WO2013163466A1 - Inhibiteurs du virus de l'hépatite c - Google Patents

Inhibiteurs du virus de l'hépatite c Download PDF

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Publication number
WO2013163466A1
WO2013163466A1 PCT/US2013/038275 US2013038275W WO2013163466A1 WO 2013163466 A1 WO2013163466 A1 WO 2013163466A1 US 2013038275 W US2013038275 W US 2013038275W WO 2013163466 A1 WO2013163466 A1 WO 2013163466A1
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compound
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esi
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PCT/US2013/038275
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Min Zhong
Leping Li
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Presidio Pharmaceuticals, Inc.
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Priority claimed from US13/456,181 external-priority patent/US9085587B2/en
Application filed by Presidio Pharmaceuticals, Inc. filed Critical Presidio Pharmaceuticals, Inc.
Publication of WO2013163466A1 publication Critical patent/WO2013163466A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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
  • HCV is a single-stranded RN A 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, El and E2, p7, an integral membrane protein, follows El and E2.
  • C core
  • E2 envelope glycoproteins
  • p7 an integral membrane protein
  • 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 is a serious health issue. It is estimated that 170 million people worldwide are chronically infected with HCV. 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 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-NCSQzR 12 together with the attached carbons of the aromatic ring to form a 5-12 member ring, containing 1-4 heteroatoms of N, O, S, P and/or Si;
  • L'or L 2 is independently selected from the group consisting of a bond, -0-, -C(R I5 R 16 )-, -NR 3 -, - S(O » -P(0 , -Si(R 4 R 5 K -C(O)-, -C(0)0-, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • n 0, 1, or 2;
  • R' is selected from hydrogen, -(CH 2 CHzO)o-8-Me, C 2 .24 alkyl optionally containing 0-6 heteroatoms of O, NR N and/or S, and 3-8 cycloalkyl optionally containing 0-2 heteroatora of O, NR N , and/or S;
  • 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]. 3 alkyl, cyclopropyl, -OMe, or -NHMe;
  • R 15 , R 16 is independently hydrogen, hydroxyl, azide, C 2 - alkeny!, CM alkyl, cyclopropyl, C alkoxy, or cyclopropoxy or R 15 and R 16 together are a carbonyl or C 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 ,7 is F, Cl or CN.
  • the compound of this embodiment may have an inhibitory activity with respect to HCV,
  • R v is selected from hydrogen, -NR'R", alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;
  • R w and R* are indenpendrntry selected from hydrogen, -C(0)H, -C(0)R Hi , -C(0)OR iv -, - C ⁇ NR'H", alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; optionally, R v and R together form a C4.8 member ring;
  • R y and R z are independently selected from hydrogen, alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; optionally, R y and R z together form a 3-8 member ring;
  • R' and R" are indenpendently selected from hydrogen, -Me, -Et, c-Pr-, c-Butyl;
  • R" 1 is selected from alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;
  • R lv is selected from alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; and R v and R VI are indenpendently selected from hydrogen, aUcyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl.
  • the compound has the structural formula:
  • X' is selected from and
  • R' 3 is selected from -CH 3 and -OCH 3 .
  • the compound may be selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B283, B284, B285, B286, B287, B288, B289, B290, B291, B293, B294, B295, B296, B297, B298, B299, B300, B301, B302, B303, B304, B305, B306, B307, B308, B309, B310, B311, B312, B313, B314, B315, B316, B317, B318, B319, B320, B321, B322,
  • R'i pa a-F
  • R u -0- is as above
  • R ⁇ is -C3 ⁇ 4.
  • the compound in this group may be selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B285, B286, B289, B300, B302, B306, B307, B308, B309, B310, B311, B314, B316, B317, B318, B319, B320, B333, B335, B336, B337, B338, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B373, B378, B379, B38
  • R'i is selected from -H, -F, -CI, -Br, -I,
  • X' is selected and R' 3 is selected from -CH 3 and -OCH3.
  • Specific compounds in this group (Group 2) are selected from the group consisting of B283, B284, B287, B288, B290, B291, B293, B422, B423, B424, B426, B432, B443, B446, B447, B455, B456, B459, B463, B464, B466, B467, B470, B478, B479, B487, B488, B489, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513, B514, B515, B516, B517, B518, B5
  • R'3 is selected from -C3 ⁇ 4 and -OCH3.
  • Specific compounds in this group are selected from the group consisting of B294, B295, B296, B297, B298, B299, B301, B303, B304, B305, B312, B313, B315, B321, B322, B323, B326, B327, B328, B329, B330, B334, B339, B340, B341, B342, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B374, B375, B376, B377, B380, B382, B387, B393, B396, B398, B403, B406, B407, B408, B410, B411, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B425, B427, B428, B429
  • R' l is selected from para-F
  • R' 2 is selected from -OH and -S0 2 Me; and R' 3 is selected from -CH 3 and -OCH 3 , as exemplified by B324, B325, B331, and B332.
  • the compound of the invention has the structural formula:
  • R' i is selected from para-F ;
  • R' 2 is selected from -OH and -S0 2 Me; and R * 3 is selected from -CH 3 and -OCH3, as exemplified by compound B359.
  • a pharmaceutical composition comprising a compound of any one of compounds above, or its pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.
  • composition may further includes additional one, two or three anti-HCV agent(s) selected from the group consisting of interferon-alpha, ribavirin, cyclosporine derivatives, HCV NS3 protease inhibitors, HCV NS4B inhibitors, HCV NS5 A inhibitors, HCV NS5B polymerase inhibitors, and p7 inhibitors.
  • anti-HCV agent(s) selected from the group consisting of interferon-alpha, ribavirin, cyclosporine derivatives, HCV NS3 protease inhibitors, HCV NS4B inhibitors, HCV NS5 A inhibitors, HCV NS5B polymerase inhibitors, and p7 inhibitors.
  • the invention includes a method of treating HCV infection in a subject comprising administering to the subject, a pharmaceutically acceptable dose of the compound above, and continuing the administering until a selected reduction in the subject's HCV titer is achieved
  • the method may use a compound selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B283, B284, B285, B286, B287, B288, B289, B290, B291, B293, B294, B295, B296, B297, B298, B299, B300, B301, B302, B303, B304, B305, B306, B307, B308, B309, B310, B311, B312, B313, B314, B315, B316, B317, B 18, B319, B320, B321, B
  • the compound is selected from the group (Group 1 ) consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262.B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B285, B286, B289, B300, B302, B306, B307, B308, B309, B310, B311, B314, B316, B317, B318, B319, B320, B333, B335, B336, B337, B338, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B373, B
  • the compound is selected from the group (Group 2) consisting of B283, B284, B287, B288, B290, B291, B293, B422, B423, B424, B426, B432, B443, B446, B447, B455, B456, B459, B463, B464, B466, B467, B470, B478, B479, B487, B488, B489, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513.
