US20130302282A1 - Inhibitors of Hepatitis C Virus - Google Patents

Inhibitors of Hepatitis C Virus Download PDF

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Publication number
US20130302282A1
US20130302282A1 US13/882,138 US201113882138A US2013302282A1 US 20130302282 A1 US20130302282 A1 US 20130302282A1 US 201113882138 A US201113882138 A US 201113882138A US 2013302282 A1 US2013302282 A1 US 2013302282A1
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compound
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nhr
cyclopropyl
hydrogen
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Min Zhong
Leping Li
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Presidio Pharmaceuticals Inc
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Presidio Pharmaceuticals Inc
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Application filed by Presidio Pharmaceuticals Inc filed Critical Presidio Pharmaceuticals Inc
Priority to US13/882,138 priority Critical patent/US20130302282A1/en
Publication of US20130302282A1 publication Critical patent/US20130302282A1/en
Assigned to PRESIDIO PHARMACEUTICALS, INC. reassignment PRESIDIO PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LI, LEPING, ZHONG, MIN
Assigned to PRESIDIO PHARMACEUTICALS, INC. reassignment PRESIDIO PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LI, LEPING, ZHONG, MIN
Assigned to PRESIDIO PHARMACEUTICALS, INC. reassignment PRESIDIO PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LI, LEPING, ZHONG, MIN
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds useful for inhibiting hepatitis C virus (“HCV”) replication, particularly functions of the non-structural 5B (“NS5B”) protein of HCV.
  • HCV hepatitis C virus
  • NS5B non-structural 5B
  • HCV is a single-stranded RNA virus that is a member of the Flaviviridae family.
  • the virus shows extensive genetic heterogeneity as there are currently seven identified genotypes and more than 50 identified subtypes.
  • viral RNA is translated into a polyprotein that is cleaved into ten individual proteins.
  • structural proteins the core (C) protein and the envelope glycoproteins, E1 and E2.
  • E1 and E2. p7, an integral membrane protein, follows E1 and E2.
  • NS5B is the RNA polymerase or replicase of the virus and is responsible for replication of both positive and negative-strand genomic RNA during the viral replicative cycle. NS5B plays an essential and critical role in viral replication, and a functional NS5B replicase is required for HCV replication and infection. Thus, inhibition of NS5B RNA-dependent polymerase activity is believed to be an effective way of treating HCV infection.
  • HCV infection can lead to chronic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality.
  • the current standard of care treatment regimen for HCV infection involves interferon-alpha, alone, or in combination with ribavirin and a protease inhibitor.
  • the treatment is cumbersome and sometimes has debilitating and severe side effects and many patients do not durably respond to treatment New and effective methods of treating HCV infection are urgently needed.
  • the present disclosure describes a class of compounds targeting the NS5B protein and methods of their use to treat HCV infection in humans.
  • the present disclosure describes a class of heterocyclic compounds targeting HCV NS5B polymerase and methods of their use to treat HCV infection in humans.
  • L 1 , L 2 and L 3 together with the attached carbons of the aromatic ring to form a 5-12 member ring, containing 0-4 heteroatoms of N, O, S, P and/or Si;
  • L 1 , L 2 , or L 3 is independently selected from a group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n is 0, 1, or 2;
  • U or V is independently CH, N, CF, CCl, or CCN;
  • Y is NR N , N, O, S, Se, or —CR a R b ;
  • R N is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 4-5 heterocycle, aryl, heteroaryl, amide, sulfonamide, or carbamate;
  • R a , R b is independently hydrogen, methyl, or together form a C 3-6 cycloalkyl bearing 0-1 heteroatom of O or NR 3 ;
  • R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR 6 —, —C(O)NHR 7 , —C(O)N(OH)R 7 , —C( ⁇ NR 7 )OMe, —C( ⁇ NOMe)NHR 7 , C( ⁇ NOH)NHR 7 , —CH(CF 3 )NHR 8 , —CH(CN)NHR 9 , —S(O) 2 NHR 10 , —C( ⁇ NCN)NHR 11 ,
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • the compounds may have an inhibitory activity with respect to HCV, as measured by the concentration of the compound effective to produce a half-maximal inhibition of HCV1b replication (EC 50 ) in a 1b_Huh-Luc/Neo-ET cell line in culture, of 1 mM or less.
  • the compounds may, have the structure wherein
  • the compounds may have the structure wherein
  • L 1 is —C(R 15 R 16 )—
  • L 3 is —N(SO 2 Me)- or —O—
  • R 15 , R 16 is independently hydrogen, hydroxyl, azide, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, or cyclopropoxy or R 15 and R 16 together are a carbonyl or C 1-4 alkenylidene or R 15 and R 16 joined together with the attached carbon are 3-6 member ring optionally containing 0-3 heteroatoms of O, NR N and/or S.
