WO2015197028A1 - Composés en tant qu'inhibiteurs du virus de l'hépatite c (vhc) et leurs utilisations en médecine - Google Patents

Composés en tant qu'inhibiteurs du virus de l'hépatite c (vhc) et leurs utilisations en médecine Download PDF

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WO2015197028A1
WO2015197028A1 PCT/CN2015/082545 CN2015082545W WO2015197028A1 WO 2015197028 A1 WO2015197028 A1 WO 2015197028A1 CN 2015082545 W CN2015082545 W CN 2015082545W WO 2015197028 A1 WO2015197028 A1 WO 2015197028A1
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hcv
alkyl
heterocyclyl
butyl
tert
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Yingjun Zhang
Hongming XIE
Xiwei Wu
Qingyun REN
Jiancun Zhang
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages

Definitions

  • the present invention pertains to the field of medicine, and relates to compounds used for the treatment of Hepatitis C virus (HCV) infection, compositions containing such compounds, and uses and methods thereof.
  • HCV Hepatitis C virus
  • HCV is a major human pathogen, infecting an estimated 170 million persons worldwide —roughly five times the number infected by human immunodeficiency virus type I. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality.
  • HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5’ untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame (ORF) .
  • ORF open reading frame
  • HCV infected cells viral RNA is translated into a polyprotein and cleaved into ten individual proteins. Structural proteins are at the amino terminus, followed by E1 and E2. Additionally, there are six non-structural proteins, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a function role in the HCV lifecycle (see, for example, Lindenbach et al., Nature, 2005, 436, 933-938, incorporated herein by reference. ) .
  • HCV human immunodeficiency virus
  • the single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is effected by two viral proteases.
  • ORF open reading frame
  • the first one is deemed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease within the N-terminal region of NS3 (also referred herein as NS3 protease) and mediates all the subsequent cleavages in downstream of NS3, with the NS3-NS4A cleavage site by cis-cleavage and the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites by trans-cleavage.
  • the NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
  • NS5B (also referred to herein as HCV polymerase) is a RNA-dependent RNA polymerase involved in the replication of HCV.
  • novel compounds used for the treatment of HCV and methods of treating HCV infection are effective as inhibitors of HCV infection, especially the non-structural 5B (NS5B) protein of HCV.
  • NS5B non-structural 5B
  • a compound having Formula (I) or a stereoisomer a geometric isomer, an enantiomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 2 is H, deuterium, F, Cl, Br, I, OH, alkyl or cycloalkyl;
  • R 6 is cycloalkyl, heterocyclyl, aryl or heteroaryl, and R 6 is optionally substituted with 1, 2, 3 or 4 R 12 ;
  • each R 8 and R 9 is independently H, OH, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocyclylalkyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • each R 10 and R 11 is independently H, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroaryl; or
  • R 10 and R 11 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • each L, R 8 , R 9 , R 10 , R 11 and R 12 is independently substituted with 1, 2, 3 or 4 R 13 ;
  • R 2 is H, deuterium, F, Cl, Br, I, OH, C 1-6 alkyl or C 3-8 cycloalkyl;
  • R 2 is H, deuterium, F, Cl, Br, I, OH, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl;
  • each R 8 and R 9 is independently H, OH, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-9 heterocyclyl-C 1-6 -alkyl, C 1-6 alkoxy, C 2-6 alkenoxy, C 2-6 alkynoxy, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
  • each R 10 and R 11 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-9 heterocyclyl-C 1-6 -alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl; or
  • R 10 and R 11 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted independently with 1, 2, 3 or 4 R 13 ;
  • each R 8 , R 9 , R 10 and R 11 is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • each R 8 and R 9 is independently H, OH, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, CHF 2 , CH 2 F, CF 3 , cyclopropyl, cyclobutyl, cyclopentyl or phenyl.
  • R 5 is H, OH, F, Cl, Br, I, CN, deuterium, methoxy or ethoxy.
  • R 6 is C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl, and R 6 is optionally substituted with 1, 2, 3 or 4 R 12 ;
  • each R 8 and R 9 is independently H, OH, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-9 heterocyclyl-C 1-6 -alkyl, C 1-6 alkoxy, C 2-6 alkenoxy, C 2-6 alkynoxy, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
  • each R 10 and R 11 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-9 heterocyclyl-C 1-6 -alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl; or
  • R 10 and R 11 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • each L, R 8 , R 9 , R 10 , R 11 and R 12 is independently substituted with 1, 2, 3 or 4 R 13 ;
  • L is a bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, C 3-6 cycloalkylene or C 2-9 heterocyclylene.
  • L is a bond, ethylene, ethenylene, ethynylene, cyclopropylene, cyclobutylene or cyclopentylene;
  • R 6 is phenyl, pyridyl, thienyl, furyl, thiazolyl, oxazolyl, piperazinyl, imidazolyl, pyrrolyl, pyrazinyl, pyridazinyl, morpholinyl, tetrahydropyridyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, or R 6 is
  • R 6 is optionally substituted with 1, 2, 3 or 4 R 12 ;
  • each R 8 and R 9 is independently H, OH, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, ethenyl, ethynyl, CF 3 , CHF 2 , CH 2 F, methoxy, ethoxy, pyrrolidinylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, phenyl, pyridyl, thienyl, furyl, thiazolyl, oxazolyl, piperazinyl, imidazolyl, pyrrolyl, pyrazinyl, pyridazinyl or pyrimidinyl;
  • each R 10 and R 11 is independently H, methyl, ethyl, propyl, isopropyl, tert-butyl, ethenyl, ethynyl, CF 3 , CHF 2 , CH 2 F, methoxy, ethoxy, pyrrolidinylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, phenyl, pyridyl, thienyl, furyl, thiazolyl, oxazolyl, piperazinyl, imidazolyl, pyrrolyl, pyrazinyl, pyridazinyl or pyrimidinyl; or
  • R 10 and R 11 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • each L, R 8 , R 9 , R 10 , R 11 and R 12 is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • R 9 is C 1-6 alkyl or C 1-6 alkoxy.
