WO2005095403A2 - Composes macrocycliques inhibiteurs de replication virale - Google Patents

Composes macrocycliques inhibiteurs de replication virale Download PDF

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Publication number
WO2005095403A2
WO2005095403A2 PCT/US2005/010494 US2005010494W WO2005095403A2 WO 2005095403 A2 WO2005095403 A2 WO 2005095403A2 US 2005010494 W US2005010494 W US 2005010494W WO 2005095403 A2 WO2005095403 A2 WO 2005095403A2
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Prior art keywords
alkyl
optionally substituted
hydroxy
alkoxy
cycloalkyl
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PCT/US2005/010494
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English (en)
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WO2005095403A3 (fr
WO2005095403B1 (fr
Inventor
Lawrence M. Blatt
Steven M. Wenglowsky
Steven W. Andrews
Kevin R. Condroski
Yutong Jiang
April L. Kennedy
George A. Doherty
John A. Josey
Peter J. Stengel
Benjamin T. Woodard
Machender R. Madduru
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Intermune, Inc.
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Priority to CA2560897A priority Critical patent/CA2560897C/fr
Priority to EP05757750A priority patent/EP1749007A2/fr
Priority to UAA200611368A priority patent/UA91677C2/ru
Priority to JP2007506466A priority patent/JP4950026B2/ja
Application filed by Intermune, Inc. filed Critical Intermune, Inc.
Priority to BRPI0509467-4A priority patent/BRPI0509467A/pt
Priority to EA200601467A priority patent/EA012389B1/ru
Priority to AU2005228894A priority patent/AU2005228894B9/en
Priority to NZ549697A priority patent/NZ549697A/en
Publication of WO2005095403A2 publication Critical patent/WO2005095403A2/fr
Publication of WO2005095403A3 publication Critical patent/WO2005095403A3/fr
Publication of WO2005095403B1 publication Critical patent/WO2005095403B1/fr
Priority to IL177917A priority patent/IL177917A0/en
Priority to TNP2006000308A priority patent/TNSN06308A1/en
Priority to NO20064933A priority patent/NO20064933L/no
Priority to IS8563A priority patent/IS8563A/is

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds, processes for their syntheses, pharmaceutical compositions, and methods for the treatment of flaviviral infections, such as hepatitis C virus (HCV) infection.
  • flaviviral infections such as hepatitis C virus (HCV) infection.
  • the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of flaviviral infection.
  • HCV infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States.
  • Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCN-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.
  • Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with significant improvements seen in the efficacy of treatment.
  • HCN is an enveloped positive strand R ⁇ A virus in the Flaviviridae family.
  • the single strand HCN R ⁇ A genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids.
  • ORF open reading frame
  • this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural ( ⁇ S) proteins of the virus.
  • ⁇ S structural and non-structural
  • the generation of mature nonstructural proteins ⁇ S2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B
  • ⁇ S2 mature nonstructural proteins
  • the first viral protease cleaves at the NS2-NS3 junction of the polyprotein.
  • the second viral protease is serine protease contained within the N-terminal region of NS3 (herein referred to as "NS3 protease").
  • NS3 protease mediates all of the subsequent cleavage events at sites downstream relative to the position of NS3 in the polyprotein (i.e., sites located between the C-terminus of NS3 and the C-terminus of the polyprotein).
  • NS3 protease exhibits activity both in cis, at the NS3-NS4 cleavage site, and in trans, for the remaining NS4A- NS4B, NS4B-NS5A, and NS5A-NS5B sites.
  • the NS4A protein is believed to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
  • the formation of the complex between NS3 and NS4A is necessary for NS3 -mediated processing events and enhances proteolytic efficiency at all sites recognized by NS3.
  • the NS3 protease also exhibits nucleoside triphosphatase and RNA helicase activities.
  • NS5B is an RNA-dependent RNA polymerase involved in the replication of HCN R ⁇ A.
  • Q is a core ring selected from:
  • the core ring can be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C 3 - cycloalkyl, C -1 n alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C ⁇ -6 alkyl, C 1-6 alkyl, substituted C ⁇ - alkyl, C ⁇ - 6 alkoxy, substituted C 1-6 alkoxy, C 6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino
  • R 1 is C ⁇ - 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 6 R 7 , halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, C ⁇
  • R 4 is H, Ci-6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C 3- cycloalkyl, C - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, C ⁇ -6 alkoxy, hydroxy-C ⁇ -6 alkyl, C ⁇ - 6 alkyl optionally substituted with up to 5 fluoro, or Ci- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is H, C ⁇ - 6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
  • R 6 and R 7 are each independently H, C ⁇ -6 alkyl, C - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C 3 - cycloalkyl, C 4 . 10 alkylcycloalkyl, C 2 .
  • R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 8 is Ci- 6 alkyl, C 3-7 cycloalkyl, C 4 , ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C ⁇ -6 alkoxy, or phenyl; or R 8 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, " nitro!, ' hydroxy7 Ci- 6 a ⁇ cy ⁇ j C 3 - 7 cycloalkyl, C 4 _ ⁇ o alkylcycloalkyl, C 2-6 alkenyl, C ⁇ - 6 alkoxy, hydroxy-C ⁇ - 6 alkyl, C ⁇ - 6 alkyl optionally substituted with up to 5 fluoro, or C ⁇ - 6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is C ⁇ .
  • R is a tetrahydrofuran ring linked through the C or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrapyranyl ring linked through the C 4 position of the tetrapyranyl ring;
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is C ⁇ - 6 alkyl, C 3 - cycloalkyl, or C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C ⁇ - alkoxy, or phenyl, or R 9 is C 6 or ⁇ o aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C 3 - cycloalkyl, C 4 - 1 o alkylcycloalkyl, C 2 - 6 alkenyl, C ⁇ - 6 alkoxy, hydroxy-C ⁇ - alkyl, or C ⁇ - 6 alkyl optionally substituted with up to 5 fluoro, C ⁇ - 6 alkoxy optionally substituted with up to 5 fluoro; or R
  • R la and R lb are each independently H, C ⁇ - 6 alkyl, C - cycloalkyl, or C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C ⁇ _ 6 alkoxy, amido, or phenyl,
  • R la and R lb are each independently H and C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, C ⁇ - 6 alkoxy, hydroxy-C ⁇ - 6 alkyl, C ⁇ - 6 alkyl optionally substituted with up to 5 fluoro, or C ⁇ - 6 alkoxy optionally substituted with up to 5 fluoro,
  • R la and R lb are each independently H, heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
  • NR la R lb is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C ⁇ - 6 alkoxy, amido, or phenyl,
  • NR la R lb is a heteroaryl selected from the group consisting of:
  • R lc is H, halo, C ⁇ - 6 alkyl, C 3 - 6 cycloalkyl, C ⁇ - 6 alkoxy, C 3 - 6 cycloalkoxy, NO 2 , N(R Id ) 2 , NH(CO)R ld , or NH(CO)NHR ld , wherein each R ld is independently H, C ⁇ - 6 alkyl, or C 3 - 6 cycloalkyl,
  • R lc is NH(CO)OR le , wherein R le is C ⁇ - 6 alkyl or C 3 - 6 cycloalkyl;
  • V is selected from O, S, or NH
  • V when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 15 , where R 15 is H, C ⁇ - 6 alkyl, C 3 - 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, or C ⁇ - 6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 is C ⁇ - 6 alkyl, C - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Ci- 6 alkoxy, Ci- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is C 6 or ⁇ o aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C - 6 alkenyl, C 1-6 alkoxy, hydroxy-C ⁇ .
  • R is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
  • R is Ci-6 alkyl, C 3 - 7 cycloalkyl, or C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Ci- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; with the proviso that the compound having the Formula I does not include a compound having the Formula II, III, or IV as defined below.
  • R 1 and R 2 are each independently H, halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2-6 alkenyl, C ⁇ - 6 alkoxy, hydroxy-Ci- 6 alkyl, or Ci- 6 alkyl optionally substituted with up to 5 fluoro, C ⁇ - 6 alkoxy optionally substituted with up to 5 fluoro, C 6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O) 2 ⁇ R 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 , C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8 , NHC(O) 2 ⁇ R 6
  • R 4 is H, Ci- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, C ⁇ - 6 alkoxy, ny ⁇ roxy-(J ⁇ - 6 alkyl, C ⁇ - 6 alkyl optionally substituted with up to 5 fluoro, or C ⁇ - 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is H, C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, C -7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ -6 alkyl, C .
  • R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 8 is Ci-6 alkyl, C 3 - 7 cycloalkyl, or C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C ⁇ - 6 alkoxy, or phenyl; or R is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ - 6 alkyl, C - cycloalkyl, C - ⁇ 0 alkylcycloalkyl, C 2 - 6 alkenyl, Ci- 6 alkoxy, hydroxy-Ci-6 alkyl, or Ci- 6 alkyl optionally substituted with up to 5 fluoro, C ⁇ - 6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is Q- 6 alkyl optionally substituted with up to 5 fluoro groups; or R is a tetrahydrofuran ring
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Ci- 6 alkyl, C 3 - cycloalkyl, or C 4 , ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C ⁇ - 6 alkoxy, or phenyl, or R 9 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q.
  • R 6 alkyl optionally substituted with up to 5 fluoro groups, NR 6 R 7 , or (CO)OH, or R 9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or Q -6 alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
  • R 10 and R 11 are each independently H, Q- 6 alkyl, C 3-7 cycloalkyl, C 4- 10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-Q -6 alkyl, Q -6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) conflictNR 6 R 7 , (CH 2 ) friendshipC(O)OR 14 where R 14 is H, Q- 6 alkyl, C 3-7 cycloalkyl, or C 4 - 10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, - 6 alkoxy, or phenyl; or R 14 is C 6 0 r 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - 10 alkylcycloalkyl,
  • R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R 10 and R 11 are combined as O;
  • R and R are each independently H, Q- 6 alkyl, C 3 - cycloalkyl, C 4 -io alkylcycloalkyl, C 6 or io aryl, hydroxy-Q- 6 alkyl, Ci- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) felicitNR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, C ⁇ - 6 alkyl, C 3 - 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 14 is C 6 0r io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q.
  • R 12 and R 13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R 12 and R 13 are each independently Q- 6 alkyl optionally substituted with (CH 2 ) n OR 8 ;
  • R 20 is H, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, C 6 or io aryl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or (CH 2 ) n NR 6 R 7 , (CH 2 ) administratC(O)OR 14 where R 14 is H, Q- 6 alkyl, C 3 .
  • R 14 is C 0r io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci-6 alkyl, C 3- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2-6 alkenyl, Q -6 alkoxy, hydroxy-Q -6 alkyl, Q -6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; said C 6 or 10 aryl, in the definition of R 12 and R 13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4
  • alkylcycloalkyl C 2 -6 alkenyl, Q- 6 alkoxy, hydroxy-Q -6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • N is selected from O, S, or ⁇ H;
  • R 21 is Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is C 6 0 , 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Ci- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R is pyridal, pyrimidal, pyraziny
  • R 22 is Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q_ 6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
  • R ld and R 1D are each independently H, Q. 6 alkyl, C 3 - 7 cycloalkyl, or C 4 . ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, Q. 6 alkoxy, amido, or phenyl;
  • R l and R lb are each independently H and C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Ci- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q-6 alkoxy optionally substituted with up to 5 fluoro;
  • R la and R lb are each independently H or heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
  • NR la R lb is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, Q -6 alkoxy, amido, or phenyl;
  • NR la R lb is a heteroaryl selected from the group consisting of:
  • R lc is H, halo, Q- 6 alkyl, C 3 _ 6 cycloalkyl, Q- 6 alkoxy, C 3 - 6 cycloalkoxy, NO 2 , N(R ld ) 2 , NH(CO)R ld , or NH(CO)NHR ld , wherein each R ld is independently H, Q- 6 alkyl, or C 3 - 6 cycloalkyl;
  • R lc is NH(CO)OR le wherein R le is C ⁇ - 6 alkyl, or Q- 6 cycloalkyl;
  • W is O orNH
  • V is selected from O, S, or NH;
  • V when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 15 , where R 15 is H, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro;
  • Q is a bicyclic secondary amine with the structure of:
  • R 21 and R 22 are each independently H, halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, C - ⁇ 0 alkylcycloalkyl, C 2-6 alkenyl, Q- 6 alkoxy, hydroxy-Ci- 6 alkyl, C ⁇ - 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro, C 6 0r io aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O) 2 NR 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 , C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8
  • R 10 and R 11 are each independently H, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 6 0 r io aryl, hydroxy-Q-6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , or (CH 2 ) friendshipC(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- cycloalkyl, or C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 14 is Ce or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇
  • R 12 and R 13 are each independently H, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 6 or in aryl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) conflictNR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, Q- 6 alkyl, " C 3-7 cycloallyl ' i or C 4 .
  • alkylcycloalkyl which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q -6 alkoxy, or phenyl; or R 14 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-C ⁇ .
  • R 12 and R 13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R 20 is H, Q. 6 alkyl, Q- cycloalkyl, C 4 - ⁇ n alkylcycloalkyl, C 6 or io aryl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH ) n NR 6 R 7 , or (CH 2 ) n C(O)OR 14 where R 14 is H, Q- 6 alkyl, C 3-7 cycloalkyl, or C 4 - ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 14 is C 6 or in aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl,
  • R and R is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q. 6 alkoxy, hydroxy-Q- 6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, hydroxy-Q- 6 alkyl, Q.6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 2c R 2d , halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 _ ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q-6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up
  • R 2c and R 2d are each independently H, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - io alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q -6 alkyl, C 3-7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, C 2 - 6 alkenyl, hydroxy-Q-e alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 2c and R 2d are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 4 is H, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 -6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is H, Q-e alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , or S(O) 2 R 8 ;
  • R is Q- 6 alkyl, C 3 - 7 cycloalkyl, or C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 8 is 0 r io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3-7 cycloalkyl, C 4- ⁇ 0 alkylcycloalkyl, C 2 .
  • R 1 is Q- 6 alkyl, C 3 - 7 cycloalkyl, C - ⁇ 0 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 5 R 6 , halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6
  • R is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 5 R 6 , halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with
  • R 3 is H, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; ' [AW 'fy ' Wis i alkyl, C(O)NR 5 R 6 , C(S)NR 5 R 6 , C(O)R 7 , C(O)OR 7 , or
  • R 5 and R 6 are each independently H, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C - cycloalkyl, ' C 4 - ⁇ 0 alkylcycloalkyl, C 2 - 6 alkenyl, hydroxy-Q- 6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q-6 alkoxy optionally substituted with up to 5 fluoro; or R 5 and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 7 is Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 7 is C or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R is Q- alkyl, Q- 4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- alkyl, or Q- 3 alkoxy; and [0087] h) the dashed line represents an optional double bond; [0088] or a pharmaceutically acceptable salt thereof. [0089]
  • the embodiments provide a compound ofthe formula:
  • Z is a group configured to hydrogen bond to an NS3 protease His57 imidazole moiety and to hydrogen bond to a NS3 protease Glyl37 nitrogen atom;
  • Pi' is a group configured to form a non-polar interaction with at least one NS3 protease SI' pocket moiety selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43;
  • L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
  • P2 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; P2 being positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Argl55, Val78, Asp79, Gln80 and Asp81;
  • R 5 is selected from the group consisting of H, C(O)NR 6 R 7 and C(O)OR 8 ;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and
  • R 8 is Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 8 is C or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R is Q-e alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the Q or C
  • R 4 is H, Ci-6 alkyl, Q- cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q-e alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is Q -6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
  • R and R are each independently H, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R is Q-e alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 8 is C or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 -e alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or _ 6 alkoxy optionally substituted with up to 5 fluoro; or R is Q- 6 alkyl optionally substituted with up to 5 fluoro groups; or R is a tetrahydrofuran ring linked through the Q or C 4 position
  • V is selected from OH, SH, or NH 2 ;
  • the dashed line represents an optional double bond
  • R 21 is Q-6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is 0.
  • io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C - cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or or R is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy,or thiophenoxy; and
  • R 22 is Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
  • Q is a core ring selected from:
  • the core ring can be unsubstituted or substituted H, halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hy r ⁇ xy-Ci ⁇ al yf, '' C 6 alkyl, " substituted Q- 6 alkyl, Ci- 6 alkoxy, substituted Q- 6 alkoxy, 01 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl
  • Q is R -R , wherein R is Q-6 alkyl, Q- cycloalkyl, C 4- ⁇ o alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR 6 R 7 , halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q
  • R 4 is H, Q-6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is Q-e alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, - 6 alkenyl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; [0 ⁇ i"9" - ' "" • ' R 8 - ⁇ s "- ⁇ 6 -gj ⁇ y ⁇ c 3
  • Y is COOR 9 , wherein R 9 is Q- 6 alkyl; or Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Q- 3 alkyl, Q- cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, Q- 3 alkyl, C 3 - 7 cycloalkyl, or Q- alkoxy, or Y is a carboxylic acid
  • V and W are each individually selected from O, S, or NH;
  • R 21 is Ci-6 alkyl, C 3 - 7 cycloalkyl, C - ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C - 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or or R 21 is pyridal, pyrimidal, pyrazinyl, thien
  • R 22 is Q-6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
  • compositions comprising preferred compounds and pharmaceutically acceptable carriers.
