US20090060867A1 - Phosphadiazine hcv polymerase inhibitors iii and vi - Google Patents

Phosphadiazine hcv polymerase inhibitors iii and vi Download PDF

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US20090060867A1
US20090060867A1 US12/198,901 US19890108A US2009060867A1 US 20090060867 A1 US20090060867 A1 US 20090060867A1 US 19890108 A US19890108 A US 19890108A US 2009060867 A1 US2009060867 A1 US 2009060867A1
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alkylene
alkyl
compound
aryl
independently
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Cyril Dousson
Dominique Surleraux
Jean-Francois Griffon
Claire Pierra
Arlene Roland
Rachid Rahali
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Idenix Pharmaceuticals LLC
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Idenix Pharmaceuticals LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • phosphadiazine polymerase inhibitor compounds 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.
  • Hepatitis C virus is known to cause at least 80% of posttransfiusion 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.
  • 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.
  • C nucleocapsid core protein
  • E1 and E2 envelope glycoproteins
  • 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 remain unknown.
  • phosphadiazine polymerase inhibitor compounds 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.
  • each R 1 is independently H, alkyl, arylalkyl, heteroarylalkyl, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
  • each R 4 is independently H, alkyl, aryl-CH 2 —, —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl,
  • each R 4′ is independently H, alkyl, aryl-CH 2 —, —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;
  • each R 5 is independently H, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or R 4 and R 5 together form a part of a 3-8 membered heterocycloalkyl ring;
  • each R 5′ is independently H, halogen, cyano, nitro, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, heteroaryl, —NR 8 R 10 , alkenyl, or alkynl;
  • each R 6′ is independently H, halogen, cyano, nitro, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , 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;
  • each R 12 is independently F, —OR 8 , —SR 8 , —NR 8 R 9 , alkyl, or aryl;
  • each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, C 1-6 alkyl-C 3-7 cycloalkylene, or C 1-10 alkyl-siloxyl;
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl;
  • each R 10 is independently H, alkyl, aryl, sulfonyl, C(O)R 8 , C(O)OR 8 or C(O)NR 8 R 9 ;
  • each Y is independently O or S
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • each R 1 is independently H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
  • each R 6 is independently H, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, or heteroaryl;
  • each R 14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , C(O)NR 8 R 9 , —OCH 2 C(O)NR 8 R 9 , —C(O)OR 8 , —O—(C 1 -C 6 hydroxyalkyl), —O—(C 1 -C 6 alkoxy), —O—(C 1 -C 6 alkylene)-cyano, —O—(C 1 -C 6 alkylene)-C(O)R 9′ , —OCHR 9′ C(O)O—R 8 , —OCHR 9′ C(O)NHOH, —O—(C 1 -C 6 alkyl)-C(O)NR 8 R 9 , —O—(
  • each n is independently an integer from 1 to 4.
  • n is an integer from 1 to 3;
  • each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, C 1-6 alkyl-C 3-7 cycloalkylene, or C 1-10 alkyl-siloxyl;
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl;
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • compositions comprising a compound disclosed herein, e.g., a compound of Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, 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.
  • a compound disclosed herein e.g., a compound of Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, 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 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 III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, 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.
  • a compound disclosed herein e.g., a compound of Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, 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 III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, 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.
  • a compound disclosed herein e.g., a compound of Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, 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.
  • a compound disclosed herein e.g., a compound of Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, 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.
  • a compound disclosed herein e.g., a compound of Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, or a, or a pharmaceutical composition thereof, for use in inhibiting replication of a virus in a host.
  • a compound disclosed herein e.g., a compound of Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, or a pharmaceutical composition thereof, for manufacture of a medcicament for inhibiting replication of a virus in a host.
  • 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.
  • primate e.g., human
  • cow, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • 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.
  • prevent 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.
  • 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.
  • 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.
  • IC 50 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 “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.
  • 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.
  • active ingredient and active substance may be an optically active isomer of a compound described herein.
  • 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.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical.
  • alkyl also encompasses both linear and branched alkyl, unless otherwise specified.
  • 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.
  • alkylene refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted
  • alkylene encompasses both linear and branched alkylene, unless otherwise specified.
  • 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.
  • 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.
  • linear C 1-6 and branched C 3-6 alkylene groups are also referred as “lower alkylene.”
  • 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).
  • C 2-6 alkylene 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.
  • 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.
  • 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.
  • alkenyl encompasses both linear and branched alkenyl, unless otherwise specified.
  • C 2-6 alkenyl 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 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.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl.
  • 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.
  • the term “alkenylene” also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations.
  • the term “alkenylene” encompasses both linear and branched alkenylene, unless otherwise specified.
  • C 2-6 alkenylene 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 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.
  • alkenylene but are not limited to, ethenylene, propenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.
  • 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.
  • alkynyl also encompasses both linear and branched alkynyl, unless otherwise specified.
  • 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.
  • alkynyl groups include, but are not limited to, ethynyl (—C ⁇ CH) and propargyl (—CH 2 C ⁇ CH).
  • C 2-6 alkynyl 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.
  • 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.
  • alkynylene also encompasses both linear and branched alkynylene, unless otherwise specified.
  • 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.
  • alkynylene groups include, but are not limited to, ethynylene (—C ⁇ C—) and propargylene (—CH 2 C ⁇ C—).
  • C 2-6 alkynyl 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.
  • cycloalkyl refers to a cyclic saturated bridged or non-bridged monovalent hydrocarbon radical, which may be optionally substituted, e.g., as described herein.
  • 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.
  • cycloalkylene refers to a cyclic saturated bridged or non-bridged divalent hydrocarbon radical, which may be optionally substituted, e.g., as described herein.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofaranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.
  • heterocyclyl 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.
  • 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.
  • 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.
  • 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.