  • composition comprising a compound disclosed herein.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition disclosed herein further comprises an anti-HCV agent.
  • the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine 5’ -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, human hepatitis C immune globulin (Civacir TM ) , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127) , dasabuvir (ABT-333) , beclabuvir (BMS-791325) , elbasvir (MK-8742) , ombitasvir (ABT-267) , neceprevir (ACH
  • the interferon is interferon ⁇ -2b, pegylated interferon ⁇ , interferon ⁇ -2a, pegylated interferon ⁇ -2a, consensus interferon- ⁇ , interferon ⁇ or a combination thereof.
  • the pharmaceutical composition further comprises at least one HCV inhibitor for inhibiting HCV replication process and/or HCV viral protein function, wherein the HCV replication process is HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV egress.
  • the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, an internal ribosome entry site (IRES) or inosine 5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • the compound or the pharmaceutical composition disclosed herein for use in inhibiting at least one of HCV replication process and HCV viral protein function, wherein the HCV replication process is HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV egress.; and wherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A, NS5B, or an internal ribosome entry site (IRES) and inosine 5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • HCV replication process is HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV egress.
  • the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A, NS5B, or an internal ribosome entry site (IRES) and inosine 5’ -monophosphat
  • a method of inhibiting at least one of HCV replication process and HCV viral protein function with the compound or the pharmaceutical composition disclosed herein wherein the HCV replication process is HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV egress; and wherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A, NS5B, or an internal ribosome entry site (IRES) and inosine 5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • the HCV replication process is HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV egress
  • the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A, NS5B, or an internal ribosome entry site (IRES) and inosine 5’ -monophosphat
  • HCV replication process is HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV egress; and wherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A, NS5B, or an internal ribosome entry site (IRES) and inosine 5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • IVS internal ribosome entry site
  • IMPDH inosine 5’ -monophosphate dehydrogenase
  • provided herein is the compound or the pharmaceutical composition disclosed herein for use in preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient.
  • provided herein is a method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein.
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient.
  • provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I) .
  • grammatical articles “one” , “a” , “an” and “the” are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context.
  • the articles are used herein to refer to one or more than one (i.e., to at least one) of the grammatical objects of the article.
  • a component means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In another embodiment, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
  • Stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers) , geometric (cis/trans) isomers, atropisomers, and the like.
  • Chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • optically active compounds i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • a specific stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration.
  • each asymmetric atom has at least 50%enantiomeric excess, at least 60%enantiomeric excess, at least 70%enantiomeric excess, at least 80%enantiomeric excess, at least 90%enantiomeric excess, at least 95%enantiomeric excess, or at least 99%enantiomeric excess in the (R) -or (S) -configuration.
  • the compounds can be present in the form of one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis-or trans-configuration.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Principles of Asymmetric Synthesis (2 nd Ed.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (lH) -one tautomers. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
  • compounds may optionally be substituted with one or more substituents, such as those illustrated above, or as exemplified by particular classes, subclasses, and species disclosed herein.
  • substituents such as those illustrated above, or as exemplified by particular classes, subclasses, and species disclosed herein.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • each substitutent is independently selected, therefor each substituent may be either the same or different.
  • substituents of the compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1-20 carbon atoms. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms. In another embodiment, the alkyl group contains 1-6 carbon atoms. In still another embodiment, the alkyl group contains 1-4 carbon atoms. In yet another embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl group examples include methyl (Me, -CH 3 ) , ethyl (Et, -CH 2 CH 3 ) , n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) , isopropyl (i-Pr, -CH (CH 3 ) 2 ) , n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ) , isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ) , sec-butyl (s-Bu, -CH (CH 3 ) CH 2 CH 3 ) , tert-butyl (t-Bu, -C (CH 3 ) 3 ) , n-pentyl (-CH 2 CH 2 CH 2 CH 3 ) , 2-pentyl (-CH (CH 3 ) CH 2 CH 2 CH 3 ) , 3-pentyl (-CH (CH 2 CH 3 )
  • heteroalkyl refers to an alkyl chain inserted with one or more heteroatoms, wherein the alkyl and heteroatom are as defined herein. Unless otherwise specified, the heteroalkyl group contains 2-10 carbon atoms. In other embodiments, the heteroalkyl group contains 2-8 carbon atoms. In still other embodiments, the heteroalkyl group contains 2-6 carbon atoms, and in yet other embodiments, the heteroalkyl group contains 2-4 carbon atoms. In other embodiments, the heteroalkyl group contains 2-3 carbon atoms.
  • heteroalkyl group examples include CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 SCH 2 -, (CH 3 ) 2 NCH 2 -, (CH 3 ) 2 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 CH 2 -, and the like.
  • alkenyl refers to a linear or branched chain monovalent hydrocarbon group of 2-12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl group is optionally substituted independently with one or more substituents described herein, and includes groups having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • the alkenyl group contains 2-8 carbon atoms.
  • the alkenyl group contains 2-6 carbon atoms.
  • the alkenyl group contains 2-4 carbon atoms.
  • alkynyl refers to a linear or branched-chain monovalent hydrocarbon group of 2-12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical is optionally substituted independently with one or more substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms.