  • the embodiments provide a method of treating a hepatitis C virus infection in an individual, the method comprising administering to the individual an effective amount of the preferred compounds.
  • [ ⁇ ' ⁇ I ⁇ ]"" ' " "The " embodiments provide a method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of the preferred compounds.
  • the embodiments provide a method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount ofthe preferred compounds.
  • hepatic fibrosis used interchangeably herein with “liver fibrosis,” refers to the growth of scar tissue in the liver that may occur in the context of a chronic hepatitis infection.
  • the terms "individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.
  • liver function refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'- nucleosidase, ?-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
  • proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alan
  • HCN ⁇ S3 protease inhibitor and "NS3 protease inhibitor” refer to any agent that inhibits the protease activity of HCN ⁇ S3/ ⁇ S4A complex.
  • NS3 inhibitor is used interchangeably with the terms “HCV NS3 protease inhibitor” and "NS3 protease inhibitor.”
  • polyol or “poly-ol” denotes a hydrocarbon including at least two hydroxyls bonded to carbon atoms, and includes sugars (reducing and nonreducing sugars), sugar alcohols and sugar acids. Polyols may include other functional groups. Examples of polyols include sugar alcohols such as mannitol and trehalose, and polyethers.
  • a "reducing sugar” is one which contains a hemiacetal group that can reduce metal ions or react covalently with lysine and other amino groups in proteins and a "nonreducing sugar” is one which does not have these properties of a reducing sugar.
  • reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose and glucose.
  • Nonreducing sugars include sucrose, trehalose, sorbose, melezitose and raffmose.
  • Mannitol, xylitol, erythritol, threitol, sorbitol and glycerol are examples of sugar alcohols.
  • sugar acids these include L-gluconate and metallic salts thereof.
  • polyether denotes a hydrocarbon containing at least three ether bonds. Polyethers may include other functional groups. Polyethers include polyethylene glycol (PEG).
  • sustained viral response refers to the response of an individual to a treatment regimen for HCN infection, in terms of serum HCN titer.
  • a sustained viral response refers to no detectable HCN R ⁇ A (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.
  • Treatment failure patients generally refers to HCN- infected patients who failed to respond to previous therapy for HCN (referred to as “nonresponders") or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as “relapsers").
  • the previous therapy generally may include treatment with IF ⁇ -a monotherapy or IF ⁇ -a combination therapy, where the combination therapy may include administration of IF ⁇ - ⁇ and an antiviral agent such as ribavirin.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof an ' d/ ⁇ r may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression ofthe disease.
  • the terms "individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, murines, simians, humans, mammalian farm animals, mammalian sport animals, and mammalian pets.
  • pirfenidone refers to 5-methyl-l-phenyl-2- (lH)-pyridone.
  • pirfenidone analog refers to any compound of Formula I, IIA or IIB in the section entitled “Pirfenidone and Analogs Thereof below.
  • a "specific pirfenidone analog,” and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1 in the section entitled “Pirfenidone and Analogs Thereof below.
  • Type I interferon receptor agonist refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds to and causes signal transduction via the receptor.
  • Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
  • Type II interferon receptor agonist refers to any naturally occurring or non-naturally occurring ligand of human Type II interferon receptor that binds to and causes signal transduction via the receptor.
  • Type II interferon receptor agonists include native human interferon-?, recombinant TEN-? species, glycosylated IFN-? species, pegylated IFN-? species, modified or variant IFN-? species, IFN-? fusion proteins, antibody agonists specific for the receptor, non-peptide agonists, and the like.
  • a Type III interferon receptor agonist refers to any naturally occurring or non-naturally occurring ligand of humanIL-28 receptor a ("IL- ' 28R”), ' the ammo ' acid sequence of which is described by Sheppard, et al., infra., that binds to and causes signal transduction via the receptor.
  • interferon receptor agonist refers to any Type I interferon receptor agonist, Type II interferon receptor agonist, or Type III interferon receptor agonist.
  • dosing event refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device.
  • the term “dosing event,” as used herein includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.
  • Continuous delivery as used herein (e.g., in the context of “continuous delivery of a substance to a tissue”) is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.
  • Controlled release as used herein (e.g., in the context of “controlled drug release”) is meant to encompass release of substance (e.g., a Type I or Type III interferon receptor agonist, e.g., IFN-a) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use.
  • substance e.g., a Type I or Type III interferon receptor agonist, e.g., IFN-a
  • Controlled release thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).
  • “Patterned” or “temporal” as used in the context of drug delivery is meant to encompass delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection).
  • “Patterned” or “temporal” drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.
  • controlled drug delivery device is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially ' n ⁇ luerice ⁇ ' ' 6y ' &e ','" env ⁇ ronmen1: of use, or releasing at a rate that is reproducible witliin the environment of use.
  • substantially continuous as used in, for example, the context of “substantially continuous infusion” or “substantially continuous delivery” is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero.
  • substantially continuous drug delivery may also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drag delivery.
  • substantially steady state as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value ofthe biological parameter as a function of time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUC8hr average).
  • the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum concentration of the drug over time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below the average area under the curve of serum concentration ofthe drug over an 8 hour period in the time course (AUC8hr average), i.e., the AUC8hr is no more than 20% above or 20% below the AUC ⁇ lir average for the serum concentration ofthe drug over the time course.
  • AUC8hr area under the curve of serum concentration of the drug over time for any 8 hour period during the time course
  • AUC8hr average the average area under the curve of serum concentration ofthe drug over an 8 hour period in the time course
  • hydrogen bond refers to an attractive force between an electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a hydrogen atom which is linked covalently to another electronegative atom (such as oxygen, nitrogen, sulfur or halogen). See, e.g., Stryer et. al. "Biochemistry", Fith Edition 2002, Freeman & Co. Nl ⁇ .' Typically, me Hydrogen bond is between a hydrogen atom and two unshared electrons of another atom.
  • a hydrogen bond between hydrogen and an electronegative atom not covalently bound to the hydrogen may be present when the hydrogen atom is at a distance of about 2.5 angstroms to about 3.8 angstroms from the not-covalently bound electronegative atom, and the angle formed by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom not-covalently bound electronegative atom) deviates from 180 degrees by about 45 degrees or less.
  • the distance between the hydrogen atom and the not-covalently bound electronegative atom may be referred to herein as the "hydrogen bond length,” and the angle formed by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom not-covalently bound electronegative atom) may be referred to herein as the "hydrogen bond angle.”
  • hydrogen bond length may range from about 2.7 angstroms to about 3.6 angstroms, or about 2.9 angstroms to about 3.4 angstroms.
  • stronger hydrogen bonds are formed when the hydrogen bond angle is closer to being linear; thus, in some instances, hydrogen bond angles may deviate from 180 degrees by about 25 degrees or less, or by about 10 degrees or less.
  • non-polar interaction refers to proximity of non-polar molecules or moieties, or proximity of molecules or moieties with low polarity, sufficient for van der Waals interaction between the moieties and/or sufficient to exclude polar solvent molecules such as water molecules.
  • polar solvent molecules such as water molecules.
  • the distance between atoms (excluding hydrogen atoms) of non-polar interacting moieties may range from about 2.9 angstroms to about 6 angstroms. In some instances, the space separating non-polar interacting moieties is less than the space that would accommodate a water molecule.
  • non- polar moiety or moiety with low polarity refers to moieties with low dipolar moments (typically dipolar moments less than the dipolar moment of O-H bonds of H 2 O and N-H bonds of NH 3 ) and/or moieties that are not typically present in hydrogen bonding or electrostatic interactions.
  • exemplary moieties with low polarity are alkyl, alkenyl, and unsubstituted aryl moieties.
  • an NS3 protease ST pocket moiety refers to a moiety of the NS3 protease that interacts with the amino acid positioned one residue C-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease * ' moieties ' tnaf interact wi ' tn amino acid S in the polypeptide substrate DLENNT-STWNLN).
  • moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43, see Yao. et. al., Structure 1999, 7, 1353.
  • an ⁇ S3 protease S2 pocket moiety refers to a moiety of the NS3 protease that interacts with the amino acid positioned two residues N-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease moieties that interact with amino acid V in the polypeptide substrate DLENNT- STWNLN).
  • exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids His57, Argl55, Nal78, Asp79, Gln80 and Asp81, see Yao. et. al, Structure 1999, 7, 1353.
  • a first moiety "positioned by" a second moiety refers to the spatial orientation of a first moiety as determined by the properties of a second moiety to which the first atom or moiety is covalently bound.
  • a phenyl carbon may position an oxygen atom bonded to the phenyl carbon in a spatial position such that the oxygen atom hydrogen bonds with a hydroxyl moiety in an ⁇ S3 active site.
  • the embodiments provide compounds of Formulas I-XIX, as well as pharmaceutical compositions and formulations comprising any compound of Formulas I- XLX.
  • a subject compound is useful for treating flaviviral infection, such as HCN infection and other disorders, as discussed below.
  • compositions are described below. For ease of discussion, the description of these embodiments is divided into Sections A, B, C, D and E. Various terms that may be defined within a particular Section are understood to apply within that Section, and also to apply elsewhere herein when reference to that particular Section is made. Likewise, any references within a Section to a particular number or label should be understood in the context of the corresponding numbering or labeling scheme used within that Section, rather than in the context of a possibly similar or identical numbering or labeling scheme used in an unrelated section, unless otherwise indicated.
  • Section A embodiments provide compounds having the general Formula
  • Q is a core ring selected from:
  • the core ring can be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl, substituted Q- 6 alkyl, Q.
  • Q is R ⁇ R 2 , wherein R 1 is Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 6 R 7 , halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - cycloalkyl, C - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy,
  • R 4 is H, Q-6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q-e alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is H, Q-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, C - ⁇ o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, Q- cycloalkyl, Q-io alkylcycloalkyl, - 6 alkenyl, hydroxy-Q- 6 alkyl, Q-e alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 8 is Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 8 is 0 r io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, - alkenyl, Q- 6 alkoxy, hydroxy-Q-6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q.
  • R 8 is Q- 6 alkyl optionally substituted with up to 5 fluoro groups; or R is a tetrahydrofuran ring linked through the Q or C position of the tetrahydrofuran ring; or R is a tetrapyranyl ring linked through the C 4 position of the tetrapyranyl ring;
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Q- 6 alkyl, Q- cycloalkyl, or C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl, or R 9 is 0r io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci- 6 alkyl, Q- cycloalkyl, C 4 _ ⁇ o alkylcycloalkyl, -6 alkenyl, Q-6 alkoxy, hydroxy-Q- 6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 9 is a Q- 6 alkyl optionally substituted
  • R la and R lb are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, or -io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl,
  • R la and R lb are each independently H and or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q-e alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro,
  • R la and R lb are each independently H, heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
  • NR la R lb is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl,
  • NR la R lb is a heteroaryl selected from the group consisting of:
  • R lc is H, halo, Q-e alkyl, Q- 6 cycloalkyl, Q- 6 alkoxy, Q- 6 cycloalkoxy, NO 2 , N(R ld ) 2 , NH(CO)R ld , or NH(CO)NHR ld , wherein each R ld is independently H, Q- 6 alkyl, or C 3 - 6 cycloalkyl,
  • R lc is NH(CO)OR le , wherein R le is Q- 6 alkyl or C 3 - 6 cycloalkyl;
  • V is selected from O, S, or NH
  • V when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 15 , where R 15 is H, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro;
  • R is Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is Ce or 10 aryl which " is"""optiona ry ' '"s ⁇ stitutea" by "up' to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C4-10 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Ci-6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or or R 21 is pyridal, pyrimidal
  • R 22 is Q- 6 alkyl, Q- 7 cycloalkyl, or Q- 1 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds
  • Section A embodiments provide compounds having the general Formula I, in which Y is sulfonimide ofthe formula -C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of Q. 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, and NR la R lb , wherein R la and R lb are each independently H, Q- 6 alkyl, or Q- 7 cycloalkyl.
  • Section A embodiments provide compounds having the general Formula I, in which the C13-C14 double bond is cis.
  • Section A embodiments provide compounds having the general Formula I, in which the C13-C14 double bond is trans.
  • the compounds of general Formula I do not include the compounds disclosed in PCT/US04/33970.
  • the compounds of general Formula I do not include the compounds of Formulas II, III, and IV in Section B below.
  • Section B embodiments provide compounds having the general Formulas II, III, and IN:
  • R 1 and R 2 are each independently H, halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, Q- 6 alkenyl, C ⁇ - 6 alkoxy, hydroxy-Q- 6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro, C 6 or io aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O) 2 NR 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 , C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8 , NHC(O)R 8 , NHC
  • oxazolyl in the definition of R and R are optionally substituted by up to two halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; said 0.
  • io aryl, pyridal, phenoxy and thiophenoxy in the definition of R and R are optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, C - cycloalkyl, C 4 .10 alkylcycloalkyl, - 6 alkenyl, _ 6 alkoxy, hydroxy-Q-e alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 4 is H, Q-6 alkyl, Q- 7 cycloalkyl, C4. 10 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C4-1 0 alkylcycloalkyl, - 6 alkenyl, Q- 6 alkoxy, " hydr ⁇ xy-Q- 6 alkylj CiY ' all yl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is H, Q-e alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, C 3 - 7 cycloalkyl, C 4 - 10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, Q- 6 alkenyl, hydroxy-Q- 6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R is Q-6 alkyl, Q- cycloalkyl, or C 4 - 10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, o or phenyl; or R is C 6 01 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, Q.
  • R 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R is Q- 6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the Q or Q position of the tetrahydrofuran ring; or R is a tetrapyranyl ring linked through the position of the tetrapyranyl ring;
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Q- 6 alkyl, Q- cycloalkyl, or C 4 - 10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl, or R 9 is 01 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-e alkyl, Q- cycloalkyl, Q- 10 alkylcycloalkyl, - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 9 is a Q- 6 alkyl optionally substituted with up to 5 fluor
  • R 10 and R 11 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, 0 . 1 0 aryl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) friendshipC(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- 7 cycloalkyl, or C 4 - 1 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q-6 alkoxy, or phenyl; or R is or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 -
  • R and R are each independently H, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or 1 0 aryl, hydroxy-Q-6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) friendshipC(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 14 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, C 2 - 6 al
  • R and R is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q- 10 alkylcycloalkyl, - 6 alkenyl, Q-6 alkoxy, hydroxy-Q-6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 12 and R 13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R 12 and R 13 are each independently Q_ 6 alkyl optionally substituted with (CH 2 ) n OR 8 ;
  • R 20 is H, Q-e alkyl, Q- 7 cycloalkyl, Q- 10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or (CH 2 ) n NR 6 R 7 , (CH 2 ) administratC(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 .
  • R 14 is or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, -io alkylcycloalkyl, - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 " a ⁇ koxy optionally ' substituted wife up to 5 fluoro; said or 10 aryl, in the definition of R 12 and R 13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, Q-e alkeny
  • n l-4;
  • V is selected from O, S, or NH
  • V when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 15 , where R 15 is H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro;
  • the dashed line represents an optional double bond
  • R is Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q, 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 21 is pyridal, pyrimidal, pyrazinyl, thienyl,
  • R is Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q_ 6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
  • Section B embodiments provide compounds having the general Formula II,
  • R 1 is H, halo, cyano, nitro, hydroxy, Q-6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, - 6 alkenyl, Q-e alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 2 is H, OCH n NR 6 R 7 , OCH n R 16 , halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 . 7 cycloalkyl, Q-10 alkylcycloalkyl, Q-e alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; said R 6 and R 7 in the definition of R 2 being each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, or Q- 10 alkylcycloalkyl; or said R 6 and R 7 in the definition of R 2 taken together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 5 is H, C(O)NR 6 R 7 or C(O)OR 8 , said R 6 and R 7 in the definition of R 5 being each independently H, Q- 6 alkyl, C 3 - 7 cycloalkyl, or Q- 10 alkylcycloalkyl;
  • R 8 is Q-6 alkyl, Q- cycloalkyl, or Q-1 0 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R is Q- 6 alkyl optionally substituted with up to 5 fluoro groups; or R is a tetrahydrofuran ring linked through the Q or C position of the tetrahydrofuran ring; or R 8 is a tetrapyranyl ring linked through the C 4 position ofthe tetrapyranyl ring; [0235] ⁇ ⁇ s " a " sulf ⁇ nimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Q- 6 alkyl, Q- 7 cycloalkyl, or C 4 - ⁇ o alkylcycloalkyl, all of which are optionally substituted from one to
  • R 10 , R 11 , R 12 and R 13 are H;
  • W is selected from O, NH, or CH 2 .
  • Section B embodiments provide compounds having the general Formulas II, III, and IV, in which p may be 0. In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV, in which p may be 1.
  • Section B embodiments provide compounds having the general Formulas II, III, and IV, in which either or both of R 1 and R 2 are H.
  • p is 0. In other embodiments p is 1.
  • Section B embodiments provide compounds having the general Formulas II, III, and IV, in which neither R 1 nor R 2 is H.
  • p is 0. In other embodiments, p is 1.
  • Section B embodiments provide compounds having the general Formulas II, III, and IV, in which R 2 is OCHvisorNR 6 R 7 or OCH n R 16 .