  • L 1 , L 2 and L 3 together with the attached carbons of the aromatic ring form a 5-12 member ring, containing 0-4 heteroatoms of N, O, S, P and/or Si;
  • L 1 , L 2 , or L 3 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n is 0, 1, or 2;
  • R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • L 1 , L 2 and L 3 together with the attached carbons of the aromatic ring form a 5-9 member ring, containing 0-4 heteroatoms of N, O, S, P and/or Si;
  • L 1 , L 2 , or L 3 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n is 0, 1, or 2;
  • R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • R 1 is hydrogen, halide, —C(O)OR 6 —, —C(O)NHR 7 , —C( ⁇ NR 7 )OMe, —C(O)N(OH)R 7 , —C( ⁇ NOMe)NHR 7 , C( ⁇ NOH)NHR 7 , —CH(CF 3 )NHR 8 , —CH(CN)NHR 9 ,
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy.
  • R 1 is hydrogen, Br, I, —COOH, —C(O)OMe, —C(O) OEt, —C(O)O tBu, —C(O)NHMe, —C(O)NHOMe, —C( ⁇ NOMe)NHMe, —C( ⁇ NOH)NHMe, —C( ⁇ NMe)OMe, —C(O)N(OH)Me, —C(O)NHS(O) 2 Me, —CH(CF 3 )NHMe, —CH(CN)NHMe, —C( ⁇ NCN)NHMe,
  • R 1 is —C(O)NHMe or
  • R 2 is selected from the group consisting of
  • R 12 is selected from the group of hydrogen, halide, —CN, —OCHF 2 , —OCF 3 , alkyl, cycloalkyl, alkoxy, cycloalkoxy, arylalkyl, aryloxy, alkenyl, alkynyl, amide, alkylsulfonyl, arylsulfonyl, sulfonamide, carbamate; m is 0, 1, 2, 3, or 4;
  • G is O, NR N , S, or CR a R b ;
  • A is N, O, S, or CR a R b ;
  • D, E is independently C or N.
  • R 2 is selected from the group consisting of
  • R 12 is selected from the group of hydrogen, halide, —CN, —OCHF 2 , —OCF 3 , alkyl, cycloalkyl, alkoxy, cycloalkoxy, arylalkyl, aryloxy, alkenyl, alkynyl, amide, alkylsulfonyl, arylsulfonyl, sulfonamide, carbamate; m is 0, 1, 2, 3, or 4;
  • G is O, NR N , S, or CR a R b ;
  • A is N, O, S, or CR a R b ;
  • D, E is independently C or N.
  • R 2 is selected from the group consisting of
  • each phenyl moiety is optionally substituted with 0-2 nitrogen atoms.
  • R 2 is
  • L 1 , L 2 , or L 3 is independently selected from the group consisting of a bond, —O—, —C(R 15 R 16 ), —NR 3 —, —S(O) n —, —P(O) n , —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR 6 —, —C(O)NHR 7 , —C(O)N(OH)R 7 , —C( ⁇ NMe)OMe, —C( ⁇ NOMe)NHR
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • L 1 , L 2 , or L 3 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR 6 —, —C(O)NHR 7 , —C(O)N(OH)R 7 , —C( ⁇ NMe)OMe, —C( ⁇ ( ⁇
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR 6 —, —C(O)NHR 7 , —C(O)N(OH)R 7 , —C( ⁇ NMe)OMe, —C( ⁇ NOMe)NHR
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, allylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 15 , R 16 is independently hydrogen, hydroxyl, azide, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, or cyclopropoxy or R 15 and R 16 together are a carbonyl or C 1-4 alkenylidene or R 15 and R 16 joined together with the attached carbon are 3-6 member ring optionally containing 0-3 heteroatoms of O, NR N and/or S.
  • L 1 or L 2 is independently selected from the group consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; and R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR
  • R 2 is an aryl or heteroaryl having one or more R 17 substituents
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 12 is independently C 1-3 alkyl, cyclopropyl, —OMe, or —NHMe
  • R 15 , R 16 is independently hydrogen, hydroxyl, azide, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, or cyclopropoxy or R 15 and R 16 together are a carbonyl or C 1-4 alkenylidene or R 15 and R 16 joined together with the attached carbon are 3-6 member ring optionally containing
  • R 17 is F, Cl or CN.
  • the compound of this embodiment may have an inhibitory activity with respect to HCV, as measured by the concentration of the compound effective to produce a half-maximal inhibition of HCV1b replication (EC 50 ) in a 1b_Huh-Luc/Neo-ET cell line in culture, of 100 nM or less.
