 1H).

Example 68

1-tert-butyl-2-(3,3-dimethyl-butyl)-4-(1-ethoxy-1-oxo-1,4-dihydro-7-methanesulfonamyl-1-benzo[1,2,4]phosphadiazin-3-yl)-5-hydroxy-2,3-dihydropyrazol-2-one

Example 68 was synthesized from intermediate 112 and intermediate 26. To a solution of intermediate 112 (0.31 mmol) in dioxane (3 ml) was added intermediate 26 (0.465 mmol). This mixture was treated dropwise with trimethyl aluminium (1.55 mmol) and stirred at 80° C. for 4 hours. Then, the reaction mixture was quenched with HCl 1N, diluted with TBDME or ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo after purification with preparative HPLC to give example 68, which was a white solid. Example 68 was characterized by the following spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) (ppm) 0.92-0.93 (m, 9H), 1.34-1.38 (m, 3H), 1.47-1.48 (m, 9H), 3.05 (s, 3H), 3.58-3.65 (m, 1H), 3.71-3.79 (m, 2H), 4.16-4.24 (m, 2H), 7.19-7.23 (m, 1H), 7.64-7.68 (m, 2H), 11.2 (brs, 0.5H), 11.5 (brs, 0.5H); ³¹P NMR (CDCl₃, 400 MHz) (ppm) 0.42 (s, 1P); and MS (ESI, EI⁺) m/z=542 (MH⁺). Example 68 is equivalent to Compound V-1.

Example 69

1-tert-butyl-2-(3,3-dimethyl-butyl)-4-(1-hydroxy-1-oxo-1,4-dihydro-7-methanesulfonamyl-1-benzo[1,2,4]phosphadiazin-3-yl)-5-hydroxy-2,3-dihydropyrazol-2-one

Example 69 was synthesized from example 68. Example 68 (0.05 mmol) was dissolved in 1,2-dichloroethane (2.5 ml) under nitrogen and tetramethylsilylbromide (0.5 mmol). The mixture was stirred at 60° C. for 2 hours and then concentrated to dryness. The residue was quenched with methanol before new concentration under vacuo. The residue was purified by chromatography (RP18) and lyophilisation to give example 69, which was a white powder. Example 69 was characterized by the following spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) (ppm) 0.85 (s, 9H), 1.26-1.30 (m, 2H), 1.36 (s, 9H), 3 (s, 3H), 3.46-3.51 (m, 2H), 7.39-7.49 (m, 3H), 9.99 (brs, 1H), 10.86 (brs, 0.5H), 11.03 (brs, 0.5H); ³¹P NMR (DMSO-d₆, 400 MHz) (ppm) −13.74 (s, 1P); and MS (ESI, EI⁺) m/z=513.89 (MH⁺). Example 69 is equivalent to Compound V-2.

Example 70

2-(3,3-dimethyl-butyl)-4-(1-hydroxy-1-oxo-1,4-dihydro-7-methanesulfonamyl-1-benzo[1,2,4]phosphadiazin-3-yl)-5-hydroxy-2,3-dihydropyrazol-2-one

Example 70 was a by-product of the reaction realized to obtain example 69, which was a white solid. Example 70 was characterized by the following spectroscopic data: 1H NMR (DMSO-d₆, 400 MHz) (ppm) 0.89 (s, 9H), 1.39-1.43 (m, 2H), 2.93 (s, 3H), 3.33-3.39 (m, 2H), 7.11 (dd, J=5.89 Hz and J=8.58 Hz, 1H), 7.24 (dd, J=2.33 Hz and J=8.63 Hz, 1H), 7.33 (dd, J=1.90 Hz and J=13.49 Hz, 1H), 9.07 (brs, 1H), 9.36 (brs, 1H), 10.61 (s, 1H); ³¹P NMR (DMSO-d₆, 400 MHz) (ppm) −13.80 (s, 1P); and MS (ESI, EI⁺) m/z=457.88 (MH⁺). Example 70 is equivalent to Compound V-3.