  • Section B embodiments provide compounds having the general Formulas II, III, and IV in which R 9 is Q- 6 alkyl, Q- 7 cycloalkyl, or Q- io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl.
  • Section B embodiments provide compounds having the general Formulas II, III, and IV in which R 9 is ⁇ - io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, C 2 - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro.
  • Section B embodiments provide compounds having the general Formulas II, III, and IV in which R 9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or Q- 6 alkoxy.
  • Section B embodiments provide compounds having the general Formulas II, III, and IN in which R 9 is a Q- 6 alkyl optionally substituted with up to 5 fluoro groups, ⁇ R 6 R 7 , or (CO)OH.
  • Section B embodiments provide compounds having the general Formulas II, III, and IV in which the dashed line in Formula (II), (III), or (IV) represents a single bond.
  • Section B embodiments provide compounds having the general Formula II:
  • R 1 and R 2 are each independently H, halo, cyano, nitro, hydroxy, Q-e alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, -6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro, Ce or io aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O) 2 NR 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 , C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8 , NHC(O)R 8 , NHC(O)
  • R 4 is H, Q-6 alkyl, C 3 - 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q-6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is H, Q-e alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
  • [0253] are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, Q.
  • R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 8 is Q- 6 alkyl, Q- 7 cycloalkyl, or Q-io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 8 is C 6 or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q-6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R is Q- 6 alkyl optionally substituted with up to 5 fluoro groups; or R is a tetrahydrofuran ring linked through the Q or C 4 position of the
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Q- 6 alkyl, C 3 - 7 cycloalkyl, Q-io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl, or R 9 is or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, - 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro, or R 9 is a Q-6 alkyl optionally substituted
  • R 10 and R 11 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, o 10 aryl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , or (CH 2 ) n C(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 1 is 0 r io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, Q
  • R and R are each independently H, Q- 6 alkyl, Q- cycloalkyl, Q-io alkylcycloalkyl, C 6 or io aryl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , or (CH 2 ) n C(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 14 is Q or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, - 6
  • R 19 1 ⁇ said or io aryl, in the definition of R and R is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3-7 cycloalkyl, C 4- ⁇ o alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 12 and R 13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or R 12 and R 13 are each independently Q- 6 alkyl optionally substituted with
  • n 0-4;
  • V is selected from O, S, or NH
  • V when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 15 , where R 15 is H, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro;
  • the dashed line represents an optional double bond
  • R 21 is Ci- 6 alkyl, Q- cycloalkyl, or -io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy,
  • Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R is or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, Q-io alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
  • R 22 is Q- 6 alkyl, Q- 7 cycloalkyl, or Q-io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
  • Section B embodiments provide compounds having the general Formula Ila:
  • R and R are each independently H, halo, cyano, hydroxy, Q- 3 alkyl, or
  • R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
  • [0270] are each independently H, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or phenyl;
  • R 8 is Q-e alkyl, Q- 7 cycloalkyl, C - ⁇ 0 alkylcycloalkyl, or 3- tetrahydofuryl.
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Ci- 3 alkyl, Q- 7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, Q- 3 alkyl, Q_ cycloalkyl, or Q- 3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
  • R 10 and R 11 are each independently H or Q- 3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • W is selected from O or NH
  • the dashed line represents an optional double bond.
  • Section B embodiments provide compounds having the general Formula Ilia:
  • R and R are each independently H, halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 4 is H
  • R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
  • R 8 is Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, or 3- tetrahydrofuryl.
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Q -3 alkyl, Q- 7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, Q- 3 alkyl, Q- cycloalkyl, or Q- 3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
  • [0283] is selected from O or NH;
  • the dashed line represents an optional double bond.
  • Section B embodiments provide compounds having the general Formula lib:
  • R 1 and R 2 are each independently H, halo, cyano, hydroxy, Q- alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
  • R 8 is Ci- 6 alkyl, C 5 - 6 cycloalkyl, or 3-tetrahydrofuryl;
  • R 9 is C ⁇ - alkyl, C 3 - cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- alkyl, or Q- 3 alkoxy;
  • R 10 and R 11 are each independently H or Q- 3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • W is selected from O or NH
  • the dashed line represents an optional double bond.
  • Section B embodiments provide compounds having the general Formula IIT-b:
  • R 1 and R 2 are each independently H, halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
  • R 8 is Q-e alkyl, Q- 6 cycloalkyl, or 3-tetrahydrofuryl
  • R 9 is C ⁇ - 3 alkyl, Q- 5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 10 and R 11 are each independently H, Q- 3 alkyl, or Q- 5 cycloalkyl;
  • W is selected from O or NH
  • the dashed line represents an optional double bond.
  • Section B embodiments provide compounds having the general Formula lie:
  • R 1 and R 2 are each independently H, chloro, fluoro, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
  • R 8 is Q-e alkyl or Q- 6 cycloalkyl
  • R 9 is C ⁇ - alkyl, C 3 - cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 10 and R 11 are each independently H or Q- 3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl or cyclobutyl;
  • Section B embodiments provide compounds having the general Formula IIIc:
  • R 1 and R 2 are each independently H, chloro, fluoro, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
  • R 8 is Q-e alkyl or Q- 6 cycloalkyl
  • R 9 is C ⁇ - 3 alkyl, Q- 4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • the dashed line represents an optional double bond.
  • Section B embodiments provide compounds having the general Formula Hid:
  • R 1 and R 2 are each independently H, halo, cyano, hydroxy, Q- 3 alkyl, or Q- alkoxy;
  • R 4 is H
  • R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
  • R 8 is Ci-e alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, or 3- tetrahydrofuryl;
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Q- 3 alkyl, C 3 - 7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, Q- alkyl, Q- 7 cycloalkyl, or Q- 3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
  • R 10 and R 11 are each independently H or Q- 3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R 20 is H, Q-6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, or io aryl, hydroxy-Q-6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) friendshipNR 6 R 7 , or (CH 2 ) friendshipC(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- 7 cycloalkyl, or Q- ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Ci- 6 alkoxy, or phenyl; or R 14 is 0 r io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, - 6 alkenyl, Q-
  • W is selected from O or NH; and [0326] the dashed line represents an optional double bond. [0327] Section B embodiments provide compounds having the general Formula
  • R 1 and R 2 are each independently H, halo, cyano, hydroxy, Q- 3 alkyl, or
  • R 4 is H;
  • R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
  • R 8 is Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or 3- tetrahydrofuryl;
  • Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is Q- 3 alkyl, C 3 - cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, Q- alkyl, Q- 7 cycloalkyl, or Q- 3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
  • R 10 and R 11 are each independently H or Q- 3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R o is H, C ⁇ - 6 alkyl, C 3 - 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, C 6 01 ⁇ 0 aryl, hydroxy-Q- 6 alkyl, C ⁇ - 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , and (CH 2 ) n C(O)OR 14 where R 14 is H, Q- 6 alkyl, C 3 - 7 cycloalkyl, or Q- ⁇ 0 allcylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alk
  • io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q-e alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; said 0.
  • io aryl in the definition of R 12 and R 13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q-e alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • W is selected from O or NH
  • the dashed line represents an optional double bond
  • Z is a fused or appended aryl heteroaryl ring system.
  • Section C embodiments provide compounds having the general Formula
  • R la and R lb are each independently H, Q- 6 alkyl, Q. 7 cycloalkyl, or Q-io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl;
  • [O ' i-t ⁇ l]" ' " or R ia' and ' R 'lD are each independently H or C 6 01 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, Q- 7 cycloalkyl, -io alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Ci-6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q. 6 alkoxy optionally substituted with up to 5 fluoro;
  • R la and R lb are each independently H or heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
  • R is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl;
  • NR a R l is a heteroaryl selected from the group consisting of:
  • R lc is H, halo, Q- 6 alkyl, Q- 6 cycloalkyl, Q- 6 alkoxy, Q- 6 cycloalkoxy, NO 2 , N(R ld ) 2 , NH(CO)R ld , or NH(CO)NHR ld , wherein each R ld is independently H, Q- 6 alkyl, or Q-e cycloalkyl;
  • R lc is NH(CO)OR le wherein R le is Q- 6 alkyl or Q- 6 cycloalkyl;
  • W is O or NH
  • V is selected from O, S, or NH
  • V when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 15 , where R 15 is H, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ 0 alkylcycloalkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro;
  • R 2 is a bicyclic secondary amine with the structure of:
  • R and R are each independently H, halo, cyano, nitro, hydroxy, . 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro, or io aryl, pyridal, pyrimidal, thienyl, furanyl, ' thiazolyl, ' oxazolyl; phenoxy, " thiophenoxy, S(O) 2 NR 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 , C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8 , NHC(O)R 8
  • R 10 and R 11 are each independently H, Q- 6 alkyl, Q- cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or io aryl, hydroxy-Q-6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , or (CH 2 ) n C(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- 7 cycloalkyl, or Q-io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 14 is Q or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, Q
  • R and R are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, Q or io aryl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, Q- 6 alkyl, - 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 14 is or io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, Q-io alkylcycloalkyl, - 6 alken
  • R 12 and R 13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R 20 is H, Q-6 alkyl, Q- 7 cycloalkyl, C - ⁇ o alkylcycloalkyl, C 6 or io aryl, hydroxy-Q-e alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, (CH ) felicitNR 6 R 7 , (CH 2 ) friendshipC(O)OR 14 where R 14 is H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 14 is Q m - io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q-7 cycloalkyl, Q- 10 alkylcycloalkyl, Q- 6 alkenyl, Q
  • R 6 and R 7 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, - 10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, Q- 6 alkenyl, hydroxy-Q-e alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is Q.6 alkyl, Q. 7 cycloalkyl, C - ⁇ 0 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR 2c R 2d , halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, " C 4 - ⁇ o' ' a ⁇ kyi ' cyc ⁇ ' oalkyl, '" ' ⁇ alkenyl, C
  • R 2b is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 2c R 2d , halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - 10 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, or Q-6 alkyl optionally substituted with up to 5 fluoro, Q- 6 alkoxy optionally substituted with up to 5
  • R 2c and R 2d are each independently H, Q-6 alkyl, Q- 7 cycloalkyl, Q- 1 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q- 10 alkylcycloalkyl, - 6 alkenyl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R c and R 2d are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 4 is H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- 10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q- 10 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 5 is H, Q-e alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , or S(O) 2 R 8 ;
  • R 8 is Q- 6 alkyl, Q- 7 cycloalkyl, or Q- 10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 8 is Q 0r 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q-6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; and
  • the dashed line represents an optional double bond.
  • Section C embodiments provide compounds having the general Formula XII.
  • R la and R lb are each independently H, Q- 6 alkyl, Q- cycloalkyl, or -io alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl;
  • R la and R lb are each independently H or heteroaryl selected from a group consisting of:
  • R , 1c c is H, halo, Q- 6 alkyl, - 6 cycloalkyl, Q- 6 alkoxy, - 6 cycloalkoxy, NO 2 , N(R ld ) , NH(CO)R ld , or NH(CO)NHR ld , wherein each R ld is independently H, Q- 6 alkyl, or - 6 cycloalkyl;
  • NR la R lb is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl;
  • R and R are each independently H, halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, or phenyl; O ⁇ - 6 "alkyl, Q. 7 cycloalkyl, C 4 - ⁇ o alkylcycloalkyl, or 3- tetrahydrofuryl;
  • R 10 and R 11 are each independently H, halo, or Q- 3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R 12 and R 13 are each independently H, halo, Q- 6 alkyl, Q- 7 cycloalkyl, -io alkylcycloalkyl, Q 0 ⁇ io aryl, hydroxy-Q- 6 alkyl, or Q- 6 alkyl optionally substituted with up to 5 halo atoms; and
  • the dashed line represents an optional double bond.
  • Section C embodiments provide compounds having the general Formula XIII.
  • R la and R lb are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl;
  • R la and R 1 are each independently H or heteroaryl selected from a group consisting of:
  • R is H, halo, Ci- 6 alkyl, C 3 - 6 cycloalkyl, Q- 6 alkoxy, C 3 - 6 cycloalkoxy, NO 2 , N(R ld ) 2 , NH(CO)R ld , or NH(CO)NHR ld , wherein each R ld is independently H, Q-6 alkyl, or Q-6 cycloalkyl;
  • R is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido or phenyl;
  • R 21 and R 22 are each independently H, halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, or phenyl;
  • R 8 is Q-e alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, or 3- tetrahydrofuryl;
  • the dashed line represents an optional double bond.
  • Section C embodiments provide compounds having the general Formula XIN.
  • R la and R lb are each independently H, Q- 6 alkyl, C 3 - 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl; [039 ] "' " " or R ' ⁇ a” ahd R 1D are each independently H or heteroaryl selected from a group consisting of:
  • R lc is H, halo, Q- 6 alkyl, Q- 6 cycloalkyl, Q- 6 alkoxy, C 3 - 6 cycloalkoxy, NO 2 , N(R ld ) 2 , NH(CO)R ld , or NH(CO)NHR ld , wherein each R ld is independently H, Q- 6 alkyl, or Q- 6 cycloalkyl;
  • NR la R lb is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, Q- 6 alkoxy, amido, or phenyl;
  • R 2a is Q or do aryl optionally substituted with up to three NR 2o R 2d , halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- cycloalkyl, Q-io alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 2c and R 2d are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- io alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, - 6 alkenyl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R c and R 2 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 2a is an unsaturated five- or six-membered heteroaryl, or such defined heteroaryl fused to another cycle be it heterocycle or any other cycle;
  • R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
  • R 6 and R 7 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, Q-io alkylcycloalkyl, or phenyl;
  • R 8 is Q-e alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, or 3- tetrahydrofuryl;
  • the dashed line represents an optional double bond.
  • Section C embodiments provide compounds having the general Formula XV.
  • R 1 and R 2 are each independently H, halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
  • R 8 is Ci- 6 alkyl, - 6 cycloalkyl, or 3-tetrahydrofuryl
  • R 9 is C ⁇ - 3 alkyl, C 3 - 5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 10 and R 11 are each independently H, Q- alkyl, or Q- 5 cycloalkyl;
  • W is selected from O or NH
  • the dashed line represents an optional double bond.
  • Section C embodiments provide compounds having the general Formula XVI.
  • R 1 and R 2 are each independently H, chloro, fluoro, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
  • R 8 is Q-e alkyl or Q- 6 cycloalkyl
  • R 9 is Q- 3 alkyl, Q- 4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 10 and R 11 are each independently H or Q- 3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl or cyclobutyl;
  • the dashed line represents an optional double bond.
  • Section C embodiments provide compounds having the general Formula XVII.
  • R 1 and R 2 are each independently H, chloro, fluoro, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy;
  • R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
  • R 8 is Q-e alkyl or Q- 6 cycloalkyl
  • R 9 is Ci- 3 alkyl, Q- 4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- 3 alkyl, or Q- 3 alkoxy; and
  • the dashed line represents an optional double bond.
  • Section D embodiments provide compounds having the general Formula XVIII:
  • R 1 is Q- 6 alkyl, Q- 7 cycloalkyl, Q-1 0 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 5 R 6 , halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q- 10 alkylcycloalkyl, Q-e alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substitute
  • R 2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 5 R , halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, Q- 10 alkylcycloalkyl, Q- 6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro
  • R 3 is H, Q- 6 alkyl, Q- 7 cycloalkyl, Q- 10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, C 3 - 7 cycloalkyl, Q-10 alkylcycloalkyl, Q-6 alkenyl, Q-6 alkoxy, hydroxy-Q- 6 alkyl, Q-6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro;
  • R 4 is Q-e alkyl, C(O)NR 5 R 6 , C(S)NR 5 R 6 , C(O)R 7 , C(O)OR 7 , or S(O) 2 R 7 ;
  • R 5 and R 6 are each independently H, Q- 6 alkyl, C 3 - 7 cycloalkyl, Q- 10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q-1 0 alkylcycloalkyl, Q- 6 alkenyl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, or Q- 6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 7 is Ci- 6 alkyl, Q- 7 cycloalkyl, or Q-1 0 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 7 is 0r 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q.
  • R 8 is Q-3 alkyl, Q- 4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Q- alkyl, or Q- 3 alkoxy;
  • the dashed line represents an optional double bond.
  • Section E embodiments provide compounds having the general Formula XIX:
  • Z is a group configured to hydrogen bond to an NS3 protease His57 imidazole moiety and to hydrogen bond to a NS3 protease Glyl37 nitrogen atom;
  • PI' is a group configured to form a non-polar interaction with at least one NS3 protease SI' pocket moiety selected from the group consisting of Lys 136, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43;
  • L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
  • P2 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; P2 being positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Argl55, Val78, Asp79, Gln80 and Asp81;
  • R J is selected from the group consisting of C(O)NR 6 R 7 and C(O)OR 8 ;
  • R 6 and R 7 are each independently H, Q-6 alkyl, C 3 - 7 cycloalkyl, Q. 10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q-6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, -6 alkenyl, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Q-6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and
  • R 8 is Q- 6 alkyl, Q- 7 cycloalkyl, Q-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Q- 6 alkoxy, or phenyl; or R 8 is Q or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q- 10 alkylcycloalkyl, Q-6 alkenyl, Q- 6 alkoxy, hydroxy-Q- 6 alkyl, Q- 6 alkyl optionally substituted with up to 5 fluoro, Ci- 6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is Q- 6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the Q or Q position of the tetrahydrofuran
  • hydrogen bond refers to an attractive force between an electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a hydrogen atom which is linked covalently to another electronegative atom (such as oxygen, nitrogen, sulfur or halogen). See, e.g., Stryer et. al. "Biochemistry", Fith Edition 2002, Freeman & Co. N.Y. Typically, the hydrogen bond is between a hydrogen atom and two unshared electrons of another atom.