  • the alkynyl group contains 2-6 carbon atoms.
  • the alkynyl group contains 2-4 carbon atoms.
  • alkynyl group examples include ethynyl (-C ⁇ CH) , propargyl (-CH 2 C ⁇ CH) , 1-propynyl (-C ⁇ C-CH 3 ) , and the like.
  • cycloalkyl refers to a monovalent or multivalent saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic or tricyclic ring system. In one embodiment, the cycloalkyl contains 3-12 carbon atoms. In another embodiment, the cycloalkyl contains 3-8 carbon atoms. In still another embodiment, the cycloalkyl contains 3-6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • heterocyclyl group examples include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl
  • heterocyclyl group wherein the ring sulfur atom is oxidized are sulfolanyl and 1, 1-dioxo-thiomorpholinyl.
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • 4-7 membered heterocyclyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, o
  • heterocyclyl group wherein the ring sulfur atom is oxidized are sulfolanyl and 1, 1-dioxo-thiomorpholinyl.
  • the 4-7 membered heterocyclyl group is optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • Examples of 4 membered heterocyclyl include, but are not limited to, azetidinyl, oxetanyl and thietanyl.
  • the 4 membered heterocyclyl group is optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • Examples of 5 membered heterocyclyl include, but are not limited to, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl and dithiolanyl.
  • Some non-limiting examples of the heterocyclyl group wherein the ring sulfur atom is oxidized are sulfolanyl.
  • the 5 membered heterocyclyl group is optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • 6 membered heterocyclyl examples include, but are not limited to, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl and thioxanyl.
  • heterocyclyl group wherein the ring sulfur atom is oxidized are 1, 1-dioxo-thiomorpholinyl.
  • the 6 membered heterocyclyl group is optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
  • 7-12 membered heterocyclyl examples include, but are not limited to, indolinyl, 1,2, 3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl and 2-oxa-5-azabicyclo [2.2.1] hept-5-yl.
  • the 7-12 membered heterocyclyl group is optionally substituted with one or more substituents described herein.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups
  • heterocyclylalkoxy refers to an alkoxy group substituted with one or more heterocyclyl groups, wherein the heterocyclylalkoxy group connect to the rest of the molecular through the oxygen atom
  • heterocyclylalkylamino refers to an alkylamino group substituted with one or more heterocyclyl groups, wherein the heterocyclylalkylamino group connect to the rest molecular through the nitrogen atom.
  • the heterocyclyl, alkyl, alkoxy and alkylamino group are as defined herein.
  • Some non-limiting examples include pyrrol-2-yl-methyl, morpholin-4-yl-ethyl, morpholin-4-yl-ethoxy, piperazin-4-yl-ethoxy, piperidin-4-yl-ethylamino, and the like.
  • n membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6 membered heterocycloalkyl
  • 1, 2, 3, 4-tetrahydro-naphthalene is an example of a 10 membered cycloalkyl group.
  • unsaturated refers to a moiety having one or more units of unsaturation.
  • heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon, including any oxidized form of nitrogen, sulfur or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl) .
  • halogen refers to Fluoro (F) , Chloro (Cl) , Bromo (Br) , or Iodo (I) .
  • aryl refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, preferably, 6 to 12 ring members, and more preferably 6 to 10 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has one or more points of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term “aryl ring” or "aromatic ring” .
  • Some non-limiting examples of the aryl group would include phenyl, naphthyl and anthracene.
  • the aryl group is optionally substituted with one or more substituents described herein.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, preferably, 5 to 10 ring members, and more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 5 to 7 ring members and that has one or more points of attachment to the rest of the molecule.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic ring” .
  • the heteroaryl group is optionally substituted independently with one or more independent substituents described herein.
  • a 5-10 membered heteroaryl group comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl group examples include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl) , triazolyl (e.g., 2-triazolyl and 5-triazolyl) , 2-thienyl, 3-thi
  • Carboxy or “carboxyl” refers to -CO 2 H, which can be used alone or with other terms, such as “carboxyalkyl” , refers to -alkyl-CO 2 H.
  • alkylamino embraces “N-alkylamino” and "N, N-dialkylamino” , wherein the amino group is independently substituted with one or two alkyl groups, respectively.
  • the alkylamino group is a lower alkylamino group having one or two alkyl groups attached to the nitrogen atom, each alkyl group contains 1 to 6 carbon atoms.
  • the alkylamino group is a lower alkylamino group having one or two alkyl groups attached to the nitrogen atom, each alkyl group contains 1 to 3 carbon atoms.
  • suitable alkylamino group include monoalkylamino or dialkylamino such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, and the like.
  • arylamino refers to an amino group substituted with one or two aryl groups, some non-limiting examples of the arylamino group include N-phenylamino, and the like.
  • the arylamino group may be further substituted on the aryl ring portion of the group.
  • aminoalkyl refers to a linear or branched alkyl group having 1 to 10 carbon atoms which is substituted with one or more amino groups.
  • the aminoalkyl group is “lower aminoalkyl” group having 1 to 6 carbon atoms and one or more amino groups.
  • Some non-limiting examples of the aminoalkyl group include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • alkylene refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms. In another embodiment, the alkylene group contains 1-4 carbon atoms. In still another embodiment, the alkylene group contains 1-3 carbon atoms, and in yet another embodiment, the alkylene group contains 1-2 carbon atoms. The alkylene group is optionally substituted with one or more substituents.
  • the substituents include, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy.
