WO2012048421A1 - Composés inhibiteurs de l'hépatite c - Google Patents

Composés inhibiteurs de l'hépatite c Download PDF

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Publication number
WO2012048421A1
WO2012048421A1 PCT/CA2011/050636 CA2011050636W WO2012048421A1 WO 2012048421 A1 WO2012048421 A1 WO 2012048421A1 CA 2011050636 W CA2011050636 W CA 2011050636W WO 2012048421 A1 WO2012048421 A1 WO 2012048421A1
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Prior art keywords
mmol
alkyl
compound
formula
hcv
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PCT/CA2011/050636
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English (en)
Inventor
Carl Thibeault
Paul J. Edwards
Cyrille Kuhn
Benoît MOREAU
Maude Poirier
Simon Surprenant
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Boehringer Ingelheim International Gmbh
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Publication of WO2012048421A1 publication Critical patent/WO2012048421A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds, and their use as inhibitors of the function of NS5A protein encoded by HCV, pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
  • HCV hepatitis C virus
  • HCV replicates to very high levels and the HCV polymerase is error-prone resulting in a wide variety of new sequence variants (Science 1998, 282, 103-107). Some new sequence variants confer resistance to drug candidates currently undergoing clinical trials. The emergence of such resistance mutations is one cause of treatment failure in HCV antiviral trials (New England Journal of Medicine 2009, 360, 1827-1838, New England Journal of Medicine 2009, 360, 1839-1850, New England Journal of Medicine 2010, 362, 1292-1303, and The Lancet 2010, 376, 705-716).
  • HCV inhibitors including NS5A inhibitors
  • NS5A inhibitors Activity of HCV inhibitors, including NS5A inhibitors, is most effectively measured in vitro using the subgenomic replicon system, in which inhibition of the physiologically relevant HCV replication complex can be directly measured (Journal of Viral Hepatitis, 2007, 14 (Suppl. 1) 64-67). Inhibition in this system has translated into clinical efficacy as shown for many clinical candidates including protease inhibitors (Antimicrobial Agents and
  • any one resistance mutant on the outcome of therapy is determined not only by the effect of the particular resistance mutant on drug potency, but also by the fitness of the resulting virus variant.
  • a resistance mutation which results in a virus with poor fitness will be more difficult to select under drug pressure, even if it results in a large decrease in potency for the drug.
  • resistance to HCV drugs is typically studied preclinically using the subgenomic replicon system. Techniques have been developed to evaluate the fitness or replication capacity of replicons bearing different resistance mutations, and thus the probable importance of these mutations in the clinic (Antimicrobial Agents and Chemotherapy 2008, 52, 1101-1 1 10).
  • WO 2010/099527, WO 2010/096462, WO 2010/1 1 1483 disclose NS5A inhibitors that are described as being useful to treat HCV infection.
  • the present invention provides a novel series of compounds having inhibitory activity against HCV replication.
  • the compounds of the invention may be used to inhibit the function of the NS5A protein encoded by HCV and may be used to reduce HCV replication.
  • Compounds of the invention also maintain potent activity against clinically relevant resistance mutations as represented by genotype 1 a Q30E and L31V resistance mutations.
  • the invention provides a
  • ring A and A' are each independently optionally substituted one time with halo;
  • R 1 is halo and R 2 is hydrogen
  • R 1 is hydrogen and R 2 is halo
  • R 4 is selected from (C _ 6 )alkyl optionally substituted one time with -0-(C-
  • R 5 is either absent or selected from the group consisting of -0-(C-
  • R 7 is selected from (C 6 )alkyl optionally substituted one time with -0-(C-
  • R 8 is either absent or selected from the group consisting of and
  • the invention provides
  • ring A and A' are each independently optionally substituted one time with halo;
  • R 4 is selected from (C-
  • R 5 is -S-(C 1-6 )alkyl
  • R 7 is selected from (Ci_ 6 )alkyl optionally substituted one time with -0-(Ci_ 6 )alkyl or
  • R 8 is either absent or selected from the group consisting of -0-(C-
  • Another aspect of this invention provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, as a medicament.
  • composition comprising an anti-hepatitis C virally effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable carrier medium or auxiliary agent.
  • the pharmaceutical composition according to this invention further comprises a therapeutically effective amount of at least one other antiviral agent.
  • the invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of a hepatitis C viral infection in a human being having or at risk of having the infection.
  • Another important aspect of the invention involves a method of treating or preventing a hepatitis C viral infection in a human being by administering to the human being an anti- hepatitis C virally effective amount of a compound of Formula (I) or (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
  • An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat a hepatitis C viral infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by the hepatitis C virus; wherein the composition comprises a compound of Formula (I) or (II), according to this invention or a pharmaceutically acceptable salt thereof in admixture with at least one pharmaceutically acceptable carrier medium or auxiliary agent.
  • Still another aspect of this invention relates to a method of inhibiting the replication of hepatitis C virus comprising exposing the virus to an effective amount of the compound of Formula (I) or (II), or a salt thereof, under conditions where replication of hepatitis C virus is inhibited.