  • a hydrogen bond between hydrogen and an electronegative atom not covalently bound to the hydrogen may be present when the hydrogen atom is at a distance of about 2.5 angstroms to about 3.8 angstroms from the not-covalently bound electronegative atom, and the angle formed by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom not-covalently bound electronegative atom) deviates from 180 degrees by about 45 degrees or less.
  • the distance between the hydrogen atom and the not-covalently bound electronegative atom may be referred to herein as the "hydrogen bond length,” and the angle formed by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom not-covalently bound electronegative atom) may be referred to herein as the "hydrogen bond angle.”
  • hydrogen bond length may range from about 2.7 'angstroms to about 3.6 angstroms, or about 2.9 angstroms to about 3.4 angstroms.
  • stronger hydrogen bonds are formed when the hydrogenbond angle is closer to linear; thus, in some instances, hydrogen bond angles may deviate from 180 degrees by about 25 degrees or less, or by about 10 degrees or less.
  • non-polar interaction refers to proximity of non-polar molecules or moieties, or proximity of molecules or moieties with low polarity, sufficient for van der Waals interaction between the moieties and/or sufficient to exclude polar solvent molecules such as water molecules.
  • polar solvent molecules such as water molecules.
  • the distance between atoms (excluding hydrogen atoms) of non-polar interacting moieties may range from about 2.9 angstroms to about 6 angstroms. In some instances, the space separating non-polar interacting moieties is less than the space that would accommodate a water molecule.
  • non- polar moiety or moiety with low polarity refers to moieties with low dipolar moments (typically dipolar moments less than the dipolar moment of O-H bonds of H 2 O and N-H bonds of NH3) and/or moieties that are not typically present in hydrogen bonding or electrostatic interactions.
  • exemplary moieties with low polarity are alkyl, alkenyl, and unsubstituted aryl moieties.
  • an NS3 protease ST pocket moiety refers to a moiety of the NS3 protease that interacts with the amino acid positioned one residue C-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease moieties that interact with amino acid S in the polypeptide substrate DLEWT-STWVLV).
  • NS3 protease moieties that interact with amino acid S in the polypeptide substrate DLEWT-STWVLV.
  • Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43, see Yao. et. al, Structure 1999, 7, 1353.
  • an NS3 protease S2 pocket moiety refers to a moiety of the NS3 protease that interacts with the amino acid positioned two residues N-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease moieties that interact with amino acid V in the polypeptide substrate DLEWT- STWVLV).
  • exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids His57, Argl55, Val78, Asp79, Gln80 and Asp81, see Yao. et. al., Structure 1999, 7, 1353.
  • a first moiety "positioned by" a second moiety refers to the spatial orientation of a first moiety as determined by the properties of a second moiety '' to" which'the ii ' rsfatom or moiety is covalently bound.
  • a phenyl carbon may position an oxygen atom bonded to the phenyl carbon in a spatial position such that the oxygen atom hydrogen bonds with a hydroxyl moiety in an NS3 active site.
  • the compound having the general Formula XIX may contain one or more moieties that form a hydrogen bond with a peptide backbone atom or side chain moiety located in the substrate binding pocket of NS3 protease.
  • the compound having the general Formula XIX may contain one or more moieties that form non-polar interactions with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease.
  • the dashed line between carbons 13 and 14 maybe a single bond or a double bond.
  • Z may be configured to form a hydrogen bond with a peptide backbone atom or side chain moiety located in the substrate binding pocket of NS3 protease, including, but not limited to, NS3 protease His57 imidazole moiety and NS3 protease Glyl37 nitrogen atom. In some instances, Z may be configured to form a hydrogen bond with both the NS3 protease His57 imidazole moiety and the NS3 protease Glyl37 nitrogen atom.
  • the PI 1 group of the compound having the general formula XIX may be configured to form a non-polar interaction with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease SI' pocket.
  • the Pi' group may form a non-polar interaction with at least one amino acid selected from Lys 136, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43.
  • the P2 group of the compound having the general formula XIX may be configured to form a non-polar interaction with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket.
  • the P2 group may form a non-polar interaction with at least one amino acid selected from His57, Argl55, V al / 8, Asp?y, tilns ⁇ and As ⁇ 81.
  • the P2 group also may be configured to form a hydrogen bond with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket.
  • the P2 group may form a hydrogen bond with at least one amino acid selected from His57, Argl55, Val78, Asp79, Gln80 and Asp ⁇ l.
  • P2 may form both a non-polar interaction and a hydrogen bond with peptide backbone or side chain moieties or atoms located in the substrate binding pocket of NS3 protease, such amino acids selected from His57, Argl55, Val78, Asp79, Gln80 and Asp81. Such hydrogen bond and non-polar interactions may occur with the same amino acid residue or with different amino acid residues in the NS3 protease S2 pocket, h some embodiments, P2 may be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic.
  • the position of the P2 group is determined by the linker L.
  • P2 may be positioned by linker L to form a non-polar interaction with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket.
  • the P2 group may be positioned by L to form a non-polar interaction with at least one amino acid selected from His57, Argl55, Val78, Asp79, Gln80 and Asp81.
  • P2 may be positioned by linker L to form a hydrogen bond with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket.
  • the P2 group may be positioned by L to form a hydrogen bond with at least one amino acid selected from His57, Argl 55, Val78, Asp79, Gln80 and Asp81.
  • P2 may be positioned to form both a non-polar interaction and a hydrogen bond peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, such as an amino acid selected from His57, Argl 55, Val78, As ⁇ 79, Gln80 and Asp81.
  • NS3 protease such as an amino acid selected from His57, Argl 55, Val78, As ⁇ 79, Gln80 and Asp81.
  • Such hydrogen bond and non-polar interactions may occur with the same amino acid residue or with different amino acid residues in the NS3 protease S2 pocket.
  • L may be a linker group that links P2 to the heterocyclic backbone ofthe compound of formula XIX.
  • Linker L may contain any of a variety of atoms and moieties suitable for positioning P2 in the IN S3 protease substrate binding pocket.
  • L may contain 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur.
  • L may contain 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur.
  • Specific exemplary groups for L include, but are not limited to, ester, amide, carbamate, thioester, and thioamide.
  • the compound of formula XIX also may contain an R 5 group, where the R group may contain a carboxyl moiety.
  • exemplary carboxyl moieties of R 5 include C(O)NR 6 R 7 and C(O)OR 8 where R 6 and R 7 are each independently H, Q- 6 alkyl, Q- 7 cycloalkyl, -io alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Q- 6 alkyl, Q- 7 cycloalkyl, Q- ⁇ 0 alkylcycloalkyl, Q.
  • Section E embodiments provide compounds wherein the C13-C14 double bond is cis. Section E embodiments provide compounds wherein the C13-C14 double bond is trans.
  • Section E embodiments provide compounds having the general Formula XIX, in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.
  • Section E embodiments provide compounds having the general Formula XIX, in which P2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Argl 55, Nal78, Asp79, Gln80 and Asp81.
  • Section E embodiments provide compounds having the the formula XFXa:
  • Section E embodiments provide compounds having the general Formula XlXa, in which L consists of from 2 to 5 atoms.
  • Section E embodiments provide compounds having the general Formula XlXa, in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.
  • Section E embodiments provide compounds having the general Formula XlXa, in which P2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Argl 55, Val78, Asp79, Gln80 and Asp ⁇ l.
  • Section E embodiments provide compounds
  • Section E embodiments provide compounds having the the formula XlXb:
  • Section E embodiments provide compounds having the general Formula XlXb, in which L consists of from 2 to 5 atoms.
  • Section E embodiments provide compounds having the general Formula XlXb, in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.
  • Section E embodiments provide compounds having the general Formula XlXb, in which P2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Argl 55, Val78, Asp79, Gln80 and Asp ⁇ l.
  • Section E embodiments provide compounds having the general Formula XTXb, wherein the C13-C14 double bond is cis. [0478] In preferred embodiments, Section E embodiments provide compounds having the general Formula XlXb, wherein the C13-C14 double bond is trans.
  • the compounds of general Fo ⁇ nula XIX do not include the compounds disclosed in PCT/US04/33970.
  • the compounds of general Formula I do not include the compounds of Formulas II, III, and IN in Section B above.
  • compositions comprising compounds of the general formulas I-XIX, and salts, esters, or other derivatives thereof.
  • a subject pharmaceutical composition comprises a subject compound; and a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipients A wide variety of pharmaceutically acceptable excipients is known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C.
  • compositions are readily available to the public.
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public. Examples of suitable pharmaceutical composition embodiments and methods for making them are described in greater detail below.
  • a subject compound inhibits the enzymatic activity of a flavirus. Whether a subject compound inhibits flavivirus may be readily determined using any known method. Flaviviral infections include those caused by flaviviruses including, but not limited to, hepatitis virus C, West Nile Virus, GB virus, Japanese Encephalitis, Dengeu virus and Yellow Fever virus. In many embodiments, a subject compound inhibits the enzymatic activity of a hepatitis virus C (HCV) protease NS3. Whether a subject compound inhibits HCV NS3 may be readily determined using any known method.
  • HCV hepatitis virus C
  • Typical methods involve a determination of whether an HCV polyprotein or other polypeptide comprising an NS3 recognition site is cleaved by NS3 in the presence of the agent.
  • a subject compound inhibits NS3 enzymatic activity by at least about 10%, at least about 15%, at least about 20%, at least about 25%o, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the enzymatic activity of NS3 in the absence ofthe compound.
  • a subject compound inhibits enzymatic activity of an HCV NS3 protease with an IQo of less than about 50 ⁇ M, e.g., a subject compound inhibits an HCV NS3 protease with an IQo of less than about 40 ⁇ M, less than about 25 ⁇ M, less than about 10 ⁇ M, less than about 1 ⁇ M, less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, or less.
  • a subject compound inhibits HCV viral replication.
  • a subject compound inhibits HCV viral replication by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to HCV viral replication in the absence of the compound.
  • Whether a subject compound inhibits HCV viral replication may be determined using methods known in the art, including an in vitro viral replication assay.
  • compositions described herein are generally useful in treatment of a flaviviral infection.
  • Whether a subject method is effective in treating a flaviviral infection may be determined by a reduction in viral load, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, or other indicator of disease response.
  • "" ' ""' i general, an " effective amount of a compound of formulas I-XI-X, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral load or achieve a sustained viral response to therapy.
  • Whether a subject method is effective in treating a flaviviral infection may be determined by measuring viral load, or by measuring a parameter associated with a flaviviral infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.
  • the method involves administering an effective amount of a compound of formulas I-XIX, optionally in combination with an effective amount of one or more additional antiviral agents.
  • an effective amount of a compound of formulas I-XDC, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral titers to undetectable levels, e.g., to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum.
  • an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral load to lower than 100 genome copies/mL serum.
  • an effective amount of a compound of formulas I- XLX, and optionally one or more additional antiviral agents is an amount that is effective to achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum ofthe individual.
  • an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is an amount that is effective to achieve a sustained viral response, e.g., no detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
  • a sustained viral response e.g., no detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
  • a subject method is effective in treating a flaviviral infection may be determined by measuring a parameter associated with a flaviviral infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below.
  • the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.
  • levels of serum alanine aminotransferase (ALT) are measured, using standard assays. In general, an ALT level of less than about 45 international units is considered normal.
  • an effective amount of a compound of fo ⁇ nulas I-XIX, and optionally one or more additional antiviral agents is an amount effective to reduce ALT levels to less than about 45 IU/ml serum.
  • a therapeutically effective amount of a compound of fo ⁇ nulas I-XIX, and optionally one or more additional antiviral agents is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level ofthe marker in an untreated individual, or to a placebo-treated individual.
  • Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • an effective amount of a compound of formulas I-XIX and an additional antiviral agent is synergistic amount.
  • a "synergistic combination" or a "synergistic amount" of a compound of formulas I-XIX and an additional antiviral agent is a combined dosage that is more effective in the therapeutic or prophylactic treatment of an HCV infection than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the compound of formulas I-XIX when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy.
  • a selected amount of a compound of formulas I- XD and a selected amount of an additional antiviral agent are effective when used in combination therapy for a disease, but the selected amount ofthe compound of formulas I- XrX and/or the selected amount ofthe additional antiviral agent is ineffective when used in monotherapy for the disease.
  • the embodiments encompass (1) regimens in which a selected amount of the additional antiviral agent enhances the therapeutic benefit of a selected amount ofthe compound of formulas I-XIX when used in combination therapy for a disease, where the selected amount of the additional antiviral agent provides no '' therapeutic '' benefit '' wnen ' usec in monotherapy for the disease (2) regimens in which a selected amount of the compound of formulas I-XIX enhances the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, where the selected amount of the compound of formulas I-XTX provides no therapeutic benefit when used in monotherapy for the disease and (3) regimens in which a selected amount of the compound of fo ⁇ nula I and a selected amount of the additional antiviral agent provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the compound of formulas I-XIX and the additional antiviral agent, respectively, provides no therapeutic benefit when used in monotherapy for the disease.
  • a "synergistically effective amount" of a compound of formulas I-XTX and an additional antiviral agent, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (l)-(3) above.
  • Whether a subject method is effective in treating an HCV infection may be determined by a reduction in viral load, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, or other indicator of disease response.
  • an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral load or achieve a sustained viral response to therapy.
  • Whether a subject method is effective in treating an HCV infection may be determined by measuring viral load, or by measuring a parameter associated with HCV infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.
  • the method involves administering an effective amount of a compound of formulas I-XTX, optionally in combination with an effective amount of one or more additional antiviral agents.
  • an effective amount of a compound of " f ⁇ 'rmulas' -XrX, " and optionally one or more additional antiviral agents is an amount that is effective to reduce viral titers to undetectable levels, e.g., to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum.
  • an effective amount of a compound of formulas I-XTX, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral load to lower than 100 genome copies/mL serum.
  • an effective amount of a compound of formulas I- XIX, and optionally one or more additional antiviral agents is an amount that is effective to achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum ofthe individual.
  • an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is an amount that is effective to achieve a sustained viral response, e.g., no detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
  • a sustained viral response e.g., no detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
  • whether a subject method is effective in treating an HCV infection may be determined by measuring a parameter associated with HCV infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.
  • ALT serum alanine aminotransferase
  • an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is an amount effective to reduce ALT levels to less than about 45 IU/ml serum.
  • a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level ofthe " m'airker in ' "'an' 1 untrea ⁇ ed '' individual, or to a placebo-treated individual.
  • Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • an effective amount of a compound of formulas I-XIX and an additional antiviral agent is synergistic amount.
  • a "synergistic combination" or a “synergistic amount" of a compound of fonnulas I-XIX and an additional antiviral agent is a combined dosage that is more effective in the therapeutic or prophylactic treatment of an HCV infection than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the compound of formulas I-XIX when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy.
  • a selected amount of a compound of formulas I- XIX and a selected amount of an additional antiviral agent are effective when used in combination therapy for a disease, but the selected amount ofthe compound of formulas I- XIX and/or the selected amount ofthe additional antiviral agent is ineffective when used in monotherapy for the disease.
  • the embodiments encompass (1) regimens in which a selected amount of the additional antiviral agent enhances the therapeutic benefit of a selected amount ofthe compound of formulas I-XIX when used in combination therapy for a disease, where the selected amount of the additional antiviral agent provides no therapeutic benefit when used in monotherapy for the disease (2) regimens in which a selected amount of the compound of formulas I-XIX enhances the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, where the selected amount of the compound of formulas I-XIX provides no therapeutic benefit when used in monotherapy for the disease and (3) regimens in which a selected amount of the compound of formula I and a selected amount of the additional antiviral agent provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the compound of formulas I-XIX and the additional antiviral agent, respectively, provides no therapeutic benefit when used in monotherapy for the disease.
  • the embodiments provide methods for treating liver fibrosis (including forms of liver fibrosis resulting from, or associated with, HCV infection), generally involving administering a therapeutic amount of a compound of fo ⁇ nulas I-XIX, and optionally one or more additional antiviral agents. Effective amounts of compounds of formulas I-XIX, with and without one or more additional antiviral agents, as well as dosing regimens, are as discussed below.
  • liver fibrosis reduction is determined by analyzing a liver biopsy sample.
  • An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade” as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage” as being reflective of long-term disease progression. See, e.g., Brunt (2000) Hepatol.
  • METAVIR Hepatology 20:15-20. Based on analysis of the liver biopsy, a score is assigned.
  • the METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity).
  • each stage in the METAVIR system is as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.
  • ,' [0l> ⁇ ' 3 ' ] ' ' '" " ''"', Kno ⁇ , e ⁇ 's 1' scoring system also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and TV
  • the Ishak scoring system is described in Ishak (1995) J. Hepatol. 22:696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.
  • the benefit of anti-fibrotic therapy may also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.