  • 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, linolcoyl, arachidonoyl, benzoyl, pyridinylcarbonyl, and furoyl.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • arylaklyl refers to an aryl group appended to an alkyl radical, such as aryl-(CH 2 )—, aryl-CH 2 —CH 2 —, and aryl-CH 2 —CH 2 —CH 2 —.
  • heteroarylalkyl refers to an heteroaryl group appended to an alkyl radical, such as heteroaryl-(CH 2 )—, heteroaryl-CH 2 —CH 2 —, and heteroaryl-CH 2 —CH 2 —CH 2 —.
  • 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.
  • all groups that can be substituted in one embodiment are “optionally substituted,” unless otherwise specified.
  • 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.
  • each R 4 is independently H, alkyl, aryl-CH 2 —, —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl;
  • each R 5′ is independently H, halogen, cyano, nitro, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, heteroaryl, —NR 8 R 10 , alkenyl, or alkynl;
  • each R 6′ is independently H, halogen, cyano, nitro, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , 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;
  • each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, C 1-6 alkyl-C 3-7 cycloalkylene, or C 1-10 alkyl-siloxyl;
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl; and
  • each R 10 is independently H, alkyl, aryl, sulfonyl, C(O)R 8 , C(O)OR 8 or C(O)NR 8 R 9 ,
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • 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:
  • each R 14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , C(O)NR 8 R 9 , —OCH 2 C(O)NR 8 R 9 , —C(O)OR 8 , —O—(C 1 -C 6 hydroxyalkyl), —O—(C 1 -C 6 alkoxy), —O—(C 1 -C 6 alkylene)-cyano, —O—(C 1 -C 6 alkylene)-C(O)R 9′ , —OCHR 9′ C(O)O—R 8 , —OCHR 9′ C(O)NHOH, —O—(C 1 -C 6 alkyl)-C(O)NR 8 R 9 , —O—(
  • each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, C 1-6 alkyl-C 3-7 cycloalkylene, or C 1-10 alkyl-siloxyl;
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl;
  • each R 9′ is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • each R 10 is independently H, alkyl, aryl, sulfonyl, C(O)R 8 , C(O)OR 8 or C(O)NR 8 R 9 ;
  • 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 CR 15 R 16 or NR 17 ;
  • each A′ is independently CR 15 R 16 , NR 17 , N, CR 15 , N-oxide, N—OR 8 —, S or O;
  • each R 15 is independently a bond, H, halogen, —NR 10 SO 2 R 8 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 NR 8 R 9 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 NR 8 R 10 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, or heteroaryl;
  • each R 16 is independengly a bond, H, halogen, —NR 10 SO 2 R 8 , —(C 1 -C 6 alkyl)-NR 9′ S(O) 2 NR 8 R 9 , —(C 1 -C 6 alkyl)-NR 9′ S(O) 2 NR 8 R 10 , —(C 1 -C 6 alkyl)-NR 9′ S(O) 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, or heteroaryl; and
  • each R 17 is independently a bond, H, alkyl, aryl-CH 2 —, —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl,
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • each pair of R 5′ and R 6′ together independently form a benzo ring having formula (A):
  • each R 14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , C(O)NR 8 R 9 , —OCH 2 C(O)NR 8 R 9 , —C(O)OR 8 , —O—(C 1 -C 6 hydroxyalkyl), —O—(C 1 -C 6 alkoxy), —O—(C 1 -C 6 alkylene)-cyano, —O—(C 1 -C 6 alkylene)-C(O)R 9′ , —OCHR 9′ C(O)O—R 8 , —OCHR 9′ C(O)NHOH, —O—(C 1 -C 6 alkyl)-C(O)NR 8 R 9 , —O—(
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl;
  • each R 9′ is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • each R 10 is independently H, alkyl, aryl, sulfonyl, C(O)R 8 , C(O)OR 8 or C(O)NR 8 R 9 ;
  • n is an integer from 1 to 4.
  • each pair of R 5′ and R 6′ together independently form a part of a ring having one of formulae C-L:
  • each R 14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , C(O)NR 8 R 9 , —OCH 2 C(O)NR 8 R 9 , —C(O)OR 8 , —O—(C 1 -C 6 hydroxyalkyl), —O—(C 1 -C 6 alkoxy), —O—(C 1 -C 6 alkylene)-cyano, —O—(C 1 -C 6 alkylene)-C(O)R 9′ , —OCHR 9′ C(O)O—R 8 , —OCHR 9′ C(O)NHOH, —O—(C 1 -C 6 alkyl)-C(O)NR 8 R 9 , —O—(
  • each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, C 1-6 alkyl-C 3-7 cycloalkylene, or C 1 - 10 alkyl-siloxyl;
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl;
  • each R 9′ is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • each R 10 is independently H, alkyl, aryl, sulfonyl, C(O)R 8 , C(O)OR 8 or C(O)NR 8 R 9 ;
  • each n is independently an integer from 1 to 3;
  • each X is independently S, O, NH, or N(C 1 -C 6 alkyl)
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • each n is independently an integer from 1 to 2. In certain embodiments, each n is 1.