  • the invention provides novel intermediates useful in the production of compounds of Formula (I) or (II).
  • the invention provides one or more intermediates selected from 7a1 , 7b1 , 7e1 , 7h6, 7i2, 7j2, 8e1 , 8f1 , 9a1 , 9c1 , 9e1 , 9f1 , 9g1, 9h1, 9i1, 9j1, 911, 12a1, 12b1, 13c1, 14a1, 14a2, 15a1, 18a2, 18b1, 18c1, 18d1, 18e1, 19a1, 19a2, 20a1, 20a2 and 20a3.
  • the invention provides novel intermediates useful in the production of compounds of Formula (I) or (II).
  • the invention provides one or more intermediates selected from 4a9, 7a1 , 7b1 , 7e1 , 7h6, 7g2, 7i2, 7j2, 8e1 , 8f1 , 9a1 , 9c1, 9e1, 9f1, 9g1, 9h1, 9i1, 9j1, 911, 9m1, 9n1, 10c1, 12a1, 12b1, 13c1, 14a1, 14a2, 15a1, 18a2, 18b1, 18c1, 18d1, 18e1, 19a1, 19a2, 20a1, 20a2 and 20a3, 21a1, 21a2, 21a3, 21a4 and 21a5.
  • . 6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
  • the first named subgroup is the radical attachment point, for example, the substituent "-C-i_ 3 - alkyl-aryl” means an aryl group which is bound to a -C-
  • substituents may be attached to either the Ci_ 3 -alkyl or aryl portion thereof or both, unless specified otherwise.
  • Ci_ n -alkyl wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
  • . 4 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 "CH(CH 3 )-, H 3 C-CH(CH 3 )- CH2-, (H 3 C) 3 C- and H 3 C-C(CH 3 ) 2 -.
  • halo as used herein is intended to mean a halogen substituent selected from fluoro, chloro or bromo.
  • a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, atropisomers) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • enantiomers of the compounds of the present invention Preparation of pure stereoisomers, e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or enantiomeric purity, are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof.
  • resolution methods generally rely on chiral recognition and include but not limited to chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization.
  • Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc, 2000.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • salts examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca-edetates/edetates, camsylates, carbonates,
  • chlorides/hydrochlorides citrates, edisylates, ethane disulfonates, estolates esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates,
  • hexylresorcinates hydrabamines, hydroxy ma leates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates/diphosphates, polygalacturonates, propionates, salicylates, stearates subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamine
  • salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention e.g. trifluoro acetate salts
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
  • other anti-HCV agent means those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms of disease.
  • agents can be selected from: immunomodulatory agents, inhibitors of HCV NS3 protease, inhibitors of the function of NS5A protein encoded by HCV, inhibitors of HCV polymerase or inhibitors of another target in the HCV life cycle.
  • anti-HCV agents examples include, a- (alpha), ⁇ - (beta), ⁇ - (delta), ⁇ - (gamma), ⁇ - (omega) or x- (tau) interferon, pegylated a- interferon, ribavirin, amantadine, taribavirin (Viramidine), Nitazoxannide, ABT-267 and BMS-791325.
  • immunomodulatory agent includes those agents (compounds or biologicals) that are effective to enhance or potentiate the immune system response in a human being.
  • Immunomodulatory agents include, but are not limited to, inosine
  • Class I interferons are a group of interferons that all bind to receptor type I, including both naturally and synthetically produced class I interferons, while class II interferons all bind to receptor type II.
  • class I interferons include, but are not limited to, ⁇ -, ⁇ -, ⁇ -, ⁇ -, and ⁇ -interferons
  • class II interferons include, but are not limited to, ⁇ -interferons.
  • inhibitor of HCV NS5A means an agent (compound or biological) that is effective to inhibit the function of HCV NS5A in a human being.
  • Inhibitors of HCV NS5A include, for example, BMS-824393, BMS-790052, ITMN-10050, ITMN-9916, EDP- 239, AZD7295, PPI-1301 and PPI-461.
  • inhibitor of HCV NS3 protease means an agent (compound or biological) that is effective to inhibit the function of HCV NS3 protease in a human being.
  • Inhibitors of HCV NS3 protease include, for example, the candidates ABT-450, ACH-1625, BMS-650032, PHX1766, VX-813, telaprevir (VX-950), AVL-181 , boceprevir (SCH-503034), narlaprevir (SCH-900518), danoprevir (ITMN-191), TMC 435350, vaniprevir (MK7009), MK 5172, Bl 201335, IDX320, GS 9256 and VX-985.
  • inhibitor of HCV polymerase means an agent (compound or biological) that is effective to inhibit the function of an HCV polymerase in a human being. This includes, for example, inhibitors of HCV NS5B polymerase. Inhibitors of HCV polymerase include, for example, the candidates RG-7128, tegobuvir (GS9190), IDX184, IDX375, PSI-7977, MK-3281 , filibuvir (PF868554), VX-222, VCH-759, ANA598, JTK-853, INX189, PSI-938, RG-7348, ABT-333, ABT-072 and Bl 207127.