  • a therapeutically effective amount of a compound of formula I, and' optionally one or more additional antiviral agents is an amount that effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies.
  • a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents reduces liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.
  • indices of liver function may also be used to evaluate the efficacy of treatment with a compound of formulas I-XTX. Morphometric computerized ' 'sem -a ⁇ ' ⁇ mated '' assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis may also be measured as an indication ofthe efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child- Pugh score.
  • An effective amount of a compound of fonnulas I-XIX, and optionally one or more additional antiviral agents is an amount that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or to a placebo-treated individual.
  • Those skilled in the art may readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.
  • Serum markers of liver fibrosis may also be measured as an indication of the efficacy of a subject treatment method.
  • Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IN collagen, C-te ⁇ ninal procollagen I peptide, and laminin.
  • Additional biochemical markers of liver fibrosis include a-2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.
  • a therapeutically effective amount of a compound of formulas I-XTX, and optionally one or more additional antiviral agents is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level ofthe marker in an untreated individual, or to a placebo-treated individual.
  • Those skilled in the art may readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e.g., enzyme- linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • immunological-based methods e.g., enzyme- linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
  • ELISA enzyme- linked immunosorbent assays
  • radioimmunoassays radioimmunoassays
  • ICG indocyanine green clearance
  • GOC galactose elimination capacity
  • ABT aminopyrine breath test
  • antipyrine clearance monoethylglycine-xylidide (MEG-X) clearance
  • caffeine clearance a combination of these agents.
  • a "complication associated with cirrhosis of the liver” refers to a disorder that is a sequellae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but it not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.
  • a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is an amount that is effective in reducing the incidence (e.g., the likelihood that an individual will develop) of a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or to a placebo-treated individual.
  • the embodiments provide methods for increasing liver function, generally involving administering a therapeutically effective amount of a compound of formulas I-XTX, and optionally one or more additional antiviral agents.
  • Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, ?-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
  • proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'
  • liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function.
  • markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, may be assessed by measuring the level of these markers in the seram, using standard immunological and enzymatic assays.
  • Splanchnic circulation and portal hemodynamics may be measured by portal wedge pressure and/or resistance using standard methods.
  • Metabolic functions may be measured by measuring the level of ammonia in the serum.
  • Whether seram proteins normally secreted by the liver are in the no ⁇ nal range may be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such seram proteins. The following are non-limiting examples.
  • the normal level of alanine transaminase is about 45 IU per milliliter of serum.
  • the normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum.
  • Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL.
  • Serum albumin levels are measured using standard assays. Normal levels of seram albumin are in the range of from about 35 to about 55 g/L.
  • Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.
  • a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is one that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more.
  • a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is an amount effective to reduce an elevated level of a seram marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.
  • a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents is also an amount effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% , , ' at ' ⁇ ea ' st '' abouf' ' 70 ' % ' at ,,' least about 80%, or more, or to increase the level of the seram marker of liver function to within a normal range.
  • Type I interferon receptor agonists include an IFN-a; an IFN- ⁇ ; an IFN-tau; an IFN-? ; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists.
  • Interferon-Alpha Interferon-Alpha
  • IFN-a any known IFN-a may be used in the embodiments.
  • interferon-alpha refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response.
  • IFN-a includes naturally occurring IFN-a; synthetic IFN-a; derivatized IFN-a (e.g., PEGylated IFN-a, glycosylated IFN-a, and the like); and analogs of naturally occurring or synthetic IFN-a; essentially any IFN-a that has antiviral properties, as described for naturally occurring IFN-a.
  • Suitable alpha interferons include, but are not limited to, naturally- occurring IFN-a (including, but not limited to, naturally occurring IFN-a2a, IFN-a2b); recombinant interferon alpha-2b such as Intron- A interferon available from Schering Corporation, Kenilworth, N.J.; recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N.
  • interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.
  • interferon alpha-nl a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-nl (INS) available from the Glaxo- Wellcome Ltd., London, Great Britain
  • interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.
  • IFN-a also encompasses consensus IFN-a.
  • Consensus IFN-a (also referred to as “CIFN” and “IFN-con” and “consensus interferon”) encompasses but is not limited to the amino acid sequences designated IFN-conl, IFN-con2 and IFN-con3 which are disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471; and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas ' (k imM iMif' nteMun Inc., Brisbane, Calif).
  • IFN-conl is the consensus interferon agent in the Infergen® alfacon-1 product.
  • the Infergen® consensus interferon product is referred to herein by its brand name (Infergen®) or by its generic name (interferon alfacon- 1).
  • DNA sequences encoding IFN-con may be synthesized as described in the aforementioned patents or other standard methods. Use of CIFN is of particular interest.
  • fusion polypeptides comprising an IFN-a and a heterologous polypeptide.
  • IFN-a fusion polypeptides include, but are not limited to, Albuferon-alphaTM (a fusion product of human albumin and IFN-a; Human Genome Sciences; see, e.g., Osbom et al. (2002) J. Pha ⁇ nacol. Exp. Therap. 303:540-548).
  • gene-shuffled forms of IFN-a See., e.g., Masci et al. (2003) Curr. Oncol. Rep. 5:108-113. PEGylated Interferon- Alpha
  • IFN-a also encompasses derivatives of IFN-a that are derivatized (e.g., are chemically modified) to alter certain properties such as seram half-life.
  • IFN-a includes glycosylated IFN-a; IFN-a derivatized with polyethylene glycol ("PEGylated IFN-a”); and the like. PEGylated IFN-a, and methods for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709; and 5,951,974.
  • PEGylated IFN-a encompasses conjugates of PEG and any of the above-described IFN-a molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, N.J.), interferon alpha 2b (Intron, Schering-Plough, Madison, N.J.), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Gennany); and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen®, InterMune, Inc., Brisbane, Calif).
  • any of the above-mentioned IFN-a polypeptides may be modified with one or more polyethylene glycol moieties, i.e., PEGylated.
  • the PEG molecule of a PEGylated IFN-a polypeptide is conjugated to one or more amino acid side chains of the IFN-a polypeptide.
  • the PEGylated IFN-a contains a PEG moiety on only one amino acid.
  • the PEGylated IFN-a contains a PEG moiety on two or more amino acids, e.g., the TJFN-a contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.
  • IFN-a may be coupled directly to PEG (i.e., without a linking group) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.
  • PEG i.e., without a linking group
  • the PEGylated IFN-a is PEGylated at or near the amino te ⁇ ninus (N-terminus) of the IFN-a polypeptide, e.g., the PEG moiety is conjugated to the IFN-a polypeptide at one or more amino acid residues from amino acid 1 through amino acid 4, or from amino acid 5 through about 10.
  • the PEGylated IFN-a is PEGylated at one or more amino acid residues from about 10 to about 28.
  • the PEGylated IFN-a is PEGylated at or near the carboxyl terminus (C-terminus) ofthe IFN-a polypeptide, e.g., at one or more residues from amino acids 156-166, or from amino acids 150 to 155.
  • the PEGylated IFN-a is PEGylated at one or more amino acid residues at one or more residues from amino acids 100-114.
  • amino acids at which PEGylation is to be avoided include amino acid residues from amino acid 30 to amino acid 40; and amino acid residues from amino acid 113 to amino acid 149.
  • PEG is attached to IFN-a via a linking group.
  • the linking group is any biocompatible linking group, where "biocompatible" indicates that the compound or group is non-toxic and may be utilized in vitro or in vivo without causing injury, sickness, disease, or death.
  • PEG may be bonded to the linking group, for example, via an ether bond, an ester bond, a thiol bond or an amide bond.
  • Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)), a nitro phenyl group (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a
  • succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) ester-activated PEGs are described in U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.
  • Pegylated IFN-a encompasses conjugates of PEG and any of the above-described IFN-a molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, N.J.), where PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, N.J.), where PEGylated Intron is known as PEG-Intron (Schering-Plough); interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as defined by determination of a consensus sequence of naturally occurring interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, N.J.), where PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron,
  • the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-a polypeptide.
  • Methods of modifying polypeptides with monomethoxy PEG via reductive alkylation are known in the art. See, e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.
  • PEG is linked to IFN-a via an SPA linking group.
  • SPA esters of PEG, and methods for making same, are described in U.S. Patent No. 5,672,662.
  • SPA linkages provide for linkage to free amine groups on the IFN-a polypeptide.
  • a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the TFN-a polypeptide.
  • a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the TFN-a polypeptide.
  • Such a bond may be formed, e.g., by condensation of an a-methoxy, omega propanoic acid activated ester of PEG (mPEGspa).
  • one monopegylated CIFN conjugate preferred for use herein has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 , and the amide bond is formed by condensation of an a-methoxy, omega propanoic acid activated ester of PEG.
  • Polyethylene glycol Polyethylene glycol
  • Polyethylene glycol suitable for conjugation to an IFN-a polypeptide is soluble in water at room temperature, and has the general formula R(O-CH -CH 2 ) envisionO-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons.
  • PEG has at least one hydroxyl group, e.g., a terminal hydroxyl group, which hydroxyl group is modified to generate a functional group that is reactive with an amino group, e.g., an epsilon amino group of a lysine residue, a free amino group at the N-terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.
  • an amino group e.g., an epsilon amino group of a lysine residue, a free amino group at the N-terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.
  • PEG is derivatized so that it is reactive with free carboxyl groups in the IFN-a polypeptide, e.g., the free carboxyl group at the carboxyl terminus of the IFN-a polypeptide.
  • Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN-a include, but are not limited to PEG- amine, and hydrazine derivatives of PEG (e.g., PEG-NH-NH 2 ).
  • PEG is derivatized such that it comprises a terminal thidcarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives.
  • -SH a terminal thidcarboxylic acid group
  • selectivity of certain amino groups over others is achieved.
  • -SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH conditions such that the e-amino groups in lysine residues are protonated and remain non-nucleophilic.
  • reactions under suitable pH conditions may make some of the accessible lysine residues to react with selectivity.
  • the PEG comprises a reactive ester such as an N- hydroxy succinimidate at the end of the PEG chain.
  • a reactive ester such as an N- hydroxy succinimidate at the end of the PEG chain.
  • Such an N-hydroxysuccinimidate- containing PK ⁇ 'm ⁇ lecu e reacts 'with select amino groups at particular pH conditions such as neutral 6.5-7.5.
  • the N-terminal amino groups may be selectively modified under neutral pH conditions.
  • accessible-NH 2 groups of lysine may also react.
  • the PEG may be conjugated directly to the IFN-a polypeptide, or through a linker.
  • a linker is added to the IFN-a polypeptide, fonning a linker-modified IFN-a polypeptide.
  • Such linkers provide various functionalities, e.g., reactive groups such sulfhydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN-a polypeptide.
  • the PEG conjugated to the IFN-a polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-a polypeptide is branched. Branched PEG derivatives such as those described in U.S. Pat. No. 5,643,575, "star-PEG's” and multi-armed PEG's such as those described in Shearwater Polymers, Inc. catalog "Polyethylene Glycol Derivatives 1997-1998.” Star PEGs are described in the art including, e.g., in U.S. Patent No. 6,046,305.
  • PEG having a molecular weight in a range of from about 2 kDa to about 100 kDa is generally used, where the term "about,” in the context of PEG, indicates that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight.
  • PEG suitable for conjugation to IFN-a has a molecular weight of from about 2 kDa to about 5 kDa, from about 5 kDa to about 10 kDa, from about 10 kDa to about 15 kDa, from about 15 kDa to about 20 kDa, from about 20 kDa to about 25 kDa, from about 25 kDa to about 30 kDa, from about 30 kDa to about 40 kDa, from about 40 kDa to about 50 kDa, from about 50 kDa to about 60 kDa, from about 60 kDa to about 70 kDa, from about 70 kDa to about 80 kDa, from about 80 kDa to about 90 kDa, or from about 90 kDa to about 100 kDa.
  • the PEG moiety may be attached, directly or via a linker, to an amino acid residue at or near the N-terminus, internally, or at or near the C- terminus of the IFN-a polypeptide. Conjugation may be carried out in solution or in the solid phase.
  • N-terminal linkage [( &O] Methods " fo ' r attaching a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-a polypeptide are known in the art. See, e.g., U.S. Patent No. 5,985,265.
  • known methods for selectively obtaining an N- te ⁇ ninally chemically modified IFN-a are used.
  • a method of protein modification by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available for derivatization in a particular protein may be used.
  • substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.
  • the reaction is performed at pH which allows one to take advantage of the pK a differences between the e-amino groups of the lysine residues and that of the a- amino group of the N-terminal residue of the protein.
  • N-terminal-specific coupling procedures such as described in U.S. Patent No. 5,985,265 provide predominantly monoPEGylated products.
  • the purification procedures aimed at removing the excess reagents and minor multiply PEGylated products remove the N-terminal blocked polypeptides.
  • such processes lead to significant increases in manufacturing costs.
  • examination of the structure of the well-characterized Infergen® Alfacon-1 CIFN polypeptide amino acid sequence reveals that the clipping is approximate 5% at the carboxyl terminus and thus there is only one major C-terminal sequence.
  • N-terminally PEGylated IFN-a is not used; instead, the IFN-a polypeptide is C-terminally PEGylated.
  • a PEG reagent that is selective for the C-terminal may be prepared with or without spacers.
  • polyethylene glycol modified as methyl ether at one end and having an amino function at the other end may be used as the starting material.
  • Preparing or obtaining a water-soluble carbodiimide as the condensing agent may be carried out.
  • Coupling IFN-a e.g., Infergen® Alfacon-1 CIFN or consensus interferon
  • a water-soluble carbodiimide as the condensing reagent is generally carried out in ' aq ⁇ eous ! medi ⁇ m with a suitable buffer system at an optimal pH to effect the amide linkage.
  • a high molecular weight PEG may be added to the protein covalently to increase the molecular weight.
  • ED AC ED AC
  • l-ethyl-3- (3-dimethylaminopropyl) carbodiimide The water solubility of ED AC allows for direct addition to a reaction without the need for prior organic solvent dissolution. Excess reagent and the isourea fo ⁇ ned as the by-product of the cross-linking reaction are both water-soluble and may easily be removed by dialysis or gel filtration.
  • a concentrated solution of ED AC in water is prepared to facilitate the addition of a small molar amount to the reaction. The stock solution is prepared and used immediately in view of the water labile nature of the reagent.
  • the optimal reaction medium to be in pH range between 4.7 and 6.0. However the condensation reactions do proceed without significant losses in yields up to pH 7.5. Water may be used as solvent.
  • the medium will be 2-(N-morpholino)ethane sulfonic acid buffer pre-titrated to pH between 4.7 and 6.0.
  • 0.1M phosphate in the pH 7-7.5 may also be used in view of the fact that the product is in the same buffer.
  • the ratios of PEG amine to the IFN-a molecule is optimized such that the C-terminal carboxyl residue(s) are selectively PEGylated to yield monoPEGylated derivative(s).
  • PEG amine has been mentioned above by name or structure, such derivatives are meant to be exemplary only, and other groups such as hydrazine derivatives as in PEG-NH-NH 2 which will also condense with the carboxyl group of the IFN-a protein, may also be used.
  • the reactions may also be conducted on solid phase.
  • Polyethylene glycol may be selected from list of compounds of molecular weight ranging from 300-40000. The choice of the various polyethylene glycols will also be dictated by the coupling efficiency and the biological perfo ⁇ nance of the purified derivative in vitro and in vivo i.e., circulation times, anti viral activities etc.
  • suitable spacers may be added to the C-terminal of the protein.
  • the spacers may have reactive groups such as SH, NH 2 or COOH to couple with appropriate PEG reagent to provide the high molecular weight IFN-a derivatives.
  • a combined solid/solution phase methodology may be devised for the preparation of C- terminal pegylated interferons. For example, the C-terminus of IFN-a is extended on a " solid' phase '' using a G ' ly-G ⁇ y-Cys-NH 2 spacer and then monopegylated in solution using activated dithiopyridyl-PEG reagent of appropriate molecular weights.
  • C-terminal PEGylation Another method of achieving C-terminal PEGylation is as follows. Selectivity of C-terminal PEGylation is achieved with a sterically hindered reagent which excludes reactions at carboxyl residues either buried in the helices or internally in IFN-a.
  • a sterically hindered reagent which excludes reactions at carboxyl residues either buried in the helices or internally in IFN-a.
  • one such reagent could be a branched chain PEG ⁇ 40kd in molecular weight and this agent could be synthesized as follows:
  • OH 3 C-(CH 2 CH 2 O)n-CH 2 CH 2 NH 2 + Glutamic Acid i.e., HOCO- CH 2 CH 2 CH(NH2)-COOH is condensed with a suitable agent e.g., dicyclohexyl carbodiimide or water-soluble EDC to provide the branched chain PEG agent OH 3 C- (CH 2 CH 2 O) n -CH 2 CH 2 NHCOCH(NH 2 )CH 2 OCH3-(CH 2 CH 2 O) n -CH 2 CH 2 NHCOCH 2 .
  • a suitable agent e.g., dicyclohexyl carbodiimide or water-soluble EDC
  • This reagent may be used in excess to couple the amino group with the free and flexible carboxyl group of IFN-a to form the peptide bond.
  • PEGylated IFN-a is separated from unPEGylated IFN-a using any known method, including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof.