  • the compound of Formula III′ has the following formula I′′ or II′′:
  • each Y is independently O or S;
  • each A is independently CR 18 or N;
  • each A′ is CR 15 R 16 , NR 17 , N, CR 15 , N-oxide, N—OR 8 —, S or O;
  • each R 12 is independently F, —OR 8 , —SR 8 , —NR 8 R 9 , alkyl, or aryl;
  • each R 14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , C(O)NR 8 R 9 , —OCH 2 C(O)NR 8 R 9 , —C(O)OR 8 , —O—(C 1 -C 6 hydroxyalkyl), —O—(C 1 -C 6 alkoxy), —O—(C 1 -C 6 alkylene)-cyano, —O—(C 1 -C 6 alkylene)-C(O)R 9′ , —OCHR 9′ C(O)O—R 8 , —OCHR 9′ C(O)NHOH, —O—(C 1 -C 6 alkyl)-C(O)NR 8 R 9 , —O—(
  • each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, C 1-6 alkyl-C 3-7 cycloalkylene, or C 1-10 alkyl-siloxyl,
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl;
  • each R 9′ is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • each R 10 is independently H, alkyl, aryl, sulfonyl, C(O)R 8 , C(O)OR 8 or C(O)NR 8 R 9 ;
  • each R 15 is independently a bond, H, halogen, —NR 10 SO 2 R 8 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 NR 8 R 9 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 NR 8 R 10 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, or
  • each R 16 is independently a bond, H, halogen, —NR 10 SO 2 R 8 , —(C 1 -C 6 alkyl)-NR 9′ S(O) 2 NR 8 R 9 , —(C 1 -C 6 alkyl)-NR 9′ S(O) 2 NR 8 R 10 , —(C 1 -C 6 alkyl)-NR 9′ S(O) 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, or heteroaryl;
  • each R 17 independently a bond, H, alkyl, aryl-CH 2 —, —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl; and
  • each R 18 is independently a bond, H, halogen, —NR 10 SO 2 R 8 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 NR 8 R 9 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 NR 8 R 10 , —(C 1 -C 6 alkylene)-NR 9′ S(O) 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, or heteroaryl;
  • each n is independently an integer from 1 to 4.
  • n is an integer from 1 to 3;
  • each R 1 is independently H, alkyd arylalkyl, heteroarylalkyl, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
  • each R 4 is independently H, alkyl, aryl-CH 2 —, —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl; and
  • each R 5 is independently H, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or R 4 and R 5 together form a part of a 3-8 membered heterocycloalkyl ring,
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • 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.
  • Compounds having formula III′ may also exist in various tautomeric forms. Accordingly, provided herein are tautomeric forms of compounds of Formula III′, for example, when R 4 is H, when R 4′ is H, or when R 4 and R 4′ are H.
  • compounds having formula III′ where R 4 and R 4′ are H may exist in, but not limited to, the following tautomeric forms III′ a , III′ b or III′ c. :
  • tautomeric forms of compounds of Formula VI′ for example, when R 4 is H, when R 4′ is H, or when R 4 and R 4′ are H.
  • compounds having formula VI′ where R 4 and R 4′ are H may exist in, but not limited to, the following tautomeric forms VI′ a , VI′ b or VI′ c :
  • each R 1 is independently H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
  • each R 5 is independently H, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or R 4 and R 5 together form a part of a 3-8 membered heterocycloalkyl ring;
  • each R 5′ is independently H, halogen, cyano, nitro, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, heteroaryl, —NR 8 R 10 , alkenyl, or alkynl;
  • each R 6′ is independently H, halogen, cyano, nitro, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , 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 R 12 is independently F, —OR 8 , —SR 8 , —NR 8 R 9 , alkyl, or aryl;
  • each Y is independently O or S
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • each R 1 is independently H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
  • each R 6 is independently H, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , 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;
  • each R 12 is independently F, —OR 8 , —SR 8 , —NR 8 R 9 , alkyl, or aryl;
  • each R 14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , C(O)NR 8 R 9 , —OCH 2 C(O)NR 8 R 9 , —C(O)OR 8 , —O—(C 1 -C 6 hydroxyalkyl), —O—(C 1 -C 6 alkoxy), —O—(C 1 -C 6 alkylene)-cyano, —O—(C 1 -C 6 alkylene)-C(O)R 9′ , —OCHR 9′ C(O)O—R 8 , —OCHR 9′ C(O)NHOH, —O—(C 1 -C 6 alkyl)-C(O)NR 8 R 9 , —O—(
  • each n is independently an integer from 1 to 4.
  • n is an integer from 1 to 3;
  • each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, C 1-6 alkyl-C 3-7 cycloalkylene, or C 1-10 alkyl-siloxyl;
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl;
  • each R 9′ is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • each R 10 is independently H, alkyl, aryl, sulfonyl, C(O)R 8 , C(O)OR 8 or C(O)NR 8 R 9 ,
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • provided herein is a compound according to any of Formulas III, III′, I′′, II′′, IIIa, VI, VI′, or VIa 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.
  • each R 1 is independently H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;
  • each R 6 is independently H, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, or heteroaryl;
  • each R 12 is independently F, —OR 8 , —SR 8 , —NR 8 R 9 , alkyl, or aryl;
  • each R 14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , C(O)NR 8 R 9 , —OCH 2 C(O)NR 8 R 9 , —C(O)OR 8 , —O—(C 1 -C 6 hydroxyalkyl), —O—(C 1 -C 6 alkoxy), —O—(C 1 -C 6 alkylene)-cyano, —O—(C 1 -C 6 alkylene)-C(O)R 9′ , —OCHR 9′ C(O)O—R 8 , —OCHR 9 C(O)NHOH, —O—(C 1 -C 6 alkyl)-C(O)NR 8 R 9 , —O—(C
  • each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, C 1-6 alkyl-C 3-7 cycloalkylene, or C 1-10 alkyl-siloxyl;
  • each R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or R 8 and R 9 together with the N atom to which they are attached form heterocyclyl;
  • each R 9′ is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;
  • each R 10 is independently H, alkyl, aryl, sulfonyl, C(O)R 8 , C(O)OR 8 or C(O)NR 8 R 9 ,
  • alkyl, aryl, arylalkyl, heteroaryl alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.
  • each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
  • R 1 is alkyl, arylalkyl, or heteroarylalkyl. In certain embodiments according to Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, R 1 is C 1-6 alkyl. In certain embodiments according to Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, R 1 is 2-cyclopropylethyl. In certain embodiments according to Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, R 1 is 3,3-dimethylbutyl. In further embodiments, R 1 has one of the following structures:
  • R 6 is II, halo, —OR 8 , —NR 8 R 9 , —C(O)R 8 , alkyl, arylakyl, aryl, or heteroaryl.