  • the alkylene group is exemplified by methylene (-CH 2 -) , ethylene (-CH 2 CH 2 -) , isopropylene (-CH (CH 3 ) CH 2 -) , ethane-1, 1-di-yl, 2-methoxypropane-1, 1-di-yl, 2-hydroxypropane-1, 1-di-yl, 2-methyl-2-hydroxypropane-1, 1-di-yl, and the like.
  • alkenylene refers to a divalent alkene group derived from a straight or branched alkene chain by the removal of two hydrogen atoms.
  • the alkenylene group is optionally substituted with one or more substituents.
  • the substituents include, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy.
  • alkynylene refers to a divalent alkene group derived from a straight or branched alkyne chain by the removal of two hydrogen atoms.
  • the alkynylene group is optionally substituted with one or more substituents.
  • the substituents include, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy.
  • Some non-limiting examples of the alkenylene group include propinylene (-CH 2 C ⁇ C-) , and the like.
  • Carbocyclylene or “cycloalkylene” refers to a saturated divalent hydrocarbon ring derived from a monocyclic ring having 3 to 12 carbon atoms or a bicyclic ring having 7 to 12 carbon atoms by the removal of two hydrogen atoms, wherein the carbocyclyl group or the cycloalkyl group is as defined herein.
  • Some non-limiting examples include cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-1-enylene, 1-cyclopent-2-enylene, and the like.
  • heterocyclylene refers to a monocyclic, bicyclic or tricyclic ring system, in which one or more ring members are independently selected from heteroatoms, and that is saturated or contains one or more units of unsaturation, but which is not aromatic and has two points of attachment to the rest of the molecule, wherein the heterocyclyl group is as defined herein.
  • Some non-limiting examples of the heterocyclylene group include piperidin-1, 4-ylene, piperazin-1, 4-ylene, tetrahydrofuran-2, 4-ylene, tetrahydrofuran-3, 4-ylene, azetidin-1, 3-ylene, pyrrolidin-1, 3-ylene, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon atom through an oxygen atom. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms. In another embodiment, the alkoxy group contains 1-4 carbon atoms. In still another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.
  • alkoxy group examples include methoxy (MeO, -OCH 3 ) , ethoxy (EtO, -OCH 2 CH 3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ) , 2-propoxy (i-PrO, i-propoxy, -OCH (CH 3 ) 2 ) , 1-butoxy (n-BuO, n-butoxy, OCH 2 CH 2 CH 2 CH 3 ) , 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH (CH 3 ) 2 ) , 2-butoxy (s-BuO, s-butoxy, -OCH (CH 3 ) CH 2 CH 3 ) , 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH 3 ) 3 ) , 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 2 CH 3 ) ,
  • alkenyloxy and alkynyloxy respectively refers to an alkenyl group and an alkynyl group connects to the rest of the molecular through an oxygen atom, wherein the alkenyl and alkynyl groups are as defined herein.
  • alkenylamino and alkynylamino respectively refers to an alkenyl group and an alkynyl group connects to the rest of the molecular through a nitrogen atom, wherein the alkenyl and alkynyl groups are as defined herein.
  • alkylthio refers to an alkyl group connects to the rest of the molecular through a sulphur atom, wherein the alkyl group is as defined herein.
  • haloalkyl refers to an alkyl, an alkenyl or an alkoxy group respectively, as the case may be, substituted with one or more halogen atoms.
  • haloalkenyl refers to an alkyl, an alkenyl or an alkoxy group respectively, as the case may be, substituted with one or more halogen atoms.
  • Some non-limiting examples include trifluoroethyl, trifluoromethoxy, and the like.
  • hydroxyalkyl or “hydroxy-substituted alkyl” refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined herein.
  • Some non-limiting examples of hydroxyalkyl group include hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, and the like.
  • amino refers to -NH 2 .
  • silyl refers to a group having Formula wherein each of R 21 , R 22 and R 23 is independently alkyl, haloalkyl or aryl.
  • Some non-limiting examples of the silyl group include tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, and the like.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxycarbonyl (Fmoc) .
  • a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include acetyl and silyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Examples of common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like.
  • prodrug refers to a compound that is transformed in vivo into a compound of Formula (I) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation of the prodrug form in blood or tissue to the parent form in blood or tissue.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains an OH group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates such as those phosphates compounds derived from the phosphonation of an OH group on the parent compound.
  • phosphates such as those phosphates compounds derived from the phosphonation of an OH group on the parent compound.
  • a thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series; Roche et al., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al, Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J Med. Chem., 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.
  • a “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof.
  • the metabolite of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
  • the invention includes metabolites of compounds disclosed herein, including metabolites produced by a process comprising contacting a compound disclosed herein with a mammal for a sufficient time period.
  • a “pharmaceutically acceptable salt” disclosed herein refers to organic or inorganic salts of a compound disclosed herein.
  • the pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
  • the pharmaceutically acceptable salt include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid, or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid, or by using other methods used in the art such as ion exchange.
  • the pharmaceutically acceptable salt include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenyl
  • compositions derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • compositions include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate and aryl sulfonate.
  • counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate and aryl sulfonate.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • solvents that form the solvate include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid and ethanolamine.
  • DMSO dimethylsulfoxide
  • hydrate refers to the complex where the solvent molecule is water.
  • the term “treat” , “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate or the like) , or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile is desirable, where practicable.
  • the compounds disclosed herein, including their salts can also be obtained in the form of their hydrates, or include other solvents such as ethanol, DMSO, and the like, used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water) ; therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds.
  • Isotopically enriched compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H (deuterium, D) , 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I, respectively.