  • the products are first separated by ion exchange chromatography to obtain material having a charge characteristic of monoPEGylated material (other multi-PEGylated material having the same apparent charge may be present), and then the monoPEGylated materials are separated using size exclusion chromatography.
  • PEGylated IFN-a that is suitable for use in the embodiments includes a monopegylated consensus interferon (CIFN) molecule comprised of a single CIFN polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly linked through a stable covalent linkage to either the N-terminal residue in the CIFN polypeptide or a lysine residue in the CIFN polypeptide.
  • the monoPEG (30 kD, linear)- ylated IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a.
  • the PEG moiety is linked to either the alpha- amino group ofthe N-terminal residue in the CIFN polypeptide or the epsilon-amino group of a lysine residue in the CIFN polypeptide.
  • the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group ofthe N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide.
  • the linkage comprises an amide bond between a propionyl group of the PEG moiety arid either the a ⁇ pha-amino group ofthe N-terminal residue or the epsilon- amino group ofthe lysine residue in the CIFN polypeptide.
  • the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-te ⁇ ninal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide, thereby fo ⁇ ning a hydrolytically stable linkage between the PEG moiety and the CIFN polypeptide.
  • the PEG moiety is linked to the N-tenninal residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group ofthe PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide.
  • the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N-terminal residue ofthe CIFN polypeptide.
  • the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon- amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon- amino group of the lysine group in the CIFN polypeptide.
  • the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the lysine residue in the CIFN polypeptide.
  • the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group ofthe surface-exposed lysine residue in the CIFN polypeptide.
  • the linkage comprises an amide bond between a propionyl group ofthe PEG moiety and the epsilon-amino group ofthe surface-exposed lysine residue in the CIFN polyp'eptfde" '
  • the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group ofthe surface-exposed lysine residue in the CIFN polypeptide.
  • the PEG moiety is linked to a lysine chosen from lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 of the CIFN polypeptide.
  • the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 of the CIFN polypeptide.
  • the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
  • the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
  • the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon- amino group ofthe chosen lysine residue in the CIFN polypeptide.
  • the PEG moiety is linked to a lysine chosen from lys 121 , lys 134 , lys 135 , and lys 165 of the CIFN polypeptide.
  • the PEG is linked to a lysine chosen from lys 121 , lys 134 , lys 135 , and lys 165 of the CIFN polypeptide.
  • the PEG is linked to a lysine chosen from lys 121 , lys 134 , lys 135 , and lys 165 of the CIFN polypeptide.
  • the PEG is linked to a lysine chosen from lys 121 , lys 134 , lys 135 , and lys 165 of the CIFN polypeptide.
  • the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
  • the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
  • the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
  • the invention contemplates embodiments of each such molecule where the CIFN polypeptide is chosen from interferon alpha-coni, interferon alpha-con 2 , and interferon alpha-con 3 , the amino acid sequences of which CIFN polypeptides are disclosed in U.S. Pat. No. 4,695,623. Populations of IFN-a
  • any of the methods of the embodiments may employ a PEGylated IFN-a composition that comprises a population of monopegylated IFNa of one or more species of monopegylated IFNa molecules as described above.
  • the subject composition comprises a population of modified IFN-a polypeptides, each with a single PEG molecule linked to a single amino acid residue ofthe polypeptide.
  • the population comprises a mixture of a first IFN-a polypeptide linked to a PEG molecule at a first amino acid residue; and at least a second IFN-a polypeptide linked to a PEG molecule at a second amino acid residue, wherein the first and second IFN-a polypeptides are the same or different, and wherein the location of the first amino acid residue in the amino acid sequence of the first IFN-a polypeptide is not the same as the location of the second amino acid residue in the second IFN-a polypeptide.
  • a subject composition comprises a population of PEG-modified IFN-a polypeptides, the population comprising an IFN-a polypeptide linked at its amino terminus to a linear PEG molecule; and an IFN-a polypeptide linked to a linear PEG molecule at a lysine residue.
  • a given modified IFN-a species represents from about 0.5% to about 99.5% of the total population of monopegylated IFNa polypeptide molecules in a population, e.g, a given modified IFN-a species represents about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5% of the total population of monopegylated IFN-a polypeptide molecules in a population.
  • a subject composition comprises a population of monopegylated IFN-a polypeptides, which population comprises at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, IFN-a polypeptides linked to PEG at the same site, e.g., at the N-terminal amino acid.
  • a subject composition comprises a population of monopegylated CIFN molecules, the population consisting of one or more species of molecules, where each species of molecules is characterized by a single CIFN polypeptide linked, directly or indirectly in a covalent linkage, to a single linear PEG moiety of about 30 kD in molecular weight, and where the linkage is to either a lysine residue in the CIFN polypeptide, or the N-terminal amino acid residue of the CIFN polypeptide. « ⁇ »- ⁇ .H '..
  • the PEG moiety is attached (directly or via a linker) to a surface-exposed lysine residue.
  • the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 of the CIFN polypeptide.
  • the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys 121 , lys 134 , lys 135 , and lys 165 ofthe CIFN polypeptide.
  • a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different.
  • a subject composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species.
  • the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
  • a subject composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species.
  • the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
  • a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide " " species of molecules "characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different.
  • a subject composition may further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide.
  • a subject composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 , where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species, h all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
  • a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys 121 , lys 134 , lys 135 , and lys 165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different.
  • a subject composition may further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a
  • a subject composition may further comprise at least one ClFN'polypeptide species of molecules characterized by a PEG moiety linked to one of lys 121 , lys 134 , lys 135 , and lys 165 , where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species.
  • the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
  • a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide.
  • a subject composition may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species.
  • the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
  • a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 in a second CIFN polypeptide,
  • the composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys 31 , lys 50 , lys 71 , lys 84 , lys 121 , lys 122 , lys 134 , lys 135 , and lys 165 , where the location ofthe linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location in any other species.
  • the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
  • a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys 121 , lys 134 , lys 135 , and lys 165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys 12 , lys , lys , and lys 165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide
  • the composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys 121 , lys 134 , lys 135 , and lys 165 , where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location ofthe linkage site in any other species.
  • the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
  • a subject composition comprises a monopegylated population of CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface- exposed lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second surface- exposed lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first surface-exposed lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second surface-exposed lysine residue in the amino acid sequence of the second CIFN polypeptide.
  • a subject composition may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species.
  • the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
  • the invention contemplates embodiments where the molecules in each such population comprise a CIFN polypeptide chosen from interferon alpha-com, interferon alpla-con 2 , and interferon alpha-con 3 .
  • Certain embodiments further feature a product that is produced by the process of reacting CIFN polypeptide with a succinimidyl ester of alpha-methoxy, omega- propionylpoly(ethylene glycol) (mPEGspa) that is linear and about 30 kD in molecular weight, where the reactants are initially present at a molar ratio of about 1:1 to about 1:5 CIFN:mPEGspa, and wliere the reaction is conducted at a pH of about 7 to about 9, followed by recovery of the monopegylated CIFN product of the reaction.
  • the reactants are initially present at a molar ratio of about 1:3 CIFN:mPEGspa and the reaction is conducted at a pH of about 8.
  • the reactants are initially present in a molar ratio of 1:2 C ⁇ FN:mPEGspa and the reaction is conducted at a pH of about 8.0.
  • the invention contemplates embodiments where the CIFN reactant is chosen from interferon alpha-coni, interferon alpha-con 2 , and interferon alpha-con 3 .
  • IFN- ⁇ interferon alpha-coni, interferon alpha-con 2 , and interferon alpha-con 3 .
  • interferon-beta includes IFN- ⁇ polypeptides that are naturally occurring; non-naturally-occurring IFN- ⁇ polypeptides; and analogs of naturally occurring or non-naturally occurring IFN- ⁇ that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN- ⁇ .
  • beta interferons may be delivered by the continuous delivery method ofthe present embodiments.
  • Suitable beta interferons include, but are not limited to, naturally-occurring IFN- ⁇ ; IFN- ⁇ la, e.g., Avonex® (Biogen, Inc.), and Rebif® (Serono, SA); IFN- ⁇ lb (Betaseron®; Berlex); and the like.
  • the IFN- ⁇ formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN- ⁇ .
  • IFN- ⁇ polypeptides may be produced by any known method. DNA sequences encoding IFN- ⁇ may be synthesized using standard methods. In many embodiments, J-FN- ⁇ polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN- ⁇ is "recombinant IFN- ⁇ .” Where the host cell is a bacterial host cell, the IFN- ⁇ is modified to comprise an N-terminal methionine.
  • IFN- ⁇ as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
  • IFN-tau may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
  • interferon-tau includes IFN-tau polypeptides that are naturally occurring; non-naturally-occurring IFN-tau polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-tau that retain antiviral activity of a parent naturally- occurring or non-naturally occurring IFN-tau.
  • Suitable tau interferons include, but are not limited to, naturally- occurring IFN-tau; Tauferon® (Pepgen Corp.); and the like.
  • IFN-tau may comprise an amino acid sequence as set forth in any one of GenBank Accession Nos. PI 5696; P56828; P56832; P56829; P56831; Q29429; Q28595; Q28594; S08072; Q08071; Q08070; Q08053; P56830; P28169; P28172; and P28171.
  • the sequence of any known IFN-tau polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
  • a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
  • sequence changes may be substitutions, insertions or deletions.
  • Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
  • Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences ' ""that" "”have ' phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
  • modifications of glycosylation e.g. those made by modifying the glycosylation patterns of a polypeptide during its
  • the IFN-tau formulation may comprise an N-blocked species, wherein the N-te ⁇ ninal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-tau.
  • IFN-tau polypeptides may be produced by any known method. DNA sequences encoding IFN-tau may be synthesized using standard methods. In many embodiments, IFN-tau polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-tau is "recombinant IFN-tau.” Where the host cell is a bacterial host cell, the IFN-tau is modified to comprise an N-terminal methionine.
  • IFN-tau as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like. IFN-?
  • interferon-omega (“IFN-? ”) includes IFN-? polypeptides that are naturally occurring; non-naturally-occurring IFN-? polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-? that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-? .
  • Suitable omega interferon include, but are not limited to, naturally-occurring IFN-? ; recombinant IFN-? , e.g., Biomed 510 (BioMedicines); and the like.
  • Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); " (a'spartic''"'a ⁇ id;' ' '"glutan ⁇ c acid) ' ; (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
  • Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
  • modifications of glycosylation e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps;
  • the IFN-? formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-? .
  • IFN-? polypeptides may be produced by any known method. DNA sequences encoding IFN-? may be synthesized using standard methods. In many embodiments, IFN-? polypeptides are the products of expression of manufactured DNA sequences transfo ⁇ ned or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like), hi these embodiments, the IFN-? is "recombinant IFN-? .” Where the host cell is a bacterial host cell, the IFN-? is modified to comprise an N-terminal methionine.
  • IFN-? as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
  • the interferon receptor agonist is in some embodiments an agonist of a Type III interferon receptor (e.g., "a Type III interferon agonist").
  • Type III interferon agonists include an IL-28b polypeptide; and IL-28a polypeptide; and IL-29 polypeptide; antibody specific for a Type III interferon receptor; and any other agonist of Type III interferon receptor, including non-polypeptide agonists.
  • Type III interferons or “Type III IFNs”
  • Each polypeptide binds a heterodimeric receptor consisting of IL- 10 receptor ⁇ chain and an IL-28 receptor a.
  • the amino acid sequences of IL-28A, IL- 28B, and IL-29 are found under GenBank Accession Nos. NP_742150, NP_742151, and NP_742152, respectively.
  • the amino acid sequence of a Type III IFN polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
  • a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
  • the sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes.
  • Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
  • Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a poTypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
  • modifications of glycosylation e.g. those made by modifying the glycosylation patterns of a poTypeptide during its synthesis and processing or in
  • polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent.
  • the backbone of the peptide may be cyclized to enhance stability (see Friedler et al. (2000) J. Biol. Chem. 275:23783-23789).
  • Analogs may be used that include residues other than naturally occurring L-amino acids, e.g. D-amino acids or " n'5h-haturally ' 'ccuMi ⁇ g ' ''syrithe ' tic amino acids.
  • the protein may be pegylated to enhance stability.
  • the polypeptides may be fused to albumin.
  • polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be dete ⁇ nined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines may be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.
  • Type II interferon receptor agonists include any naturally-occurring or non-naturally-occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor.
  • Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non- peptide chemical agonists; and the like.
  • Type II interferon receptor agonist A specific example of a Type II interferon receptor agonist is IFN-? and variants thereof. While the present embodiments exemplify use of an IFN-? polypeptide, it will be readily apparent that any Type II interferon receptor agonist may be used in a subject method. Interferon-Gamma
  • the nucleic acid sequences encoding IFN- ⁇ polypeptides may be accessed from public databases, e.g., Genbank, journal publications, etc. While various mammalian IFN- ⁇ polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN- ⁇ coding sequence may be found in Genbank, accession numbers XI 3274; N00543; and ⁇ M_000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265; and ' V00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274); and Rinderknecht et al. (1984) J.B.C. 259:6790.
  • IFN-?lb (Actimmune®; human interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinantly in E.coli and is unglycosylated. Rinderl ⁇ iecht et al. (1984) J. Biol. Chem. 259:6790-6797. Recombinant IFN-? as discussed in U.S. Patent No. 6,497,871 is also suitable for use herein.
  • the IFN- ⁇ to be used in the methods of the present embodiments may be any of natural IFN- ⁇ s, recombinant IFN- ⁇ s and the derivatives thereof so far as they have an IFN- ⁇ activity, particularly human IFN- ⁇ activity.
  • Human IFN- ⁇ exhibits the antiviral and anti-proliferative properties characteristic of the interferons, as well as a number of other immunomodulatory activities, as is known in the art.
  • IFN- ⁇ is based on the sequences as provided above, the production of the protein and proteolytic processing may result in processing variants thereof.
  • the unprocessed sequence provided by Gray et al., supra, consists of 166 amino acids (aa).
  • coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN- ⁇ is cleaved after residue 23, to produce a 143 aa protein, or 144 aa if the terminal methionine is present, as required for expression in bacteria.
  • the mature protein may additionally be cleaved at the C terminus after reside 162 (referring to the Gray et al. sequence), resulting in a protein of 139 amino acids, or 140 amino acids if the initial methionine is present, e.g. if required for bacterial expression.
  • the N-terminal methionine is an artifact encoded by the mRNA translational "start" signal AUG that, in the particular case of E. coli expression is not processed away. In other microbial systems or eukaryotic expression systems, methionine may be removed.
  • IFN- ⁇ peptides for use in the subject methods, any of the native IFN- ⁇ peptides, modifications and variants thereof, or a combination of one or more peptides may be used.
  • IFN- ⁇ peptides of interest include fragments, and may be variously truncated at the carboxyl terminus relative to the full sequence. Such fragments continue to exhibit the characteristic properties of human gamma interferon, so long as amino acids 24 to about 149 (numbering from the residues of the unprocessed polypeptide) are present. Extraneous sequences may be substituted for the amino acid sequence following amino acid 155 without loss of activity. See, for example, U.S. Patent No. 5,690,925.
  • Native IFN- ⁇ moieties include molecules variously extending from amino acid residues 24-150; 24-151, 24-152; 24- 153, 24-155; and 24-157. Any of these variants, and other variants known in the art and having IFN- ⁇ activity, may be used in the present methods.
  • the sequence of the IFN- ⁇ polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
  • a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e., will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
  • the sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non- conservative changes.
  • Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
  • Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like.
  • One embodiment contemplates the use of IFN-? variants with one or more non- naturally occurring glycosylation and/or pegylation sites that are engineered to provide glycosyl- and/or PEG-derivatized polypeptides with reduced serum clearance, such as the IFN- ? polypeptide variants described in International Patent Publication No. WO 01/36001.
  • glycosylation e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g., by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes.
  • sequences that have phosphorylated amino acid residues e.g., phosphotyrosine, phosphoserine, or phosphothreonine.
  • polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent.
  • the backbone of the peptide may be cyclized to enhance stability (see Friedler et al. (2000) J. Biol. Chem. 275:23783-23789).
  • Analogs maybe used "that include” residues ' "other "th ' an naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids.
  • the protein may be pegylated to enhance stability.
  • polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be dete ⁇ nined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines may be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.
  • the polypeptides may also be isolated and purified in accordance with conventional methods of recombinant synthesis.
  • a lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique.
  • the compositions which are used will comprise at least 20% by weight of the desired product, more usually at least about 75% by weight, preferably at least about 95% by weight, and for therapeutic purposes, usually at least about 99.5% by weight, in relation to contaminants related to the method of preparation of the product and its purification. Usually, the percentages will be based upon total protein.
  • Pirfenidone (5-methyl-l-phenyl-2-(lH)-pyridone) and specific pirfenidone analogs are disclosed for the treatment of fibrotic conditions.
  • a "fibrotic condition” is one that is amenable to treatment by administration of a compound having anti-fibrotic activity.
  • Ri carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alkyls (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.
  • Ri may further include substitutions on the carbocyclic or heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4- nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2, 5- dichlorocyclohexyl, guanidinyl-cyclohexenyl and the like.
  • substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4- nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2, 5- dichlorocycl
  • R 2 alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.