  • R 1 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • the compound in this embodiment may be selected from the group consisting of compounds identified by ID NOS: B5, B15, B20, B33, B35, B45, B67, B85, B92, B94, B107, B118, B120, B121, B127, B128, B130, B131, B132, B138, B139, B145, B148, B158, B163, B168, B169, B171, B187, B190, B191, B192, B196, B197, B198, B201, B207, B208, B212, B214, B218, B221, B226, B232, B233, B236, B237, B238, B239, B240, B2, B3, B4, BC B7, B9, B16, B18, B19, B22, B29, B31, B32, B34, B36, B47, B48, B54, B55, B57, B60, B63, B71, B84, B93, B100, B101, B106, B108,
  • the above compounds include compounds identified by ID NOS: B5, B15, B20, B33, B35, B45, B67, B85, B92, B94, B107, B118, B120, B121, B127, B128, B130, B131, B132, B138, B139, B145, B148, B158, B163, B168, B169, B171, B187, B190, B191, B192, B196, B197, B198, B201, B207, B208, B212, B214, B218, B221, B226, B232, B233, B236, B237, B238, B239, and B240.
  • a 7 or 8 member ring having an internal oxygen atom as exemplified by compounds B45, B118, B148, B197, B168, B187, B190; B192, B196, B207, B214, B191, B212, B218, B221, B222, B226, B232, B233, B236, B237, B238, B239, and B240;
  • R 1 in this embodiment may be
  • R 2 in this embodiment may be a phenyl substituted with one or more R 17 substituents.
  • R 2 in this embodiment may be a 4-phenoxyphenyl and the phenoxy group is substituted with one or more R 17 substituents.
  • R 2 in this embodiment may be selected from
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents, R 3 is selected from the
  • R 17 is H, F, Cl or CN
  • V is CH, N, CF, CCl, or CCN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n is 0, 1, or 2;
  • R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H
  • R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents;
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl;
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl;
  • R 15 , R 16 is independently hydrogen, hydroxyl, azide, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, or cyclopropoxy or
  • R 15 and R 16 together are a carbonyl or C 1-4 alkenylidene or R 15 and R 16 joined together with the attached carbon are 3-6 member ring optionally containing 0-3 heteroatoms of O, NR N and/or S; and
  • R 17 is H, F, Cl or CN.
  • R 1 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • Exemplary compounds in this embodiment include those identified by ID NOS: B89, B96, B97, B125, B126, and B129.
  • R 1 in this embodiment may be
  • R 2 in this embodiment may be a phenyl substituted with one or more R 17 substituents.
  • R 2 in this embodiment may be a 4-phenoxyphenyl and the phenoxy group is substituted with one or more R 17 substituents.
  • R 2 in this embodiment may be selected from
  • a fifth aspect of the invention is a compound of formula IV.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl or CN.
  • a sixth aspect of the invention is a compound of formula V.
  • L 1 or L 2 is independently selected from the group consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —Si(R 4 R 5 )—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n is 0, 1, or 2;
  • R N is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 4-5 heterocycle, aryl, heteroaryl, amide, sulfonamide, or carbamate;
  • R 2 is an aryl or
  • R 17 is H, F, Cl or CN
  • V is CH, N, CF, CCl, or CCN.
  • a seventh aspect of the invention is a compound of formula VI.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the group of hydrogen, alkylcarbon
  • R 17 is H, F, Cl or CN
  • V is CH, N, CF, CCl, or CCN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) 4 —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the group
  • R 17 is H, F, Cl or CN.
  • a ninth aspect of the invention is a compound of formula VIII.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —Si(R 4 R 5 )—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents, R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalky
  • R 17 is H, F, Cl or CN
  • V is CH, N, CF, CCl, or CCN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the group of hydrogen
  • R 17 is H, F, Cl or CN.
  • L 1 , L 2 and —(SO 2 Me)- together with the attached carbons of the aromatic ring form a 5-12 member ring, containing 1-4 heteroatoms of N, O, S, P and/or Si;
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl or CN
  • V is CH, N, CF, ca, or CCN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl or CN.
  • a thirteenth aspect of the invention provides a pharmaceutical composition comprising the compounds of the invention, including the exemplary compounds identified by the above ID NOS.
  • the composition may be formulated for oral delivery, and may include a second and/or third anti-HCV agents.
  • the compound administered may be one or more of the exemplary compounds identified by the above ID NOS.
  • the method may include administering to the subject, either in a single or separate administrations, a second anti-HCV, agent selected from the group consisting of interferon-alpha, ribavirin, or both.
  • the administering may be by oral route.
  • the compound for use in the treatment of HCV infection in an infected subject.
  • the compound may be one of those identified by ID NOS above.
  • the invention included all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereomers such as racemates.
  • the stereoisomers or their precursors can be either asymmetrically synthesized or obtained by separations of the racemates according to methods commonly known in the art.
  • the invention is intended to include all isotopically labeled analogs of the compounds of the invention.
  • Isotopes include those atoms having the same atomic number but different mass.
  • isotopes of hydrogen include 2 H(D) and 3 H(T) and isotopes of carbon include 13 C and 14 C.
  • Isotopically labeled compounds of the invention can be prepared according to methods commonly known in the art. Such compounds may have various potential uses as, but not limited to, standards and reagents in determining biological/pharmacological activities. For those stable isotopically labeled compounds of the invention, they may have the potential to favorably modulate biological, pharmacological, or pharmacokinetic properties.