  • inhibitor of another target in the HCV life cycle means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HCV in a human being other than by inhibiting the function of the HCV NS3 protease. This includes agents that interfere with either host or HCV viral targets necessary for the HCV life cycle or agents which specifically inhibit in HCV cell culture assays through an undefined or incompletely defined mechanism.
  • Inhibitors of another target in the HCV life cycle include, for example, agents that inhibit viral targets such as Core, E1 , E2, p7, NS2/3 protease, NS3 helicase, NS4A, NS5B polymerase, NS5A and internal ribosome entry site (IRES), or host targets such as cyclophilin B, phosphatidylinositol 4-kinase Ilia, CD81 , SR- B1 , Claudin 1 , VAP-A, VAP-B.
  • viral targets such as Core, E1 , E2, p7, NS2/3 protease, NS3 helicase, NS4A, NS5B polymerase, NS5A and internal ribosome entry site (IRES)
  • host targets such as cyclophilin B, phosphatidylinositol 4-kinase Ilia, CD81 , SR- B1 , Claudin 1 , VAP-
  • inhibitors of another target in the HCV life cycle include SCY-635, ITX5061 , NOV-205, BIT-225, NA808, MK-1220, PF-4878691 , MX-3253, GS 9450, ISIS-14803, NIM-81 1 , and DEBIO-025.
  • HIV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HIV in a human being. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HIV in a human being. HIV inhibitors include, for example, nucleoside inhibitors, non-nucleoside inhibitors, protease inhibitors, fusion inhibitors and integrase inhibitors.
  • HAV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HAV in a human being. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HAV in a human being.
  • HAV inhibitors include Hepatitis A vaccines, for example, Havrix ® (GlaxoSmithKline), VAQTA ® (Merck) and Avaxim ® (Aventis Pasteur).
  • HBV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HBV in a human being. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HBV in a human being.
  • HBV inhibitors include, for example, agents that inhibit HBV viral DNA polymerase or HBV vaccines.
  • HBV inhibitors include Lamivudine (Epivir-HBV ® ), Adefovir Dipivoxil, Entecavir, FTC (Coviracil ® ), DAPD (DXG), L-FMAU (Clevudine ® ), AM365 (Amrad), Ldt (Telbivudine), monoval-LdC (Valtorcitabine), ACH-126,443 (L-Fd4C) (Achillion), MCC478 (Eli Lilly), Racivir (RCV), Fluoro-L and D nucleosides, Robustaflavone, ICN 2001-3 (ICN), Bam 205 (Novelos), XTL- 001 (XTL), Imino-Sugars (Nonyl-DNJ) (Synergy), HepBzyme; and immunomodulator products such as: interferon alpha 2b, HE2000 (Hollis-Eden), Theradigm (Ep
  • treatment is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of the hepatitis C disease and/or to reduce viral load in a patient.
  • treatment also encompasses the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood.
  • prevention means the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease.
  • terapéuticaally effective amount means an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.
  • the amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
  • Ring A and A'-A Ring A and A' are each independently optionally substituted one time with halo.
  • Ring A and A'-B Ring A and A' are each independently optionally substituted one time with F.
  • Ring A and A'-C Ring A and A' are each unsusbtituted.
  • R 1 /R 2 -A R 1 is halo and R 2 is hydrogen; or R 1 is hydrogen and R 2 is halo.
  • R 1 /R 2 -B R 1 is F or CI and R 2 is hydrogen; or R 1 is hydrogen and R 2 is F or CI.
  • R 1 /R 2 -C R 1 is CI and R 2 is hydrogen; or R 1 is hydrogen and R 2 is CI.
  • R 1 /R 2 -D R 1 is F and R 2 is hydrogen; or R 1 is hydrogen and R 2 is F.
  • R 3 -A: 3 is selected from the group consisting of:
  • R 4 -A R 4 is selected from (C- ! ⁇ alkyl optionally substituted one time with
  • R 4 -B R 4 is selected from (C ⁇ alkyl optionally substituted one time with
  • R 4 -C R 4 of:
  • R 5 -A R 5 is either absent or selected from the group consisting of -0-(C-
  • R 5 -B R 5 is either absent or selected from the group consisting of -0-(C -3 )alkyl and -S-(C 1-3 )alkyl.
  • R 5 -C R 5 is either absent or selected from the group consisting of -0-(C-,)alkyl and -S-(d)alkyl.
  • R 6 -A R 6 is selected from the group consisting of:
  • R 6 -B R is selected from the group consisting of:
  • R 7 -A is selected from (C _ 6 )alkyl optionally substituted one time with
  • R 7 -B R 7 is selected from (C-
  • R 7 -C R 7
  • R -A R is either absent or selected from the group consisting of -0-(Ci_ 6 )alkyl and -S-(C 1 -6 )alkyl.
  • R 8 -B R 8 is either absent or selected from the group consisting of -0-(Ci_ 3 )alkyl and -S-(C 1 -3 )alkyl.