  • X may be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring.
  • the substituents may be the same or different.
  • Substituents may include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like.
  • the substituents may be optionally further substituted with 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halo groups. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4- nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.
  • Thymosin-a (ZadaxinTM; available from SciClone Pha ⁇ naceuticals, Inc., San Mateo, CA) is a synthetic form of thymosin alpha 1, a hormone found naturally in the circulation and produced by the thymus gland. Thymosin-a increases activity of T cells and NK cells. ZadaxinTM formulated for subcutaneous injection is a purified sterile lyophilized preparation of chemically synthesized thymosin alpha 1 identical to human thymosin alpha 1.
  • Thymosin alpha 1 is an acetylated polypeptide with the following sequence: Ac - Ser - Asp - Ala - Ala - Val - Asp - Thr - Ser - Ser - Glu - lie - Thr - Thr - Lys - Asp - Leu - Lys - Glu - Lys - Lys - Glu - Val - Val - Glu - Glu - Ala - Glu - Asn - OH, and having a molecular weight of 3,108 daltons.
  • the lyophilized preparation contains 1.6 mg synthetic thymosin-a, 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8.
  • Ribavirin l- ⁇ -D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide
  • ICN Pharmaceuticals, Inc. Costa Mesa, Calif.
  • the embodiments also contemplate use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830).
  • the ribavirin may be administered orally in capsule or tablet form.
  • ribavirin As they become available are contemplated, such as by nasal spray, transdermally, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.
  • Ribavirin is generally administered in an amount ranging from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day. In some embodiments, ribavirin is administered throughout the entire course of NS3 inhibitor therapy. Levovirin
  • Levovirin is the L-enantiomer of ribavirin, and exhibits the property of enhancing a Thl immune response over a Th2 immune response. Levovirin is manufactured by ICN Pha ⁇ naceuticals.
  • Levovirin has the following structure:
  • Viramidine is a 3-carboxamidine derivative of ribavirin, and acts as a prodrug of ribavirin. It is efficiently converted to ribavirin by adenosine deaminases.
  • Viramidine has the following structure:
  • Nucleoside analogs that are suitable for use in a subject combination therapy include, but are not limited to, ribavirin, levovirin, viramidine, isatoribine, an L- ribofuranosyl nucleoside as disclosed in U.S. Patent No. 5,559,101 and encompassed by Formula I of U.S. Patent No.
  • a subject method comprises administering an effective amount of a NS3 inhibitor and an effective amount of a tumor necrosis factor-a (TNF-a) antagonist.
  • TNF-a antagonists for use herein include agents that decrease the level of TNF-a synthesis, agents that block or inhibit the binding of TNF-a to a TNF-a receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction.
  • TNFR TNF-a receptor
  • every reference to a "TNF-a antagonist" or “TNF antagonist” herein will be understood to mean a TNF-a antagonist other than pirfenidone or a pirfenidone analog.
  • TNF receptor polypeptide and "TNFR polypeptide” refer to polypeptides derived from TNFR (from any species) which are capable of binding TNF.
  • TNFR Two distinct cell-surface TNFRs have described: Type II TNFR (or p75 TNFR or TNFRII) and Type I TNFR (or p55 TNFR or TNFRI).
  • Type II TNFR or p75 TNFR or TNFRII
  • Type I TNFR or p55 TNFR or TNFRI
  • the mature full- length human p75 TNFR is a glycoprotein having a molecular weight of about 75-80 kilodaltons (kD).
  • the mature full-length human p55 TNFR is a glycoprotein having a molecular weight of about 55-60 kD.
  • TNFR polypeptides are derived from TNFR Type I and/or TNFR type li.
  • Soluble TNFR includes p75 TNFR polypeptide; fusions of p75 TNFR with heterologous fusion partners, e.g., the Fc portion of an immunoglobulin.
  • ' [0 ' 652J TNFR " polypeptide may be an intact TNFR or a suitable fragment of
  • TNFR polypeptides including soluble TNFR polypeptides, appropriate for use in the present embodiments.
  • the TNFR polypeptide comprises an extracellular domain of TNFR.
  • the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR linked to a constant domain of an immunoglobulin molecule.
  • the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 TNFR linked to a constant domain of an IgGl molecule.
  • an lg used for fusion proteins is human, e.g., human IgGl .
  • TNFR polypeptides may be used in the present embodiments.
  • Multivalent forms of TNFR polypeptides possess more than one TNF binding site.
  • the TNFR is a bivalent, or dimeric, form of TNFR.
  • a chimeric antibody polypeptide with TNFR extracellular domains substituted for the variable domains of either or both ofthe immunoglobulin heavy or light chains would provide a TNFR polypeptide for the present embodiments.
  • TNFR:Fc chimeric TNFR:antibody polypeptide
  • a subject method involves administration of an effective amount of the soluble TNFR ENBREL® .
  • ENBREL® is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNFR linked to the Fc portion of human IgGl.
  • the Fc component of ENBREL® contains the CH2 domain, the CH3 domain and hinge region, but not the CHI domain of IgGl.
  • ENBREL® is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al.
  • Monoclonal antibodies that bind TNF-a.
  • Monoclonal antibodies include "humanized” mouse monoclonal antibodies; chimeric antibodies; monoclonal antibodies that are at least about 80%, at least about 90%, at least about 95%, or 100% human in amino acid sequence; and the like. See, e.g., WO 90/10077; " WO" 90 O ' r5;” “ arid "' WO 92/02 ' ⁇ 90.
  • Suitable monoclonal antibodies include antibody fragments, such as Fv, F(ab') 2 and Fab; synthetic antibodies; artificial antibodies; phage display antibodies; and the like.
  • Suitable monoclonal antibodies include Infliximab (REMICADE®, Centocor); and Adalimumab (HUMIRATM, Abbott).
  • REMICADE® is a chimeric monoclonal anti-TNF-a antibody that includes about 25% mouse amino acid sequence and about 75% human amino acid sequence.
  • REMICADE® comprises a variable region of a mouse monoclonal anti-TNF-a antibody fused to the constant region of a human IgGl.
  • HUMIRATM is a human, full-length IgGl monoclonal antibody that was identified using phage display technology. Piascik (2003) J. Am. Pharm. Assoc. 43:327-328.
  • SAPK inhibitors are known in the art, and include, but are not limited to 2-alkyl imidazoles disclosed in U.S. Patent No. 6,548,520; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,489,325; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,569,871; heteroaryl aminophenyl ketone compounds disclosed in Published U.S. Patent Application No. 2003/0073832; pyridyl imidazole compounds disclosed in U.S. Patent No.
  • a stress-activated protein kinase is a member of a family of mitogen-activated protein kinases which are activated in response to stress stimuli.
  • SAPK include, but are not limited to, p38 (Lee et al. (1994) Nature 372:739) and c-jun N-terminal kinase (JNK).
  • TNF antagonist activity may be assessed with a cell-based competitive binding assay.
  • radiolabeled TNF is mixed with serially diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions of the suspension are centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions determined. TNF antagonist activity is assessed by inhibition of TNF binding to the cells in the presence ofthe TNF antagonist.
  • TNF antagonists may be analyzed for the ability to neutralize TNF activity in vitro in a bioassay using cells susceptible to the cytotoxic activity of TNF as target cells.
  • target cells cultured with TNF, are treated with varying amounts of TNF antagonist and subsequently are examined for cytolysis.
  • TNF antagonist activity is assessed by a decrease in TNF-induced target cell cytolysis in the presence ofthe TNF antagonist.
  • Some embodiments provides a method comprising administering an effective amount of a subject NS3 inhibitor and an effective amount of an HCN non- structural protein-5 ( ⁇ S5; RNA-dependent RNA polymerase) inhibitor to an HCV patient in need thereof.
  • Suitable NS5B inhibitors include, but are not limited to, a compound as disclosed in U.S. Patent No. 6,479,508 (Boehringer-lngelheim); a compound as disclosed in any of International Patent Application Nos. PCT/CA02/01127, PCT/CA02/01128, and PCT/CA02/01129, all filed on July 18, 2002 by Boehringer Ingelheim; a compound as disclosed in U.S. Patent No.
  • NS5 inhibitors that are specific NS5 inhibitors, e.g., NS5 inhibitors that inhibit NS5 RNA-dependent RNA polymerase and that lack significant inhibitory effects toward other RNA dependent RNA polymerases and toward DNA dependent RNA polymerases.
  • Additional antiviral therapeutic agents that may be administered in combination with a subject NS3 inhibitor compound include, but are not limited to, " irihiBitors “' of " “ ih ⁇ sirie” mohdphbsphate dehydrogenase (IMPDH); ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors; and the like.
  • IMPDH mohdphbsphate dehydrogenase
  • ribozymes that are complementary to viral nucleotide sequences
  • antisense RNA inhibitors and the like.
  • IMPDH inhibitors that are suitable for use in a subject combination therapy include, but are not limited to, NX-497 ((S)-N-3-[3-(3-methoxy-4-oxazol-5-yl- phenyl)-ureido]-benzyl-carbamic acid tetrahydrofi ⁇ ran-3-yl-ester); Vertex Pha ⁇ naceuticals; see, e.g., Markland et al. (2000) Antimicrob. Agents Chemother.
  • Ribozyme and antisense antiviral agents that are suitable for use in a subject combination therapy include, but are not limited to, ISIS 14803 (ISIS Pharmaceuticals/Elan Corporation; see, e.g., Witherell (2001) Curr Opin Investig Drugs. 2(11):1523-9); HeptazymeTM; and the like.
  • an additional antiviral agent is administered during the entire course of ⁇ S3 inhibitor compound treatment.
  • an additional antiviral agent is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent treatment may begin before the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment may begin after the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment may begin after the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; or the additional antiviral agent treatment may begin before the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends.
  • the active agent(s) e.g., compound of formula I, and optionally one or more additional antiviral agents
  • the agent may be incorporated into a variety of formulations for therapeutic administration.
  • agents “of the present embodiments may be formulated into pha ⁇ naceutical compositions by combination with appropriate, pha ⁇ naceutically acceptable earners or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous fo ⁇ ns, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.
  • compositions are provided in formulation with a pha ⁇ naceutically acceptable excipient(s).
  • a pha ⁇ naceutically acceptable excipient A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pha ⁇ nacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Fo ⁇ ns and Drug Delivery Systems (1999) H.C.
  • compositions such as vehicles, adjuvants, carriers or diluents
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • an agent is formulated in an aqueous buffer.
  • Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers varying in strengths from 5mM to lOOmM.
  • the aqueous buffer includes reagents that provide for an isotonic solution. Such reagents include, but are not limited to, sodium chloride; and sugars e.g., mannitol, dextrose, sucrose, and the like.
  • the aqueous buffer further includes a non- ionic surfactant such as polysorbate 20 or 80.
  • the formulations may further include a preservative.
  • Suitable preservatives include, but are not limited to, a benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the formulation is stored at about 4°C. Formulations may also be lyophilized, in which case they generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, ' f' tyop ⁇ i ⁇ zed formulations may be stored over extended periods of time, even at ambient temperatures.
  • cryoprotectants such as sucrose, trehalose, lactose, maltose, ' f' tyop ⁇ i ⁇ zed formulations may be stored over extended periods of time, even at ambient temperatures.
  • administration of the agents may be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdennal, intratracheal,etc, administration.
  • administration is by bolus injection, e.g., subcutaneous bolus injection, intramuscular bolus injection, and the like.
  • compositions of the present embodiments may be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection are prefened.
  • Subcutaneous administration of a pharmaceutical composition of the present embodiments is accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328.
  • a combination of a subcutaneous injection port and a device for administration of a pharmaceutical composition of the embodiments to a patient through the port is referred to herein as "a subcutaneous injection port delivery system.”
  • subcutaneous administration is achieved by bolus delivery by needle and syringe.
  • the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • the agents may be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
  • conventional additives such as lactose, mannitol, corn starch or potato starch
  • binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins
  • disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate
  • the agents may be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic " acids or propylene '' glycol; and if " desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an aqueous or nonaqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic " acids or propylene '' glycol
  • conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • the agents may be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • the compounds of the present embodiments may be administered rectally via a suppository.
  • the suppository may include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
  • Unit dosage fo ⁇ ns for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predete ⁇ nined amount of the composition containing one or more inhibitors.
  • unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds of the embodiments calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms ofthe present embodiments depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
  • the pha ⁇ naceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents, are readily available to the public.
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • a subject method will in some embodiments be carried out by administering an NS3 inhibitor that is a compound of formulas I-XIX, and optionally one or more additional antiviral agent(s).
  • the method further includes administration of one or more interferon receptor agonist(s).
  • Interferon receptor agonists are described above.
  • the method further includes administration of pirfenidone or a pirfenidone analog. Pirfenidone and pirfenidone analogs are described above.
  • Additional antiviral agents that are suitable for use in combination therapy include, but are not limited to, nucleotide and nucleoside analogs.
  • Non-limiting examples include azidothymidine (AZT) (zidovudine), and analogs and derivatives thereof; 2',3'-dideoxyinosine (DDI) (didanosine), and analogs and derivatives thereof; 2',3'- dideoxycytidine (DDC) (dideoxycytidine), and analogs and derivatives thereof; 2'3,'- didehydro-2',3'-dideoxythymidine (D4T) (stavudine), and analogs and derivatives thereof; combivir; abacavir; adefovir dipoxil; cidofovir; ribavirin; ribavirin analogs; and the like.
  • the method further includes administration of ribavirin.
  • Ribavirin, l- ⁇ -D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif, is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. The embodiments also contemplate use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830).
  • the ribavirin may be administered orally in capsule or tablet form, or in the same or different administration form and in the same or different route as the interferon receptor agonist.
  • other types of administration of both medicaments as they become available are contemplated, such as by nasal spray, transdermally, intravenously, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.
  • an additional antiviral agent is administered during the entire course of NS3 inhibitor compound treatment.
  • an additional antiviral agent is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent treatment may begin before the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment may begin after the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment may begin after the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; or the additional antiviral agent treatment may begin before the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends.
  • the ' N ' S 3 " inhibitor compounds ofthe embodiments are suitable for use in formulations that require good solubility in water.
  • the compounds of the embodiments may be used in formulations that are free of sugar alcohols and polyols, such as trihydric or higher sugar alcohols, e.g., glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol, and free of other alcohols, such as propylene glycol and poly (ethylene glycol) (PEG), or other agent used to compensate for inadequate solubility in water, hi one aspect, the embodiments provide the subject NS3 inhibitor compound in a capsule, tablet or caplet formulation, where the capsule, tablet or caplet fonnulation provides an adequate bioavailability because of the superior water solubility of the compound.
  • the solubility of the subject compound permits the administration of dosages equal to or greater than 1
  • the NS3 inhibitor compound of the embodiments may be used in acute or chronic therapy for HCV disease.
  • the NS3 inhibitor compound is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
  • the NS3 inhibitor compound may be administered 5 times per day, 4 times per day, tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly. In other embodiments, the NS3 inhibitor compound is administered as a continuous infusion.
  • an NS3 inhibitor compound of the embodiments is administered orally.
  • an ⁇ S3 inhibitor compound of the embodiments may be administered to the patient at a dosage from about 0.01 mg to about 100 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day.
  • the NS3 inhibitor compound is administered at a dosage of about 0.5 mg to about 75 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day.
  • the " amount of active ingredient that may be combined with carrier materials to produce a dosage form may vary depending on the host to be treated and the particular mode of administration.
  • a typical pharmaceutical preparation may contain from about 5% to about 95% active ingredient (w/w).
  • the pha ⁇ naceutical preparation may contain from about 20% to about 80% active ingredient.
  • dose levels may vary as a function of the specific NS3 inhibitor compound, the severity of the symptoms and the susceptibility of the subject to side effects.
  • Preferred dosages for a given NS3 inhibitor compound are readily determinable by those of skill in the art by a variety of means.
  • a preferred means is to measure the physiological potency of a given interferon receptor agonist.
  • multiple doses of NS3 inhibitor compound are administered.
  • an NS3 inhibitor compound is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ribavirin.
  • Ribavirin may be administered in dosages of about 400 mg, about 800 mg, about 1000 mg, or about 1200 mg per day.
  • One embodiment provides any ofthe above-described methods modified to include co-administering to the patient a therapeutically effective amount of ribavirin for the duration ofthe desired course of NS3 inhibitor compound treatment.
  • Another embodiment provides any of the above-described methods modified to include co-administering to the patient about 800 mg to about 1200 mg ribavirin "orally" per day “for "the duration of the desired course of NS3 inhibitor compound treatment.
  • Another embodiment provides any of the above-described methods modified to include co-administering to the patient (a) 1000 mg ribavirin orally per day if the patient has a body weight less than 75 kg or (b) 1200 mg ribavirin orally per day if the patient has a body weight greater than or equal to 75 kg, where the daily dosage of ribavirin is optionally divided into to 2 doses for the duration of the desired course of NS3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of levovirin.
  • Levovirin is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day.
  • levovirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day for the desired course of NS3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of viramidine.
  • Viramidine is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day.
  • viramidine is administered orally in dosages of about 800, or about 1600 mg per day for the desired course of NS3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of thymosin-a.