  • alkanoyl as used herein contemplates a carbonyl group with a lower alkyl group as a substituent.
  • alkenyl as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals, including both the E- and Z-forms, containing from two to eight carbon atoms.
  • the alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , CO 2 R, C(O)R, —O—R, —N(R N ) 2 , —N(R N )C(O)R, —N(R N )S(O) 2 R, —SR, —C(O)N(R N ) 2 , —OC(O)R, —OC(O)N(R N ) 2 , S(O)R, SO 2 R, —SO 3 R, —S(O) 2 N(R N ) 2 , phosphate, phosphonate, cycloalkyl, cycloalkenyl, ary
  • alkoxy as used herein contemplates an oxygen with a lower alkyl group as a substituent and includes methoxy, ethoxy, butoxy, trifluoromethoxy and the like. It also includes divalent substituents linked to two separated oxygen atoms such as, without limitation, —O—CF 2 —O—, —O—(CH 2 ) 1-4 —O—(CH 2 CH 2 —O) 1-4 — and —(O—CH 2 CH 2 —O) 1-4 —.
  • alkoxycarbonyl as used herein contemplates a carbonyl group with an alkoxy group as a substituent.
  • alkyl as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms.
  • lower alkyl as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
  • the alkyl group may be optionally substituted with one or more substituents selected from halogen, —CN, —NO 2 , —C(O) 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N )C(O)R, —N(R N )S(O) 2 R, —SR, —C(O)N(R N ) 2 , —OC(O)R, —OC(O)N(R N ) 2 , —SOR, —SO 2 R, —SO 3 R, —S(O) 2 N(R N ) 2 , phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halogen, —CN, —NO 2 , —C(O) 2 R, —C(O)R, —O—R, —N(R N
  • alkylene refers to the groups “alkyl,” “alkenyl” and “alkynyl” respectively, when they are divalent, ie, attached to two atoms.
  • alkylsulfonyl as used herein contemplates a sulfonyl group which has a lower alkyl group as a substituent.
  • alkynyl as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to eight carbon atoms and having at least one carbon-carbon triple bond.
  • alkynyl includes, for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-1-butynyl and the like.
  • the alkynyl group may be optionally substituted with one or more substituents selected from halo, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N )C(O)R, —N(R N )S(O) 2 R, —SR, —C(O)N(R N ) 2 , —OC(O)R, —OC(O)N(R N ) 2 , —SOR, —SO 2 R, —SO 3 R, —S(O) 2 N(R N ) 2 , phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2
  • amino as used herein contemplates a group of the structure —NR N 2 .
  • amino acid as used herein contemplates a group of the structure
  • the present invention also includes, without limitation, D-configuration amino acids, beta-amino acids, amino acids having side chains as well as all non-natural amino acids known to one skilled in the art.
  • aralkyl as used herein contemplates a lower alkyl group which has as a substituent an aromatic group, which aromatic group may be substituted or unsubstituted.
  • the aralkyl group may be optionally substituted with one or more substituents selected from halogen, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N )C(O)R, —N(R N )S(O) 2 R, —SR, —C(O)N(R N ) 2 , —OC(O)R, —OC(O)N(R N ) 2 , —SOR, —SO 2 R, —SO 3 R, —S(O) 2 N(R N ) 2 , phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • aryl as used herein contemplates substituted or unsubstituted single-ring and multiple aromatic groups (for example, phenyl, pyridyl and pyrazole, etc.) and polycyclic ring systems (naphthyl and quinolinyl, etc.).
  • the polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are “fused”) wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • the aryl group may be optionally substituted with one or more substituents selected from halogen, alkyl, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N )C(O)R, —N(R N )S(O) 2 R, —SR, —C(O)N(R N ) 2 , —OC(O)R, —OC(O)N(R N ) 2 , —SOR, —SO 2 R, —SO 3 R, —S(O) 2 N(R N ) 2 , —SiR 3 , —P(O)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halogen, alkyl, —CN, —NO 2 , —CO 2 R, —
  • arylsulfonyl as used herein contemplates a sulfonyl group which has as a substituent an aryl group.
  • the term is meant to include, without limitation, monovalent as well as multiply valent aryls (eg, divalent aryls).
  • carbonyl as used herein contemplates a group of the structure
  • cycloalkyl as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing from three to twelve carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkyl also includes polycyclic systems having two rings in which two or more atoms are common to two adjoining rings (the rings are “fused”).
  • the cycloalkyl group may be optionally substituted with one or more substituents selected from halo, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N )C(O)R, —N(R N )S(O) 2 R, —SR, —C(O)N(R N ) 2 , —OC(O)R, —OC(O)N(R N ) 2 , —SOR, —SO 2 R, —S(O) 2 N(R N ) 2 , phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N
  • cycloalkenyl as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing from four to twelve carbon atoms in which there is at least one double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl and the like.