  • R 6 is hydrogen or halogen.
  • R 6 is H, I, Cl, F, methyl, isobutyl, t-butyl, phenyl or benzyl.
  • R 6 is F.
  • R 6 is heteroaryl. In certain embodiments according to Formula III, IIIa, VI, or VIa, R 6 is (S)-tert-butyl. In further embodiments, R 6 is heteroaryl having one of the following structures.
  • R 12 is F, —OR 8 , —SR 8 , —NR 8 R 9 , alkyl, or aryl.
  • R 12 is C 1-6 alkoxy.
  • R 12 is methoxy.
  • R 12 is ethoxy.
  • R 12 is OH. In certain embodiments according to Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, R 12 is NH 2 . In certain embodiments according to Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, R 12 is —CH 2 -cyclopropyl, isopropyl, —CH 2 CH 2 CH 2 —C(O)NHCH 3 , —CH 2 CH 2 CH 2 —C(O)NH 2 , or —CH 2 CH 2 OCH 3 .
  • R 14 is H, halogen, —NR 10 SO 2 R 8 , —OR 8 , —NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , OCH 2 C(O)NR 8 R 9 , —C(O)OR 8 , alkyl, aryl, or heteroaryl where R 8 , R 9 and R 10 are as defined herein.
  • R 14 is hydrogen.
  • R 14 is —NR 10 SO 2 R 8 where R 8 is methyl and R 10 is H or alkyl such as methyl or ethyl. In some embodiments according to Formula III, III′, I′′, II′′, IIIa, VI, VI′, or VIa, R 14 is OCH 2 C(O)NR 8 R 9 where each of R 8 and R 9 is independently H or alkyl.
  • R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, or C 1-6 alkyl-C 3-7 cycloalkylene, each optionally substituted as described herein.
  • R 8 l is C 1-6 alkyl, optionally substituted as described herein.
  • R 8 is C 3-7 cycloalkyl, optionally substituted as described herein.
  • R 8 is cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R 8 is C 6-14 aryl, optionally substituted as described herein. In certain embodiments, R 8 is heteroaryl, optionally substituted as described herein. In certain embodiments, R 8 is heterocyclyl, optionally substituted as described herein.
  • R 8 is C 1-6 alkyl. In certain embodiments according to Formula III or IIIa, R 8 is methyl.
  • R 9 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl.
  • R 1 is alkyl; R 6 is H, alkyl or halogen; R 12 is —OR 8 ; R 14 is H or —NHSO 2 R 8 ; and each R 8 is independently H or alkyl.
  • R 1 is alkyl; R 6 is halogen; R 12 is —OR 8 ; R 14 is H or —NHSO 2 R 8 ; and each R 8 is independently H or alkyl.
  • R 1 is alkyl; R 6 is F; R 12 is —OR 8 ; R 14 is H or —NHSO 2 R 8 ; and each R 8 is independently H or alkyl.
  • R 1 is alkyl; R 6 is F; R 12 is —OR 8 ; R 14 is H or —NHSO 2 Me; and R 8 is H, methyl or ethyl.
  • each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
  • R 1 is 2-cyclopropylethyl; R 6 is H, alkyl or halogen; R 12 is —OR 8 ; R 14 is H or —NHSO 2 R 8 ; and each R 8 is independently H or alkyl.
  • R 6 is halogen; R 12 is —OR 8 ; R 14 is H or —NHSO 2 R 8 ; and each R 8 is independently H or alkyl.
  • R 1 is 2-cyclopropylethyl; R 6 is F; R 12 is —OR 8 ; R 14 is H or —NHSO 2 R 8 ; and each R 8 is independently H or alkyl.
  • R 1 is 2-cyclopropylethyl, R 6 is F; R 12 is —OR 8 ; R 14 is H or —NHSO 2 Me; and R 8 is H, methyl or ethyl.
  • R 1 is C 1-6 alkyl
  • R 6 is C 1-6 alkyl
  • R 12 is —OR 8
  • R 14 is —NHSO 2 R 8
  • each R 8 is independently methyl or ethyl.
  • each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
  • R 1 is alkyl; R 6 is H, alkyl or halogen; R 12 is —OR 8 ; R 14 is H; and R 8 is H or alkyl.
  • R 1 is alkyl; R 6 is halogen; R 12 is —OR 8 ; R 14 is H; and R 8 is H or alkyl.
  • R 1 is alkyl; R 6 is F; R 12 is —OR 8 ; R 14 is H; and R 8 is H or alkyl.
  • R 1 is alkyl; R 6 is F; R 12 is —OR 8 ; R 14 is H; and R 8 is H, methyl or ethyl.
  • each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
  • R 1 is 3,3-dimethylbutyl; R 6 is H, alkyl or halogen; R 12 is —OR 8 ; R 14 is —NHSO 2 R 8 ; and each R 8 is independently H or alkyl.
  • R 1 is 3,3-dimethylbutyl; R 6 is halogen; R 12 is —OR 8 ; R 14 is —NHSO 2 R 8 ; and each R 8 is independently H or alkyl.
  • R 1 is 3,3-dimethylbutyl;
  • R 6 is F;
  • R 12 is —OR 8 ;
  • R 14 is —NHSO 2 R 8 ; and each R 8 is independently H or alkyl,
  • R 1 is 3,3-dimethylbutyl;
  • R 6 is F;
  • R 12 is —OR 8 ;
  • R 14 is —NHSO 2 Me; and
  • R 8 is H, methyl or ethyl.
  • the compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified.
  • 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.
  • 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.
  • 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.
  • the compound provided herein 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,
  • 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, dietbanolamine, diethylamine, dimethylamine, dipropylamine, diusopropylamine, 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-hydroxyeth
  • the compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula III, 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.
  • a compound of Formula III can be prepared according to Scheme 1.