  • Thymosin-a (ZadaxinTM) is generally administered by subcutaneous injection. Thymosin-a may be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously for the desired course of NS3 inhibitor compound treatment. In many embodiments, thymosin-a is administered twice per week for the desired course of NS3 inhibitor compound treatment.
  • Effective dosages of thymosin-a range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg.
  • thymosin-a is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
  • Thymosin-a may be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • thymosin-a is administered for the desired course of NS3 inhibitor compound treatment.
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of an interferon receptor agonist.
  • a compound of formula I and a Type I or III interferon receptor agonist are co-administered in the treatment methods ofthe embodiments.
  • Type I interferon receptor agonists suitable for use herein include any interferon-a (IFN-a).
  • the interferon-a is a PEGylated interferon-a.
  • the interferon-a is a consensus interferon, such as INFERGEN® interferon alfacon-1.
  • the interferon-a is a monoPEG (30 kD, linear)-ylated consensus interferon.
  • Effective dosages of an IFN-a range from about 3 ⁇ g to about 27 ⁇ g, from about 3 MU to about 10 MU, from about 90 ⁇ g to about 180 ⁇ g, or from about 18 ⁇ g to "about ⁇ g " " ⁇ ffec ⁇ ive dosages of Infergen® consensus IFN-a include about 3 ⁇ g, about 6 ⁇ g, about 9 ⁇ g, about 12 ⁇ g, about 15 ⁇ g, about 18 ⁇ g, about 21 ⁇ g, about 24 ⁇ g, about 27 ⁇ g, or about 30 ⁇ g, of drag per dose.
  • Effective dosages of IFN-a2a and IFN-a2b range from 3 million Units (MU) to 10 MU per dose.
  • Effective dosages of PEGASYS®PEGylated IFN-a2a contain an amount of about 90 ⁇ g to 270 ⁇ g, or about 180 ⁇ g, of drag per dose.
  • Effective dosages of PEG-INTRON®PEGylated IFN-a2b contain an amount of about 0.5 ⁇ g to 3.0 ⁇ g of drug per kg of body weight per dose.
  • Effective dosages of PEGylated consensus interferon (PEG-CIFN) contain an amount of about 18 ⁇ g to about 90 ⁇ g, or from about 27 ⁇ g to about 60 ⁇ g, or about 45 ⁇ g, of CIFN amino acid weight per dose of PEG-CIFN.
  • Effective dosages of monoPEG (30 kD, linear)-ylated CIFN contain an amount of about 45 ⁇ g to about 270 ⁇ g, or about 60 ⁇ g to about 180 ⁇ g, or about 90 ⁇ g to about 120 ⁇ g, of drug per dose.
  • IFN-a may be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
  • the Type I or Type III interferon receptor agonist and/or the Type II interferon receptor agonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
  • Dosage regimens may include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or monthly administrations.
  • Some embodiments provide any of the above-described methods in which the desired dosage of IFN-a is administered subcutaneously to the patient by bolus delivery qd, qod, tiw, biw, qw, qow, three times per month, or monthly, or is administered subcutaneously to the patient per day by substantially continuous or continuous delivery, for the desired treatment duration.
  • Other embodiments provide any of the above-described methods in which the desired dosage of PEGylated IFN-a (PEG-IFN-a) is administered subcutaneously to the patient by bolus delivery qw, qow, three times per month, or monthly for the desired treatment duration.
  • an NS3 inhibitor compound and a Type II interferon receptor agonist are co-administered in the treatment methods of the embodiments.
  • Type II interferon receptor agonists suitable tor use herein include any interferon-? (IFN-?).
  • Effective dosages of IFN- ⁇ may range from about 0.5 ⁇ g/m 2 to about 500 ⁇ g/m 2 , usually from about 1.5 ⁇ g/m 2 to 200 ⁇ g/m 2 , depending on the size of the patient. This activity is based on 10 6 international units (U) per 50 ⁇ g of protein. IFN-? may be administered daily, every other day, three times a week, or substantially continuously or continuously.
  • IFN-? is administered to an individual in a unit dosage fo ⁇ n of from about 25 ⁇ g to about 500 ⁇ g, from about 50 ⁇ g to about 400 ⁇ g, or from about 100 ⁇ g to about 300 ⁇ g. In particular embodiments of interest, the dose is about 200 ⁇ g IFN-?. hi many embodiments of interest, IFN-?lb is administered.
  • the amount of IFN-? per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 ⁇ g IFN-? per kg body weight to about 1.48 ⁇ g IFN-? per kg body weight.
  • an IFN-? dosage ranges from about 150 ⁇ g/m 2 to about 20 ⁇ g/m 2 .
  • an IFN-? dosage ranges from about 20 ⁇ g/m 2 to about 30 ⁇ g/m 2 , from about 30 ⁇ g/m 2 to about 40 ⁇ g/m 2 , from about 40 ⁇ g/m 2 to about
  • the dosage groups range from about 25 ⁇ g/m to about 100 ⁇ g/m . h other embodiments, the dosage groups range from about 25 ⁇ g/m 2 to about 50 ⁇ g/m 2 .
  • a Type I or a Type III interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen.
  • the first dosing regimen of Type I or a Type III interferon receptor agonist generally involves administration of a higher dosage of the Type I or Type III interferon receptor agonist.
  • the first dosing regimen comprises administering CIFN at about 9 ⁇ g, about 15 ⁇ g, about 18 ⁇ g, or about 27 ⁇ g.
  • the first dosing regimen may encompass a single dosing event, or " ait least two o more dosing events.
  • the first dosing regimen ofthe Type I or Type III interferon receptor agonist may be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
  • the first dosing regimen of the Type I or Type III interferon receptor agonist is administered for a first period of time, which time period may be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.
  • the second dosing regimen of the Type I or Type III interferon receptor agonist (also referred to as "the maintenance dose”) generally involves administration of a lower amount ofthe Type I or Type III interferon receptor agonist.
  • the second dosing regimen comprises administering CIFN at a dose of at least about 3 ⁇ g, at least about 9 ⁇ g, at least about 15 ⁇ g, or at least about 18 ⁇ g.
  • the second dosing regimen may encompass a single dosing event, or at least two or more dosing events.
  • the second dosing regimen of the Type I or Type III interferon receptor agonist may be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
  • a "priming" dose of a Type II interferon receptor agonist (e.g., IFN-?) is included.
  • IFN-? is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type III interferon receptor agonist. This period of time is referred to as the "priming" phase.
  • the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type III interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist. In these embodiments, the total time of treatment with Type II interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days, hi still other embodiments, the " type II Interferon ' receptor agonist treatment is discontinued once Type I or a Type III interferon receptor agonist treatment begins.
  • the Type I or Type III interferon receptor agonist is administered in single dosing regimen.
  • the dose of CIFN is generally in a range of from about 3 ⁇ g to about 15 ⁇ g, or from about 9 ⁇ g to about 15 ⁇ g.
  • the dose of Type I or a Type III interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times per month, once monthly, or substantially continuously.
  • the dose of the Type I or Type III interferon receptor agonist is administered for a period of time, which period may be, for example, from at least about 24 weeks to at least about 48 weeks, or longer.
  • a "priming" dose of a Type II interferon receptor agonist (e.g., IFN-?) is included.
  • IFN-? is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type III interferon receptor agonist. This period of time is referred to as the "priming" phase.
  • the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type III interferon receptor agonist.
  • the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist.
  • the total time of treatment with the Type II interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days.
  • Type II interferon receptor agonist treatment is discontinued once Type I or a Type III interferon receptor agonist treatment begins.
  • an NS3 inhibitor compound, a Type I or III interferon receptor agonist, and a Type II interferon receptor agonist are co-administered for the desired duration of treatment in the methods of the embodiments.
  • an NS3 inhibitor compound, an interferon-a, and an interferon-? are co- administered for the desired duration of treatment in the methods ofthe embodiments.
  • Some embodiments provide methods using an amount of a Type I or Type III interferon receptor agonist, a Type II interferon receptor agonist, and an NS3 mnitutor compound, effective for the treatment of HCV infection in a patient.
  • the embodiments provide methods using an effective amount of an IFN-a, IFN-?, and an NS3 inhibitor compound in the treatment of HCV infection in a patient.
  • One embodiment provides a method using an effective amount of a consensus IFN-a, IFN-? and an NS3 inhibitor compound in the treatment of HCV infection in a patient.
  • an effective amount of a consensus interferon (CIFN) and IFN-? suitable for use in the methods ofthe embodiments is provided by a dosage ratio of 1 ⁇ g CIFN: 10 ⁇ g IFN-?, where both CIFN and IFN-? are unPEGylated and unglycosylated species.
  • One embodiment provides any ofthe above-described methods modified to use an effective amount of INFERGEN®consensus IFN-a and IFN-? in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 30 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-?
  • NS3 inhibitor compound containing an amount of about 10 ⁇ g to about 300 ⁇ g of drug per dose of IFN-?, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN-a and IFN-? in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 9 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-?
  • NS3 inhibitor compound containing an amount of about 10 ⁇ g to about 100 ⁇ g of drug per dose of IFN-?, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN-a and IFN-? in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g of drug per dose of INFERGEN®, ' subcutaneously qd, ' q ⁇ "d,' "' tiw, " biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of TEN-?
  • NS3 inhibitor compound containing an amount of about 10 ⁇ g to about 50 ⁇ g of drug per dose of IFN-?, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN-a and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 9 ⁇ g of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-?
  • NS3 inhibitor compound containing an amount of about 90 ⁇ g to about 100 ⁇ g of drug per dose of IFN-?, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN-a and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 30 ⁇ g of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-?
  • NS3 inhibitor compound containing an amount of about 200 ⁇ g to about 300 ⁇ g of drug per dose of IFN-?, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-a and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 4 ⁇ g to about 60 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-?
  • PEG-CIFN PEGylated consensus IFN-a
  • NS3 inhibitor compound containing an amount of about 30 ⁇ g to about 1,000 ⁇ g of drag per week in divided doses " administered " subcutaneously qd, " qod, tiw, biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-a and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 18 ⁇ g to about 24 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of 1FN-?
  • PEG-CIFN PEGylated consensus IFN-a
  • NS3 inhibitor compound containing an amount of about 100 ⁇ g to about 300 ⁇ g of drag per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • an effective amount of IFN-a 2a or 2b or 2c and IFN-? suitable for use in the methods of the embodiments is provided by a dosage ratio of 1 million Units (MU) IFN-a 2a or 2b or 2c : 30 ⁇ g IFN-?, where both IFN-a 2a or 2b or 2c and IFN-? are unPEGylated and unglycosylated species.
  • MU 1 million Units
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drag per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-?
  • NS3 inhibitor compound containing an amount of about 30 ⁇ g to about 600 ⁇ g of drag per dose of IFN-?, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-?
  • a dosage of IFN-a 2a, 2b or 2c containing an amount of about 10 MU of drag per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-? containing an amount of about 300 ⁇ g of drug per dose of IFN-?, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYS®PEGylated TFN-a2a and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 90 ⁇ g to about 360 ⁇ g, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-?
  • NS3 inhibitor compound containing an amount of about 30 ⁇ g to about 1,000 ⁇ g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYS®PEGylated IFN-a2a and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 180 ⁇ g of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-? containing an amount of about 100 ⁇ g to about 300 ⁇ g, of drag per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated TEN-a2b and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 ⁇ g to about 3.0 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IJPN-?
  • NS3 inhibitor compound containing an amount of about 30 ⁇ g to about 1,000 ⁇ g of drug per week administered in " divided 'doses ' " subcutaneously " qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN-a2b and IFN-? in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 1.5 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-?
  • NS3 inhibitor compound containing an amount of about 100 ⁇ g to about 300 ⁇ g of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered subcutaneously qd or tiw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered subcutaneously qd or tiw; 50 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered subcutaneously qd or tiw; 100 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered subcutaneously qd or tiw; and 50 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered subcutaneously qd or tiw; and 100 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered subcutaneously qd or tiw; 25 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered subcutaneously qd or tiw; 200 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered subcutaneously qd or tiw; and 25 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN-a administered su cufaneou ' s ⁇ y' " qd ⁇ r iw; " and 200 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; and 50 ⁇ g Actimmune® human IFN- ?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a ' ' admimstefed " 'subcutahebusly every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; and 50 ⁇ g Actimmune® human IFN- ?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- " a IdMissered's ⁇ Bcuf-ihebusly every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN-?lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
  • ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- a administered subcutaneously every 10 days or qw; and 50 ⁇ g Actimmune® human IFN- ?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • One embodiment provides any ofthe above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ' a adminisfefed ' subcutanebusly every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ?lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
  • any of the above-described methods involving administering an NS3 inhibitor, a Type I interferon receptor agonist (e.g., an IFN-a), and a Type II interferon receptor agonist (e.g., an IFN-?), may be augmented by administration of an effective amount of a TNF-a antagonist (e.g., a TNF-a antagonist other than pirfenidone or a pirfenidone analog).
  • a TNF-a antagonists e.g., a TNF-a antagonist other than pirfenidone or a pirfenidone analog.
  • Exemplary, non-limiting TNF-a antagonists that are suitable for use in such combination therapies include ENBREL®, REMICADE®, and HUMIRATM.
  • One embodiment provides a method using an effective amount of ENBREL®; an effective amount of IFN-a; an effective amount of IFN-?; and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage ENBREL® containing an amount of from about 0.1 ⁇ g to about 23 mg per dose, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment.
  • One embodiment provides a method using an effective amount of REMICADE®, an effective amount of IFN-a with or without an effective amount of IFN-?; and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of REMICADE® containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE®, intravenously qd, qod, tiw, biw,
  • One embodiment provides a method using an effective amount of HUMIRATM an effective amount of IFN-a; an effective amount of IFN-?; and an effective amount or an ⁇ M&J inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of HUMIRATM containing an amount of from about 0.1 ⁇ g to about 35 mg, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRATM, subcutaneously qd, qod, tiw, biw, qw, qow, tliree times per month,
  • the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of pirfenidone or a pirfenidone analog.
  • an NS3 inhibitor compound, one or more interferon receptor agonist(s), and pirfenidone or pirfenidone analog are co-administered in the treatment methods of the embodiments.
  • an NS3 inhibitor compound, a Type I interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered.
  • an NS3 inhibitor compound, a Type I interferon receptor agonist, a Type II interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered.
  • Type I interferon receptor agonists suitable for use herein include any IFN-a, such as interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, and PEGylated IFN-a 's, such as peginterferon alfa- 2a, peginterferon alfa-2b, and PEGylated consensus interferons, such as monoPEG (30 kD, linear)-ylated consensus interferon.
  • Type II interferon receptor agonists suitable for use herein include any interferon-?.
  • Pirfenidone or a pirfenidone analog may be administered once per month, twice per month, tliree times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • Effective dosages of pirfenidone or a specific pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally in one to five divided doses per day.
  • Other doses and fo ⁇ nulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822.
  • One embodiment provides any ofthe above-described methods modified to include co-administering to the patient a therapeutically effective amount of pirfenidone or a pirfenidone analog for the duration of the desired course of NS3 inhibitor compound treatment.

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Abstract

La présente invention concerne des composés représentés par les formules générales (I à XIX), ainsi que des compositions, et notamment des compositions pharmaceutiques à base d'un composé de l'invention. L'invention concerne également un procédé permettant de traiter des infections flavivirales, hépatite C comprise, ainsi que la fibrose hépatique, en administrant à l'individu atteint une quantité suffisante d'un composé ou d'une composition de l'invention.
PCT/US2005/010494 2004-03-30 2005-03-29 Composes macrocycliques inhibiteurs de replication virale WO2005095403A2 (fr)

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EA200601467A EA012389B1 (ru) 2004-03-30 2005-03-29 Макроциклические соединения в качестве ингибиторов вирусной репликации
UAA200611368A UA91677C2 (ru) 2004-03-30 2005-03-29 Макроциклические соединения как ингибиторы вирусной репликации
JP2007506466A JP4950026B2 (ja) 2004-03-30 2005-03-29 ウイルス複製阻害剤としての大環状化合物
NZ549697A NZ549697A (en) 2004-03-30 2005-03-29 Macrocyclic compounds as inhibitors of viral replication
BRPI0509467-4A BRPI0509467A (pt) 2004-03-30 2005-03-29 compostos macrocìclicos como inibidores de replicação viral
EP05757750A EP1749007A2 (fr) 2004-03-30 2005-03-29 Composes macrocycliques inhibiteurs de replication virale
AU2005228894A AU2005228894B9 (en) 2004-03-30 2005-03-29 Macrocyclic compounds as inhibitors of viral replication
CA2560897A CA2560897C (fr) 2004-03-30 2005-03-29 Composes macrocycliques inhibiteurs de replication virale
IL177917A IL177917A0 (en) 2004-03-30 2006-09-06 Macrocyclic compounds as inhibitors of viral replication
TNP2006000308A TNSN06308A1 (en) 2004-03-30 2006-09-27 Macrocyclic compounds as inhibitors of viral replication
NO20064933A NO20064933L (no) 2004-03-30 2006-10-27 Makrosykliske forbindelser som inhibitorer av viral replikasjon
IS8563A IS8563A (is) 2004-09-22 2006-10-30 Makrósýklísk efnasambönd sem hindra veirueftirmyndun

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