  • R 8 -C R 8 is either absent or selected from the group consisting of -0-(Ci)alkyl and -S-(d)alkyl.
  • Ring A and A'-A Ring A and A' are each independently optionally substituted one time with halo.
  • Ring A and A'-B Ring A and A' are each independently optionally substituted one time with F.
  • Ring A and A'-C Ring A and A' are each unsusbtituted.
  • R 4 -A R 4 is selected from (C _ 6 )alkyl optionally substituted one time with
  • R 4 -B R 4 is selected from (C-
  • R 5 -A R 5 is -S-(C 1-6 )alkyl.
  • R 5 -B R 5 is -S-(C 1 _ 3 )alkyl.
  • R 5 -C R 5 is -S-(d)alkyl.
  • R 6 -A R 6 is selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 7 -A R 7 is selected from (C ⁇ alkyl optionally substituted one time with -0-(Ci -6 )alkyl or -0-(Ci -6 )haloalkyl.
  • R 7 -B R 7 is selected from (Ci_ 4 )alkyl optionally substituted one time with
  • R 7 -C of:
  • R -A R is either absent or selected from the group consisting of -0-(Ci_ 6 )alkyl and
  • R 8 -B R 8 is either absent or -S-(Ci_ 3 )alkyl.
  • R 8 -C R 8 is either absent or -S-(Ci)alkyl.
  • Examples of most preferred compounds according to this invention are compounds 1001 , 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 101 1 , 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1021 , 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031 , 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041 , 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051 , 1052, 1053, 1054, 1055 and 1056.
  • Examples of most preferred compounds according to this invention are compounds 1001 , 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 101 1 , 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1020, 1021 , 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031 , 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041 , 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051 , 1052, 1053 and 1054.
  • Examples of most preferred compounds according to this invention are compounds 1001 , 1002, 1003, 1004, 1005, 1006, 1008, 1009, 1010, 101 1 , 1012, 1013, 1014, 1015, 1016, 1020, 1021 , 1022, 1023, 1024, 1025, 1026, 1027, 1029, 1030, 1031 , 1032, 1033, 1035, 1036, 1037, 1038, 1039, 1040, 1041 , 1042, 1043, 1044, 1046, 1047, 1048, 1049, 1053, 1054.
  • Examples of most preferred compounds according to this invention are compounds 1017, 1024, 1036, 1037, 1038, 1039, 1045 and 1047.
  • Examples of most preferred compounds according to this invention are compounds 1024, 1036, 1037, 1038, 1039 and 1047.
  • Examples of most preferred compounds according to this invention are compounds 1006, 1007, 101 1 , 1020, 1024, 1034, 1035, 1037, 1045 and 1051.
  • Examples of most preferred compounds according to this invention are compounds 1006, 101 1 , 1020, 1024, 1035 and 1037.
  • Examples of most preferred compounds according to this invention are compounds 1006, 101 1 , 1020, 1024, 1035, 1037 and 1045.
  • An example of a most preferred compound according to this invention is compound 1006.
  • An example of a most preferred compound according to this invention is compound 101 1.
  • An example of a most preferred compound according to this invention is compound 1020.
  • An example of a most preferred compound according to this invention is compound 1024.
  • An example of a most preferred compound according to this invention is compound 1035.
  • An example of a most preferred compound according to this invention is compound 1037.
  • An example of a most preferred compound according to this invention is compound 1045.
  • An example of a most preferred compound according to this invention is compound 1056.
  • Suitable preparations for administering the compounds of Formula (I) and (II) will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc.
  • the content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole.
  • Suitable tablets may be obtained, for example, by mixing one or more compounds according to Formula (I) or (II) with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants .
  • excipients for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • the tablets may also consist of several layers.
  • the pharmaceutical composition of this invention may additionally comprise at least one other anti-HCV agent.
  • combination therapy is contemplated wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, is co-administered with at least one additional agent selected from: an antiviral agent, an immunomodulatory agent, an inhibitor of HCV NS3 protease, an inhibitor of HCV polymerase, an inhibitor of another target in the HCV life cycle, an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form. Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the dose range of the compounds of the invention applicable per day is usually from 0.01 to 100 mg/kg of body weight, preferably from 0.1 to 50 mg/kg of body weight.
  • Each dosage unit may conveniently contain from 5% to 95% active compound (w/w).
  • Preferably such preparations contain from 20% to 80% active compound.
  • the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
  • composition of this invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
  • Retention times (t R ) for each compound are measured using the standard analytical HPLC or UPLC conditions described below. As is well known to one skilled in the art, retention time values are sensitive to the specific measurement conditions.
  • the retention time values may vary when measured, for example, on different HPLC or UPLC instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual HPLC or UPLC columns, or, when measured on the same instrument and the same individual column, the values may vary, for example, between individual measurements taken on different occasions.
  • a person skilled in the art will recognize that obvious modifications to the synthetic methods, including the amount of time indicated to perform the various steps, may be required to generate each of the specific compounds listed in the Examples section.