  • compound 1A can be reacted with hydrazine to form compound 1B which can be reacted with base to form compound 1C.
  • Compound 1C, or a derivative thereof can be cyclized with carbonate in the presence of, for example, triphosgene, to form cyclic compound 1D.
  • Cyclic compound 1D can be coupled with alcohol R B OH to form cyclic compound 1E.
  • Cyclic compound 1E can be reacted with ethylcyanoacetate to form cyclic carbonitrile 1F.
  • Cyclic carbonitrile 1F can be coupled with a bromoaniline to form compound 1G.
  • Compound 1G can be coupled with triethylphosphite to form compound 1H.
  • Compound 1H can be cyclized, for example, in dimethylacetamide with heat to form phosphadiazine 1I.
  • the ethyl group can be removed from the phosphadiazine group of compound 1I to yield hydroxyphosphadiazine compound 1J.
  • Hydroxyphosphadiazine compound 1J can be coupled with a variety R D compounds to form further phosphadiazine derivatives, such as aminophosphadiazine compounds.
  • Protecting groups can be used where suitable according to the judgment of one of skill in the art.
  • a compound of Formula III can also be prepared according to Scheme 2.
  • compound 2A can react with substituted hydrazine R b —NH—NH 2 in the presence of ethanol and sodium acetate to form compound 2B.
  • Compound 2B can couple with cyanoacetic acid in the presence of a coupling agent to form compound 2C.
  • Compound 2C can be cyclized by potassium tert-butoxide in the presence of tert-butanol to form cyclic compound 2D.
  • compound 2C can be cyclized by 2N NaOH at room temperature to form cyclic compound 2D.
  • Cyclic compound 2D can couple with compound J in the presence oft for example, trimethylaluminum (AlMe 3 ), dioxane, and dimethylacetamide (DMA) at 160° C., to form compound 2E.
  • AlMe 3 trimethylaluminum
  • DMA dimethylacetamide
  • the ethyl group of the phosphadiazine group of compound 2E can be removed to yield hydroxyphosphadiazine compound 2F.
  • Hydroxyphosphadiazine compound 2F can couple with a variety R D compounds to form phosphadiazine 2G, such as aminophosphadiazine compounds.
  • Protecting groups can be used where suitable according to the judgment of one of skill in the art.
  • an intermediate compound 2D can be prepared according to Scheme 3.
  • compound 3A or a derivative thereof can react with substituted hydrazine R B —NH—NH 2 in the presence of ethanol and sodium acetate to form compound 3B, where R B is a substituted benzyl.
  • R B is a substituted benzyl.
  • Compound 3B can couple with ethyl 3-chloro-3-oxopropanoate in the presence of, for example, dioxane, to form compound 3C.
  • Compound 3C can be cyclized by 2N of NaOH at room temperature to form cyclic compound 3D.
  • compound 3C can be cyclized by 2N NaOH at room temperature to form cyclic compound 3D.
  • Cyclic compound 3D can react with cyclohexanamine in the presence of, for example, acetonitrile, at 150° C. for 15 minutes, to form compound 3E.
  • Compound 3E can react with Phosphorus chloride oxide to form compound 3F.
  • Compound 3F can react with NaOH in the presence of, for example, tetrahydrofuran, at room temperature, to form compound 2D.
  • Protecting groups can be used where suitable according to the judgment of one of skill in the art.
  • a compound of Formula III can also be prepared according to Scheme 4.
  • compound 4A can be reacted with substituted hydrazine, in the presence of, for example, trifluoroacetic acid (TFA) and dimethyl sulfoxide (DMSO), at 70° C., to form compound 4B.
  • Compound 4B can be cyclized by reaction with sodium acetate in the presence of, for example, dimethylformamide (DMF), to form cyclic compound 4C.
  • Cyclic compound 4C can be coupled with R B —Br to form compound 4D.
  • Cyclic compound 4D can couple with compound J in the presence of, for example, trimethylaluminum (AlMe 3 ) and dioxane at 85° C., to form compound 4E.
  • the ethyl group of the phosphadiazine group of compound 4E can be removed to yield hydroxyphosphadiazine compound 4F.
  • the hydroxyl group of the phosphadiazine group of compound 4F can be replaced by a methoxy group by reacting first with malonyl dichloride, in the presence of, for example, dichloromethane (DCM) and dimethylformamide (DMF) at room temperature, followed by reaction with R D —OH at room temperature, to form compound 4G.
  • DCM dichloromethane
  • DMF dimethylformamide
  • an intermediate compound 2D can be prepared according to Scheme 5.
  • Compound 5E can react with N-iodosuccinimide (NIS) in the presence of, for example, dimethylformamide (DMF), to form compound 5F.
  • NMS N-iodosuccinimide
  • Compound 5F can react with potassium carbonate in the presence of, for example, dimethyl sulfoxide (DMSO) and acetone, to form compound 5G.
  • Compound 5G can first react with boronic acid in the presence of, for example, palladium catalyst, sodium carbonate, and tetrahydrofuran (THF), followed by reacting with sodium hydroxide, to form compound 5H.
  • compound 5F can react with pyrazole in the presence of, for example, cesium carbonate, dimethylformamide (DMF), and copper(I) iodide, to form compound 5H where R is pyrazole.
  • DMF dimethylformamide
  • Protecting groups can be used where suitable according to the judgment of one of skill in the art.
  • compound 5H can be synthesized by further reacting the intermediate compound 5E.
  • compound 5E can be reacted with N-Bromosuccinimide (NBS) in the presence of, for example, dimethylformamide (DMF), or with bromine and water at 100° C. to form compound 5I.
  • NBS N-Bromosuccinimide
  • DMF dimethylformamide
  • compound 5I can be reacted with potassium carbonate in the presence of for example, dimethyl sulfoxide (DMSO) and acetone, to form compound 5J.
