WO2016182934A1 - Anti-viral compounds - Google Patents

Anti-viral compounds Download PDF

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Publication number
WO2016182934A1
WO2016182934A1 PCT/US2016/031281 US2016031281W WO2016182934A1 WO 2016182934 A1 WO2016182934 A1 WO 2016182934A1 US 2016031281 W US2016031281 W US 2016031281W WO 2016182934 A1 WO2016182934 A1 WO 2016182934A1
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WO
WIPO (PCT)
Prior art keywords
compound
weeks
formula
hcv
invention features
Prior art date
Application number
PCT/US2016/031281
Other languages
French (fr)
Inventor
Hui-Ju J. CHEN
Sanjay Chemburkar
David A. Degoey
Vikram KALTHOD
Allan C. Krueger
John T. Randolph
Rolf Wagner
Original Assignee
Abbvie Inc.
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Publication of WO2016182934A1 publication Critical patent/WO2016182934A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/30—Only oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
    • C07F9/6521—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the present invention relates to compounds effective in inhibiting replication of Hepatitis C virus ("HCV").
  • HCV Hepatitis C virus
  • the present invention also relates to compositions comprising these compounds and methods of using these compounds to treat HCV infection.
  • the HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family.
  • the enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame.
  • the open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids.
  • the polyprotein comprises a core protein, envelope proteins El and E2, a membrane bound protein p7, and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.
  • Chronic HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma.
  • Chronic hepatitis C may be treated with peginterferon-alpha in combination with ribavirin.
  • Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral elimination from the body is often incomplete. Therefore, there is a need for new therapies to treat HCV infection.
  • the present invention features compounds having Formula I A , and pharmaceutically acceptable salts thereof,
  • the present invention features compounds having Formula I B , Ic, ID, IE, IF or I G , and phannaceutically acceptable salts thereof, as well as prodrugs tliereof, wherein for each compound of Formula I B , X, Ri, R 2 , R3, R 4 and R 5 are as defined in Table 1; and likewise, for each compound of Formula I c , ID, , h or I G , X, R b R 2 , R 3 , Rt and R 5 are as defined in Table 1.
  • a compound of Formula I refers to a compound having Formula I A , 3 ⁇ 4, Ic, fc- I E , IF or I G as defined herein.
  • the present invention features compounds having Formula IIA, HB, He, HD, II E , IIF or II G , and pharmaceutically acceptable salts thereof, as well as prodrugs thereof,
  • Formula II F Formula II G wherein for each compound of Formula II A , HB, He, IID, ⁇ ⁇ , IIF or II G , X, R 1; R 2 , R3, R4 and R5 are as defined in Table 1.
  • a compound of Formula II refers to a compound having Formula II A , IIB, He, IID, HE, 3 ⁇ 4 or II G as defined herein.
  • the present invention features compounds having Formula III A , HIB, Hie, IIID, IIIE, IIIF or III G , and pharmaceutically acceptable salts thereof, as well as prodrugs thereof,
  • a compound of Formula III refers to a compound having Formula III A, IIIB, HI C , III D , III E , IIIF or III G as defined herein.
  • the present invention features phosphoramidate prodrugs of compounds having Formula IIIA, IIIB, Hie, HID, HIE, IHF or III G as described immediately hereinabove, wherein for each compound of Formula IIIA, HIB, Hie, HID, HIE, IHF or III G , X, R 1; R 2 , R3, R4 and R5 are as defined in Table 1.
  • a compound of Formula ⁇ refers to a phosphoramidate prodrug of a compound having III A , IIIB, Hie, HID, HIE, IIIF or III G as defined herein.
  • the present invention features compounds having Formula IVA, IVB, IVC,
  • Formula IVA Formula IVB Formula IVr Formula IVD Formula IVE Formula IV G wherein for each compound of Formula IV A , IV B , IV C , IV D , IV E . IVF or IV G , X, R 1; R 2 , R3, R4 and R 5 are as defined in Table 1.
  • a compound of Formula IV refers to a compound having Formula IV A . IVB, IVC, IVD, IV E , IV f or IV G as defined herein.
  • the present invention features compounds having Formula V A , VB, VC, V D , V E , V F or V G ,
  • Formula V G wherein for each compound of Formula VA, VB, VC, VD, VE, VF or VG, X, Ri, R2, R3, Rt and R5 are as defined in Table 1.
  • a compound of Formula V refers to a compound having Formula V A , VB, VC, VD, VE, VF or VG as defined herein.
  • the present invention features compounds having Formula VI A , VIB, Vic, VID, VIE, VIF or VIG, and pharmaceutically acceptable salts thereof, Formula VI A Formula VI B Formula Vic Formula VI D Formula VIE wherein for each compound of Formula VIA, VIB, VIC, VID, V3 ⁇ 4, VIF or VIG, X, Ri, R2, R3, Rt and R5 are as defined in Table 1, and wherein Pi is (HO)2P(0)-0-P(0)(OH)-.
  • a compound of Formula VI refers to a compound Formula VIA, VIB, VIC, VID, V3 ⁇ 4, VIF or VIG having as defined herein.
  • the present invention features compounds having Formula VI'A, VI'B, VI'c, VI'D, VI'E, VI'F or VI' G, and pharmaceutically acceptable salts thereof,
  • Formula VI'F Formula VI' G wherein for each compound of Formula VF A , VI' B , VF C , VI' D , VI' E , VI' F or VI' Q, X, Ri, R 2 , R 3 , Rt and R5 are as defined in Table 1, and wherein Pi is (0 ⁇ )2P(0)-0-P(0)(0 ⁇ )-.
  • a compound of Formula VI' refers to a compound Formula VI' A , VI'B, VI'C, VI'D, VI' E, VI' F or VI' G having as defined herein.
  • the present invention features compounds having Formula VI" A , VI"B, VF'c, VI"D, VI"E, VI"F or VI'O, and pharmaceutically acceptable salts thereof,
  • a compound of Formula VI refers to a compound Formula VF ' A , VF 'B, VI' 'C, VI"D, VI' ⁇ , VI' 'F or VI' ⁇ having as defined herein.
  • the present invention features compounds having Formula VII A , VIIB, VIIc, VIID, VIIE, VIIF or VIIG,, and pharmaceutically acceptable salts thereof,
  • a compound of Formula VII refers to a compound having Formula VII A , VII B , VII C , VII D , VII E , VII F or VII G as defined herein.
  • the present invention features compounds having Formula VIII A , VIIIB, VIIIc, VIIID, VIIIE, VIIIF or VIIIG, and pharmaceutically acceptable salts thereof,
  • a compound of Formula Vlll refers to a compound having Formula VIH A , VIH B , Vlll c , VIII D , VIII E , VIII F or VIII G as defined herein.
  • the present invention features compounds having Formula IX A , IXB, IXC, IXD, IXE, IXF or IX G , and pharmaceutically acceptable salts thereof,
  • a compound of Formula IX refers to a compound having Formula IXA, IXB, IXC, IXD, IXE, IXF or IX G as defined herein.
  • the present invention features compounds having Formula A 1; A 2 , A3, A 4 , A 5 , A 6 or A 7 , and pharmaceutically acceptable salts thereof,
  • a compound of Formula A refers to a compound having Formula A 1; A 2 , A 3 , A 4 , A 5 , A 6 or A 7 as defined herein.
  • the present invention features Compound No. 3 according to Table 1, wherein the compound has Formula I.
  • the present invention features Compound No. 3 according to Table 1, wherein the compound has Formula II.
  • the present invention features Compound No. 3 according to Table 1, wherein the compound has Formula III.
  • the present invention features Compound No. 3 according to Table 1, wherein the compound has Formula ⁇ . [0024] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 3 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 3 according to Table wherein the compound has Formula IV" .
  • the present invention features Compound No. 3 according to Table wherein the compound has Formula V.
  • the present invention features Compound No. 3 according to Table wherein the compound has Formula VI.
  • the present invention features Compound No. 3 according to Table wherein the compound has Formula VII.
  • the present invention features Compound No. 3 according to Table wherein the compound has Formula VIII.
  • the present invention features Compound No. 3 according to Table wherein the compound has Formula IX.
  • the present invention features Compound No. 3 according to Table wherein the compound has Formula A.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula I.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula II.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula III.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula ⁇ .
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula IV" .
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula V. [0041] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula VI.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula VII.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula VIII.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula IX.