  • the compounds of the invention include isotopically enriched compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 14 C and 18 F, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically enriched compounds are useful in metabolic studies (with 14 C) , reaction kinetic studies (with, for example 2 H or 3 H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F-enriched compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-enriched compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom) , at least 4000 (60% deuterium incorporation) , at least 4500 (67.5% deuterium incorporation) , at least 5000 (75% deuterium incorporation) , at least 5500 (82.5% deuterium incorporation) , at least 6000 (90% deuterium incorporation) , at least 6333.3 (95% deuterium incorporation) , at least 6466.7 (97% deuterium incorporation) , at least 6600 (99% deuterium incorporation) , or at least 6633.3 (99.5% deuterium incorporation) .
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, DMSO-d
  • provided herein are methods of preparing, methods of separating, and methods of purifying the compounds disclosed herein.
  • a pharmaceutical composition comprising the compound disclosed herein.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition is a liquid, solid, semi-solid, gel or an aerosol form.
  • ком ⁇ онент there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound disclosed herein and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect or any combination thereof.
  • coadministration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient) , and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound disclosed herein and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound disclosed herein and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • inhibiting HCV viral protein should be understood broadly, which comprises inhibiting the expression level of HCV viral protein, inhibiting activity level of HCV viral protein, viral assembly and egress level.
  • the expression level of HCV protein includes, but is not limited to, translation level of the viral protein, posttranslational modification level of the viral protein, replication level of genetic material in offsprings, and so on.
  • novel compounds used for the treatment of HCV and methods of treating HCV infection are effective as inhibitors of HCV infection, especially the non-structural 5B (NS5B) protein of HCV.
  • NS5B non-structural 5B
  • a compound having Formula (I) or a stereoisomer a geometric isomer, an enantiomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • R 2 is H, deuterium, F, Cl, Br, I, OH, alkyl or cycloalkyl;
  • R 6 is cycloalkyl, heterocyclyl, aryl or heteroaryl, and R 6 is optionally substituted with 1, 2, 3 or 4 R 12 ;
  • each R 8 and R 9 is independently H, OH, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocyclylalkyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • each R 10 and R 11 is independently H, deuterium, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroaryl; or
  • R 10 and R 11 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • each L, R 8 , R 9 , R 10 , R 11 and R 12 is independently substituted with 1, 2, 3 or 4 R 13 ;
  • R 2 is H, deuterium, F, Cl, Br, I, OH, C 1-6 alkyl or C 3-8 cycloalkyl;
  • R 2 is H, deuterium, F, Cl, Br, I, OH, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl;
  • each R 8 and R 9 is independently H, OH, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-9 heterocyclyl-C 1-6 -alkyl, C 1-6 alkoxy, C 2-6 alkenoxy, C 2-6 alkynoxy, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
  • each R 10 and R 11 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-9 heterocyclyl-C 1-6 -alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl; or
  • R 10 and R 11 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted independently with 1, 2, 3 or 4 R 13 ;
  • each R 8 , R 9 , R 10 and R 11 is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • each R 8 and R 9 is independently H, OH, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, CHF 2 , CH 2 F, CF 3 , cyclopropyl, cyclobutyl, cyclopentyl or phenyl.
  • R 5 is H, OH, F, Cl, Br, I, CN, deuterium, methoxy or ethoxy.
  • R 6 is C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl, and R 6 is optionally substituted with 1, 2, 3 or 4 R 12 ;
  • each R 8 and R 9 is independently H, OH, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-9 heterocyclyl-C 1-6 -alkyl, C 1-6 alkoxy, C 2-6 alkenoxy, C 2-6 alkynoxy, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
  • each R 10 and R 11 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-9 heterocyclyl-C 1-6 -alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl; or
  • R 10 and R 11 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • each L, R 8 , R 9 , R 10 , R 11 and R 12 is independently substituted with 1, 2, 3 or 4 R 13 ;
  • L is a bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, C 3-6 cycloalkylene or C 2-9 heterocyclylene.
  • L is a bond, ethylene, ethenylene, ethynylene, cyclopropylene, cyclobutylene or cyclopentylene;
  • R 6 is phenyl, pyridyl, thienyl, furyl, thiazolyl, oxazolyl, piperazinyl, imidazolyl, pyrrolyl, pyrazinyl, pyridazinyl, morpholinyl, tetrahydropyridyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, or R 6 is
  • R 6 is optionally substituted with 1, 2, 3 or 4 R 12 ;
  • each R 8 and R 9 is independently H, OH, amino, methyl, ethyl, propyl, isopropyl, tert-butyl, ethenyl, ethynyl, CF 3 , CHF 2 , CH 2 F, methoxy, ethoxy, pyrrolidinylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, phenyl, pyridyl, thienyl, furyl, thiazolyl, oxazolyl, piperazinyl, imidazolyl, pyrrolyl, pyrazinyl, pyridazinyl or pyrimidinyl;
  • each R 10 and R 11 is independently H, methyl, ethyl, propyl, isopropyl, tert-butyl, ethenyl, ethynyl, CF 3 , CHF 2 , CH 2 F, methoxy, ethoxy, pyrrolidinylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, phenyl, pyridyl, thienyl, furyl, thiazolyl, oxazolyl, piperazinyl, imidazolyl, pyrrolyl, pyrazinyl, pyridazinyl or pyrimidinyl; or
  • R 10 and R 11 together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • each L, R 8 , R 9 , R 10 , R 11 and R 12 is optionally substituted with 1, 2, 3 or 4 R 13 ;
  • R 9 is C 1-6 alkyl or C 1-6 alkoxy.
  • a compound disclosed herein comprises a compound of formula (I) , a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.