Example 71

1-tert-butyl-2-(3,3-dimethyl-butyl)-4-(1-methoxy-1-oxo-1,4-dihydro-7-methanesulfonamyl-1-benzo[1,2,4]phosphadiazin-3-yl)-5-hydroxy-2,3-dihydropyrazol-2-one

Example 71 was synthesized from example 69. To a stirred solution of example 69 (0.042 mmol) in dichloromethane (2 ml) and a few drops of dimethylformamide, oxalyl chloride (0.0063 mmol) was added dropwise, under nitrogen. The reaction mixture was stirred at room temperature, under nitrogen for 24 hours. Methanol was then added and the mixture was stirred for one hour. Solvents were concentrated under reduced pressure and the crude material was purified using preparative HPLC to yield example 71, which was a white solid. Example 71 was characterized by the following spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.92-0.93 (m, 9H), 1.33-1.44 (m, 2H), 1.47-1.48 (m, 9H), 3.06 (s, 3H), 3.58-3.66 (m, 1H), 3.69-3.77 (m, 1H), 3.82 (d, J=12.36 Hz, 3H), 7.18-7.24 (m, 1H), 7.65-7.70 (m, 2H), 8.04 (brs, 1H), 11.22 (brs, 0.5H), 11.55 (brs, 0.5H); ³¹P NMR (CDCl₃, 400 MHz) (ppm) 2.25 (s, 1P); and MS (ESI, EI⁺) m/z=527.92 (MH⁺). Example 71 is equivalent to Compound V-4.

Example 72

HCV Polymerase Assay

The HCV polymerase assay was performed in 96-well streptavidin-coated microtiter plates (Pierce) using 50 nM HCV genotype 1b polymerase (strain J4) from Replizyme, 15 μM bromo-UTP, 1 μg/ml 5′-biotynilated oligo (rU12), 1 μg/ml poly(rA) in 20 mM Tris-HCl pH 7.5, 5 mM MgCl₂, 0.5 μg/ml BSA, 1 mM DTT, 0.02 U/μl RNasin, 5% DMSO and 25 mM KCL. The 60-μl reaction was incubated at 35° for 60 min and terminated by adding 20 μL 0.5 M EDTA pH 8.0. The BrUTP incorporated onto the biotinylated primer was quantified by ELISA using a peroxidase-labeled anti-BrdU monoclonal antibody (Roche) and TMB (Sigma) substrate and the plates were read at 630 nm with the Tecan Sunrise Stectrophotometer. The compounds were routinely solubilised at a concentration of 15 mM in DMSO and tested at a variety of concentrations in assay buffer containing a final DMSO concentration of 5%. The IC₅₀values were determined from the percent inhibition versus concentration data using a sigmoidal non-linear regression analysis based on four parameters with Tecan Magellan software.
The biological results are summarized in Table 1 (IC₅₀), wherein A represents a value smaller than 100 nM, B represents a value between 100 nM to 10 μM, and C represents a value greater than 10 μM.