  • the present invention features Compound No. 31 according to Table wherein the compound has Formula A.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula I.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula II.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula III.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula ⁇ .
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula IV" .
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula V.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula VI.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula VII.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula VIII.
  • the present invention features Compound No. 35 according to Table wherein the compound has Formula IX. [0058] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula A.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula I.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula II.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula III.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula ⁇ .
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula IV" .
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula V.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula VI.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula VII.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula VIII.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula IX.
  • the present invention features Compound No. 43 according to Table wherein the compound has Formula A.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula I.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula II.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula III. [0075] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula ⁇ .
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula IV" .
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula V.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula VI.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula VII.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula VIII.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula IX.
  • the present invention features Compound No. 47 according to Table wherein the compound has Formula A.
  • the present invention features Compound No. 59 according to Table wherein the compound has Formula I.
  • the present invention features Compound No. 59 according to Table wherein the compound has Formula II.
  • the present invention features Compound No. 59 according to Table wherein the compound has Formula III.
  • the present invention features Compound No. 59 according to Table wherein the compound has Formula ⁇ .
  • the present invention features Compound No. 59 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 59 according to Table wherein the compound has Formula IV.
  • the present invention features Compound No. 59 according to Table wherein the compound has Formula IV" .
  • the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula V.
  • the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula VI.
  • the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula VII.
  • the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula VIII.
  • the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula IX.
  • the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula A.
  • the present invention features Compound No. 1 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 2 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 9 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 10 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 127 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 128 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 129 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 130 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 11 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 12 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 13 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 14 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 131 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 132 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 133 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • the present invention features Compound No. 134 according to Table 1, wherein the compound has Formula I, II, III, ⁇ , IV, IV, IV", V, VI,. VII, VIII, IX, or A.
  • a suitable prodrug has chemically or metabolically cleavable group(s) and becomes, by solvolysis or under physiological conditions, a compound that is pharmaceutically active in vivo.
  • a prodrug can be formed in a conventional manner by reaction of a functional group of the compound (such as an amino, hydroxy or carboxy group).
  • Prodrugs often offer advantages of better metabolism, potency, solubility, tissue compatibility, or delayed release in mammals.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine.
  • prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivatives of alcohol or amine functional groups within the compounds of the invention.
  • prodrugs can be aliphatic or aromatic esters derived from acidic groups on a compound of the invention.
  • prodrugs can be aliphatic or aromatic esters of hydroxyl or amino groups on a compound of the invention.
  • Phosphate prodrugs of hydroxyl groups are preferred prodrugs.
  • prodrugs used herein are phosphoramidate prodrugs.
  • any compound, salt or prodrug according to any aspect, embodiment, example and preference described herein can be isotopically substituted.
  • Preferred isotopic substitutions include substitutions with stable or nonradioactive isotopes such as deuterium, 13 C, 15 N or 18 0.
  • Incorporation of a heavy atom, such as substitution of deuterium for hydrogen can give rise to an isotope effect that could alter the pharmacokinetics of the drug.
  • at least 5 mol % (e.g., at least 10 mol %) of hydrogen in a compound of the present invention is substituted with deuterium.
  • at least 25 mole % of hydrogen in a compound of the present invention is substituted with deuterium.
  • At least 50, 60, 70, 80 or 90 mole % of hydrogen in a compound of the present invention is substituted with deuterium.
  • the natural abundance of deuterium is about 0.015%.
  • Deuterium substitution or enrichment can be achieved, without limitation, by either exchanging protons with deuterium or by synthesizing the molecule with enriched or substituted starting materials. Other methods known in the art can also be used for isotopic substitutions.
  • the present invention features methods of using any compound/salt/prodrug according to any aspect, embodiment, example and preference described herein to treat HCV infection.
  • a compound, salt or prodrug has inhibitory activity against HCV polymerase.
  • the method comprises administering an effective amount of such a compound, salt or prodrug to an HCV patient in need thereof.
  • the patient is infected with HCV genotype 1.
  • the patient is infected with HCV genotype 2.
  • the patient is infected with HCV genotype 3.
  • the patient is infected with HCV genotype 4.
  • the patient is infected with HCV genotype 5.
  • the patient is infected with HCV genotype 6.
  • different compounds of the invention may have different anti -viral activities and/or toxicity/safety profiles. Compounds with less antiviral activities can be dosed more frequently and/or with greater amounts. Compounds with higher antiviral activities can be dosed less frequently and/or with lesser amounts. Moreover, a compound that does not have a commercially desired toxicity/safety profile does not prevent its utility under patent law as an anti-viral agent, despite the fact that the US FDA might not approve it for human treatment due to the agency's benefit-cost analyses and/or other non-patent related concerns.
  • the present invention features methods for treating HCV infection in a subject in need of such treatment.
  • the methods comprise administering at least two direct acting antiviral agents (DAAs) to the subject for a duration of no more than 12 weeks, or for another duration as set forth herein.
  • DAAs direct acting antiviral agents
  • Said at least two DAAs comprise (1) a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and (2) another DAA.
  • the other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor.
  • the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196, both of which are incorporated herein by reference in their entireties. Highly preferably, the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568. Also, highly preferably, the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196. In one example, the duration of the treatment is 12 weeks. The duration of the treatment can also be, for example, no more than 8 weeks.
  • the two or more DAAs are administered in amounts effective to provide a sustained virological response (SVR) or achieve another desired measure of effectiveness in the subject.
  • SVR sustained virological response
  • the subject is not administered ribavirin during the treatment regimen.
  • the subject is also not administered interferon during the treatment regimen.
  • the methods exclude the administration of interferon or ribavirin to the subject, thereby avoiding the side effects associated with interferon and ribavirin.
  • the present invention features methods for treating a population of subjects having HCV infection.
  • the methods comprise administering at least two DAAs to the subjects for a duration of no more than 12 weeks.
  • Said at least two DAAs comprise (1) a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and (2) another DAA.
  • the other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor.
  • the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor.
  • the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196, both of which are incorporated herein by reference in their entireties.
  • the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568.
  • the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196.
  • said at least two DAAs are administered to the subjects in amounts effective to result in SVR or another measure of effectiveness in at least about 70% of the population, preferably at least about 80% of the population, or more preferably at least about 90% of the population.
  • the subjects are not administered ribavirin during the treatment regimen.
  • the subjects are also not administered interferon during the treatment regimen.
  • the methods exclude the administration of interferon or ribavirin to the subject, thereby avoiding the side effects associated with interferon and ribavirin.
  • Non-limiting examples of the other DAAs include PSI-7977 (sofosbuvir), PSI-938, BMS- 790052 (daclatasvir), BMS-650032 (asunaprevir), BMS-791325, GS-5885 (ledipasvir), GS-9451 (tegobuvir), GS-9190, GS-9256, BI-201335, BI-27127, telaprevir, VX-222, TMC-435 (simepravir), MK- 5172, MK-7009 (vaniprevir ), danoprevir, paritaprevir, ombitasvir, ABT-493, and R7128 (mericitabine).
  • the DAAs can be administered in any effective dosing schemes and/or frequencies; for example, they can each be administered daily.
  • Each DAA can be administered either separately or in combination, and each DAA can be administered once a day, twice a day, or three times a day.
  • the DAAs employed herein are administered once daily.
  • the present invention features a combination of a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and another DAA, for use to treat HCV infection.
  • the other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor.
  • the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos.
  • the treatment comprises administering the DAAs to a subject infected with HCV.
  • the duration of the treatment regimen is no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks.
  • the duration of the treatment can also last, for example, no more than eight weeks (e.g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks).
  • the treatment does not include administering interferon or ribavirin.
  • the DAAs can be administered concurrently or sequentially. Preferably, the DAAs are administered once daily.
  • the patient being treated is infected with HCV genotype 1, such as genotype la or lb.
  • the patient is infected with HCV genotype 2.
  • the patient is infected with HCV genotype 3.
  • the patient is infected with HCV genotype 4.
  • the patient is infected with HCV genotype 5.
  • the patient is infected with HCV genotype 6.
  • the patient is a HCV -treatment naive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment.
  • the interferon non-responder patients include partial interferon responders and interferon rebound patients.
  • the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1.
  • the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 7 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 6 weeks, and the subject being treated is a naive patient infected with HCV genotype 1.
  • the treatment lasts for 5 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 4 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 3 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV selected from genotypes 2, 3, 4, 5 or 6.