  • a compound disclosed herein comprises a compound of formula (I) , a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a Formulation and/or the mammal being treated therewith. Persons skilled in the art can choose the “pharmaceutically acceptable” substance or composition specifically according to other components and the object being treated with (such as man) .
  • the compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of formula (I) and/or for separating enantiomers of compounds of formula (I) .
  • the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; a pyranosidyl acid, such as glucuronic acid and galacturonic acid; an alpha hydroxy acid, such as citric acid and tartaric acid; an amino acid, such as aspartic acid and glutamic acid; an aromatic acid, such as benzoic acid and cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid and ethanesulfonic acid, and the like.
  • an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid
  • a pyranosidyl acid such as glucuronic acid and galacturonic
  • the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, and the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like.
  • the pharmaceutical composition disclosed herein comprises any one of the compounds in the present disclosure.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition can be used for treating HCV infection or a HCV disorder, especially it is effective as inhibitor of the non-structural 5B (NS5B) protein of HCV.
  • NS5B non-structural 5B
  • the pharmaceutical composition disclosed herein further comprises an additional anti-HCV agent.
  • the anti-HCV agent refers to any known agents for anti-HCV and they are different from the compounds disclosed herein.
  • the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine 5’ -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR TM ) , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127) , dasabuvir (ABT-333) , becla
  • the interferon is interferon ⁇ -2b, pegylated interferon ⁇ , interferon ⁇ -2a, pegylated interferon ⁇ -2a, consensus interferon- ⁇ , interferon ⁇ or a combination thereof.
  • the pharmaceutical composition disclosed herein further comprises at least one HCV inhibitor, and the HCV inhibitor inhibits at least one of HCV replication process and HCV viral protein function, wherein the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A, NS5B, or an internal ribosome entry site (IRES) and inosine 5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress
  • therapeutically effective amounts of a compound of formula (I) may be administered as the raw chemical
  • therapeutically effective amount refers to the total amount of each active component that is sufficient to show a meaningful patient benefit (e.g., a reduction in viral load) .
  • a meaningful patient benefit e.g., a reduction in viral load
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof are as described above.
  • the carrier (s) , diluents (s) or excipient (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • pharmaceutically acceptable refers to those compounds, materials, composition and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram ( “mg/kg” ) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • mg/kg milligram per kilogram
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Treatment may be initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
  • compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 to 80%of the dosage normally administered in a monotherapy regimen.
  • Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual) , rectal, nasal, topical (including buccal, sublingual or transdermal) , vaginal or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier (s) or excipient (s) . Oral administration or administration by injection is preferred.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solution or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or ⁇ -lactose, corn sweetener, natural gum and synthetic resin such as Arabic gum, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluents or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt and/or
  • absorption agent such as betonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadiamucilage or solution of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadiamucilage or solution of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
  • the compounds of formula (I) can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carrier to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly ( ⁇ -caprolactone) , polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly ( ⁇ -caprolactone) , polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 1986, 3 (6) , 318.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patch.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, insufflators or other suitable device.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting HCV replication process and/or HCV viral protein function, wherein the HCV replication process is a whole viral cycle consisting of HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly and HCV egress; and wherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A, NS5B, or an internal ribosome entry site (IRES) and inosine 5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • any one of the compounds or the pharmaceutical compositions disclosed herein can be used for treating HCV infection or a HCV disorder, especially it is effective as inhibitor of the non-structural 5B (NS5B) protein of HCV.
  • a method which comprises administering the compound or the pharmaceutical composition disclosed herein, further comprises administering to the patient additional anti-HCV agents for a combination therapy, wherein the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine 5’ -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR TM ) , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127) , dasabuvir (ABT-333) , beclabuvir (BMS
  • the treatment method that includes administering a compound or composition disclosed herein can further include administering to the patient an additional anti-HCV agent, wherein the additional anti-HCV drug can be administered together with the compound or composition disclosed herein in which the compound or composition is as a single dosage form or as part of a multiple dosage form separately.
  • the additional anti-HCV agent may be administered at the same time with the compound disclosed herein or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
  • an “effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders.
  • the compounds and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compound or composition can also be administered with one or more other therapeutic agents, as discussed above.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for formula (I) , above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • Anhydrous THF, dioxane, toluene and ether were obtained by refluxing the solvent with sodium.
  • Anhydrous CH 2 Cl 2 and CHCl 3 were obtained by refluxing the solvent with CaH 2 .
  • EtOAc, PE, hexane, N, N-dimethylacetylamine (DMAC) and N, N-dimethylformamide (DMF) were treated with anhydrous Na 2 SO 4 prior to use.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • MS data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column was operated at 30 °C) .
  • G1329A autosampler and G1315D DAD detector were applied in the analysis, and an ESI source was used on the LC-MS spectrometer.
  • MS data were also determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A Quaternary pump and a G1316A TCC (column was operated at 30 °C) .
  • G1329A autosampler and G1315D DAD detector were applied in the analysis, and an ESI source was used on the LC-MS spectrometer.
  • Dess-Martin (Dess-Martin periodinane) (1, 1, 1-triacetoxy) -1, 1-dihydro-1, 2-benziodoxol-3 (1H) -one
  • Lawesson s Reagent 2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane 2, 4-disulfide
  • Compound 3 can be prepared by the process illustrated in Scheme 1, wherein each R 2 , R 4 , R 5 and R 7 is as defined herein, and R 15 is H, Br, I or -CO 2 Me.
  • Compound 1 can react with acrylic acid to form compound 2 in an organic solvent such as toluene under a refluxing condition.
  • Compound 2 can convert to compound 3 by reacting with urea in a suitable solvent under a heating condition.