  • compound 5J can first react with boronic acid in the presence of, for example, palladium catalyst, sodium carbonate, and tetrahydrofuran (THF), followed by reacting with sodium hydroxide, to form compound 5H.
  • DMSO dimethylformamide
  • THF tetrahydrofuran
  • a compound of Formula VI can also be prepared according to Scheme 6.
  • compound 6A can react with allyl bromide following the procedure as described in Patent WO 2007/150001 and J. Org. Chem, 1993,618 to form compound 6B.
  • Compound 6B can be reacted with monochloroamine in the presence of, for example, methyl tertiary butyl ether (MTBE) and Aliquat® 336 to form hydrazine intermediate 6C.
  • MTBE methyl tertiary butyl ether
  • Compound 6C can be coupled with R B —Br to form compound 6D.
  • Compound 6D can be hydrolyzed to give compound 6E.
  • Compound 6E can be cyclized following the procedure as described in J. Med. Chem, 2006, 49(3), 971 to form compound 6F.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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, hydroxyeth
  • 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.
  • 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.
  • 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)
  • DFC dry-filled capsule
  • 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.
  • liquid, semisolid, and solid dosage forms 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • antioxidants such as but
  • 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.
  • 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.
  • compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • 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.
  • compositions provided herein may be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • 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.
  • 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).
  • 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.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous 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 emuls
  • 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.
  • liquid polyethylene glycol e.g., polyethylene glycol 300 and polyethylene glycol 400
  • propylene glycol e.g., 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 carboxymethylcellulose, 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 ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).
  • cyclodextrins including ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).
  • 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.
  • the pharmaceutical compositions are provided as ready-to-use sterile solutions.
  • 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.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
  • 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.
  • 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.
  • compositions provided herein may be administered topically to the skin, orifices, or mucosa.
  • topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
  • 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.
  • compositions may also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM (Chiron Corp., Emeryville, Calif.), and BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, Oreg.).
  • electroporation iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection
  • BIOJECTTM Bioject Medical Technologies Inc., Tualatin, Oreg.
  • 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 antioxidant
  • 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.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • 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.
  • 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.
  • 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.
  • a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • 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.
  • 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 committing 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.
  • 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.
  • modified release dosage forms may be formulated as a modified release dosage form.
  • 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.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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 seleroglucan; 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 a
  • 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,
  • 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.
  • 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.
  • 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).
  • an osmotic controlled release device including one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • 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).
  • 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.
  • 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
  • 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, glut
  • Osmotic agents of different dissolution rates may be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEMTM 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.
  • the active ingredients) 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.
  • 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 copo
  • 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.
  • 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).
  • 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.
  • 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.
  • 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 ⁇ m to about 3 mm, about 50 ⁇ m to about 2.5 mm, or from about 100 ⁇ m to about 1 mm in diameter.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the subject is a mammal.
  • the subject is a human.
  • 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 III 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.
  • the host is a cell.
  • the host is a human cell.
  • the host is a mammal.
  • the host is human.
  • 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.
  • 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 ofthe 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • diseases associated with HCV infection include chronic hepatitis, cirrhosis, hepatocarcinoma, or extra hepatic manfestation.
  • 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.
  • the polymerase is hepatitis C NS5B polymerase.
  • 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.
  • 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.
  • 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.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound provided herein
  • a first therapy 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, 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.
  • a second therapy e.g., a prophylactic or therapeutic agent
  • a therapy e.g., a prophylactic or therapeutic agent
  • a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder.
  • a synergistic effect of a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • HCV 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.
  • the pharmacokinetics, biodistribution or other parameters of the drug can be altered by such combination or alternation therapy.
  • combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
  • 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.
  • a HCV protease inhibitor including, but not limited to, Medivir HCV protease inhibitor (Medivir/Tobotec); ITMN-191 (InterMune), SCH 503034 (Schering), VX950 (Vertex); substrate
  • 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, Llinas-Brunet et al., Bioorg. Med. Chem. Lett. 1998, 8, 1713-1718; Steinkuhler et al., Biochemistry 1998, 37, 8899-8905; U.S. Pat. Nos.
  • 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 Tett. 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 at, 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.
  • siRNA short interfering RNA
  • 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 nuclotides 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • an anti-hepatitis C virus polymerase inhibitor such as ribavirin, viramidine, NM 283 (valopicitabine), PSI-6130, R1626, HCV-796, or R7128.
  • 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),
  • INTRON® A interferon alfa-2b
  • PEGASYS® Peginterferon alfa-2a
  • ROFERON® A recombinant interferon alfa-2a
  • INFERGEN® interferon alfacon-1
  • PEG-INTRON® pegylated interferon alfa-2b
  • 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.
  • an anti-hepatitis C virus protease inhibitor such as ITMN-191, SCH 503034, VX950 (telaprevir), or Medivir HCV protease inhibitor.
  • one or more compounds provided herein are administered in combination or alternation with an anti-hepatitis C virus vaccine, including, but not limited to, TG105, PEVIPROTM, CGI-5005, HCV/MF59, GV1001, IC41, and INNO0101 (E1).
  • an anti-hepatitis C virus vaccine including, but not limited to, TG105, PEVIPROTM, CGI-5005, HCV/MF59, GV1001, IC41, and INNO0101 (E1).
  • 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.
  • 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.
  • 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.
  • an anti-hepatitis C virus immunomodulator such as ZADAXIN® (thymalfasin), NOV-205, or oglufanide.
  • 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.
  • steroidal drugs including, but not limited to the group including, aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone.
  • 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, diclox
  • 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.
  • thrombolytics known in the art, including, but not limited to the group including anistreplase, reteplase, t-PA (alteplase activase), streptokinase, tenecteplase, and urokinase.