  • Group 2 consisting of B283, B284, B287, B288, B290, B291, B293, B422, B423, B424, B426, B432, B443, B446, B447, B455, B456, B459, B463, B464, B466, B467,
  • the compound is selected from the group (Group 3) consisting of B294, B295, B296, B297, B298, B299, B301, B303, B304, B305, B312, B313, B315, B321, B322, B323, B326, B327, B328, B329, B330, B334, B339, B340, B341, B342, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B374, B375, B376, B377, B380, B382, B387, B393, B396, B398, B403, B406, B407, B408, B410, B411, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B425, B427, B
  • 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 ,3 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 ofhalogen, -CN, -N(1 ⁇ 4, CC3 ⁇ 4R, C(0)R, -O-R, -N(R N ) 2 , - N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R,
  • alkoxycarbonyl contemplates a carbonyl group with an alkoxy group as a substituent.
  • alkyl contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms.
  • lower alkyP 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, -N0 2 , -C(0) 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, - N(R N )S(0)2R, -SR, -C(0)N(R N ) 2 , -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -SO3R, -S(0)2N(R N ) 2i phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halogen, -CN, -N0 2 , -C(0) 2 R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R,
  • alkylene alkenylene and alkynylene
  • alkynylene 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- carbo triple bond.
  • alkynyl includes, for example ethynyl,
  • alkynyl group may be optionally substituted with one or more substituents selected from halo, -CN, -N0 2 , -C0 2 R, - C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R,
  • amino as used herein contemplates a group of the structure -NR N 2 .
  • D or the L configuration includes but is not limited to the twenty "standard” amino acids: isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartate, cysteine, glutamate, glutamtne, glycine, proline, serine, tyrosine, arginine and histidine.
  • 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 a substituent on 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, -NO2, -CO2R, -C(0)R, -O-R, -N(R N )2, -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR,
  • 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, -NO2, - CC3 ⁇ 4R, -C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, - OC(0)N(R N ) 2 , -SOR, -S0 2 R, -SO3R, -SiO ⁇ N ⁇ , -SiR 3 , -P(0)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halogen, alkyl, -CN, -NO2, - CC3 ⁇ 4R, -C(0)R, -O-R, -N(R N
  • 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).
  • Carboxyl as used herein contemplates a group of the structure [055]
  • cycloalkyt 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 , -CO2R, -C(0)R, -O-R, -N( N > 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N >2, - OC(0)R, -OC(0)N(R N ) 2 , -SOR, -S0 2 R, -S(0) 2 N(R N ) 2 , phosphate, phosphonate, alkyl,
  • 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 , -C0 2 R, - C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N ) 2 , -OC(0)R, - OC(0)N(R N ) 2 , -SOR, -S0 2 R, -S(0) 2 N(R N ) 2 , phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, -CN, -NO 2 , -C0 2 R, - C(0)R, -O-R, -N(R N ) 2 , -N(R N )C(0)R, -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
  • 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 morpholtno, 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 , -CO2R, -C(0)R, - O-R, -N(R N ) 2 , -N(R N )C(0)R, -N(R N )S(0) 2 R, -SR, -C(0)N(R N >2, -OC(0)R, -OC(0)N(R N ) 2 , -SOR, -SO2R, -SO3R, -S(0) 2 N(R N ) 2 , -S1R3, -P(0)R, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from the group consisting of halo, alkyl, -CN, -NO 2 , -CO2R, -C(0)R, - O-R,
  • 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, malic acid, maleic acid, rumaric 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-naphthalenesulfonic acid 4-toluenesulfonic acid, camphorsulfonic acid,
  • 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 etal., 1977, J. Pharm. Sci. 66:1-19).
  • 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" is selected from the group consisting of hydrogen, Ci-Cio alkyl, Cj-
  • 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, -N0 2 , halogen, d to C )2 alkyl, C
  • Each R N is independendy selected from the group consisting of hydrogen, -OH, Ci to Cu alkyl, Cj toC 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'or L 2 is independently selected from the group consisting of a bond, -0-, -C(R 15 R I6 > -NR 3 -, - S(0) admir-, -P(O)-, -SifR ⁇ 5 )-, -C(O)-, -C(0)0-, and substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea, and sulfonamide;
  • R* is selected from hydrogen, -(CH2CH 2 0)o ⁇ -Me, C 2 -24 alkyl optionally containing 0-6 heteroatoms of O, NR N and/or S, and 3-8 cycloalkyl optionally containing 0-2 heteroatom of O, NR N , and/or S;
  • R 2 is an aryl or heteroaryl having one or more R i7 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 C1.3 alkyl, cyclopropyl, -OMe, or -NHMe;
  • R 15 , R 16 is independently hydrogen, hydroxyl, azide, C2-4 alkenyl, C2- 4 alkynyl, C alkyl, cyclopropyl, CM alkoxy, or cyclopropoxy or R 13 and R 16 together are a carbonyl or C
  • 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;
  • R 17 is F, Cl orCN.
  • the compound of this aspect 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 HCVlb replication (EC 50 ) in a lb_Huh-Luc Neo-ET cell line in culture, of lOO nM or less.
  • R u is selected from hydrogen, -C(0)H, -C(0)R in , -C(0)OR iv , -CiONR'R , alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;
  • R v is selected from hydrogen, -NR'R", alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;
  • R w and R* are independrntly selected from hydrogen, -C(0)H, -C(0)R Ui , -C(0)OR iv -, - C(0)NR v R vi , alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; optionally, R v and R w together form a C4.8 member ring;
  • R y and R z are independently selected from hydrogen, alkoxyls, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl; optionally, R y and R x together form a 3-8 member ring;
  • R' and R u are indenpendently selected from hydrogen, -Me, -Et, oPr-, c-Butyl;
  • R'" is selected from alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;
  • R 1V is selected from alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl;
  • R v and R VI are indenpendently selected from hydrogen, alkyoxyl, alkyls, cycloalkyls, aryls, heteroaryls, and aralkyl.
  • the compound of this aspect may have the structure in which R 12 0 is one of
  • R 1 in mis aspect may be
  • R 2 in this aspect may be a phenyl substituted with one or more R 17 substituents.
  • R 2 in this aspect may be a 4-phenoxyphenyl and the phenoxy group is substituted with one or mor 17 substituents.
  • the compound may have the particular sterochemical structure shown below:
  • the compound in this group may be selected from the group consisting of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262.B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B285, B286, B289, B300, B302, B306, B307, B308, B309, B310, B311, B314, B316, B317, B318, B319, B320, B333, B335, B336, B337, B338, B343, B344, B345, B346, B347, B348, B349, B350, B351, B352, B353, B354, B373, B378, B379, B38
  • R' I is selected from -H, -F, -CI, -Br, -I,
  • n 0, 1 , 2
  • X' is selected and « N-0(CH 2 )j-23CH 3 , and
  • R' 3 is selected from -C3 ⁇ 4 and -OCH3.