  • the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 7 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6.
  • the treatment lasts for 6 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 5 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 4 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 3 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6.
  • the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 11 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 7 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 6 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 5 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 4 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 3 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.
  • the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 11 weeks, and the subject being treated is a non- responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 7 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 6 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 5 weeks, and the subject being treated is a non- responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 4 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • the treatment lasts for 3 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
  • a treatment regimen of the present invention generally constitutes a complete treatment regimen, i.e., no subsequent interferon-containing regimen is intended.
  • a treatment or use described herein generally does not include any subsequent interferon-containing treatment.
  • a treatment or use described herein does not include any subsequent ribavirin-containing treatment.
  • the methods of the present invention can provide effective treatment of HCV infection without the use of interferon or ribavirin and for a shorter period of time, for example and without limitation, a treatment duration of no more than twelve weeks, alternatively no more than eleven weeks, alternatively no more than ten weeks, alternatively no more than nine weeks, alternatively no more than eight weeks, alternatively no more than seven weeks, alternatively no more than six weeks, alternatively no more than five weeks, alternatively no more than four weeks, or alternatively, no more than three weeks.
  • the present invention features methods for treating HCV infection in a subject comprising administering at least two DAAs, in the absence of interferon and ribavirin, to the subject for a duration of no more than twelve weeks, alternatively no more than eight weeks. Put another way, the methods exclude interferon and ribavirin.
  • Said at least two DAAs comprise a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and another DAA, which can be co-administered, or administered separately or independently, with the same or different dosing frequencies.
  • said at least two DAAs are administered once a day. They can also be administered, for example, twice a day or three times a day.
  • the other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor.
  • the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor.
  • the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196.
  • the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568.
  • the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196.
  • SVR means that the virus is undetectable at the end of therapy and for at least 8 weeks after the end of therapy (SVR8); preferably, the virus is undetectable at the end of therapy and for at least 12 weeks after the end of therapy (SVR12); more preferably, the virus is undetectable at the end of therapy and for at least 16 weeks after the end of therapy (SVR16); and highly preferably, the virus is undetectable at the end of therapy and for at least 24 weeks after the end of therapy (SVR24).
  • SVR24 is often considered as a functional definition of cure; and a high rate of SVR at less than 24 week post-treatment (e.g., SVR8 or SVR12) can be predictive of a high rate of SVR24.
  • a treatment regimen of the invention comprises treating a population of subjects having HCV infection (e.g. treatment naive subjects), and the regimen comprises administering at least two DAAs to the subjects for a duration of no more than 12 weeks, or for another duration disclosed herein, wherein said at least two DAAs comprise a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and another DAA, and are administered to the subjects in amounts effective to provide an SVR (e.g., SVR12 or SVR24) in at least about 70% of the population, alternatively at least about 75% of the population, alternatively at least about 80% of the population, alternatively at least about 85% of the population, alternatively at least about 90% of the population, alternatively at least about 95% of the population, alternatively about 100% of the population.
  • SVR e.g., SVR12 or SVR24
  • the other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor.
  • the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor.
  • the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196.
  • the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568.
  • the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196.
  • a treatment regimen of the invention comprises treating a population of IFN experienced subjects (e.g., interferon non-responders) having HCV infection, and the method comprises administering at least two DAAs to the subjects for a duration of no more than 12 weeks, or for another duration disclosed herein, wherein said at least two DAAs comprise (1) a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein (hereinafter "Compound 1"), and another DAA (hereinafter “Compound 2”), and are administered to the subjects in amounts effective to provide an SVR (e.g., SVR12 or SVR24) in at least about 50% of the population, alternatively at least about 55% of the population, alternatively at least about 60% of the population, alternatively at least about 65% of the population, alternatively at least about 70% of the population, alternatively at least about 75% of the population, alternatively at least about 80% of the population, alternatively at least about 85% of the population, alternatively at least about 90%
  • SVR e.g
  • Compound 2 can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor.
  • Compound 2 is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor.
  • Compound 2 is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196.
  • Compound 2 is the compound of Example 35 of US Patent Application Publication No. 2010/0317568.
  • Compound 2 is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 8 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 7 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 6 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 5 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 4 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 3 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 24 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 13 to 23 weeks (e.g., the duration of the treatment is selected from 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 weeks) and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 12 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • a HCV polymerase inhibitor can be a nucleoside polymerase inhibitor, a nucleotide polymerase inhibitor, a non-nucleoside polymerase inhibitor, or a non-nucleotide polymerase inhibitor.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 1 1 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 10 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2.
  • the treatment lasts 9 weeks and does not include administration of any interferon or ribavirin.
  • the DAAs can be administered at the same or different dosing frequencies.
  • the patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon.
  • the patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6.
  • HCV genotype 1 such as HCV genotype la or HCV genotype lb
  • HCV genotype 2 or 3 such as HCV genotype 4 or 6.
  • the treatment according to this aspect of the technology may also be effective against other HCV genotypes.
  • the DAAs can be administered around the same time or at different times.
  • said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.
  • Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
  • a method of the present invention can be used to treat a naive patient or a treatment experienced patient.
  • Treatment experienced patients include interferon non-responders (e.g., null responders), partial responders, and relapsers.
  • a method of the present invention can also be used to treat patients who are not candidates for interferon treatment.
  • Patients who are not candidates for interferon treatment include, but are not limited to, one or more of the following groups: patients intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions which preclude them from taking interferon, and patients who have an increased risk of side effects or infection by taking interferon.
  • one or more additional DAAs can be optionally used in the treatment regimen in addition to Compound 1 and Compound 2.
  • additional DAAs can be HCV protease inhibitors, HCV nucleoside or nucleotide polymerase inhibitors, HCV non-nucleoside polymerase inhibitors, HCV NS3B inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5B inhibitors, HCV entry inhibitors, cyclophilin inhibitors, or combinations thereof.
  • HCV protease inhibitors for this purpose include, but are not limited to, telaprevir (Vertex), boceprevir (Merck), BI-201335 (Boehringer Ingelheim), GS-9451 (Gilead), and BMS-650032 (BMS).
  • protease inhibitors include, but are not limited to, ACH-1095 (Achillion), ACH- 1625 (Achillion), ACH-2684 (Achillion), AVL-181 (Avila), AVL-192 (Avila), BMS-650032 (BMS), danoprevir (RG7227/ITMN-191, Roche), GS-9132 (Gilead), GS-9256 (Gilead), IDX- 136 (Idenix), IDX- 316 (Idenix), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir (Schering-Plough Corp), PHX- 1766 (Phenomix), TMC-435 (Tibotec), vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-500 (Vertex), VX-813 (Vertex), VX-985 (Vertex), or a combination thereof
  • Preferred non-nucleoside HCV polymerase inhibitors for use in the present invention include, but are not limited to, GS-9190 (Gilead), BI-207127 (Boehringer Ingelheim), and VX-222 (VCH-222) (Vertex & ViraChem).
  • Preferred nucleotide HCV polymerase inhibitors include, but are not limited to, PSI-7977 (Gilead), and PSI-938 (Gilead).
  • HCV polymerase inhibitors include ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX- 102 (Idenix), IDX- 184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), RG7128 (Roche), TMC64912 (Medivir), GSK625433 (GlaxoSmithKline), BC
  • a polymerase inhibitor may be a nucleoside or nucleotide polymerase inhibitor, such as GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Gilead), PSI-938 (Gilead), RG7128 (Roche), TMC64912 (Medivir), ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combination therefore.
  • a polymerase inhibitor may also be a non-nucleoside polymerase inhibitor, such as PF- 00868554 (Pfizer), ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir (Gilead),, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), or a combination thereof.
  • PF- 00868554 Pfizer
  • ANA-598 Anadys
  • Preferred NS5A inhibitors include, but are not limited to, BMS-790052 (BMS) and GS-5885 (Gilead).
  • suitable NS5A inhibitors include GSK62336805 (GlaxoSmithKline), ACH-2928 (Achillion), AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BMS-790052 (BMS), BMS-824393 (BMS), GS-5885 (Gilead), PPI-1301 (Presidio), PPI-461 (Presidio) A-831 (Arrow Therapeutics), A-689 (Arrow Therapeutics) or a combination thereof.
  • Non-limiting examples of suitable cyclophilin inhibitors include alisporovir (Novartis & Debiopharm), NM-811 (Novartis), SCY-635 (Scynexis), or a combination thereof.