  • cycloalkenyl also includes polycyclic systems having two rings in which two or more atoms are common to two adjoining rings (the rings are “fused”).
  • the cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N )C(O)R, —N(R N )S(O) 2 R, —SR, —C(O)N(R N ) 2 , —OC(O)R, —OC(O)N(R N ) 2 , —SOR, —SO 2 R, —S(O) 2 N(R N ) 2 , phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N
  • halo or “halogen” as used herein includes fluorine, chlorine, bromine and iodine.
  • heteroalkyl as used herein contemplates an alkyl with one or more heteroatoms.
  • heteroatom particularly, within a ring system, refers to N, O and S.
  • heterocyclic group contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member.
  • Preferred heterocyclic groups are those containing five or six ring atoms which includes at least one hetero atom and includes cyclic amines such as morpholino, piperidino, pyrrolidino and the like and cyclic ethers, such as tetrahydrofuran, tetrahydropyran and the like.
  • Aromatic heterocyclic groups also termed “heteroaryl” groups, contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, oxodiazole, thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine and the like.
  • heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two or more atoms are common to two adjoining rings (the rings are “fused”) wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • polycyclic heteroaromatic systems examples include quinoline, isoquinoline, cinnoline, tetrahydroisoquinoline, quinoxaline, quinazoline, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, indazole, purine, benzotriazole, pyrrolepyridine, pyrrazolopyridine and the like.
  • the heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, —CN, —NO 2 , —CO 2 R, —C(O)R, —O—R, —N(R N ) 2 , —N(R N )C(O)R, —N(R N )S(O) 2 R, —SR, —C(O)N(R N ) 2 , —OC(O)R, —OC(O)N(R N ) 2 , —SOR, —SO 2 R, —SO 3 R, —S(O) 2 N(R N ) 2 , —SiR 3 , —P(O)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from the group consisting of halo, alkyl, —CN, —NO 2
  • oxo as used herein contemplates an oxygen attached with a double bond.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is made with counterions understood in the art to be generally acceptable for pharmaceutical uses and which possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, mane acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxye
  • salts of amino acids such as arginates and the like, and salts of organic acids like glucurmic or galactunoric acids and the like (see, e.g., Berge et al., 1977 , J. Pharm. Sci. 66:1-19).
  • phosphate and phosphonate refer to the moieties having the following structures, respectively:
  • salts and “hydrates” refers to the hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity, flowability and manufacturability of the resulting bulk drug.
  • sulfonamide as used herein contemplates a group having the structure
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkanoyl, or C 1 -C 10 alkoxycarbonyl.
  • Substituted sulfonyl as used herein contemplates a group having the structure
  • alkylsulfonyl including, but not limited to alkylsulfonyl and arylsulfonyl.
  • thiocarbonyl means a carbonyl wherein an oxygen atom has been replaced with a sulfur.
  • Each R is independently selected from hydrogen, —OH, —CN, —NO 2 , halogen, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide, amino, and oxo.
  • Each R N is independently selected from the group consisting of hydrogen, —OH, C 1 to C 12 alkyl, C 1 to C 12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.
  • Two R N may be taken together with C, O, N or S to which they are attached to form a five to seven membered ring which may optionally contain a further heteroatom.
  • the compounds of the present invention may be used to inhibit or reduce the activity of HCV, particularly HCV's NS5B protein.
  • inhibition and reduction of activity of the NS5B protein refers to a lower level of the measured activity relative to a control experiment in which the cells or the subjects are not treated with the test compound.
  • the inhibition or reduction in the measured activity is at least a 10% reduction or inhibition.
  • reduction or inhibition of the measured activity of at least 20%, 50%, 75%, 90% or 100%, or any number in between, may be preferred for particular applications.
  • L 1 , L 2 and L 3 together with the attached carbons of the aromatic ring to form a 5-12 member ring, containing 0-4 heteroatoms of N, O, S, P and/or Si;
  • L 1 , L 2 , or L 3 is independently selected from a group of divalent substituents consisting of a bond, —O—, —C(R 15 R 18 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n is 0, 1, or 2;
  • U or V is independently CH, N, CF, CCl, or CCN;
  • Y is NR N , N, O, S, Se, or —CR a R b ;
  • R N is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 4-5 heterocycle, aryl, heteroaryl, amide, sulfonamide, or carbamate;
  • R a , R b is independently hydrogen, methyl, or together form a C 3-6 cycloalkyl bearing 0-1 heteroatom of O or NR 3 ;
  • R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR 6 —, —C(O)NHR 7 , —C(O)N(OH)R 7 , —C( ⁇ NR 7 )OMe, —C( ⁇ NOMe)NHR 7 , C( ⁇ NOH)NHR 7 , —CH(CF 3 )NHR 8 , —CH(CN)NHR 9 , —S(O) 2 NHR 10 , —C( ⁇ NCN)NHR 11 ,
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • L 1 , L 2 and L 3 together with the attached carbons of the aromatic ring form a 5-12 member ring, containing 0-4 heteroatoms of N, O, S, P and/or Si;
  • L 1 , L 2 , or L 3 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n is 0, 1, or 2;
  • R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • L 1 , L 2 and L 3 together with the attached carbons of the aromatic ring form a 5-9 member ring, containing 0-4 heteroatoms of N, O, S, P and/or Si;
  • L 1 , L 2 , or L 3 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 13 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n is 0, 1, or 2;
  • R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • R 1 is hydrogen, halide, —C(O)OR 6 —, —C(O)NHR 7 , —C( ⁇ NR 7 )OMe, —C(O)N(OH)R 7 , —C( ⁇ NOMe)NHR 7 , C( ⁇ NOH)NHR 7 , —CH(CF 3 )NHR 8 , —CH(CN)NHR 9 ,
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy.