  • Specific compounds in this group are selected from the group consisting of B283, B284, B287, B288, B290, B291, B293, B422, B423, B424, B426, B432, B443, B446, B447, B455, B456, B459, B463, B464, B466, B467, B470, B478, B479, B487, B488, B489, B491, B492, B493, B494, B495, B496, B497, B498, B499, B500, B501, B502, B503, B504, B505, B506, B507, B508, B509, B510, B511, B512, B513, B514, B515, B516, B517, B518, B519, B520, B521, B522, B523, B524, B525, B526, B527, B528, B529, B530, B531, B532, B533, B534, B535, B
  • Specific compounds in this group are selected from the group consisting of B294, B295, B296, B297, B298, B299, B301, B303, B304, B305, B312, B313, B315, B321, B322, B323, B326, B327, B328, B329, B330, B334, B339, B340, B341, B342, B355, B356, B357, B358, B360, B361, B362, B363, B364, B365, B366, B367, B368, B369, B370, B371, B372, B374, B375, B376, B377, B380, B382, B387, B393, B396, B398, B403, B406, B407, B408, B410, B411, B412, B413, B414, B415, B416, B417, B418, B419, B420, B421, B425, B427, B428, B429
  • the compound of the invention has the structural formula:
  • R'2 is selected from -OH and -SOaMe; and R'j is selected from -CH3 and -OCH3, as exemplified by compound B359.
  • This compound can be prepared in accordance with Scheme 39 detailed below.
  • the compounds of the invention may be prepared by a variety of synthetic routes, samples of which 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 preferably 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 and techniques can be in found in these and other references:
  • PPTs Pyridinium / oluenesulfonate
  • Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA).
  • ⁇ NMR spectra were recorded on a Broker 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 constants) 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 HP 1 100 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 N3 ⁇ 4OAc in
  • the compound of the invention includes a compound having the structural formula:
  • R' l is selected from para-
  • R * 2 is selected from -OH and -S0 2 Me; and R'3 is selected from -CH ⁇ and -OCH3, as exemplified by B324, B325, B331, and B332.
  • This compound can be synthesized in accordance with the scheme 40 below. 0102]
  • the compound of the invention has the structural formula:
  • R' I is selected from para- ⁇ ;
  • R' 2 is selected from -OH and -S0 2 Me; and R'3 is selected from -CH 3 and -OCH3, as exemplified by compound B359.
  • Step 1 Refer to Scheme 4. To a solution of compound 3-1 (prepared by following the procedures described in WO200759421 with some modifications) (4.00 g, 10.3 mmol) in CH 2 C1 2 (30 mL) was added BC1 3 (I N in CH 2 C1 2 , 20.6 mmol) at 0 °C. After stirring at rt for 1 hr, the reaction mixture was added ice water (100 mL). The mixture was extracted with CH 2 C1 2 (800 mL x 2) and the combined organic extracts were washed with water and brine and dried with anhydrous Na 2 SO_ ⁇ . The solvent was removed and the residue was dried in vacuo to give crude compound 4-1 (3.4 g, 96% yield) as a yellow solid. LC-MS (ESI): mlz 346 [M + H] + .
  • Step 2 To a solution of compound 4-1 (3.4 g, 9.8 mmol) in CH 2 C1 2 (100 mL) were added DMAP (120 mg, 0.980 mmol) and D1EA (1.52 g, 11.8 mmol), followed Tf z O (3.20 g, 1 1.3 mmol) at 0 °C. After stirring at 0 °C for 2 hrs, the reaction mixture was added ice water (100 mL). The organic layer was separated, washed with water and brine, and dried with anhydrous Na 2 S0 4 . The solvent was removed and the residue was dried in vacuo to give crude compound 4-2 (4.6 g, quantitative yield) as a yellow solid. LC-MS (ESI): mlz 478 [M + H] + .
  • Step 5 To a solution of compound 4-5 (1.80 g, 4.85 mmol) in CH 2 C1 2 (50 mL) was added DMAP (6 mg) and anhydrous pyridine (3.07 g, 38.8 mmol), followed by MsCl (1.60 g, 14.5 mmol) at 0 °C. After stirring at rt for 2 hrs, the reaction mixture was added ice water (50 mL).
  • Step 6 To a suspension of NaH (0.21 g, 60% in mineral oil, 5.31 mmol) in anhydrous THF (160 mL) was added a solution of compound 4-6 (1.40 g, 2.65 mmol) in anhydrous THF (40 mL) at 0 °C. After stirring at rt for 2 hrs, the reaction mixture was added sat. aq. NH4CI (10 mL). The resulting mixture was concentrated and the residue was diluted with EtOAc (100 mL). The mixture was washed with water and brine and dried with anhydrous NaiSC The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum).
  • Step 7 To a solution of compound 4-7 (50 mg, 0.12 mmol) in MeOH THF (2 mL/4 mL) was added LiOH (2.0 N, 0.46 mmol). The resulting mixture was stirred at 70 °C for 2 hrs, cooled to rt and acidified with 1 N aq. HC1 (5 mL). Subsequently, the suspension was filtered and the solid was washed with waster and dried in vacuo to give crude compound 4-8 (46 mg, 95% yield) as a white solid, which was used directly for the next step without further purification.
  • Step 1 Refer to Scheme 8. To a stirred solution of compound 4-2 (9.00 g, 18.9 mmol) in DMF (100 mL) were added Et 3 N (7.84 mL, 56.6 mmol), Pd(OAc) 2 (212 mg, 0.94 mmol), dppp (469 mg, 1.13 mmol) and butyl vinyl ether (12.1 mL, 94.4 mmol) under an atmosphere of Ar. After stirring at 100 °C for 2 hrs, the reaction mixture was concentrated. The residue was diluted with EtOAc (250 mL) and the resulting mixture was washed with water (100 mL x 3) and dried with anhydrous Na2SC>4.
  • Step 2 A solution of compound 8-1 (3.90 g, 9.13 mmol) in THF (60 mL) was added 1 N aq. HC1 (10 mL) at rt. After stirring at rt for 15 min, the reaction mixture was concentrated and the residue was diluted with DCM (100 mL). The resulting mixture was washed with brine and dried with anhydrous Na 2 S04. The solvent was removed and the residue was dried in vacuo to give crude compound 8-2 (3.27 g, 96% yield) as a yellow solid, which was used for the next step without further purification.
  • Step 3 To a stirred solution of compound 8-2 (2.00 g, 5.38 mmol) in EtOAc (50 mL) was added SnCl 2 2H 2 0 (3.47 g, 16.2 mmol). After stirring at 80 °C for 1 hr, the reaction mixture was added sat. aq. NaHC0 3 (50 mL) and the resulting mixture was stirred at rt for 30 min.