  • 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, chloramine, 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,
  • ECE endothelin converting enzyme
  • thromboxane receptor antagonists such as ifetroban
  • potassium channel openers such as thrombin inhibitors, such as hirudin
  • growth factor inhibitors such as modulators of PDGF activity
  • platelet activating factor (PAF) antagonists such as GPIIb/IIIa blockers (e.g., abciximab, 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 VIIa Inhibitors and Factor Xa Inhibitors
  • renin inhibitors neutral endopeptidase (NEP) inhibitors
  • squalene synthetase inhibitors include 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, hydrofiumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject.
  • 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.
  • 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.
  • 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.
  • 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,
  • intermediate 66 32 mmol
  • dichloromethane 120 ml
  • ethanol 50 ml
  • sulphuric acid 38.4 mmol
  • the reaction mixture was refluxed for 16 hours and cooled down to room temperature.
  • Saturated NaHCO 3 was added, the organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to yield intermediate 67, which was an yellow oil.
  • Intermediate 80 (137 mmol) was stirred in HCl 4M/dioxane (200 ml) for 4 hours. A white precipitate was filtered, washed with diethylether and dried over P 2 O 5 to yield intermediate 81, which was a white powder.
  • Intermediate 88 was synthesized from intermediate 87 following the procedure as described for intermediate 81, which was a white powder. Intermediate 88 was characterized by the following spectroscopic data: 1 H NMR (D 2 O, 400 MHz) ⁇ (ppm) 0.79 (s, 3H), 0.80 (s, 3H), 1.40-1.46 (m, 2H), 1.49-1.59 (m, 1H), 3.03-3.07 (m, 2H).
  • Intermediate 109 was synthesized from intermediate 99 and 1-bromo-3-methylbutane (Avocado) following the procedure as described for intermediate 101, which was a beige powder.
  • Intermediate 110 was synthesized from intermediate 99 and 4-fluoro-3-methylbenzylbromide (Apollo) following the procedure as described for intermediate 101, which was a beige powder.
  • Intermediate 114 was synthesized from pyrrole 2-carboxylic acid (44.66 mmol, Fluka) and allyl bromide (48.25 mmol, Acros) following the procedure as described in Patent WO 2007/150001 and J. Org. Chem, 1993,618 to give intermediate 114, which was a yellow oil.
  • Intermediate 115 was synthesized from intermediate 114 following the procedure as described in J. Org. Chem, 2004, 1368 and Patent WO 2007/150001 to give intermediate 115, which was a yellow oil.
  • Intermediate 118 was synthesized from intermediate 117 and triphosgene following the procedure as described in J. Med. Chem, 2006, 49(3), 971 to give intermediate 118, which was a yellow powder.
  • Intermediate 130 was characterized by the following spectroscopic data: 1 H NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm) 0.90 (s, 9H), 1.47-1.51 (m, 2H), 3.90-3.94 (m, 2H).
  • Intermediate 129 (0.286 mmol) in dimethylamine (2N) in solution in THF (2 ml) was stirred at 80° C. for 16 hours. Solvents were removed under reduced pressure to yield intermediate 131, which was a pale brown solid. Intermediate 131 was characterized by the following spectroscopic data: 1 H NMR (DMSO-d 6 , 400 MHz) ⁇ (ppm) 0.86 (s, 9H), 1.42-1.46 (m, 2H), 2.71 (s, 3H), 2.93 (s, 3H), 3.77-3.81 (m, 2H).
  • Example 41 is equivalent to Compound III-121.
  • Example 42 was synthesized from example 41.
  • Example 42 is equivalent to Compound III-21.
  • Example 43 was synthesized from example 42. To a stirred solution of example 42 (41 mg, 0.074 mmol) in dichloromethane (2 ml) and a few drops of dimethylformamide, oxalyl chloride (10 ⁇ l, 0.111 mmol) was added dropwise under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. Methanol (1 ml) was then added and the mixture stirred for one hour. Solvents were concentrated under reduced pressure and the crude material purified using preparative reverse phase HPLC to give example 43, as a white lyophilized powder.
  • Example 43 is equivalent to Compound III-51.
  • example 43 To a stirred suspension of example 43 (30 mmol) in anh THF (1.7 ml) was added a few drop of TEA and acetylchloride (6 ⁇ l). The mixture was stirred at room temperature for 5 hours. Purification by preparative HPLC yield example 44, which was a yellow powder.
  • Example 44 is equivalent to Compound III-134.
  • Example 45 was synthesized from intermediate 26 and intermediate 79 following the same procedure as described for example 41.
  • Example 45 was a white lyophilized powder.
  • Example 45 is equivalent to Compound III-125.
  • Example 46 was synthesized from example 45.
  • Example 46 is equivalent to Compound III-127.
  • Example 47 was synthesized from example 46 following the same procedure as described for example 43.
  • Example 47 was a white lyophilized powder.
  • MS (ESI, EI + ) m/z 566 (MH + ).
  • Example 47 is equivalent to Compound III-128.
  • Example 48 was synthesized from intermediate 26 and intermediate 86 following the same procedure as described for example 41.
  • Example 48 was a hygroscopic pale yellow powder.
  • Example 48 is equivalent to Compound III-131.
  • Example 49 was synthesized from example 48.
  • Example 49 is equivalent to Compound III-132.
  • Example 50 was synthesized from intermediate 26 and intermediate 90 following the same procedure as described for example 41.
  • Example 50 was a hygroscopic white powder.
  • Example 50 is equivalent to Compound III-122.
  • Example 51 was synthesized from example 50.
  • Example 52 was synthesized from example 51 following the same procedure as described for example 43.
  • MS (ESI, EI + ) m/z 552 (MH + ).
  • Example 52 is equivalent to Compound III-52.
  • Example 53 was synthesized from example 49 following the same procedure as described for example 43.
  • Example 53 is equivalent to Compound III-133.
  • Example 54 was synthesized from intermediate 26 and intermediate 92 following the same procedure as described for example 41.