  • HCV entry inhibitors include ITX-4520 (iTherx), ITX- 5061 (iTherx), or a combination thereof.
  • the present invention features methods for treating patients infected with HCV genotype 1, such as la or lb.
  • the methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2.
  • Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment.
  • the patients may be treatment naive patients or treatment experienced patients.
  • the treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
  • the present invention features methods for treating patients with HCV genotype 2 or 3 infection.
  • the methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2.
  • Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment.
  • the patients may be treatment naive patients or treatment experienced patients.
  • the treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
  • the present invention features methods for treating patients with HCV genotype 2 infection.
  • the methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2.
  • Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment.
  • the patients may be treatment naive patients or treatment experienced patients.
  • the treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
  • the present invention features methods for treating patients with HCV genotype 3 infection.
  • the methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2.
  • Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment.
  • the patients may be treatment naive patients or treatment experienced patients.
  • the treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
  • the present invention features methods for treating patients with HCV genotype 4 infection.
  • the methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2.
  • Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment.
  • the patients may be treatment naive patients or treatment experienced patients.
  • the treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
  • the present invention features methods for treating patients with HCV genotype 5 infection.
  • the methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2.
  • Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment.
  • the patients may be treatment naive patients or treatment experienced patients.
  • the treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
  • the present invention features methods for treating patients with HCV genotype 6 infection.
  • the methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2.
  • Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment.
  • the patients may be treatment naive patients or treatment experienced patients.
  • the treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the disease undergoing therapy.
  • Compound 1 and Compound 2 may be co-formulated in a single dosage form.
  • suitable dosage forms include liquid or solid dosage forms.
  • Compound 1 and Compound 2 are formulated in a single solid dosage form in which at least one of the DAAs is in an amorphous form, or highly preferably molecularly dispersed, in a matrix which comprises a pharmaceutically acceptable water-soluble polymer and a pharmaceutically acceptable surfactant.
  • the other DAAs can also be in an amorphous form or molecularly dispersed in the matrix, or formulated in different form(s) (e.g., in a crystalline form). More preferably, each of the two DAAs is in an amorphous form, or highly preferably molecularly dispersed, in a matrix which comprises a pharmaceutically acceptable water-soluble polymer and a pharmaceutically acceptable surfactant.
  • the patient being treated can be a treatment-naive patient.
  • the patient being treated can be an interferon non-responder.
  • the patient being treated can be an interferon null-responder.
  • the patient being treated can be without cirrhosis.
  • the patient being treated can be a cirrhotic patient.
  • the patient being treated can be a patient with compensated cirrhosis.

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Abstract

The present invention features compounds effective in inhibiting active against Hepatitis C virus ("HCV") polymerase. The invention also features processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

Description

ANTI- VIRAL COMPOUNDS
FIELD OF THE INVENTION
[0001] The present invention relates to compounds effective in inhibiting replication of Hepatitis C virus ("HCV"). The present invention also relates to compositions comprising these compounds and methods of using these compounds to treat HCV infection.
BACKGROUND OF THE INVENTION
[0002] The HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family. The enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids. The polyprotein comprises a core protein, envelope proteins El and E2, a membrane bound protein p7, and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.
[0003] Chronic HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C may be treated with peginterferon-alpha in combination with ribavirin. Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral elimination from the body is often incomplete. Therefore, there is a need for new therapies to treat HCV infection.
DETAILED DESCRIPTION
[0004] In one aspect, the present invention features compounds having Formula IA, and pharmaceutically acceptable salts thereof,
Figure imgf000002_0001
and wherein for each compound of Formula IA, X, Ri, R2, R3, R4 and R5 are as defined in Table 1 :
Table 1. Compoimd No. X R3 J¾4 5
1 0 CI F OH H H
2 0 CI F OH H F
3 0 F F OH OH H
4 0 F F OH OH F
5 0 F F OH OH D
6 C=CH2 F F OH OH H
7 C i l l; F F OH OH F
8 C i l l; F F OH OH D
9 0 CI F OH OH H
10 0 CI F OH OH F
11 0 CI CI OH H H
12 0 CI Cf OH H F
13 0 CI Cf OH OH H
14 0 CI CI OH OH F
15 (' ( 1 CI F OH H H
16 C C'i 1 · CI F OH H F
17 C=CH2 CI F OH OH H
18 C==CH2 CI F OH OH F
19 (' ( 1 CI CI OH H H
20 C=CH2 CI CI OH H F
2 C=CH2 CI Cf OH OH H zz C C! l; CI a OH OH F
71 C=CH2 CH3 F OH H H
24 C=CH2 CH3 F OH H F
25 C=CH2 CH3 F OH OH H
26 C C! l; CH3 F OH OH F
ΊΊ C=CH2 CH3 OH OH H H
28 ( I I - CH3 OH OH H F
29 C=CH2 CH3 OH OH OH H
30 C==CH2 CH3 OH OH OH F
31 0 CHjOH F OH H H
32 0 CHjOH F OH H F
33 0 CHjOH F OH OH H
34 0 CH2OH F OH OH F
3 0 CH2OH CN OH H H
36 0 CH2OH CN OH H F
37 0 CH2OH CN OH OH H Compoimd No. X I¾2 ¾ J¾4 R5
38 0 Cl t.-OH CN OH OH F
39 0 CH2OH H OH H H
40 0 CH2OH H OH H F
41 0 CH2OH H OH OH H
42 0 CI S , Oi l H OH OH F
43 0 CH2OH OH OH H H
44 0 CH2OH OH OH H F
45 0 CH2OH OH OH OH H
46 0 CH2OH OH OH OH F
47 0 F ( i l O! l OH H H
48 0 F CH2OH OH H F
49 0 F CH2OH OH OH H
50 0 F CH2OH OH OH F
51 0 CN CHjOH OH H H
52 0 CN CHjOH OH H F
53 0 CN CH2OH OH OH H
54 0 CN CH2OH OH OH F
55 0 H CH2OH OH H H
56 0 H CH2OH OH H F
57 0 H CH2OH OH OH H
58 0 H CH2OH OH OH F
59 0 OH CH2OH OH H H
60 0 OFI ( i l O! l OH H F
61 0 OFI CH2OH OH OH H
62 0 OH CH2OH OH OH F
63 C=CH2 CH2OH F OH H H
64 C=CH2 CH2OH F OH H F
65 ( I I - CH2OH F OH OH H
66 C=CH2 CH2OH F OH OH F
67 C=CH2 CH2OH CN OH H H
68 (' ( I CH2OH CN OH H F
69 C=CH2 CH2OH CN OH OH H
70 C=CH2 CH2OH CN OH OH F
71 C C! l; CH2OH H OH H H
72 (' ( 1 CH2OH H OH H F
73 C=CH2 CH2OH H OH OH H
74 C=CH2 CH2OH H OH OH F
75 C i l l; CH2OH OH OH H H
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
[0005] For Compound Nos. 95-118, R2 and R3, taken together with the atoms to which they are attached, form a ring, as indicated in Table 1. As shown below, each compound number in Table 1 can represent compounds of different formulas but with the same X, R1; R2, R3, R4 and R5 moieties. [0006] In another aspect, the present invention features compounds having Formula IB, Ic, ID, IE, IF or IG, and phannaceutically acceptable salts thereof, as well as prodrugs tliereof, wherein for each compound of Formula IB, X, Ri, R2, R3, R4 and R5 are as defined in Table 1; and likewise, for each compound of Formula Ic, ID, , h or IG, X, Rb R2, R3, Rt and R5 are as defined in Table 1.
Figure imgf000009_0001
Formula IB
Figure imgf000009_0002
Formula Ir
Figure imgf000009_0003
Formula ID
Figure imgf000009_0004
Formula IE Formula IF
Figure imgf000010_0001
Formula IG
[0007] As used herein, a compound of Formula I refers to a compound having Formula IA, ¾, Ic, fc- IE, IF or IG as defined herein.
[0008] In another aspect, the present invention features compounds having Formula IIA, HB, He, HD, IIE, IIF or IIG, and pharmaceutically acceptable salts thereof, as well as prodrugs thereof,
Formula IIA
Figure imgf000010_0002
Formula ¾
Figure imgf000011_0001
Formula IIC
Figure imgf000011_0002
Formula IID
Figure imgf000011_0003
Formula IIE
Formula IIF
Figure imgf000011_0004
Formula IIG wherein for each compound of Formula IIA, HB, He, IID, ΠΕ, IIF or IIG, X, R1; R2, R3, R4 and R5 are as defined in Table 1. As used herein, a compound of Formula II refers to a compound having Formula IIA, IIB, He, IID, HE, ¾ or IIG as defined herein.