Example 73

HCV Replicon Assay

General procedure: Huh-7 cells containing HCV Con1 subgenomic replicon (GS4.1 cells) were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 110 mg/L sodium pyruvate, 1× non-essential amino acids, 100 U/mL penicillin-streptomycin, and 0.5 mg/mL G418 (Invitrogen). For dose-response testing, the cells were seeded in 96-well plates at 7.5×10³cells/well in a volume of 50 μL, and incubated at 37° C./5% CO₂. Three hours after plating, 50 μL of ten 2-fold serial dilutions of compounds (highest concentration, 75 μM) were added, and cell cultures were incubated at 37° C./5% CO₂in the presence of 0.5% DMSO. Alternatively, compounds were tested at a single concentration of 15 μM. In all cases, Huh-7 cells lacking the HCV replicon served as negative control. The cells were incubated in the presence of compounds for 72 hr after which they were monitored for expression of the NS4A protein by enzyme-linked immunosorbent assay (ELISA). For this, the plates were then fixed for 1 min with acetone/methanol (1:1, v/v), washed twice with phosphate-buffered saline (PBS), 0.1% Tween 20, blocked for 1 hr at room temperature with TNE buffer containing 10% FBS and then incubated for 2 hr at 37° C. with the anti-NS4A mouse monoclonal antibody A-236 (ViroGen) diluted in the same buffer. After washing three times with PBS, 0.1% Tween 20, the cells were incubated 1 hr at 37° C. with anti-mouse immunoglobulin G-peroxidase conjugate in TNE, 10% FBS. After washing as described above, the reaction was developed with O-phenylenediamine (Zymed). The reaction was stopped after 30 min with 2 N H₂SO₄, and absorbance was read at 492 nm using Sunrise Tecan spectrophotometer. EC₅₀values were determined from the % inhibition versus concentration data using a sigmoidal non-linear regression analysis based on four parameters with Tecan Magellan software. When screening at a single concentration, the results were expressed as % inhibition at 15 μM.
The biological results are summarized in Table 1 (EC₅₀and CC₅₀), wherein A represents a value smaller than 100 nM, B represents a value between 100 nM to 10 μM, and C represents a value greater than 10 μM.

TABLE 1

	IC50	EC50	CC50
Compound	(μM)	(μM)	(μM)

(V-2)	A	B	C

(V-3)	B	C	C

(V-4)	A	B	C

The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

1. A compound of Formula V′:

or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

R¹is H, alkyl, arylalkyl, heteroarylalkyl, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

R⁴is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;

R^4′ is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;

R⁵is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴and R⁵together form a part of a 3-8 membered heterocycloalkyl ring;

R^5′ is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, heteroaryl, —NR⁸R¹⁰, alkenyl, or alkynl;

R^6′ is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R^5′ and R^6′ together form a part of a 3-8 membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring;

R¹²is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;

each R⁸is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, heterocyclyl, C_1-6alkyl-C_3-7cycloalkylene, or C_1-10alkyl-siloxyl;

each R⁹is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹together with the N atom to which they are attached form heterocyclyl;

each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹;

Y is O or S; and

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.

2. The compound of claim 1, wherein each pair of R^5′ and R^6′ together independently forms a part of a 3-8 membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring.

3. The compound of claim 1, wherein the compound of Formula V′ has the following formula I^″ or II″:

wherein

each A is independently CR¹⁸or N;

each A′ is independently CR¹⁵R¹⁶, NR¹⁷, N, CR¹⁵, N-oxide, N—OR⁸—, S or O;

each of R¹⁵is independently a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹⁶is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkyl)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkyl)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkyl)-NR^9′S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹⁷is a bond, H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;

R¹⁸is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R¹⁰, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;

each R¹⁴is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^9′, —OCHR^9′C(O)O—R⁸, —OCHR^9′C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′C(O)R⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —OCHR^9′C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^9′, —O—(C₁-C₆alkyl)-S(O)₂R^9′, —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^9′S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^9′—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′C(O)R⁸, —(C₁-C₆alkylene)-NR^9′S(O)₂R⁸, —(C₁-C₆alkylene)-NR^9′C(O)OR⁸, —(C₁-C₆alkylene)-NR^9′C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^9′S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^9′S(O)₂NR⁸R⁹, —NR^9′S(O)₂NR⁸R¹⁰, —S(O)R^9′, —S(O)₂R^9′, or —S(O)₂NR⁸R⁹;

n is independently an integer from 1 to 4;

m is independently an integer from 1 to 3;

R¹²is —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl; and

Z has the following structure:

4. A compound of Formula V:

or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

R¹is alkyl, arylalkyl, heteroarylalkyl, H, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