  • Step 4 To a stirred solution of compound 8-3 (900 mg, 2.64 mmol) in anhydrous pyridine (15 mL) was added MsCl (0.25 mL, 3.17 mmol) at 0 °C. After stirring at rt for 1 hr, the reaction mixture was diluted with EtOAc (100 mL) and the resulting mixture was washed with 2 N aq. HC1 (20 mL x 2) and H 2 0 (50 mL x 3) and dried with anhydrous Na 2 S0 4 . The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum
  • Step 5 To a solution of compound 8-4 (380 mg, 0.91 mmol) in MeOH (10 mL) and THF (10 mL) was added NaBH 4 ( 172 mg, 4.54 mmol) in several portions at 0 °C. After stirring at 0 °C for 15 min, the reaction was quenched by adding acetone (1 mL). The mixture was concentrated and the residue was diluted with EtOAc (100 mL). The resulting mixture was washed with 2 N aq. HC1 (20 mL) and H 2 0 (50 mL x 3) and dried with anhydrous Na 2 S0 4 . The solvent was removed
  • Step 7 To a solution of compound 8-7 (40 mg, 0.09 mmol) in MeOH THF (2 mL/4 mL) was added 2.0 N aq. LiOH (0.18 mmol, 0.36 mmol). After stirring at 75 °C for 3 hrs, the reaction mixture was cooled to 0 °C and acidified with 2N aq. HC1 adjust pH value to 5 ⁇ 6. Subsequently, the suspension was filtered and the solid was washed with water and dried in vacuo to give compound 8-8 (38 mg, 97% yield) as a white solid, which was used for the next step without further purification.
  • Step 8 To a solution of compound 8-8 (40 mg, 0.10 mmol) in DMF (3 mL) was added HATU (43 mg, 0.12 mmol). The resulting mixture was stirred at rt for 60 min and DIE A (0.16 mL, 0.95 mmol) and MeNH 2 HCl (20 mg, 0.29 mmol) were added. After stirring at rt for 15 min, the reaction mixture was added into water (30 mL). The suspension was filtered and the solid was washed with water and dried in vacuo. The residue was dissolved in DCM (1.5 mL) and the solution was added into hexane (40 mL).
  • MeOH/liquid CO2 10/90 (v V), flow rate: 60 g/min and back pressure: 100 bar).
  • Step 1 Refer to Scheme 15. To a solution of NaH (80 g, 60% mineral oil dispersion, 2 mol) in toluene (1.2 L) was added diethyl carbonate (295 g, 2.50 mol) at 0 °C. After stirring at rt for 2 hrs, the mixture was added drop wise to a solution of compound 15-1 (99 g, 0.50 mol) in toluene (400 mL) at reflux. After refluxing overnight, the reaction mixture was cooled to rt and sequentially treated with HOAc (140 mL) and aq. HC1 (2 M, 864 mL).
  • Step 3 To a solution of compound 15-3 (26 g, 72 mmol) in NMP (200 mL) was added Cs 2 C0 3 (47.0 g, 144 mmol). After stirring at rt for 20 min, 2-bromopropane (20.0 ml, 216 mmol) was added. The resulting mixture was stirred at 80 °C for 4 hrs, then diluted with ammonia and agitated for 30 min. The mixture was diluted with water (200 mL) and the aqueous phase was extracted with EtOAc (150 mL x 3). The combined organic extracts were washed with water (200 mL x 3) and dried with anhydrous Na 2 S0 4 . The solvent was removed and the residue was dried in vacuo to give compound 15-4 (27.5 g, 95% yield) as a colorless oil.
  • Step 5 A mixture of compound 15-5 (5.0 g, 1 1.2 mmol), 4-fluorophenol (1.7 g, 14.5 mmol), Pd(OAc) 2 (250 mg, 1.12 mmol), -BuXphose (380 mg, 0.9 mmol) and K 3 PO 4 (4.8 g, 22.4 mmol) in toluene (50 mL) was stirred at 100°C under an atmosphere of Ar and monitored by LC- MS. After 2 hrs, the reaction mixture was concentrated and the residue was diluted with water (100 mL).
  • Step 9 To a solution of compound 15-9 (1.4 g, 3.4 mmol) in EtOAc (50 mL) was added SnCl 2 2H 2 0 (2.8 g, 13.6 mmol) at rt and the resulting mixture was stirred at 80 °C for 1 hr. The mixture was cooled to rt and d its pH value was adjusted to 8 ⁇ 9 by adding saturated aq.
  • Step 10 To a solution of compound 15-10 (1.1 g, 2.5 mmol) in anhydrous pyridine (20 mL) was added MsCl ( 1.8 mL) at 0 °C. After the mixture was stirred at 30 °C for 2 hrs, LC-MS analysis indicated that the reaction went to completion. The mixture was diluted with water (100 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with sat. aq. NH 4 C1 (50 mL x 3) and brine (50 mL) and dried with anhydrous Na 2 S0 4 . The solvent was removed and the residue was dried in vacuo to give crude compound 15-11 (1.1 g, 90% yield) as a yellow solid. LC-MS (ESI): mlz 512.1 [M + H] + .
  • Step 11 To a solution of compound 15-11 (1.1 g, 2.1 mmol) in THF (30 mL) was added aBH 4 (560 mg, 14.7 mmol) in portions at 0 °C. After stirring at 0 °C for 30 min, LC-MS analysis indicated that the reaction went to completion and acetone (2 mL) was added to quench excess amount of NaB3 ⁇ 4. The mixture was concentrated and the residue was diluted with EtOAc (100 mL). The resulting mixture was washed with water (50 mL x 3) and brine (50 mL) and dried with anhydrous Na 2 SO.t. The solvent was removed and the residue was dried in vacuo to give compound 15-12 (0.9 g, 90% yield) as a yellow solid. LC-MS (ESI): mlz 514.1 [M + H] + .
  • Step 12 To a solution of compound 15-12 (0.9g, 1.7 mmol) in anhydrous DCM (30 mL) was added NaH (60% in paraoil, 200 mg, 5 mmol) at 0 °C, followed by compound 8-6 ( 1.1 g, 2.55 mmol). After stirring at 0 °C for 3 hrs and at it for 12 hrs, the reaction was quenched by adding saturated aq. NH 4 C1 (10 mL). The resulting mixture was extracted with DCM (30 mL x 3) and the combined organic extracts were washed with brine (50 mL) and dried with anhydrous Na 2 S0 4 . The solvent was removed and the residue was purified by silica gel column
  • Step 13 To a solution of compound 15-13 (520 mg, 0.96 mmol) in MeOH/THF (4 mL/8 mL) was added aq. LiOH (2.0 M, 2 mL) at rt. After stirring at 80 °C for 12 hrs, the reaction mixture was cooled to rt and adjusted its pH value to 2 ⁇ 3 by adding aq. HC1 (2.0 M). The organic solvent was removed and the residue was diluted with EtOAc (50 mL). The organic layer was isolated, washed with brine (25 mL) and dried with anhydrous Na2SC>4. The solvent was removed and the residue was dried in vacuo to give crude compound 15-14 (442 mg, 90% yield) as a white solid.