[0009] In still another aspect, the present invention features compounds having Formula IIIA, HIB, Hie, IIID, IIIE, IIIF or IIIG, and pharmaceutically acceptable salts thereof, as well as prodrugs thereof,
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000013_0002
wherein for each compound of Formula IIIA, IIIB, HIC, IIID, IIIE, IIIF or IIIG, X, R1; R2, R3, R4 and R5 are as defined in Table 1. As used herein, a compound of Formula III refers to a compound having Formula III A, IIIB, HIC, IIID, IIIE, IIIF or IIIG as defined herein.
[0010] In still another aspect, the present invention features phosphoramidate prodrugs of compounds having Formula IIIA, IIIB, Hie, HID, HIE, IHF or IIIG as described immediately hereinabove, wherein for each compound of Formula IIIA, HIB, Hie, HID, HIE, IHF or IIIG, X, R1; R2, R3, R4 and R5 are as defined in Table 1. As used herein, a compound of Formula ΙΙΓ refers to a phosphoramidate prodrug of a compound having IIIA, IIIB, Hie, HID, HIE, IIIF or IIIG as defined herein.
[0011] In yet another aspect, the present invention features compounds having Formula IVA, IVB, IVC,
Figure imgf000013_0003
Formula IVA
Figure imgf000014_0001
Formula IVB
Figure imgf000014_0002
Formula IVr
Figure imgf000014_0003
Formula IVD
Figure imgf000014_0004
Formula IVE
Figure imgf000014_0005
Figure imgf000015_0001
Formula IVG wherein for each compound of Formula IVA, IVB, IVC, IVD, IVE. IVF or IVG, X, R1; R2, R3, R4 and R5 are as defined in Table 1. As used herein, a compound of Formula IV refers to a compound having Formula IVA. IVB, IVC, IVD, IVE, IVf or IVG as defined herein.
[0012] In yet another aspect, the present invention features compounds having Formula VA, VB, VC, VD, VE, VF or VG,
Figure imgf000015_0002
Formula VA
Figure imgf000015_0003
Formula VB
Figure imgf000015_0004
Formula Vr
Figure imgf000016_0001
Formula VD
Figure imgf000016_0002
Formula VE
Formula VF
Figure imgf000016_0003
Formula VG wherein for each compound of Formula VA, VB, VC, VD, VE, VF or VG, X, Ri, R2, R3, Rt and R5 are as defined in Table 1. As used herein, a compound of Formula V refers to a compound having Formula VA, VB, VC, VD, VE, VF or VG as defined herein.
[0013] In yet another aspect, the present invention features compounds having Formula VIA, VIB, Vic, VID, VIE, VIF or VIG, and pharmaceutically acceptable salts thereof,
Figure imgf000017_0001
Formula VIA
Figure imgf000017_0002
Formula VIB
Figure imgf000017_0003
Formula Vic
Figure imgf000017_0004
Formula VID
Figure imgf000017_0005
Formula VIE
Figure imgf000018_0001
wherein for each compound of Formula VIA, VIB, VIC, VID, V¾, VIF or VIG, X, Ri, R2, R3, Rt and R5 are as defined in Table 1, and wherein Pi is (HO)2P(0)-0-P(0)(OH)-. As used herein, a compound of Formula VI refers to a compound Formula VIA, VIB, VIC, VID, V¾, VIF or VIG having as defined herein.
[0014] In yet another aspect, the present invention features compounds having Formula VI'A, VI'B, VI'c, VI'D, VI'E, VI'F or VI' G, and pharmaceutically acceptable salts thereof,
Figure imgf000018_0002
Figure imgf000019_0001
Formula VI' c
Figure imgf000019_0002
Formula VI' D
Figure imgf000019_0003
Formula VI'E
Formula VI'F
Figure imgf000019_0004
Formula VI' G wherein for each compound of Formula VFA, VI'B, VFC, VI'D, VI'E, VI'F or VI' Q, X, Ri, R2, R3, Rt and R5 are as defined in Table 1, and wherein Pi is (0~)2P(0)-0-P(0)(0~)-. As used herein, a compound of Formula VI' refers to a compound Formula VI'A, VI'B, VI'C, VI'D, VI' E, VI' F or VI' G having as defined herein.
[0015] In yet another aspect, the present invention features compounds having Formula VI" A, VI"B, VF'c, VI"D, VI"E, VI"F or VI'O, and pharmaceutically acceptable salts thereof,
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000021_0002
wherein for each compound of Formula VI" A, VT 'B, VT 'C, VI"D, VI"E, VI"f or VI"G, X, RB R2, R3, R4 and R5 are as defined in Table 1, and wherein PT is a protected monophosphate prodrug substitution. As used herein, a compound of Formula VI" refers to a compound Formula VF 'A, VF 'B, VI' 'C, VI"D, VI' Έ, VI' 'F or VI' Ό having as defined herein.
[0016] In a further aspect, the present invention features compounds having Formula VIIA, VIIB, VIIc, VIID, VIIE, VIIF or VIIG,, and pharmaceutically acceptable salts thereof,
Figure imgf000021_0003
Figure imgf000022_0001
Formula VIIB
Figure imgf000022_0002
Formula VIIC
Figure imgf000022_0003
Formula VIID
Figure imgf000022_0004
Formula VIIE
Figure imgf000022_0005
Formula VIIF
Figure imgf000023_0001
wherein for each compound of Formula VIIA, VHB, VIIc, VIID, VIIE, VIIf or VIIG, X, R1; R2, R3, R4 and R5 are as defined in Table 1. As used herein, a compound of Formula VII refers to a compound having Formula VIIA, VIIB, VIIC, VIID, VIIE, VIIF or VIIG as defined herein.
[0017] In a further aspect, the present invention features compounds having Formula VIIIA, VIIIB, VIIIc, VIIID, VIIIE, VIIIF or VIIIG, and pharmaceutically acceptable salts thereof,
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0003
wherein for each compound of Formula VIHA, VIHB, Vlllc, VIIID, VIIIE, VIIIF or VIIIG, X, Rb R2, R3, R4 and R5 are as defined in Table 1. As used herein, a compound of Formula Vlll refers to a compound having Formula VIHA, VIHB, Vlllc, VIIID, VIIIE, VIIIF or VIIIG as defined herein.
[0018] In a further aspect, the present invention features compounds having Formula IXA, IXB, IXC, IXD, IXE, IXF or IXG, and pharmaceutically acceptable salts thereof,
Figure imgf000025_0001

Figure imgf000026_0001
Figure imgf000026_0002
wherein for each compound of Formula IXA, IXB, IXC, IXD, IXE, IXF or IXG, X, R1; R2, R3, R4 and R5 are as defined in Table 1. As used herein, a compound of Formula IX refers to a compound having Formula IXA, IXB, IXC, IXD, IXE, IXF or IXG as defined herein.
[0019] In a further aspect, the present invention features compounds having Formula A1; A2, A3, A4, A5, A6 or A7, and pharmaceutically acceptable salts thereof,
Figure imgf000027_0001

Figure imgf000028_0001
Figure imgf000028_0002
wherein for each compound of Formula A1; A2, A3, A4, A5, A6 or A7, X, R1; R2, R3, R4 and R5 are as defined in Table 1. As used herein, a compound of Formula A refers to a compound having Formula A1; A2, A3, A4, A5, A6 or A7 as defined herein.
[0020] In another aspect, the present invention features Compound No. 3 according to Table 1, wherein the compound has Formula I.
[0021] In another aspect, the present invention features Compound No. 3 according to Table 1, wherein the compound has Formula II.
[0022] In another aspect, the present invention features Compound No. 3 according to Table 1, wherein the compound has Formula III.
[0023] In another aspect, the present invention features Compound No. 3 according to Table 1, wherein the compound has Formula ΙΙΓ. [0024] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula IV.
[0025] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula IV.
[0026] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula IV" .
[0027] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula V.
[0028] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula VI.
[0029] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula VII.
[0030] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula VIII.
[0031] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula IX.
[0032] In another aspect, the present invention features Compound No. 3 according to Table wherein the compound has Formula A.
[0033] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula I.