  • Analytical UPLC is carried out under standard conditions using a Waters ACQUITY UPLC ® HSS T3 column (1 .8 ⁇ , 2.1 x 50 mm) eluting with a segmented linear MeCN gradient containing 0.06%TFA (v/v) over 2.6 min at 0.9 ml/min.
  • Analytical UPLC is also carried out under standard conditions using a Waters ACQUITY UPLC ® BEH C18 column (1.8 ⁇ , 2.1 x 30 mm) eluting with a linear methanol gradient containing 10 mM Ammonium Bicarbonate (pH 10) over 2.2 min at 0.75 ml/min or a Waters ACQUITY UPLC ® HSS C18 column (1.8 ⁇ , 2.1 x 30 mm) eluting with a linear MeOH gradient containing 10 mM Ammonium Formate (pH 3.8) over 2.3 min at 0.8 ml/min.
  • Mass spectral analyses are recorded using electrospray mass spectrometry.
  • HATU N,N,N',N'-tetramethyl-0-(7-azabenzotriazol-1-yl)uronium
  • LC-MS liquid chromatography-mass spectrometry; m/z: mass-to-charge ratio; [M+H] + : protonated molecular ion; Me: methyl; MeCN: acetonitrile; MeOH: methanol; MS: mass spectrometry; NMP: N-methyl-2-pyrrolidone; OBD: optimum bed density; Pd(dppf)CI 2 : 1 ,1 '- bis(diphenylphosphino)-ferrocenedichloropalladium(ll); Ph: phenyl; Pr: propyl; Prep LCMS: preparative liquid chromatography-mass spectrometry; RBF: round bottom flask; RP
  • Step 1
  • Step 1
  • 3a3 (7.8 g, 16.8 mmol) is dissolved in DMF (52 mL), potassium thioacetate (2.5 g, 21.8 mmol) is added and the reaction mixture is heated to 65°C for 2 h and stirred at RT for 16 h.
  • the resulting reaction mixture is diluted with EtOAc (200 mL), washed with brine (200 mL) containing 1 N HCI to adjust the pH of the aqueous layer to approximately 4.
  • the organic layer is washed with brine (200 mL), dried over Na 2 S0 4 , filtered and concentrated in vacuo.
  • Step 1
  • reaction solution is stirred for 10 min at the same temperature and is then warmed to RT. After 16 h of stirring, the reaction solution is diluted with toluene (80 mL) and cooled to -20°C. Water (500 mL) is added dropwise at ⁇ -20°C to 0°C. The organic phase is separated, washed with water (2 ⁇ 500 mL), saturated aqueous sodium bicarbonate (500 mL) and dried over MgS0 4 . The reaction mixture is filtered, concentrated under reduced pressure and subjected to flash chromatography (5%
  • 5a4 (1.3 g, 3 mmol) is stirred with Pd(OH) 2 (10 % ,100 mg) in MeOH (10 mL). Air is removed under vacuum and a hydrogen atmosphere (1 atm; balloon) is made. After three cycles, the reaction mixture is stirred for 24 h then filtered and concentrated in vacuo to afford 5a5.
  • 3a5 (0.67 g, 2.6 mmol) is dissolved in MeCN (12.6 mL). 7a1 (Matrix) (0.65 g, 2.3 mmol) and DIPEA (0.41 mL, 2.3 mmol) are added and the reaction is stirred at RT for 16 h. The MeCN is evaporated and toluene (17 mL) is added. The resulting solids are removed and NH 4 OAc (1.8 g, 23.4 mmol) is added to the toluene solution. The solution is heated to 100°C overnight and concentrated in vacuo.
  • Example 7 starting from the appropriate dibromoketone derivative and the appropriate protected amino acid.
  • Step 1
  • the reaction mixture is poured into a saturated aqueous solution of NaHC0 3 (800 mL) and EtOAc is added. The layers are separated and the organic layer is washed with a saturated aqueous solution of NaHC0 3 , water, dried over Na 2 S0 4 , filtered and concentrated in vacuo.
  • the product is purified by flash
  • Step 1
  • Step 1
  • Example 8 starting from the appropriate halogeno derivative.
  • Example 9 starting from the appropriate halogeno derivative and boronic acid or boronic ester derivative.
  • Step 1
  • 11a1 (3.7 g, 12.8 mmol) is suspended in DCM (35 mL) and treated with DIPEA (2.6 mL, 14.8 mmol). 2-(trimethylsilyl)ethoxycarbonyl-0-succinimide (3.5 g, 20.6 mmol) is added and the mixture is stirred at RT for 2.5 h. The reaction mixture is diluted with DCM and neutralized with water. The layers are separated and the aqueous layer is extracted with DCM. The organic layers are combined, dried over MgS0 4 , filtered and concentrated. Purification by flash chromatography (0-50% EtOAc:hexanes) affords 11a2.