  • Step 14 Compound 15-14 (442 mg, 0.86 mmol) was dissolved in DMF (5 mL), followed by addition of HATU (450 mg, 1.17 mmol). After stirring at rt for I hr, the reaction mixture was added DIPEA (503 mg, 3.9 mmol) and MeNH 2 HCl (157 mg, 2.34 mmol). The resulting mixture was stirred at rt for another 1 hr before being concentrated The residue was diluted with water (25 mL) and EtOAc (50 mL). The organic layer was isolated, washed with brine (25 mL), and dried with anhydrous Na 2 S0 .
  • compound 28-5b can be obtained using compound 28-7b as the starting material described in Scheme 28.
  • MeOH/liquid CO2 30/70 (v/v); CO 2 flow rate: 2.1 g min and co-solvent flow rate: 0.9 g min; back pressure: 150 bar).
  • compound 28-13b can be obtained using compound 28-1 lb as th
  • Step 1 Refer to Scheme 29. To a solution of compound 4-2 (9.0 g, 18.9 mmol) in DME (200 mL) and H 2 0 (400 mL) were added 2 C0 3 (7.8 g, 56.6 mmol), Pd(dppf)Cl 2 (1.5 g, 1.9 mmol) and 4,4,5,5-tetramethyl-2-vinyl- 1 ,3,2-dioxaborolane (4.4 g, 28.3 mmol). After stirring at 60 °C for 2 hrs under an atmosphere of Ar, the reaction mixture was concentrated and the residue was partitioned between water (150 mL) and EtOAc (150 mL).
  • Step 2 To a solution of compound 29-1 (1.2 g, 3.4 mmol) in THF (50 mL), EtOH (20 mL) and HOAc (40 mL) was slowly added Zn ( 1.3 g, 20.1 mmol) at 0 °C. After stirring at rt for 2 hrs, the reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between water (80 mL) and EtOAc (80 mL) and the organic layer was extracted with EtOAc (60 mL x 3). The organic extracts were combined and washed with water (80 mL x 2), sat.
  • Step 4 To a solution of compound 29-3 (700 mg, 1.7 mmol) in DMF (30 mL) were added K2C(1 ⁇ 4 (719 mg, 5.2 mmol) and I (144 mg, 0.87 mmol), followed by 2-bromobenzyl chloride (534 mg, 2.6 mmol). After stirring at 70 °C for 3 hrs, the reaction mixture was concentrated and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (3 x 40 mL) and the combined organic extracts were washed with water (80 mL x 3) and brine (50 mL) and dried over anhydrous NaaSO-j.
  • Step 6 To a solution of compound 29-5 (150 mg, 0.31 mmol) in EtOH (30 mL) was added 5% Pd/C (w w, 200 mg). After stirring at 50 °C for several hours under an atmosphere of 3 ⁇ 4, the reaction mixture was filtered through a pad of Celite ® 545. The filtered cake was washed with EtOH (15 mL x 2). The filtrate was concentrated and the residue was dried in vacuo to give crude compound 29-6 (149 mg, 99% yield) as a yellow solid.
  • Step 7 Following the same procedure as that for for the preparation of compound 1-16 described in Scheme 1 and replacing compound 1-14 with 29-6, compound 29-7 was obtained (130 mg, 90% yield) as a pale brown solid.
  • Step 3 To a stirred solution of compound 34a-l (94.0 mg, 0.20 mmol) in DCE (20 mL) at 85°C was added TsOH (94 mg, 0.49 mmol). After refluxing overnight, the reaction mixture was concentrated. The residue was diluted with DCM (50 mL) and the resulting mixture was washed with sat. aq. NaHCCb (50 mL) and brine (50 mL), and dried over anhydrous Na2S(> .
  • Step 1 Refer to Scheme 34b. To a stirred solution of compound 34b-l (3.0 g, 17.2 mmol) in dry THF (20 mL) was added L1AIH 4 (1.3 g, 34.4mmol) in portions at 0 °C. After stirring at rt overnight, the reaction was quenched by slowly adding isopropanol (10 mL) at 0 °C. The suspension was filtered through Celite ® 545 and the filtrate was concentrated. The residue was dried in vacuo to give crude compound 34b-2 (2.0 g) as a white solid, which was used directly for the next step without further purification.
  • L1AIH 4 1.3 g, 34.4mmol
  • (5S.7S) 36j-3a and (5S,7 ?)-36j-3b were obtained as white solid.
  • (5S,7S)-36j-3a LC-MS (ESI): miz 608.1 [M + H] + ; 1 H NMR (500 MHz, ⁇ /-DMSO): 6 8.51 (q, J - 4.0 Hz, I H), 8.43 (d, j - 5.0
  • 39-12b-2 4-F-PhO-.
  • R' 39.13b-2 R s4-F-PhO-.
  • Step 1 Refer to Scheme 39a. To a stirred solution of compound 39a- 1 (5.1 g, 17 mmol) (prepared by following the procedure descried in WO200759421 with some modifications) in CH 3 CN (300 mL) was added Selectfluor ® (7.25 g, 20.4 mmol) portion-wise at rt. After stirring at rt overnight, the reaction mixture was concentrated. The residue was added water (50 mL) and the resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SC>4 and concentrated.
  • Step 2 To a stirred solution of H 0 3 (5 mL) in DCM (15 mL) at 0°C was added a solution of compound 39a-2 (954 mg, 3 mmol) in DCM (15 mL) dropwise (Caution: the reaction mixture must be kept around 0 °C). After stirring at 0 °C for 1 hr, the reaction mixture was slowly warmed to rt and diluted with ice-water (15 mL). The organic phase was washed with 3 ⁇ 40 (25 mL x 3), dried over anhydrous a 2 S0 4 , and concentrated. The residue was dried in vacuo to give crude compound 39a-3 (850 mg) as a dark yellow solid, which was used for the next step without further purification.
  • Step 3 To a stirred solution of crude compound 39a-3 ( 1.24 g, about 3.4 mmol) in DCM (50 mL) was added DIPEA (1.7mL, 10.2 mmol) and DMAP (5 mg, 0.34 mmol), followed by Tf 2 0 (0.86 mL, 5.1 mmol) at 0 °C. After stirring at rt for 5 hrs, the reaction mixture was diluted with water (50 mL) and DCM (50 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na2S0 4 . and concentrated.