[0034] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula II.
[0035] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula III.
[0036] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula ΙΙΓ.
[0037] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula IV.
[0038] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula IV.
[0039] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula IV" .
[0040] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula V. [0041] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula VI.
[0042] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula VII.
[0043] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula VIII.
[0044] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula IX.
[0045] In another aspect, the present invention features Compound No. 31 according to Table wherein the compound has Formula A.
[0046] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula I.
[0047] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula II.
[0048] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula III.
[0049] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula ΙΙΓ.
[0050] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula IV.
[0051] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula IV.
[0052] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula IV" .
[0053] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula V.
[0054] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula VI.
[0055] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula VII.
[0056] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula VIII.
[0057] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula IX. [0058] In another aspect, the present invention features Compound No. 35 according to Table wherein the compound has Formula A.
[0059] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula I.
[0060] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula II.
[0061] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula III.
[0062] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula ΙΙΓ.
[0063] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula IV.
[0064] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula IV.
[0065] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula IV" .
[0066] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula V.
[0067] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula VI.
[0068] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula VII.
[0069] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula VIII.
[0070] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula IX.
[0071] In another aspect, the present invention features Compound No. 43 according to Table wherein the compound has Formula A.
[0072] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula I.
[0073] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula II.
[0074] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula III. [0075] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula ΙΙΓ.
[0076] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula IV.
[0077] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula IV.
[0078] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula IV" .
[0079] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula V.
[0080] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula VI.
[0081] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula VII.
[0082] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula VIII.
[0083] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula IX.
[0084] In another aspect, the present invention features Compound No. 47 according to Table wherein the compound has Formula A.
[0085] In another aspect, the present invention features Compound No. 59 according to Table wherein the compound has Formula I.
[0086] In another aspect, the present invention features Compound No. 59 according to Table wherein the compound has Formula II.
[0087] In another aspect, the present invention features Compound No. 59 according to Table wherein the compound has Formula III.
[0088] In another aspect, the present invention features Compound No. 59 according to Table wherein the compound has Formula ΙΙΓ.
[0089] In another aspect, the present invention features Compound No. 59 according to Table wherein the compound has Formula IV.
[0090] In another aspect, the present invention features Compound No. 59 according to Table wherein the compound has Formula IV.
[0091] In another aspect, the present invention features Compound No. 59 according to Table wherein the compound has Formula IV" . [0092] In another aspect, the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula V.
[0093] In another aspect, the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula VI.
[0094] In another aspect, the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula VII.
[0095] In another aspect, the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula VIII.
[0096] In another aspect, the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula IX.
[0097] In another aspect, the present invention features Compound No. 59 according to Table 1, wherein the compound has Formula A.
[0098] Likewise, in another aspect, the present invention features Compound No. 1 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0099] Likewise, in another aspect, the present invention features Compound No. 2 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[00100] Likewise, in another aspect, the present invention features Compound No. 9 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[00101] Likewise, in another aspect, the present invention features Compound No. 10 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0100] Likewise, in another aspect, the present invention features Compound No. 127 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0101] Likewise, in another aspect, the present invention features Compound No. 128 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0102] Likewise, in another aspect, the present invention features Compound No. 129 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0103] Likewise, in another aspect, the present invention features Compound No. 130 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0104] Likewise, in another aspect, the present invention features Compound No. 11 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0105] Likewise, in another aspect, the present invention features Compound No. 12 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0106] Likewise, in another aspect, the present invention features Compound No. 13 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A. [0107] Likewise, in another aspect, the present invention features Compound No. 14 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0108] Likewise, in another aspect, the present invention features Compound No. 131 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0109] Likewise, in another aspect, the present invention features Compound No. 132 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0110] Likewise, in another aspect, the present invention features Compound No. 133 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0111] Likewise, in another aspect, the present invention features Compound No. 134 according to Table 1, wherein the compound has Formula I, II, III, ΙΙΓ, IV, IV, IV", V, VI,. VII, VIII, IX, or A.
[0112] Any compound according to any of the above-described aspects can be prepared and used in prodrug forms. A suitable prodrug has chemically or metabolically cleavable group(s) and becomes, by solvolysis or under physiological conditions, a compound that is pharmaceutically active in vivo. A prodrug can be formed in a conventional manner by reaction of a functional group of the compound (such as an amino, hydroxy or carboxy group). Prodrugs often offer advantages of better metabolism, potency, solubility, tissue compatibility, or delayed release in mammals. Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivatives of alcohol or amine functional groups within the compounds of the invention. For example, prodrugs can be aliphatic or aromatic esters derived from acidic groups on a compound of the invention. For another example, prodrugs can be aliphatic or aromatic esters of hydroxyl or amino groups on a compound of the invention. Phosphate prodrugs of hydroxyl groups are preferred prodrugs. Preferably, prodrugs used herein are phosphoramidate prodrugs.
[0113] In yet another aspect, any compound, salt or prodrug according to any aspect, embodiment, example and preference described herein can be isotopically substituted. Preferred isotopic substitutions include substitutions with stable or nonradioactive isotopes such as deuterium, 13C, 15N or 180. Incorporation of a heavy atom, such as substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. In one example, at least 5 mol % (e.g., at least 10 mol %) of hydrogen in a compound of the present invention is substituted with deuterium. In another example, at least 25 mole % of hydrogen in a compound of the present invention is substituted with deuterium. In a further example, at least 50, 60, 70, 80 or 90 mole % of hydrogen in a compound of the present invention is substituted with deuterium. The natural abundance of deuterium is about 0.015%. Deuterium substitution or enrichment can be achieved, without limitation, by either exchanging protons with deuterium or by synthesizing the molecule with enriched or substituted starting materials. Other methods known in the art can also be used for isotopic substitutions.
[0114] In another aspect, the present invention features methods of using any compound/salt/prodrug according to any aspect, embodiment, example and preference described herein to treat HCV infection. Such a compound, salt or prodrug has inhibitory activity against HCV polymerase. The method comprises administering an effective amount of such a compound, salt or prodrug to an HCV patient in need thereof. In one embodiment, the patient is infected with HCV genotype 1. In another embodiment, the patient is infected with HCV genotype 2. In yet another embodiment, the patient is infected with HCV genotype 3. In yet another embodiment, the patient is infected with HCV genotype 4. In yet another embodiment, the patient is infected with HCV genotype 5. In yet another embodiment, the patient is infected with HCV genotype 6.
[0115] It is contemplated that different compounds of the invention may have different anti -viral activities and/or toxicity/safety profiles. Compounds with less antiviral activities can be dosed more frequently and/or with greater amounts. Compounds with higher antiviral activities can be dosed less frequently and/or with lesser amounts. Moreover, a compound that does not have a commercially desired toxicity/safety profile does not prevent its utility under patent law as an anti-viral agent, despite the fact that the US FDA might not approve it for human treatment due to the agency's benefit-cost analyses and/or other non-patent related concerns.
[0116] In yet another aspect, the present invention features methods for treating HCV infection in a subject in need of such treatment. The methods comprise administering at least two direct acting antiviral agents (DAAs) to the subject for a duration of no more than 12 weeks, or for another duration as set forth herein. Said at least two DAAs comprise (1) a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and (2) another DAA. The other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor. Preferably, the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196, both of which are incorporated herein by reference in their entireties. Highly preferably, the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568. Also, highly preferably, the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196. In one example, the duration of the treatment is 12 weeks. The duration of the treatment can also be, for example, no more than 8 weeks. Preferably, the two or more DAAs are administered in amounts effective to provide a sustained virological response (SVR) or achieve another desired measure of effectiveness in the subject. The subject is not administered ribavirin during the treatment regimen. The subject is also not administered interferon during the treatment regimen. Put another way, the methods exclude the administration of interferon or ribavirin to the subject, thereby avoiding the side effects associated with interferon and ribavirin.
[0117] In another aspect, the present invention features methods for treating a population of subjects having HCV infection. The methods comprise administering at least two DAAs to the subjects for a duration of no more than 12 weeks. Said at least two DAAs comprise (1) a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and (2) another DAA. The other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor. Preferably, the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196, both of which are incorporated herein by reference in their entireties. Highly preferably, the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568. Also, highly preferably, the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196. Preferably, said at least two DAAs are administered to the subjects in amounts effective to result in SVR or another measure of effectiveness in at least about 70% of the population, preferably at least about 80% of the population, or more preferably at least about 90% of the population. The subjects are not administered ribavirin during the treatment regimen. The subjects are also not administered interferon during the treatment regimen. Put another way, the methods exclude the administration of interferon or ribavirin to the subject, thereby avoiding the side effects associated with interferon and ribavirin.