  • Step 1
  • Step 1
  • Aryl bromide 15b1 (322 mg, 0.69 mmol) and 4-acetylphenylboronic acid 18a1 (Aldrich) (1 19 mg, 0.73 mmol) are charged in a flask to which is added DME (3.5 mL) and a 2M Na 2 C0 3 aqueous solution (1 mL, 2 mmol). The flask is purged for 10 min by bubbling argon into the reacton mixture. Pd(dppf)CI 2 * CH 2 Cl 2 (25 mg, 0.030 mmol) is added and the reaction mixture is heated at 90°C for 16h. The reaction mixture is cooled to RT and partitioned between DCM and water.
  • Example 18 starting from the appropriate bromo derivative and the appropriate boronic acid derivative.
  • Step 1
  • Compound 1027 is prepared analogously to the procedure described in Example 19 starting from the appropriate ketone derivative and the appropriate carboxylic acid derivative.
  • Step 1
  • Step 3 20a2 (210 mg, 0.49 mmol) is dissolved in MeCN (2.2 mL). 3a5 (127 mg, 0.49 mmol) and DIPEA (0.085 mL, 0.49 mmol) are added and the reaction mixture is stirred at RT for 2 h. The MeCN is evaporated, then the mixture is placed into toluene (4.6 mL) and the salts are removed by filtration. NH 4 OAc (750 mg, 9.7 mmol) is added and the solution is heated to 100°C for 16h. The reaction mixture is cooled to RT, concentrated in vacuo, diluted with EtOAc and washed with water and brine. The organic layer is dried over Na 2 S0 4 , filtered and concentrated in vacuo. Purification by flash chromatography (0-100 %
  • Step 1
  • the mixture is reduced to ⁇ 100 mL and is filtered through a filter frit into a 1 L RBF containing ammonium acetate (102 g, 1.32 mol).
  • the original 1 L RBF is rinsed with 2x100 mL of toluene and the washes are passed through the solids within the filter frit.
  • Stirring is initiated and the mixture is purged with argon.
  • the mixture is heated to 98-102 °C and agitated for 6 h.
  • the mixture is cooled to RT until complete conversion (>99 A%, 220 nm).
  • the mixture is washed with water.
  • the mixture is again concentrated to via reduced pressure. 1 ,4-dioxane (100 mL) is added and the mixture is reduced.
  • 1 ,4-dioxane 150 mL is added and the mixture is stirred.
  • the mixture is purged with argon, heated to 45-52 °C and agitated until a homogeneous solution is obtained.
  • 264 mL (1.06 mol) of a 4 N HCI solution in 1 ,4-dioxane is added drop-wise.
  • the mixture is agitated at 45-52 °C until complete conversion (>99 A, 220 nm).
  • the mixture is cooled to 10-12 °C and agitated at 10-12°C for 30 min; the solids are collected by filtration.
  • the filtrate is charged back to the RBF and cooled to 10-12 °C.
  • the filtrate is passed through the filter pad, and the resulting solids are washed with 1 ,4-dioxane (50 ml.) pre-cooled to 1 1-13 °C.
  • the solids are suction dried for 1 h and dried in a vacuum oven at 50°C under house vacuum with a nitrogen bleed for 15 h. 21a2 (52.4 g) is recovered.
  • 21a2 (10.0 g, 23.6 mmol), 6a2 (4.54 g, 25.9 mmol), TBTU (8.23 g, 25.9 mmol) are added to a 250 mL 2 neck RBF, and the mixture is purged with argon.
  • /V,/V-dimethylformamide 75 mL
  • diisopropylethylamine 20.5 mL, 118 mmol
  • the mixture is stirred and agitated at RT until complete conversion (>98 A% conversion, 220 nm with respect to 21a2).
  • the mixture is diluted with ethyl acetate (120 mL) and transferred to a separatory funnel.
  • the filtrate is added back to the RBF and the temperature of the filtrate is adjusted to -5 to 0 °C.
  • the solution is then passed through the filter medium.
  • the solids are then washed with precooled (-5 to 0 °C) acetonitrile (20 mL).
  • the solids are suction dried for 1 h and then dried in a vacuum oven (50 °C at house vacuum with a nitrogen bleed) for 10-15 h to afford 21a4 (10.2 g).
  • the mixture temperature is then adjusted to 18-22 °C.
  • the mixture is transferred to a separatory funnel and diluted with isopropyl acetate (200 mL).
  • the resulting solution is washed with water (200mL and then 50 mL).
  • the organic layer is dried with anhydrous sodium sulfate, filtered and then concentrated via reduced pressure.
  • the resulting material is subjected to flash silica chromatography (short column, 40-60% EtOAc/hexs) to produce 21a5 (7.80 g).
  • 21a4 (7.20 g, 13.1 mmol), 21a5 (7.54 g, 13.8 mmol), Pd(dppf)CI 2 complex with dichloromethane (480 mg, 0.59 mmol), sodium carbonate (6.96 g, 65.7 mmol) is added to a RBF (500 mL), and the mixture is purged with argon. 1 ,2-dimethoxyethane (75 mL) and water (25 mL) are added to the mixture. The mixture is stirred, evacuated and purged with argon (3X). The temperature is adjusted to 72-77°C, and the mixture is agitated until complete conversion (>98 A% conversion, 220 nm, with respect to 21a4).