  • Step 4 To a solution of the compound 39a-4 (1.5 g, 3.0 mmol) in DME (50 mL) and 2 M Na 2 C0 3 solution (4 mL) was added Pd(PPh 3 ) 2 Cl2 (210 mg, 0.3 mmol), the resulting mixture was saturated with N2. Next, vinylboronic acid pinacol ester (0.6 mL, 4.5 mmol) was added and the resulting mixture was stirred at 80 °C for 4 hrs under an atmosphere of N 2 . Subsequently, the mixture was concentrated and the residue was added water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (25 mL x 3).
  • Step 5 To a stirred solution of the compound 39a-5 (1.0 g, 2.7 mmol) in EtOAc (30 mL) was added SnC 2 -2H20 ( 1.22 g, 5.4 mmol) portion-wise. After refluxing for 1 hr under an atmosphere of N 2 , the reaction mixture was cooled to rt and slowly added saturated aq. NaHC0 3 solution (20 mL). The mixture was filtered through Celite ® 545 and the filtered cake was washed with EtOAc (25 mL x 3). The organic phase of the filtrate was dried over anhydrous Na 2 S0 4 and concentrated.
  • Step 7 Following the same procedure as that used for preparing compound (55,75)-34-2a shown in Scheme 34a and replacing compound 34a-2 with 39a-7, compound 39a-8 (35 mg, 25% yield) was obtained as a white solid.
  • Step 8 Following the same procedure as that used for preparing compound 1-15 shown in Scheme 1 (WO2012/058125) and replacing compound 1-14 with 39a-8, compound 39a-9 was obtained as a light solid.
  • Step 9 Following the same procedure as that used for preparing compound 1-16 shown in Scheme 1 (WO2012/058125) and replacing compound 1-15 with 39a-9, compound 39-12a-l was obtained as a white solid.
  • Step 1 Refer to Scheme 40. To a stirred solution of 6-amino-pyridin-2-ol (5g, 45.5 mmol) in acetic acid (50 mL) was added a solution of N-iodosuccinimide (20.45 g, 90.9 mmol) in acetic acid (90 mL). After stirring at rt for lhr, the resulting precipitate was collected by filtration, washed with acetic acid, and dried in vacuo to give compound 40-2 (12.5g, 84% yield) as yellow solid.
  • Step 2 A solution of compound 40-2 (10 g, 27.6 mmol) in Ac 2 0 (50 mL) was stirred at 90 °C for 1 hr and then concentrated. The residue was carefully added saturated aq. NaHCOj solution (100 mL) at 0 °C and the resulting mixture was extracted with DCM (150 mL x 3). The organic extracts were combined, dried over anhydrous Na 2 S0 4 , and concentrated. The residue was dried in vacuo to give compound 40-3 ( 15 g, 68 % yield) as a light yellow solid. LC-MS (ESI): m/z 510.5 [M + H] + . (0292] Step 3.
  • Step 5 To a stirred solution of compound 40-5a (5 g, 14.1 mol) in anhydrous THF (50 mL) was added 1 M TBAF in THF (14.1 mL). After refluxing for 16 hrs, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography
  • Step 6 To a stirred solution of compound 40-6a (5.0 g, 14 mmol) and anhydrous Et 3 N ( 11.6 mL, 85 mmol) in dry DCM (200 mL) at 0 °C was added MsCl (4.3 mL, 56 mmol) dropwise. After stirring at rt for 16 hrs, the reaction mixture was concentrated and the residue was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL x3). The organic extracts were combined, dried with anhydrous Na 2 SC>4, and concentrated. The residue was dried in vacuo and then dissolved in MeOH (150 mL), followed by adding LiOH ( 1 M aq. solution, 25 mL).
  • Step 7 To a stirred solution of the compound 40-7a (2.5 g, 5.8 mmol) in DME (30 mL) and 2 M aq. Na 2 C0 3 solution (7.5 mL) was added Pd(PPh 3 ) 2 Cl 2 (407 mg, 0.58 mmol), followed by vinylboronic acid pinacol ester (1.13 g, 8.7 mmol) under an atmosphere of N 2 . After stirring at 80 °C for 4 hrs, the reaction mixture was concentrated and the residue was poured into water ( 100 mL). The mixture was extracted with EtOAc (50 mL x 3). The extracts were combined, washed with brine, dried with anhydrous Na 2 S0 4 , and concentrated. The residue was purified by silica gel column chromatography (DCM) to give compound 40-8a (900 mg, 47% yield) as a yellow solid.
  • Step 11 To a solution of compound 40- 11 a ( 100 mg, 0.19 mmol) and Et 3 N (0.13 mL, 0.94 mmol) in DMF (3 mL) and MeOH (3 mL) was added ( 13 mg, 0.019 mmol) under an atmosphere of N 2 . Subsequently, the reaction mixture was saturated with CO and stirred at 60 °C for 24 hrs under an atmosphere of CO. The reaction mixture was concentrated and the residue was diluted with water (25 mL). The mixture was extracted with EtOAc (25 mL x 4). The organic extracts were combined, washed with brine, dried with anhydrous a 2 S0 4 , and concentrated.
  • Step 1 Refer to Scheme 42a. To a stirred solution of sodium propane-2-thiolate (/-PrSNa) (120 mg, 1.22 mmol) in anhydrous DMF (8 mL) was added I (267 mg, 1.62 mmol) at rt under an atmosphere of N 2 . After stirring at rt for 30 min, compound 36e-l (500 mg, 0.81 mmol) was added in small portions. The resulting mixture was stirred at rt overnight and then diluted with ice water. The suspension was filtered and the solid was washed with water and dried in vacuo to give crude compound 42a-l (450 mg, 67% purity based on LC-MS), which was used for the next step without further purification.
  • Step 2 To a stirred solution of compound 42a-l (450 mg, 0.81 mmol) in acetone (50 mL) was added hydrogen peroxide (20 mL, 30 wt. % in H 2 Q at rt. After stirring at 60 °C overnight, the reaction mixture was cooled to rt and quenched with saturated aq. Na 2 S0 3 solution (20 mL). The mixture was concentrated to remove acetone and the resulting suspension was filtered. The solid was washed with water and purified by preparative HPLC to give compound 42a-2 (110 mg, 25% yield) as a white solid.
  • icai activity of the compounds of the invention was determined using an HCV replicon assay.
  • the lb_Huh-Luc/Neo-ET cell line persistently expressing a bicistronic genotype lb replicon in Huh 7 cells was obtained from ReBLikon GMBH. This cell line was used to test compound inhibition using luciferase enzyme activity readout as a measurement of compound inhibition of replicon levels.
  • Biological activity of the compounds of the invention was determined using an HCV replicon assay.
  • the 1 b_Huh-Luc Neo-ET cell line persistently expressing a bicistronic genotype lb replicon in Huh 7 cells was obtained from ReBLikon GMBH. This cell line was used to test compound inhibition using luciferase enzyme activity readout as a measurement of compound inhibition of replicon levels.