[0118] Non-limiting examples of the other DAAs include PSI-7977 (sofosbuvir), PSI-938, BMS- 790052 (daclatasvir), BMS-650032 (asunaprevir), BMS-791325, GS-5885 (ledipasvir), GS-9451 (tegobuvir), GS-9190, GS-9256, BI-201335, BI-27127, telaprevir, VX-222, TMC-435 (simepravir), MK- 5172, MK-7009 (vaniprevir ), danoprevir, paritaprevir, ombitasvir, ABT-493, and R7128 (mericitabine).
[0119] In any method described herein, the DAAs can be administered in any effective dosing schemes and/or frequencies; for example, they can each be administered daily. Each DAA can be administered either separately or in combination, and each DAA can be administered once a day, twice a day, or three times a day. Preferably, the DAAs employed herein are administered once daily.
[0120] In yet another aspect, the present invention features a combination of a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and another DAA, for use to treat HCV infection. The other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor. Preferably, the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196, both of which are incorporated herein by reference in their entireties. Highly preferably, the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568. Also, highly preferably, the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196. The treatment comprises administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks. The duration of the treatment can also last, for example, no more than eight weeks (e.g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment does not include administering interferon or ribavirin. The DAAs can be administered concurrently or sequentially. Preferably, the DAAs are administered once daily. As a non-limiting example, the patient being treated is infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient is infected with HCV genotype 2. As another non-limiting example, the patient is infected with HCV genotype 3. As another non-limiting example, the patient is infected with HCV genotype 4. As another non-limiting example, the patient is infected with HCV genotype 5. As another non-limiting example, the patient is infected with HCV genotype 6. As yet another non-limiting example, the patient is a HCV -treatment naive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. As used in this application, the interferon non-responder patients include partial interferon responders and interferon rebound patients. See GUIDANCE FOR INDUSTRY - CHRONIC HEPATITIS C VIRUS INFECTION: DEVELOPING DIRECT-ACTING ANTIVIRAL AGENTS FOR TREATMENT (FDA, September 2010, draft guidance) for the definitions of naive, partial responder, responder relapser (i.e., rebound), and null responder patients. The interferon non-responder patients also include null responder patients. In one example of this aspect of the invention, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 7 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 6 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 5 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 4 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 3 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV selected from genotypes 2, 3, 4, 5 or 6. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 7 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 6 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 5 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 4 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 3 weeks, and the subject being treated is a naive patient infected with selected from genotypes 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 7 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 6 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 5 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 4 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 3 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In another example, the treatment lasts for 11 weeks, and the subject being treated is a non- responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 7 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 6 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 5 weeks, and the subject being treated is a non- responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 4 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6. In yet another example, the treatment lasts for 3 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV selected from genotype 2, 3, 4, 5 or 6.
[0121] A treatment regimen of the present invention generally constitutes a complete treatment regimen, i.e., no subsequent interferon-containing regimen is intended. Thus, a treatment or use described herein generally does not include any subsequent interferon-containing treatment. Preferably, a treatment or use described herein does not include any subsequent ribavirin-containing treatment.
[0122] The methods of the present invention can provide effective treatment of HCV infection without the use of interferon or ribavirin and for a shorter period of time, for example and without limitation, a treatment duration of no more than twelve weeks, alternatively no more than eleven weeks, alternatively no more than ten weeks, alternatively no more than nine weeks, alternatively no more than eight weeks, alternatively no more than seven weeks, alternatively no more than six weeks, alternatively no more than five weeks, alternatively no more than four weeks, or alternatively, no more than three weeks.
[0123] In one aspect, the present invention features methods for treating HCV infection in a subject comprising administering at least two DAAs, in the absence of interferon and ribavirin, to the subject for a duration of no more than twelve weeks, alternatively no more than eight weeks. Put another way, the methods exclude interferon and ribavirin. Said at least two DAAs comprise a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and another DAA, which can be co-administered, or administered separately or independently, with the same or different dosing frequencies. Preferably, said at least two DAAs are administered once a day. They can also be administered, for example, twice a day or three times a day. The other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor. Preferably, the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196. Highly preferably, the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568. Also, highly preferably, the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196.
[0124] Various measures may be used to express the effectiveness of a method of the present invention. One such measure is SVR, which, as used herein, means that the virus is undetectable at the end of therapy and for at least 8 weeks after the end of therapy (SVR8); preferably, the virus is undetectable at the end of therapy and for at least 12 weeks after the end of therapy (SVR12); more preferably, the virus is undetectable at the end of therapy and for at least 16 weeks after the end of therapy (SVR16); and highly preferably, the virus is undetectable at the end of therapy and for at least 24 weeks after the end of therapy (SVR24). SVR24 is often considered as a functional definition of cure; and a high rate of SVR at less than 24 week post-treatment (e.g., SVR8 or SVR12) can be predictive of a high rate of SVR24.
[0125] In some embodiments, a treatment regimen of the invention comprises treating a population of subjects having HCV infection (e.g. treatment naive subjects), and the regimen comprises administering at least two DAAs to the subjects for a duration of no more than 12 weeks, or for another duration disclosed herein, wherein said at least two DAAs comprise a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein, and another DAA, and are administered to the subjects in amounts effective to provide an SVR (e.g., SVR12 or SVR24) in at least about 70% of the population, alternatively at least about 75% of the population, alternatively at least about 80% of the population, alternatively at least about 85% of the population, alternatively at least about 90% of the population, alternatively at least about 95% of the population, alternatively about 100% of the population. The other DAA can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor. Preferably, the other DAA is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, the other DAA is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196. Highly preferably, the other DAA is the compound of Example 35 of US Patent Application Publication No. 2010/0317568. Also, highly preferably, the other DAA is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196.
[0126] In some embodiments, a treatment regimen of the invention comprises treating a population of IFN experienced subjects (e.g., interferon non-responders) having HCV infection, and the method comprises administering at least two DAAs to the subjects for a duration of no more than 12 weeks, or for another duration disclosed herein, wherein said at least two DAAs comprise (1) a compound/salt/prodrug according to any aspect, embodiment, example and preference described herein (hereinafter "Compound 1"), and another DAA (hereinafter "Compound 2"), and are administered to the subjects in amounts effective to provide an SVR (e.g., SVR12 or SVR24) in at least about 50% of the population, alternatively at least about 55% of the population, alternatively at least about 60% of the population, alternatively at least about 65% of the population, alternatively at least about 70% of the population, alternatively at least about 75% of the population, alternatively at least about 80% of the population, alternatively at least about 85% of the population, alternatively at least about 90% of the population, alternatively at least about 95% of the population, or alternatively about 100% of the population.
[0127] In any aspect, embodiment, example and preference described herein, Compound 2 can be, for example, selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, or a cyclophilin inhibitor. Preferably, Compound 2 is an HCV protease inhibitor, an HCV polymerase inhibitor, or an HCV NS5A inhibitor. More preferably, Compound 2 is an HCV NS5A inhibitor, such as those described in US Patent Application Publication Nos. 2010/0317568 and 2012/0004196. Highly preferably, Compound 2 is the compound of Example 35 of US Patent Application Publication No. 2010/0317568. Also, highly preferably, Compound 2 is the compound of Example 3.52 of US Patent Application Publication No. 2012/0004196.
[0128] In one aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 8 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0129] In another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 7 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0130] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 6 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir. [0131] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 5 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0132] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 4 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0133] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 3 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0134] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 24 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0135] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 13 to 23 weeks (e.g., the duration of the treatment is selected from 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 weeks) and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0136] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 12 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir. As used in this application, a HCV polymerase inhibitor can be a nucleoside polymerase inhibitor, a nucleotide polymerase inhibitor, a non-nucleoside polymerase inhibitor, or a non-nucleotide polymerase inhibitor.