  • Compound 5 can be prepared by the process illustrated in Scheme 2, wherein each R 4 , R 5 and R 7 is as defined herein, and R 15 is H, Br, I or -CO 2 Me.
  • Compound 4 can be prepared by adding a solution of (E) -3-methoxyacryloyl isocyanate in benzene to a solution of compound 1 in a solvent such as dimethylformamide or dimethylacetamide at a temperature from -40 °C to -15 °C under an inert atmosphere and stirring the mixture at rt for 0.5 to 4 h.
  • Compound 4 can convert to compound 5 in the presence of an acid in a mixture of water and ethanol at a temperature from about 90 °C to about 110 °C, or compound 4 can undergo cyclization to afford the objective compound 5 in the presence of a base desclosed in Ueno, Y. eatl., J. Org. Chem. 70: 7925-7935 (2005) .
  • Compound 9 can be prepared by the process illustrated in Scheme 3. Compound 6 can undergo Curtius rearrangement and hydrolysis to form compound 8, and then compound 8 can convert to the objective compound 9 through diazotization.
  • Compound 14 can be prepared by the process illustrated in Scheme 4, wherein each of R 4 and R 7 is as defined herein, and each of X 1 and X 2 is independently Br or I.
  • Compound 10 can react with an electrophilic halide source such as iodine chloride to form a dihalide compound 11.
  • Compound 11 can react with an alkylating agent such as methyl sulfate to afford compound 12 in the presence of a base such as potassium carbonate in acetone under a refluxing condition.
  • the objective compound 14 can be prepared by reacting compound 12 with uracil, compound 13, cuprous iodide and potassium phosphate in dimethylsulfoxide at a temperature from about 40 °Cto 100 °C.
  • Compound 15 can be prepared by the process illustrated in Scheme 5.
  • the objective compound 15 can be prepared by reacting compound 9 with uracil, compound 13, cuprous iodide and potassium phosphate in dimethylsulfoxide at a temperature from about 40 °C to about 100 °C.
  • Compound 18 can be prepared by the process illustrated in Scheme 6, wherein each R 2 , R 3 , R 4 , R 5 and R 7 is as defined herein, each Z is independently CH or N, and X 1 is Cl, Br, I or OTf.
  • Compound 16 can undergo Suzuki coupling reaction with compound 17 to form the objective compound 18.
  • Compound 20 can be prepared by the process illustrated in Scheme 7, wherein each R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined herein, and X 1 is Cl, Br, I or OTf.
  • Suzuki reaction of compound 17 with compound 19 can afford the objective compound 20 in the presence of a base (such as potassium carbonate, potassium phosphate, potassium tert-butoxide, sodium carbonate, cesium carbonate or cesium fluoride, and the like) , and a catalyst (such as tris (dibenzylideneacetone) dipalladium (0) , palladium acetate, bis(triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium, dichloro [1, 1'-bis (di-tert-butylphosphino) ferrocene] palladium (II) or dichloro [1, 1'-bis (di-tert-
  • Compound 20 can also be prepared by the process illustrated in Scheme 8, wherein each R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined herein, and X 1 is Cl, Br, I or OTf.
  • Sonogashira coupling reaction of compound 21 with trimethylsilylacetylene can afford compound 22 in the presence of cuprous (I) iodide and palladium; the group TMS of compound 22 can be removed in the present of a base (such as triethylamine, diethylamine, N-di (isopropyl) ethylamine, tetrabutylammonium bromide, potassium fluoride, potassium carbonate or potassium bicarbonate and the like) to afford compound 23; compound 17 can react with compound 23 in the present of copper and palladium by Sonogashira coupling reaction to afford compound 24; the acetylenic bond of compound 24 in the present of a reductive agent to form a double bond to afford compound 20.
  • Compound 29 can also be prepared by the process illustrated in Scheme 9, wherein R 2 , R 4 , R 5 , R 7 are as defined herein, Z is NH, O or S.
  • Compound 25 can react with compound 26 in the present of activied carbon under a refluxing condition to afford compound 27 by cyclization; reduction reaction of the nitro group of compound 27 can afford compound 28; compound 28 can react with methylsulfonyl chloride to afford compound 29.
  • Compound 32 can also be prepared by the process illustrated in Scheme 10, wherein R 2 , R 3 , R 4 , R 5 and R 7 are as defined herein; Z 1 is CH 2 , NH, O or S; Z 2 is CH or N; X 1 is Cl, Br, I or OTf.
  • Compound 30 can react with compound 31 by Suzuki coupling reaction to afford compound 32.
  • Compound 41 can also be prepared by the process illustrated in Scheme 11, wherein R 2 , R 4 , R 5 , R 6 and R 7 are as defined herein.
  • Compound 33 can react with compound 34 in an organic solvent to afford compound 35; compound 35 can react with urea in a solvent such as acetic acid under a heating condition to afford compound 36; hydrolyzation of compound 36 in the present of a base and then through acidification to afford compound 37; a mixture of compound 37 and sulfoxide chloride can be refluxed to afford compound 38; reduction reaction of compound 38 in the present of lithium tri-tert-butoxyaluminum hydride at -78 °C to afford aldehyde compound 39; compound 39 can react with compound 40 in the present of potassium tert-butoxide to afford compound 41.