  • Compounds of the invention can inhibit multiple genotypes of HCV selected but not limited to la, l b, 2a, 3a, and 4a.
  • the ECs 0 s are measured in the corresponding replicon assays that are similar to HCV lb replicon assay as described above.
  • Exemplary compounds of the disclosed invention are illustrated in the Tables attached as Appendix A and Appendix B.
  • Apendix A shows inhibitory activity of the compound against HCV lb.
  • the biological activity against HCV lb is indicated as being *, **, ***, or *** ⁇ , which corresponds to EC*) ranges of EC50 > 1000 nM, 100 nM ⁇ EC 50 ⁇ 1000 nM, 10 nM ⁇ ECso ⁇ 100 nM, or EC50 ⁇ 10 nM, respectively.
  • Appendix A shows structures of compounds of the invention identified by ID NOD B243- B577, and ECJO values determined for the compounds. Of these, all of compounds B243-B282, B285-B289, B292, B294-B426, B429-B438, B440-B443, B445-B469, B471-B540, B542-B549, B551 -B552, B554-B556, B558-B559, B561 -B575 had a measured activity of either 10 nM ⁇ EC50 ⁇ 100 nM, or EC50 ⁇ 10 nM.
  • the invention includes a pharmaceutical composition comprising one or more of the compounds named above, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.
  • the composition may further include one, two or three anti-HCV agent(s) selected from the group consisting of interferon-alpha, ribavirin, cyclosporine derivatives, NS3 protease inhibitors, NS4B inhibitors, NS5A inhibitors, NS5B polymerase inhibitors, and p7 inhibitors.
  • the compounds described herein may be formulated in a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds, optionally together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.
  • excipients are known to those of skill in the art.
  • Pharmaceutically acceptable salts can be used in the compositions of the present invention and include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates and the like.
  • mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates and the like
  • organic acids such as acetates, propionates, malonates, benzoates and the like.
  • the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc.
  • the compound comprised within the pharmaceutical composition includes isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like.
  • the composition will generally take the form of a tablet, capsule, a softgel capsule nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents and the like.
  • ⁇ 03521 In yet another aspect, provided herein is the use of the compounds of the invention in the manufacture of a medicament, e.g., for the treatment of hepatitis C.
  • a method of treating hepatitis C comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention, optionally contained in a pharmaceutical composition.
  • a pharmaceutically or therapeutically effective amount of the composition will be delivered to the subject.
  • the precise effective amount will vary from subject to subject and will depend upon the species, age, the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, the effective amount for a given situation can be determined and optimized by routine experimentation.
  • the subject may be administered as many doses as is required to reduce and/or alleviate the signs, symptoms or causes of the disorder in question, or bring about any other desired alteration of a biological system.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of this invention for a given disease.
  • a treatment regimen using one or more of the compounds provided herein, optionally in combination with one or more anti-HCV agents, will generally involve administering a therapeutically effective dose of the compound, which can readily be determined by one skilled in the art taken into account variables as previously described.
  • a typical dose of a compound as provided herein will generally range from about 10 mg to 1000 mg a day.
  • Representative dosage ranges include from about 10 mg to 900 mg a day, or from about 30 mg to about 700 mg a day, from about 50 mg to about 600 mg a day.
  • a therapeutically effective dosage amount will typically range from 0.1 mg kg body weight to about 30 mg/kg body weight, or from about 0.1 mg kg body weight to about 15 mg kg body weight.
  • the compound may be administered once or multiple times (two to three times) daily, once a week, twice a week, three times a week, etc., over a time course effective to achieve a positive virologic response.
  • Representative courses of treatment include but are not limited to 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, and the like.
  • a positive virologic response generally refers to undetectable HCV RNA in serum as measured by PCR and a biochemical response (normalization of aminotransferase levels).
  • post-treatment biopsies are generally less preferable to an assessment based upon a virologic response.
  • the treatment compound may be one or more of the compounds of B243, B244, B245, B246, B248, B249, B252, B253, B255, B256, B257, B258, B259, B260, B261, B262,B263, B264, B265, B266, B267, B268, B269, B270, B271, B272, B273, B274, B275, B276, B277, B278, B279, B280, B281, B282, B283, B284, B285, B286, B287, B288, B289, B290, B291, B293, B294, B295, B296, B297, B298, B299, B300, B301, B302, B303, B304, B305, B306, B307, B308, B309, B310, B31 1, B312, B313, B314, B315, B316, B317, B318, B319, B320, B321, B322,
  • the administering may be by oral administration. Also disclosed is a compound as named above for use in treating HCV infection in an infected subject.
  • treatment by administering a compound as provided herein is effective to result in at least a 2 log reduction in HCV RNA levels over the course of treatment.
  • HCV RNA will still remain positive (detectable) after a course of treatment, although ideally, treatment is effective to achieve undetectable HCV RNA after completing a round of therapy.
  • Subjects may also be assessed following completion of therapy to confirm maintenance of a positive and sustained virologic response (undetectable HCV RNA levels).
  • follow-up assessments may be carried out over the course of months or even years following treatment.
  • J0357[ The compounds of the present invention and their isomeric forms and pharmaceutically acceptable salts thereof are useful in treating and preventing HCV infection alone or when used in combination with other compounds targeting viral or cellular elements or functions involved in the HCV life cycle.
  • Classes of compounds useful in the invention may include, without limitation, all classes of HCV an ivirals, both direct-acting and indirect-acting ('cell-targeted' inhibitors of HCV replication).
  • mechanistic classes of agents that may be useful when combined with the compounds of the present invention include, for example, nucleoside and non-nucleoside inhibitors of the HCV protease inhibitors, helicase inhibitors, NS5A inhibitors, NS4B inhibitors and medicinal agents that functionally inhibit the internal ribosomal entry site (IRES), other NS5B inhibitors and other medicaments that inhibit HCV cell attachment or virus entry, HCV RNA translation, HCV RNA transcription, replication or HCV maturation, assembly or virus release.
  • IRS internal ribosomal entry site
  • telaprevir VX- 950
  • boceprevir SCH-503034
  • narlaprevir SCH-900518
  • ITMN-191 R-7227
  • TMC-435350 a.k.a.
  • nucleosidic HCV polymerase (replicase) inhibitors useful in the invention include, but are not limited to, ALS2200, R7128, PSI-7851, PS1-7977 (GS-7977), PSI-938, PSI-879, PSI-6130, IDX-184, IDX-102, ⁇ -189, R1479, R1626, UNX-08189, and various other nucleoside and nucleo
  • NS5A inhibitors useful in the invention include, but are not limited to, ⁇ -46 , PPI-668, BMS-790052, BMS-824393, GS-5885, EDP-239, ACH-2928, AZD-7295, IDX-719, IDX-380, ABT-267, GS -2336805, CF-102, A-831 and ⁇ -9916.