[0137] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 1 1 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0138] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 10 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0139] In yet another aspect, the present invention features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of at least two DAAs, wherein said at least two DAAs comprise Compound 1 and Compound 2. The treatment lasts 9 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient; a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-re sponder, or a null responder; or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3; or HCV genotype 4, 5 or 6. The treatment according to this aspect of the technology may also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times. In addition to Compound 1 and Compound 2, said at least two DAAs can also include one or more additional DAAs selected from, for example, HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. Non-limiting examples of such additional DAAs include PSI-7977, PSI-938, TMC-435, BMS-790052, BMS-650032, GS-5885, GS- 9190, GS-9451, BI-201335, BI-207127, telaprevir, VX-222, mericitabine, and danoprevir.
[0140] A method of the present invention can be used to treat a naive patient or a treatment experienced patient. Treatment experienced patients include interferon non-responders (e.g., null responders), partial responders, and relapsers. A method of the present invention can also be used to treat patients who are not candidates for interferon treatment. Patients who are not candidates for interferon treatment include, but are not limited to, one or more of the following groups: patients intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions which preclude them from taking interferon, and patients who have an increased risk of side effects or infection by taking interferon.
[0141] In any method described herein, one or more additional DAAs can be optionally used in the treatment regimen in addition to Compound 1 and Compound 2. These additional DAAs can be HCV protease inhibitors, HCV nucleoside or nucleotide polymerase inhibitors, HCV non-nucleoside polymerase inhibitors, HCV NS3B inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5B inhibitors, HCV entry inhibitors, cyclophilin inhibitors, or combinations thereof.
[0142] Preferred HCV protease inhibitors for this purpose include, but are not limited to, telaprevir (Vertex), boceprevir (Merck), BI-201335 (Boehringer Ingelheim), GS-9451 (Gilead), and BMS-650032 (BMS). Other suitable protease inhibitors include, but are not limited to, ACH-1095 (Achillion), ACH- 1625 (Achillion), ACH-2684 (Achillion), AVL-181 (Avila), AVL-192 (Avila), BMS-650032 (BMS), danoprevir (RG7227/ITMN-191, Roche), GS-9132 (Gilead), GS-9256 (Gilead), IDX- 136 (Idenix), IDX- 316 (Idenix), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir (Schering-Plough Corp), PHX- 1766 (Phenomix), TMC-435 (Tibotec), vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-500 (Vertex), VX-813 (Vertex), VX-985 (Vertex), or a combination thereof
[0143] Preferred non-nucleoside HCV polymerase inhibitors for use in the present invention include, but are not limited to, GS-9190 (Gilead), BI-207127 (Boehringer Ingelheim), and VX-222 (VCH-222) (Vertex & ViraChem). Preferred nucleotide HCV polymerase inhibitors include, but are not limited to, PSI-7977 (Gilead), and PSI-938 (Gilead). Other suitable and non-limiting examples of suitable HCV polymerase inhibitors include ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX- 102 (Idenix), IDX- 184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), RG7128 (Roche), TMC64912 (Medivir), GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst), ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/V ertex), or a combination thereof. A polymerase inhibitor may be a nucleoside or nucleotide polymerase inhibitor, such as GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Gilead), PSI-938 (Gilead), RG7128 (Roche), TMC64912 (Medivir), ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combination therefore. A polymerase inhibitor may also be a non-nucleoside polymerase inhibitor, such as PF- 00868554 (Pfizer), ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir (Gilead),, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), or a combination thereof.
[0144] Preferred NS5A inhibitors include, but are not limited to, BMS-790052 (BMS) and GS-5885 (Gilead). Non-limiting examples of suitable NS5A inhibitors include GSK62336805 (GlaxoSmithKline), ACH-2928 (Achillion), AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BMS-790052 (BMS), BMS-824393 (BMS), GS-5885 (Gilead), PPI-1301 (Presidio), PPI-461 (Presidio) A-831 (Arrow Therapeutics), A-689 (Arrow Therapeutics) or a combination thereof.
[0145] Non-limiting examples of suitable cyclophilin inhibitors include alisporovir (Novartis & Debiopharm), NM-811 (Novartis), SCY-635 (Scynexis), or a combination thereof.
[0146] Non-limiting examples of suitable HCV entry inhibitors include ITX-4520 (iTherx), ITX- 5061 (iTherx), or a combination thereof.
[0147] Specific examples of other DAA agents that are suitable for inclusion in a method of the present invention include, but are not limited to, AP-H005, A-831 (Arrow Therapeutics) (NS5A inhibitor), A-689 (Arrow Therapeutics) (NS5A inhibitor), INX08189 (Inhibitex) (polymerase inhibitor), ITMN-191 (Intermune/Roche) (NS3/4A Protease inhibitor), VBY-376 (Protease Inhibitor) (Virobay), ACH-1625 (Achillion, Protease inhibitor), IDX136 (Idenix, Protease Inhibitor), IDX316 (Idenix, Protease inhibitor), VX-813 (Vertex), SCH 900518 (Schering-Plough), TMC-435 (Tibotec), ITMN-191 (Intermune, Roche), MK-7009 (Merck), IDX-PI (Novartis), R7128 (Roche), PF-868554 (Pfizer) (non- nucleoside polymerase inhibitor), PF-4878691 (Pfizer), IDX-184 (Idenix), IDX-375 (Idenix, NS5B polymerase inhibitor), PPI-461 (Presidio), BILB-1941 (Boehringer Ingelheim), GS-9190 (Gilead), BMS- 790052 (BMS), CTS-1027 (Conatus), GS-9620 (Gilead), PF-4878691 (Pfizer), RO5303253 (Roche), ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), GSK62336805 (GlaxoSmithKline), or any combinations thereof.
[0148] In some embodiments, the present invention features methods for treating patients infected with HCV genotype 1, such as la or lb. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment. The patients may be treatment naive patients or treatment experienced patients. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
[0149] In some embodiments, the present invention features methods for treating patients with HCV genotype 2 or 3 infection. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment. The patients may be treatment naive patients or treatment experienced patients. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
[0150] In some embodiments, the present invention features methods for treating patients with HCV genotype 2 infection. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment. The patients may be treatment naive patients or treatment experienced patients. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
[0151] In some embodiments, the present invention features methods for treating patients with HCV genotype 3 infection. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment. The patients may be treatment naive patients or treatment experienced patients. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
[0152] In some embodiments, the present invention features methods for treating patients with HCV genotype 4 infection. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment. The patients may be treatment naive patients or treatment experienced patients. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
[0153] In some embodiments, the present invention features methods for treating patients with HCV genotype 5 infection. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment. The patients may be treatment naive patients or treatment experienced patients. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
[0154] In some embodiments, the present invention features methods for treating patients with HCV genotype 6 infection. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), such as no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAs comprise Compound 1 and Compound 2. Compound 1 and Compound 2 can be administered in therapeutically effective amounts to provide a SVR (for example, SVR12 or SVR24) after the completion of the treatment. The patients may be treatment naive patients or treatment experienced patients. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.
[0155] It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the disease undergoing therapy.
[0156] In any method described herein, Compound 1 and Compound 2 may be co-formulated in a single dosage form. Non-limiting examples of suitable dosage forms include liquid or solid dosage forms. Preferably, Compound 1 and Compound 2 are formulated in a single solid dosage form in which at least one of the DAAs is in an amorphous form, or highly preferably molecularly dispersed, in a matrix which comprises a pharmaceutically acceptable water-soluble polymer and a pharmaceutically acceptable surfactant. The other DAAs can also be in an amorphous form or molecularly dispersed in the matrix, or formulated in different form(s) (e.g., in a crystalline form). More preferably, each of the two DAAs is in an amorphous form, or highly preferably molecularly dispersed, in a matrix which comprises a pharmaceutically acceptable water-soluble polymer and a pharmaceutically acceptable surfactant.
[0157] In any method described herein, the patient being treated can be a treatment-naive patient.
[0158] In any method described herein, the patient being treated can be an interferon non-responder.
[0159] In any method described herein, the patient being treated can be an interferon null-responder.
[0160] In any method described herein, the patient being treated can be without cirrhosis.
[0161] In any method described herein, the patient being treated can be a cirrhotic patient.
[0162] In any method described herein, the patient being treated can be a patient with compensated cirrhosis.
[0163] The foregoing description of the present invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise one disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention. Thus, it is noted that the scope of the invention is defined by the claims and their equivalents.

Claims

WHAT IS CLAIMED IS:
1. A compound of any formula described hereinabove, or a pharmaceutically acceptable salt thereof or a prodrug thereof.
2. A method for treating HCV, comprising administering a compound, salt or prodrug of claim 1 to an HCV patient.
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