  • Step 8) 1- (3-bromo-5- (tert-butyl) -2-fluoro-4-methoxyphenyl) pyrimidine-2, 4 (1H, 3H) -dione
  • Step 1) 1- (3-bromo-5- (tert-butyl) -2-fluoro-4-methoxyphenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 2) N- (6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-yl) methanesulfonamide
  • Step 2) 1- (tert-butyl) -4-fluoro-3-iodo-2-methoxy-5-nitrobenzene
  • Step 5 1- (5- (tert-butyl) -2-fluoro-3-iodo-4-methoxyphenyl) -pyrimidine-2, 4 (1H, 3H) -dione
  • Step 2) 1- (tert-butyl) -5-iodo-2-methoxy-4-methylbenzene
  • Step 4) 1- (3-bromo-5- (tert-butyl) -4-methoxy-2-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione
  • reaction mixture was cooled to rt and diluted with EtOAc (40 mL) , and then washed with water (15 mL ⁇ 2) and saturated aqueous NaCl solution (15 mL) , dried over anhydrous Na 2 SO 4 .
  • the mixture was concentrated in vacuo.
  • Step 9) 1- (3-bromo-5- (tert-butyl) -2-fluoro-4-methoxyphenyl) pyrimidine-2, 4 (1H, 3H) -dione
  • the reaction mixture was filtered.
  • the filtrate was diluted with EtOAc (80 mL) , and then washed with water (20 mL ⁇ 2) and saturated aqueous NaCl solution (20 mL) , dried over anhydrous Na 2 SO 4 .
  • the mixture was concentrated in vacuo.
  • reaction mixture was diluted with DCM (100 mL) , and then washed with water (30 mL ⁇ 2) and saturated aqueous NaCl solution (30 mL) , dried over anhydrous Na 2 SO 4 and concentrated in vacuo.
  • the reaction mixture was cooled to rt and diluted with EtOAc (80 mL) , and then washed with water (25 mL ⁇ 2) and saturated aqueous NaCl solution (25 mL) , dried over anhydrous Na 2 SO 4 , and filtered through a Celite pad. The mixture was concentrated in vacuo.
  • Step 2) 1- (3-bromo-5- (tert-butyl) -4-methoxy-2-methylphenyl) -5-fluoropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1) 3'- (tert-butyl) -5'- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -6'-fluoro-2'-methoxy- [1, 1'-biphenyl] -4-carbaldehyde
  • reaction mixture was diluted with EtOAc (40 mL) , and then washed with water (15 mL ⁇ 2) and saturated aqueous NaCl solution (15 mL) , dried over anhydrous Na 2 SO 4 . The mixture was concentrated in vacuo.
  • Step 2) (E) -N'- ( (3'- (tert-butyl) -5'- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -6'-fluoro-2'-methoxy- [1, 1'-biphenyl] -4-yl) methylene) methanesulfonohydrazide
  • the reaction mixture was diluted with EtOAc (80 mL) , and then washed with water (30 mL ⁇ 2) and saturated aqueous NaCl solution (30 mL) , dried over anhydrous Na 2 SO 4 . The mixture was concentrated in vacuo.
  • Step 2 N- ( (3-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamoyl) methanesulfonamide
  • reaction mixture was diluted with EtOAc (40 mL) , and then washed with water (15 mL ⁇ 2) and saturated aqueous NaCl solution (15 mL) , dried over anhydrous Na 2 SO 4 . The mixture was concentrated in vacuo.
  • the up layer was diluted with MTBE (400 mL) , and then washed with water (100 mL ⁇ 2) and saturated aqueous NaCl (100 mL) , dried over anhydrous Na 2 SO 4 .
  • the mixture was concentrated in vacuo.
  • Step 8) 1- (5- (tert-butyl) -2-fluoro-4-methoxy-3- (5-nitrobenzo [d] oxazol-2-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1) N- (6- (3- (tert-butyl) -5- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -6-fluoro-2- methoxyphenyl) naphthalen-2-yl) methanesulfonamide
  • Step 8) 1- (3-bromo-5- (tert-butyl) -4-chloro-2-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione
  • reaction mixture was diluted with EtOAc (40 mL) , and then washed with water (15 mL ⁇ 2) and saturated aqueous NaCl solution (15 mL) , dried over anhydrous Na 2 SO 4 . The mixture was concentrated in vacuo.
  • Step 4) 1- (3-bromo-2-fluoro-4-methoxy-5- (trifluoromethyl) phenyl) pyrimidine-2, 4 (1H, 3H) -dione
  • reaction mixture was diluted with EtOAc (40 mL) , and then washed with water (15 mL ⁇ 2) and saturated aqueous NaCl solution (15 mL) , dried over anhydrous Na 2 SO 4 . The mixture was concentrated in vacuo.
  • Step 6) 1- (5-bromo-2-fluoro-3-iodo-4-methoxyphenyl) pyrimidine-2, 4 (1H, 3H) -dione
  • Step 2) (2- (benzyloxy) -4-fluorophenyl) methanol
  • Step 16 N- (6- (3-amino-5- (1- ( (tert-butyldimethylsilyl) oxy) -2-methylpropan-2-yl) -2-fluoro-6-methoxyphenyl) naphthalen-2-yl) methanesulfonamide
  • Step 7) 1- (3-bromo-5- (tert-pentyl) -2-fluoro-4-methoxyphenyl) pyrimidine-2, 4 (1H, 3H) -dione

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Abstract

La présente invention concerne des composés de formule (I), ou un stéréoisomère, un isomère géométrique, un énantiomère, un tautomère, un N-oxyde, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament associé, qui sont utilisés dans le traitement d'une infection par le VHC ou l'hépatite C. L'invention porte en outre sur des compositions pharmaceutiques contenant ces composés et sur des procédés d'utilisation des composés de l'invention ou de compositions pharmaceutiques associées pour traiter une infection par le VHC ou l'hépatite C.
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