  • Non-nucleosidic HCV polymerase (replicase) inhibitors useful in the invention include, but are not limited to, VCH-759, VCH-916, VCH-222 (VX-222), ANA-598, M -3281, ABT-333, ABT- 072, PF-00868554 (filibuvir), BI-207127, GS-9190, A-837093, GS -625433, J T-109, GL- 59728 and GL-60667.
  • HCV P7 inhibitors useful in the present invention include BIT-225 and other P7 inhibitors, as well as HCV NS4B inhibitors including but not limited to histamine agents that antagonize HCV NS4B function.
  • NS5B inhibitors of the present invention may be used in combination with cyclophyllin and immunophyllin antagonists (eg, without limitation, DEBIO compounds, NM- 81 1, SCY-635, EP-CyP282, as well as cyclosporine and its derivatives), kinase inhibitors, inhibitors of heat shock proteins (e.g., HSP90 and HSP70), other immunomodulatory agents that may include, without limitation, interferons (-alpha, -beta, -omega, -gamma, -lambda or synthetic) such as Intron ATM, Roferon-ATM, Canferon-A300TM, AdvaferonTM, InfergenTM, HumoferonTM, Sumiferon MPTM, AlfaferoneTM, IFN- ⁇ TM, FeronTM and the like; polyethylene glycol derivatized (pegylated) interferon compounds, such as PEG interferon-a-2a (Pegas
  • any of the above- described methods involving administering an NS5B inhibitor, a Type I interferon receptor agonist (e.g., an IFN-a) and a Type II interferon receptor agonist (e.g., an IFN- ⁇ ) can be augmented by administration of an effective amount of a TNF- antagonist
  • a Type I interferon receptor agonist e.g., an IFN-a
  • a Type II interferon receptor agonist e.g., an IFN- ⁇
  • TNF- antagonists that are suitable for use in such combination therapies include ENBRELTM, REMICADETM and HUMI ATM.
  • J0360J NS5B inhibitors of the present invention may also be used with alternative forms of interferons and pegylated interferons, ribavirin or its analogs (e.g., tarabavarin, levoviron), microRNA, small interfering RNA compounds (e.g., S1RPLEX-140-N and the like) and microR A agents (such as micro-RNA-122), nucleotide or nucleoside analogs, multifunction inhibitors such as nitazoxanide, immunoglobulins, hepatoprotectants, anti-inflammatory agents and other direct and indirect inhibitors of HCV replication.
  • ribavirin or its analogs e.g., tarabavarin, levoviron
  • microRNA small interfering RNA compounds
  • microR A agents such as micro-RNA-122
  • nucleotide or nucleoside analogs such as multifunction inhibitors such as nitazoxanide, immunoglobulins, hepatoprotect
  • Inhibitors of other targets in the HCV life cycle include NS3 helicase inhibitors; NS4A co- factor inhibitors; and sense oligonucleotide inhibitors, such as ISIS- 14803, ISlS-11, AVI-4065 and the like; vector-encoded short hairpin RNA (shRNA); HCV specific ribozymes such as heptazyme, RPI-13919 and the like; entry inhibitors such as HepeX-C, HuMax-HepC and the like; alpha glucosidase inhibitors such as celgosivir, UT-231B and the like; KPE-02003002 and BIVN 401 and IMPDH inhibitors.
  • NS3 helicase inhibitors such as ISIS- 14803, ISlS-11, AVI-4065 and the like
  • shRNA vector-encoded short hairpin RNA
  • HCV specific ribozymes such as heptazyme, RPI-13919 and the like
  • entry inhibitors
  • HCV inhibitor compounds include those disclosed in the following publications: U.S. Pat. No. 5,807,876; U.S. Pat. No. 6,498,178; U.S. Pat. No. 6,344,465; U.S. Pat. No. 6,054,472; U.S. Pat. No. 7,759,495; U.S. Pat. No. 7,704,992; U.S. Pat. No.
  • combinations of, for example, ribavirin a NS3 protease inhibitor, a replicase inhibitor and interferon may be administered as multiple combination therapy with at least one of the compounds of the present invention.
  • the present invention is not limited to the
  • combination therapies of the present invention include any chemically compatible combination of a compound of this inventive group with other compounds of the inventive group or other compounds outside of the inventive group, as long as the combination does not eliminate the anti-viral activity of the compound of this inventive group or the anti-viral activity of the pharmaceutical composition itself
  • Combination therapy can be sequential, that is treatment with one agent first and then a second agent (for example, where each treatment comprises a different compound of the invention or where one treatment comprises a compound of the invention and the other comprises one or more biologically active agents) or it can be treatment with both agents at the same time (concurrently).
  • Sequential therapy can include a reasonable time after the completion of the first therapy before beginning the second therapy. Treatment with both agents at the same time can be in the same daily dose or in separate doses.
  • the dosages for both concurrent and sequential combination therapy will depend on absorption, distribution, metabolism and excretion rates of the components of the combination therapy as well as other factors known to one of skill in the art. Dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules may be adjusted over time according to the individual's need.

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Abstract

La présente invention concerne une catégorie de composés qui inhibent le virus de l'hépatite C (VHC), des compositions contenant ledit composé, et des méthodes d'utilisation de ladite composition dans le traitement d'individus infectés par le VHC.
PCT/US2013/038275 2012-04-25 2013-04-25 Inhibiteurs du virus de l'hépatite c WO2013163466A1 (fr)

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US13/456,181 US9085587B2 (en) 2010-10-26 2012-04-25 Inhibitors of hepatitis C virus
US201261641769P 2012-05-02 2012-05-02
US61/641,769 2012-05-02
US13/544,261 2012-07-09
US13/544,261 US8614207B2 (en) 2010-10-26 2012-07-09 Inhibitors of hepatitis C virus
US201261722779P 2012-11-05 2012-11-05
US61/722,779 2012-11-05
US201261746548P 2012-12-27 2012-12-27
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CN105418620A (zh) * 2014-09-23 2016-03-23 天津药明康德新药开发有限公司 一种4-(叔丁氧羰基)八氢呋喃并[3,2-b]吡啶-6-羧酸的合成方法
CN113173911A (zh) * 2021-04-20 2021-07-27 梯尔希（南京）药物研发有限公司 吡虫啉代谢物5-羟基吡虫啉的合成方法

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JP2014500861A (ja) * 2010-10-26 2014-01-16 プレシディオ ファーマシューティカルズ インコーポレイテッド Ｃ型肝炎ウイルスの阻害剤
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CN113173911A (zh) * 2021-04-20 2021-07-27 梯尔希（南京）药物研发有限公司 吡虫啉代谢物5-羟基吡虫啉的合成方法

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