  • the temperature is adjusted to 18-22 °C and the mixture is diluted with isopropyl acetate (150 mL) and water (150 mL).
  • the resulting bi-phasic solution is mixed for 10 min, and the resulting solution is passed through a short celite plug.
  • the aqueous phase is cut and the resulting organic layer is washed with water (150 mL) and then concentrated via reduced pressure.
  • the residue is subjected to flash silica chromatography (EtOAc) and further dried at 9-15 mbar at 55 °C to afford 1024 (9.81 g).
  • HCVPVI a and HCVPVI b Two subgenomic replicons designated HCVPVI a and HCVPVI b are generated based on the wildtype sequence for genotype 1 a, strain H77 (GenBank accession no. AF009606) and the wildtype sequence CON-1 genotype b (GenBank accession number AJ238799), see Science 1999, 285: 1 10-1 13.
  • HCV genotype 1 a subgenomic fragment NS2-NS3- NS4A-NS4B-NS5A-NS5B is drawn from the reference nucleic acid encoding residues 81 1 to 301 1 of AF009606, HCV genotype 1 b subgenomic fragment NS2-NS3-NS4A-NS4B- NS5A-NS5B is drawn from the reference nucleic acid encoding residues 81 1 to 3010 of CON-1 (GenBank accession number AJ238799).
  • Both subgenomic replicons contain a hybrid HCV-poliovirus (PV) 5'UTR, a modified luciferase reporter gene expressed as a luciferase-FMDV2A-neomycin phosphotransferase gene fusion and a NS2-NS5B subgenomic fragment with its 3'UTR.
  • PV HCV-poliovirus
  • the replication of both HCV NS2-NS5B subgenomic replicons is enhanced by cell-culture adaptive mutations in the NS3 and the NS4B coding regions for the genotype 1 a replicon and in the NS3, NS4A and NS5A coding regions for the genotype 1 b.
  • Stable replicon cell lines are established as described, for example, in Science 1999, 285: 1 10-1 13.
  • the amount of luciferase expressed by selected cells directly correlates with the level of HCV RNA replication, as measured by real-time PCR.
  • HCV replicon RNA replication assay To generate cell lines harboring the replicon containing the NS3 substitutions, Huh-7 cells are electroporated with 1-10 of purified in vitro transcripts and stable cell lines are selected in the presence of G418 (0.25 mg /ml).
  • the stable HCV replicon cells are maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS and 0.25 mg/ml G418 (standard medium). During the assay, DMEM supplemented with 10% FBS, containing 0.5% DMSO and lacking neomycin are used as assay medium.
  • DMEM Dulbecco's Modified Eagle Medium
  • the cell stocks are trypsinized and diluted in assay medium to distribute 70 ⁇ (8,000 ells) in black 96-well plates. The plates are then incubated at 37° until compound addition.
  • the test compound in 100% DMSO is first diluted in assay medium to a final DMSO concentration of 0.5%.
  • Serial dilutions are prepared in assay medium to generate nine-concentration dose response curves.
  • a fixed volume from each well of the compound dilution plate is transferred to a corresponding well of the cell culture plate.
  • the cell culture plate is incubated at 37°C with 5% C0 2 for 72 hours.
  • the medium is aspirated from the 96-well assay plate and a volume of 50 ⁇ of 1X Glo Lysis Buffer (Promega) is added to each well.
  • the luciferase activity is determined using Bright- Glo luciferase substrate (Promega) according to the manufacturer's instructions and the luminescence is detected on a Packard Topcount instrument.
  • the luminescence (CPS) in each well of the culture plate is a measure of the amount of HCV RNA replication in the presence of various concentrations of inhibitor. The % inhibition is calculated for each inhibitor concentration and used to determine the concentration that results in 50% inhibition of HCV replication (EC 50 ).
  • HCVPVI a is subgenomic replicon genotype 1 a (strain H77) used to generate replicons containing the Q30E and L31V resistant variants in the HCV NS5A gene.
  • HCVPVI a contains a hybrid HCV-poliovirus (PV) 5'UTR, a modified luciferase reporter gene expressed as a luciferase-FMDV2A-neomycin phosphotransferase gene fusion and a NS2- NS5B subgenomic fragment with its 3'UTR.
  • PV HCV-poliovirus
  • Replication of the HCV NS2-NS5B subgenomic replicon is enhanced by cell-culture adaptive mutations in the NS3 and NS4B coding regions and the amount of luciferase expressed by selected cells directly correlates with the level of HCV replication, as measured by real-time PCR .
  • Stable replicon cell lines are established as taught by Lohman et al., 1999. Science 285: 1 10-113 and the desired amino acid substitutions are introduced by site-directed mutagenesis using Quick Change (Agilent Technologies Inc., Stratagene Products) according to the manufacturer's instructions.
  • the stable replicon cell lines are generated by transfection of in vitro transcribed replicon RNA and selection of replicating replicon containing cells in the presence of Geneticin® G418 (Invitrogen).