  • R 1 is hydrogen, Br, I, —COOH, —C(O)OMe, —C(O) OEt, —C(O)OtBu, —C(O)NHMe, —C(O)NHOMe, —C( ⁇ NOMe)NHMe, —C( ⁇ NOH)NHMe, —C( ⁇ NMe)OMe, —C(O)N(OH)Me, —C(O)NHS(O) 2 Me, —CH(CF 3 )NHMe, —CH(CN)NHMe, —C( ⁇ NCN)NHMe,
  • R 1 is —C(O)NHMe or
  • R 2 is selected from the group consisting of
  • R 12 is selected from the group of hydrogen, halide, —CN, —OCHF 2 , —OCF 3 , alkyl, cycloalkyl, alkoxy, cycloalkoxy, arylalkyl, aryloxy, alkenyl, alkynyl, amide, alkylsulfonyl, arylsulfonyl, sulfonamide, carbamate; m is 0, 1, 2, 3, or 4;
  • G is O, NR N , S, or CR a R b ;
  • A is N, O, S, or CR a R b ;
  • D, E is independently C or N.
  • R 2 is selected from the group consisting of:
  • R 12 is selected from the group of hydrogen, halide, —CN, —OCHF 2 , —OCF 3 , alkyl, cycloalkyl, alkoxy, cycloalkoxy, arylalkyl, aryloxy, alkenyl, alkynyl, amide, allylsulfonyl, arylsulfonyl, sulfonamide, carbamate; m is 0, 1, 2, 3, or 4;
  • G is O, NR N , S, or CR a R b ;
  • A is N, O, S, or CR a R b ;
  • D, E is independently C or N.
  • R 2 is selected from the group consisting of
  • each phenyl moiety is optionally substituted with 0-2 nitrogen atoms.
  • R 2 is
  • L 1 , L 2 , or L 3 is independently selected from the group consisting of a bond, —O—, —C(R 15 R 16 ), —NR 3 —, —S(O) n —, —P(O) n —, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR 6 —, —C(O)NHR 7 , —C(O)N(OH)R 7 , —C( ⁇ NMe)OMe, —C( ⁇ NOMe)N
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C 1-4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • L 1 , L 2 , or L 3 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR 6 —, —C(O)NHR 7 , —C(O)N(OH)R 7 , —C( ⁇ NMe)OMe, —C( ⁇ ( ⁇
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 6 is hydrogen, allyl, C f4 alkyl, cyclopropyl, or benzyl
  • R 7 is hydrogen, C 1-4 alkyl, cyclopropyl, C 1-4 alkoxy, cyclopropoxy, alkylsulfonyl, or cycloalkylsulfonyl
  • R 8 , R 9 , R 10 , or R 11 is independently hydrogen, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 1 is selected from hydrogen, halide, —CF 3 , —CN, —C(O)H, —C(O)OR 6 —, —C(O)NHR 7 , —C(O)N(OH)R 7 , —C( ⁇ NMe)OMe, —C( ⁇ NOMe)NHR
  • R 2 is a substituted or unsubstituted aryl or heteroaryl
  • R 3 is selected from the group of hydrogen, alkylcarbonyl, cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl, alkylsulfonyl and cycloalkylsulfonyl
  • R 4 and R 5 are independently methyl, ethyl, or cyclopropyl
  • R 15 and R 16 are independently hydrogen, hydroxyl, azide, C 2-4 alkynes, C 2-4 alkynes, C 1-4 alkyls, cyclopropyl, C 1-4 alkoxys, or cyclopropoxy or R 15 and R 16 together are a carbonyl or C 1-4 alkenyls.