  • Example 54 is equivalent to Compound III-129.
  • Example 55 was synthesized from intermediate 26 and intermediate 93 following the same procedure as described for example 41.
  • Example 55 is equivalent to Compound III-123.
  • Example 56 was synthesized from intermediate 26 and intermediate 95 following the same procedure as described for example 41.
  • Example 56 which was a mixture of isomers E and Z was obtained as a pale yellow solid.
  • Example 56 is equivalent to Compound III-123.
  • Example 56 (0.05 mmol) was dissolved in MeOH (15 ml) and THF (15 ml) and was hydrogenated with H cube® (Thales Nanotechnology, 1 ml/min, mode full H 2 ), at 25° C. Solvent were removed under reduced pressure. The crude material was purified by silica gel chromatography to yield example 57, which was a white lyophilised solid.
  • Example 58 was synthesized from intermediate 26 and intermediate 94 following the same procedure as described for example 41.
  • Example 58 is equivalent to Compound III-130.
  • Example 59 was synthesized from example 58 following the procedure as described for example 57, which was a white lyophilised solid.
  • Example 59 is equivalent to Compound III-135.
  • Example 60 was synthesized from example 43 following the procedure as described for example 44, which was a white lyophilised solid.
  • MS (ESI, EI + ) m/z 622 (MH + ).
  • Example 60 is equivalent to Compound III-126.
  • Example 61 was synthesized from intermediate 96 and intermediate 26 following the same procedure as described for example 41.
  • Example 61 is equivalent to Compound III-136.
  • Example 62 is equivalent to Compound III-137.
  • Example 63 was synthesized from intermediate 101 and intermediate 26 following the same procedure as described for example 41.
  • Example 63 is equivalent to Compound III-138.
  • Example 64 was synthesized from intermediate 102 and intermediate 26 following the same procedure as described for example 41.
  • MS (ESI, EI + ) m/z 550 (MH + ).
  • Example 64 is equivalent to Compound III-164.
  • Example 65 was synthesized from intermediate 103 and intermediate 26 following the same procedure as described for example 41.
  • Example 65 is equivalent to Compound III-165.
  • Example 66 was synthesized from intermediate 104 and intermediate 26 following the same procedure as described for example 41.
  • Example 66 is equivalent to Compound III-139.
  • Example 67 was synthesized from intermediate 106 and intermediate 26 following the same procedure as described for example 41.
  • Example 68 was synthesized from intermediate 107 and intermediate 26 following the same procedure as described for example 41.
  • Example 68 is equivalent to Compound III-141.
  • Example 69 was synthesized from intermediate 108 and intermediate 26 following the same procedure as described for example 41.
  • Example 70 was synthesized from intermediate 109 and intermediate 26 following the same procedure as described for example 41.
  • Example 70 is equivalent to Compound III-143.
  • Example 71 was synthesized from intermediate 110 and intermediate 26 following the same procedure as described for example 41.
  • Example 71 is equivalent to Compound III-144.
  • Example 72 was synthesized from intermediate 111 and intermediate 26 following the same procedure as described for example 41.
  • Example 72 is equivalent to Compound III-145.
  • Example 73 was synthesized from intermediate 112 and intermediate 26 following the same procedure as described for example 41.
  • Example 73 is equivalent to Compound III-146.
  • Example 74 was synthesized from example 65.
  • Example 65 (0.05 mmol) was dissolved in 1,2-dichloroethane (2.5ml) under nitrogen and trimethylsilylbromide (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 74, which was a beige powder.
  • Example 74 is equivalent to Compound III-147.
  • Example 75 was synthesized from example 74 following the same procedure as described for example 43.
  • Example 75 is equivalent to Compound III-59.
  • Example 76 was synthesized from example 66 following the procedure as described for example 74, which was a pale yellow powder.
  • Example 76 is equivalent to Compound III-148.
  • Example 77 was synthesized from example 76 following the same procedure as described for example 43.
  • Example 77 is equivalent to Compound III-149.
  • Example 78 was synthesized from example 63 following the procedure as described for example 74, which was a yellow solid.
  • Example 78 is equivalent to Compound III-43.
  • Example 79 was synthesized from example 78 following the same procedure as described for example 43.
  • Example 79 is equivalent to Compound III-53.
  • Example 80 was synthesized from example 72 following the procedure as described for example 74, which was a yellow powder.
  • Example 80 is equivalent to Compound III-150.
  • Example 81 was synthesized from example 80 following the same procedure as described for example 43.
  • Example 81 is equivalent to Compound III-151.
  • Example 82 was synthesized from example 68 following the procedure as described for example 74, which was a yellow powder.
  • Example 82 is equivalent to Compound III-152.
  • Example 83 was synthesized from example 82 following the same procedure as described for example 43.
  • MS (ESI, EI + ) m/z 550 (MH + ).
  • Example 83 is equivalent to Compound III-153.
  • Example 84 was synthesized from example 69 following the procedure as described for example 74, which was a yellow powder.
  • Example 84 is equivalent to Compound III-154.
  • Example 85 was synthesized from example 84 following the same procedure as described for example 43.
  • MS (ESI, EI + ) m/z 608 (MH + ).
  • Example 85 is equivalent to Compound III-155.

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US7932240B2 (en) 2011-04-26
AU2008296997A1 (en) 2009-03-12
WO2009032176A1 (en) 2009-03-12
JP2010537986A (ja) 2010-12-09
JP5514108B2 (ja) 2014-06-04
US20090060866A1 (en) 2009-03-05
CN101842378A (zh) 2010-09-22
CA2697546A1 (en) 2009-03-12
HK1137028A1 (en) 2010-07-16
UA95715C2 (ru) 2011-08-25
EP2183260B1 (de) 2011-06-01
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ES2367550T3 (es) 2011-11-04
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US20090060872A1 (en) 2009-03-05
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