  • SEQ ID NO: 1 is a nucleotide sequence representing the HCV genotype 1 a subgenomic fragment NS2-NS3-NS4A-NS4B-NS5A-NS5B with resistant variant Q30E in the NS5A portion.
  • SEQ ID NO: 1 is 6609 bases wherein nucleotide bases 1-651 of SEQ ID NO:1 encode NS2, nucleotide bases 652-2544 encode NS3, nucleotide bases 2545-2706 encode NS4A, nucleotide bases 2707-3489 encode NS4B, nucleotide bases 3490-4833 encode NS5A, and nucleotide bases 4834-6606 encode NS5B.
  • NS5A mutation Q30E is encoded by the codon of bases 3577-3579 of SEQ ID NO:1.
  • SEQ ID NO: 2 is the corresponding polypeptide with adaptive mutations introduced in the NS3 and NS4B coding regions over the reference sequence.
  • the reference sequence is GenBank accession number AF009606, residues 81 1 to 301 1 wherein residue 81 1 corresponds to residue 2 in SEQ ID NO: 2, residue 1 being methionine.
  • the adaptive mutations are at residues 471 , 549, 622, 1000 and 1030 of SEQ ID NO: 2 and the HCV NS5A resistant mutation Q30E corresponds to residue 1 193 of SEQ ID NO: 2.
  • SEQ ID NO: 3 is a nucleotide sequence representing the HCV genotype 1 a subgenomic fragment NS2-NS3-NS4A-NS4B-NS5A-NS5B with resistant variant L31 V in the NS5A portion.
  • SEQ ID NO: 3 is 6609 bases wherein nucleotide bases 1-651 of SEQ ID NO:3 encode NS2, nucleotide bases 652-2544 encode NS3, nucleotide bases 2545-2706 encode NS4A, nucleotide bases 2707-3489 encode NS4B, nucleotide bases 3490-4833 encode NS5A, and nucleotide bases 4834-6606 encoded NS5B.
  • NS5A mutation L31V is encoded by the codon of bases 3580-3582 of SEQ ID NO: 3.
  • SEQ ID NO: 4 is the corresponding polypeptide with adaptive mutations introduced in the NS3 and NS4B coding regions over the reference sequence.
  • the reference sequence is GenBank accession number AF009606, residues 81 1 to 301 1 where 81 1 corresponds to residue 2 in SEQ ID NO:4, residue 1 being methionine.
  • the adaptive mutation are at residues 471 , 549, 622, 1000 and 1030 of SEQ ID NO: 4 and the HCV NS5A resistant mutation L31V corresponds to residue 1 194 of SEQ ID NO: 4.
  • HCV replicon RNA replication assay The stable HCV replicon cells are maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS and 0.25 mg/ml G418 (Standard Medium), while the replication assay uses DMEM supplemented with 10% FBS, containing 0.5% DMSO and lacking G418 (Assay Medium).
  • DMEM Dulbecco's Modified Eagle Medium
  • the cell stocks are trypsinized and diluted in Assay Medium; 70 ⁇ (about 8,000 cells) are distributed in black 96-well plates. The plates are then incubated at 37° until compound addition.
  • the test compound in 100% dimethyl sulfoxide (DMSO) is first diluted in Assay Medium to a final DMSO concentration of 0.5%.
  • Serial dilutions are prepared in Assay Medium to generate nine concentrations dose response curves.
  • a fixed volume from each well of the compound dilution plate is transferred to a corresponding well of the cell culture plate.
  • the cell culture plate is incubated at 37°C with 5% C0 2 for 72 h.
  • the medium is aspirated from the 96-well assay plate and a volume of 50 ⁇ of 1X Glo Lysis Buffer (Promega) is added to each well.
  • Luciferase activity is determined using Bright-Glo luciferase substrate (Promega) according to the manufacturer's instructions and the luminescence detected on a Packard Topcount instrument.
  • Luminescence counts per second CPS from each well of the culture plate is a measure of the amount of HCV RNA replication in the presence of various concentrations of inhibitor. The % inhibition is calculated for each inhibitor concentration and used to determine the concentration that results in 50% inhibition of HCV replication (EC 50 ) as a measure of potency against the NS5A genotype 1 a resistant variants by the non-linear regression routine Symyx® Assay Explorer 3.2 SP1.
  • Table 2 provides the EC 50 determined for the compounds of the invention against each of HCV NS5A genotype 1 a resistant variants Q30E and L31V when measured according to the assay, together with the EC 50 of two prior art compounds as determined according to the same assay.

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Abstract

L'invention concerne des composés de Formules (I) et (II), où R1, R2, R3, R6, A et A' sont définis présentement. Les composés sont utiles en tant qu'inhibiteurs de la fonction de la protéine NS5A codée par le VHC, pour le traitement d'une infection par le virus de l'hépatite C.
PCT/CA2011/050636 2010-10-14 2011-10-11 Composés inhibiteurs de l'hépatite c WO2012048421A1 (fr)

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