  • a compound has the structure:
  • R 1 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R 1 may be
  • R 2 may be
  • One Group of exemplary, high-activity compounds are identified by ID NOS: B5, B15, B20, B33, B35, B45, B67, B85, B92, B94, B107, B118, B120, B121, B127, B128, B130, B131, B132, B138, B139, B145, B148, B158, B163, B168, B169, B171, B187, B190, B191, B192, B196, B197, B198, B201, B207, B208, B212, B214, B218, B221, B226, B232, B233, B236, B237, B238, B239, and B240 in Appendix A, and a second group of high-activity compounds are identified by ID NOS: B2, B3, B4, B6, B7, B9, B16, B18, B19, B22, B29, B31, B32, B34, B36, B47, B48, B54, B55, B57, B60, B63, B
  • a 7 or 8 member ring having an internal oxygen atom as exemplified by compounds B45, B118, B148, B197, B168, B187, B190; B192, B196, B207, B214, B191, B212, B218, B221, B222, B226, B232, B233, B236, B237, B238, B239, and B240;
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents, R 3 is selected from the
  • R 17 is H, F, Cl or CN
  • V is CH, N, CF, CCl, or CCN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl, or CN.
  • a fifth aspect of the invention is a compound of formula IV.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl or CN.
  • a sixth aspect of the invention is a compound of formula V.
  • L 1 or L 2 is independently selected from the group consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2;
  • R N is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 4-5 heterocycle, aryl, heteroaryl,
  • R 17 is H, F, Cl or CN
  • V is CH, N, CF, CCl, or CCN.
  • a seventh aspect of the invention is a compound of formula VI.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl or CN
  • V is CH, N, CF, CCl, or CCN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl or CN.
  • a ninth aspect of the invention is a compound of formula VIII.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents, R 3 is selected from the
  • R 17 is H, F, Cl or CN
  • V is CN, N, CF, CCl, or CCN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl or CN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, a or CN
  • V is CH, N, CF, CCl, or CCN.
  • L 1 or L 2 is independently selected from the group of divalent substituents consisting of a bond, —O—, —C(R 15 R 16 )—, —NR 3 —, —S(O) n —, —P(O)—, —Si(R 4 R 5 )—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide; n is 0, 1, or 2; R 2 is an aryl or heteroaryl and may be substituted with one or more R 17 substituents; R 3 is selected from the
  • R 17 is H, F, Cl or CN.
  • a thirteenth aspect of the invention provides a pharmaceutical composition comprising the compounds of the invention.
  • a fourteenth aspect of the invention provides use of the compounds of the invention in the manufacture of a medicament.
  • the medicament is for the treatment of hepatitis C.
  • a fifteenth aspect of the invention provides a method of treating hepatitis C comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention.
  • the compounds of the invention may be prepared by a variety of synthetic routes, samples of them are illustrated in the synthetic schemes outlined below.
  • the synthesis starts with constructing the central scaffolds such as benzofuran, benzothiophene, imidazopyridine or pyrazolopyridine by employing various synthetic techniques known to those skilled in the art. (e.g. in Heterocyclic Chemistry, J. A. Joule and K. Mills, J Wiley and Sons, 2010.).
  • further functional group manipulations including but not limited to chain elongation, amidation, esterification, cyclization are performed as necessary to lead to the target molecules.
  • the central cores may be preferred to be introduced toward the end of the synthesis.
  • protection-deprotection and, in some cases, orthogonal protection-deprotection strategies are required to accomplish the desired transformation. More comprehensive descriptions of these synthetic methodologies, techniques can be in found in these and other references: Comprehensive Organic Transformations, R. C. Larock Ed., Wiley-RCH, 1999. Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ed. J Willey and Sons, 1999.
  • Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA).
  • 1 H NMR spectra were recorded on a Bruker 400 MHz or 500 MHz NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons.
  • Electrospray spray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-Packard 1100 MSD electrospray mass spectrometer using the HP1 100 HPLC for sample delivery.
  • Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parentheses) or a single m/z value for the M+H (or, as noted, M ⁇ H) ion containing the most common atomic isotopes. Isotope patterns correspond to the expected formula in all cases. Normally the analyte was dissolved in methanol at 0.1 mg/mL and 5 microliter was infused with the delivery solvent into the mass spectrometer, which scanned from 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode, using an acetonitrile/water gradient (10%-90%) acetonitrile in water with 0.1% formic acid as delivery solvent.
  • the compounds provided below could also be analyzed in the negative ESI mode, using 2 mM NH 4 OAc in acetonitrile/water as delivery solvent. Enantiomeric purity was determined using a Hewlett-Packard Series 1050 system equipped with a chiral HLPC column (ChiralPak AD, 4.6 mm ⁇ 150 mm) and isocratic elution using 5:95 isopropanol-hexane as mobile phase.
  • Scheme A describes a general approach to building fused rings with different sizes that are attached to benzazole moieties and some chemical transformations on these fused rings.
  • Reduction of NO 2 substituted benzazole A-1, followed by sulfonylation gives A-3, which is installed a substituted terminal alkyne to afford A-5.
  • a [Pd]-mediated ring cyclization forms A-6.
  • A-6 can be prepared using A-7 as a starting material for the Heck reaction.
  • Hydrogenation of A-6 generates A-8, which can also be obtained from A-10 by hydrogenation.
  • A-10 can be converted from A-6 through an isomerization.