R⁶is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹²is —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;

n is an integer from 1 to 4;

each R^9′ is independently hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_6-14aryl, heteroaryl, or heterocyclyl; and

each R¹⁰is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸or C(O)NR⁸R⁹,

5. The compound of claim 4 according to Formula Va:

or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

6. The compound of claim 4, wherein the compound has the structure of Formula Va.

7. The compound of claim 4, wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.

8. The compound of claim 4, wherein R¹is C_1-6alkyl.

9. The compound of claim 8, wherein R¹is 3,3-dimethylbutyl.

10. The compound of claim 4, wherein R⁶is hydrogen or halogen.

11. The compound of claim 4, wherein R⁶is tert-butyl.

12. The compound of claim 4, wherein R¹²is C_1-6alkoxy.

13. The compound of claim 12, wherein R¹²is methoxy.

14. The compound of claim 12, wherein R¹²is ethoxy.

15. The compound of claim 4, wherein R¹²is NH₂.

16. The compound of claim 4, wherein R¹²is OH.

17. The compound of claim 4, wherein R¹⁴is hydrogen.

18. The compound of claim 4, wherein R¹⁴is —NHSO₂R⁸.

19. The compound of claim 18, wherein R⁸is C_1-6alkyl.

20. The compound of claim 19, wherein R⁸is methyl.

21. The compound of claim 4, wherein R¹is 3,3-dimethylbutyl; R⁶is tert-butyl; R¹²is methoxy, ethoxy, fluoro, NH₂or OH; and R¹⁴is hydrogen or —NHSO₂Me.

22. The compound of claim 4 according to the following formula:

23. The compound of claim 4 according to the following formula:

24. The compound of claim 4 according to the following formula:

25. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers.

26. The pharmaceutical composition of claim 25, further comprising a second antiviral agent.

27. The pharmaceutical composition of claim 26, wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a nucleoside analogue, a liotoxin, acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

28. The pharmaceutical composition of claim 27, wherein the second antiviral agent is an interferon.

29. The pharmaceutical composition of claim 28, wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, interferon alphcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma-1b.

30. The pharmaceutical composition of claim 25, wherein the composition is formulated for single dose administration.

31. The pharmaceutical composition of claim 25, wherein the composition is formulated as an oral, parenteral, or intravenous dosage form.

32. The pharmaceutical composition of claim 31 wherein the oral dosage form is a tablet or capsule.

33. The pharmaceutical composition of claim 25, wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram daily.

34. A method for treating or preventing an HCV infection, which comprises administering the compound of claim 1.

35. A method for treating or preventing an HCV infection, which comprises administering the pharmaceutical composition of claim 25.

36. A method of treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection, comprising administering the compound of claim 1.

37. A method of treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection, comprising administering the pharmaceutical composition of claim 25.

38. The method of claim 34, wherein the method comprises administering a second antiviral agent, in combination or alternation.

39. The method of claim 35, wherein the method comprises administering a second antiviral agent, in combination or alternation.

40. The method of claim 38, wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a nucleoside analogue, a liotoxin, acerulenin, an antisense phosphorothioate ologodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

41. The method of claim 39, wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a nucleoside analogue, a liotoxin, acerulenin, an antisense phosphorothioate ologodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

42. The method of claim 38, wherein the second antiviral agent is an interferon.

43. The method of claim 39, wherein the second antiviral agent is an interferon.

44. The method of claim 42, wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, interferon alphcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma-1b.

45. The method of claim 43, wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, interferon alphcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma-1b.

46. A method for inhibiting replication of a virus in a host, which comprises contacting the host with the compound of claim 1.

47. A method for inhibiting replication of a virus in a host, which comprises contacting the host with the pharmaceutical composition of claim 25.

48. The method of claim 46, wherein the host is a human.

49. The method of claim 47, wherein the host is a human.

50. A method for inhibiting replication of a virus, which comprises contacting the virus with the compound of claim 1.

51. A method for inhibiting replication of a virus, which comprises contacting the virus with the pharmaceutical composition of claim 25.

52. A method for inhibiting the activity of a polymerase, which comprises contacting the polymerase with the compound of claim 1.

53. A method for inhibiting the activity of a polymerase, which comprises contacting the polymerase with the pharmaceutical composition of claim 25.

54. The method of claim 52, wherein the polymerase is an HCV NS5B polymerase.

55. The method of claim 53, wherein the polymerase is an HCV NS5B polymerase.