  • Cleavage of the double bond of A-6 using conditions such as onzonolysis gives A-9, which can be readily converted into A-11 to A-21 following typical reduction, ⁇ -alkylation, O-alkylation, elimination, and/or hydrogenation conditions.
  • Scheme B describes a general approach to B-3 bearing two substituents at the benzylic carbon. N-alkylation of A-3 with B-1 gives B-2, which is readily converted to B-3 through an intra-molecular Heck reaction when X 1 is a halide.
  • B-3 can be prepared using B-4 as a precursor.
  • Scheme C describes a general approach to cyclopropyl-substituted analogs C-1, C-2, C-3 and C-4 from A-6, A-10, A-13 and A-18, respectively.
  • Scheme D describes a general approach to analog D-2 from A-6. Hydroboration of A-6 gives D-1, in which the —OH can be readily converted into its mesylate, toyslate, or halide. Subsequent nucleophilic substitution with a nucleophile generates D-2.
  • Scheme E describes an alternative approach to build fused rings with different sizes that are attached to benzazole moieties.
  • Sonogashira reaction of either A-1 or E-3 and E-1 gives E-2, which is hydrogenated to afford E-4.
  • Selective sulfonylation of E-4, followed by ring closure forms A-14.
  • Conversion the triple bond of E-2 into a carbonyl group, followed by reduction of the —NO 2 , sulfonylation and ring closure generates A-9.
  • Scheme F describes a general approach to analogs F-4 and F-7 from A-2. Sulfonylation of F-1 with F-2 gives F-3, which undergoes cyclization to afford F-4. Similarly, F-7 can be prepared using F-6 instead of F-2 to react with F-1.
  • Scheme G describes a general approach to fused analogs G-6, G-7, G-8, G-12 and G-14.
  • Heck reaction of A-1 with G-1 gives G-2, which can also be prepared from E-2.
  • Scheme H describes a general way to prepare H-5, H-6 and H-7. Suzuki coupling of A-1 and H-1 gives H-2, which is converted to H-4 following the same strategy depicted in Scheme E. Further transformations of H-4 may readily afford H-5. H-6 and H-7. Similarly, H-9 can be synthesized by replacing A-1 with suitable starting materials.
  • Scheme I describes general ways to build a functionalized benzofuran moiety.
  • O-protection of I-1, followed by Sonogashira reaction with a substituted alkyne gives I-3, which is de-protected in the presence of an acid to afford I-4.
  • This compound undergoes a [Pd]-mediated ring cyclization to form I-5, which can be readily converted to I-7 by following a two-step sequence of saponification and amide formation.
  • I-4 can be converted to I-5 through a two-step transformation of NIS or NBS-promoted cyclization and [Pd] mediated carbonylation.
  • Scheme J describes a general way to build a functionalized pyrazole-pyridine moiety.
  • N-amination of J-1 gives pyridium salt J-2, which undergoes a ring cyclization with alkynecarboxylate J-3 to form substituted pyrazole-pyridine J-4.
  • Saponification of J-4, followed by amide formation affords J-5.
  • Scheme K describes a general way to build a functionalized imidazole-pyridine moiety. Cyclization of substituted aminopyridine K-1 with bromo-ketoester K-2 gives the cyclized product K-3, which can be readily converted to K-4 by following a two-step sequence of saponification and amide coupling.
  • Scheme L describes a general way to build a functionalized benzothiophene moiety.
  • Sonogashira reaction of L-1 with a substituted alkyne gives L-2, which is converted to thio-ether L-3.
  • An I 2 -promoted ring cyclization of L-3 affords benzothiophene L-4.
  • the iodo group can be readily transformed into a carboxylate to form functionalized L-5, which undergoes saponification and amide formation to give L-6.
  • Scheme M describes general ways to build a functionalized 2H-indazole moiety.
  • a Cu-mediated N-arylation gives a mixture of 1H-inzaole M-2 and the desired 2H-indazole M-3. The latter can be readily converted to M-4 following a two-step sequence of saponification and amide formation.
  • 2H-indazole M-5 can be brominated at the C-3 position to give M-6, which undergoes a [Pd]-mediated carbonylation to afford M-3.
  • Scheme N describes a general way to build a functionalized indole moiety.
  • a condensation of N-1 and keto-ester N-2 gives N-3.
  • Reduction of N-3, followed by a ring formation affords substituted indole N-4, which can be readily converted to N-5 S by following a two-step sequence of saponification and amide formation.
  • Method B To a solution of compound 18-4 (100 mg, 0.224 mmol) and pyridine (106 mg, 1.34 mmol) in DCM (5 mL) was added methyl chloroformate (37 mg, 0.47 mmol) at 0° C. and the resulting mixture was stirred at it for 30 min. The reaction was quenched by adding several drops of sat. aq. NaHCO 3 and the mixture was concentrated. The residue was diluted with DCM (60 mL) and the mixture was washed with brine (25 mL) and dried with anhydrous Na 2 SO 4 .

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