WO2014082381A1 - Composés de type noyau spiro utilisables en tant qu'inhibiteurs du virus de l'hépatite c, compositions pharmaceutiques en contenant et leurs utilisations - Google Patents

Composés de type noyau spiro utilisables en tant qu'inhibiteurs du virus de l'hépatite c, compositions pharmaceutiques en contenant et leurs utilisations Download PDF

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WO2014082381A1
WO2014082381A1 PCT/CN2013/001466 CN2013001466W WO2014082381A1 WO 2014082381 A1 WO2014082381 A1 WO 2014082381A1 CN 2013001466 W CN2013001466 W CN 2013001466W WO 2014082381 A1 WO2014082381 A1 WO 2014082381A1
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alkyl
independently
aryl
heterocyclyl
deuterium
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PCT/CN2013/001466
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English (en)
Inventor
Yingjun Zhang
Jiancun Zhang
Hongming XIE
Qingyun REN
Xiwei Wu
Changping FU
Bailin HU
Shifeng Li
Qinghong Fang
Yong Lei
Feng Luo
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Sunshine Lake Pharma Co., Ltd.
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Publication of WO2014082381A1 publication Critical patent/WO2014082381A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • C07D401/14—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 three or more hetero 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • the present disclosure relates to a field of medicine, and more particularly to compounds for treating Hepatitis C virus (HCV) infection, compositions comprising such compounds, use of the compounds and the compositions thereof, 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 1. 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). [0006] Considerable heterogeneity is found within nucleotide and encoded amino acid sequence throughout the HCV genome. At least seven major genotypes have been characterized, and more than 50 subtypes have been described.
  • RNA is translated into a polyprotein that is cleaved into ten individual proteins.
  • structural proteins follows El 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).
  • 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.
  • the first one is believed 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 downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
  • 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 that is involved in the replication of HCV.
  • HCV NS5A protein is described, for example, in Tan et al., Virology, 2001, 284, 1-12; and in Park et al., J. Biol. Chem., 2003, 278, 30711-30718.
  • novel Spiro ring compounds and methods of their use to treat HCV infection are novel Spiro ring compounds and methods of their use to treat HCV infection. Specifically, it has been found that the fused ring compounds disclosed herein, and compositions thereof, are effective as inhibitors of HCV infection, especially the HCV NS5A protein. [001 1 ] In one aspect, provided herein are compounds having Formula (I) as shown below:
  • each X 1 and X 2 is independently O, S, NR 6 , or CR 7 R 7a ;
  • Wi is a carbocyclyl or heterocyclyl ring;
  • W 2 is a carbocyclyl, heterocyclyl, spiro bicyclyl, spiro heterobicyclyl, fused bicyclyl or fused heterobicyclyl ring; each X, X', Y 1 , Y 2 , Y 1 and Y 2' is independently N or CR 7 ;
  • R 13 and R 13a are optionally joined to form a 4-7 membered ring; and each R 13 and R 13a is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl; with the proviso that where R 13 and R 13a are bonded to the same nitrogen atom, R 13 and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, or a substituted or unsubstituted spiro bicyclic ring or fused bicyclic ring, wherein each of alkylene, alkenylene, cycloalkylene, heterocycloalkylene, -(CR 8 R 8a ) n -0-(CR 8 R 8a ) p -, -(CR 8 R 8a ) n -N(R 5 )-(CR 8 R 8a ) p
  • Wi is a C3_g carbocyclyl or C 2 _io heterocyclyl ring
  • W 2 is a C3_g carbocyclyl, C 2 _io heterocyclyl, C 5 _i 2 spiro bicyclyl, C 5 _i 2 spiro heterobicyclyl, C 5 _i 2 fused bicyclyl or C 5 _i 2 fused heterobicyclyl ring.
  • each of A and A' is independently a bond, Ci_ 6 alkylene, C 2 _ 6 alkenylene _ 8 cycloalkylene, C 2 0 heterocycloalkylene, -(CR 8 R 8a ) n -0-(CR 8 R 8a ) p -, -(CR 8 R 8a ) n -N(R 5 )-(CR 8 R 8a ) p -
  • each X 1 and X 2 is independently O, S, NR 6 , or CR 7 R 7a ;
  • each e is independently 0, 1, 2, 3 or 4;
  • each Y 1 and Y 2 is independently N or CR 7 ;
  • each c and d is independently 1 or 2;
  • A' is inde endently selected from
  • each of R 1 , R 2 , R 3 and R 4 is independently H, deuterium, Ci_g alkyl, Ci_g
  • R 1 and R 2 together with X-CH they are attached to, or R 3 and R 4 , together with X'-CH they are attached to, optionally form a 3-8 membered heterocycle, _i 2 fused bicycle, _i 2 fused heterobicycle, C5 2 spiro bicycle or C5 2 spiro heterobicycle.
  • R 1 , R 2 and Y-X-CH together form one of the following monovalent
  • R , R and Y'-X'-CH together form one of the following monovalent
  • the compound may have formula (II):
  • a and A' is independently
  • the compound may have formula (III):
  • the compound may have formula (IV):
  • the compound may have formula (V):
  • the compound may have formula (VI):
  • i 0, 1, 2, 3 or 4;
  • W3 is a C3_io carbocyclyl or C2-10 heterocyclyl ring.
  • the compound may have fonnula (VII):
  • the compound may have formula (VIII):
  • the compound may have formula (IX):
  • the com ound may have formula (X):
  • each of Y and Y' is independently a monovalent group derived from an a-amino acid.
  • the a-amino acid is isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophane, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, ⁇ , ⁇ -dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline.
  • the a-amino acid is in the D configuration. [0033] In other embodiments, the a-amino acid is in the L configuration.
  • each of Y and Y' is independently
  • each of Y and Y' is independently -U-(CR 9 R 9a ) t -NR u -(CR 9 R 9a ) t -R 12 .
  • each of Y and Y' is independently -U-(CR 9 R 9a ) r R 12 .
  • each of Y and Y' is independently -[U-(CR 9 R 9a ) t -NR 10 -(CR 9 R 9a ) t ] k -U-(CR 9 R 9a ) t -O-(CR 9 R 9a ) t -R 12 .
  • each of Y and Y' is independently -U-(CR 9 R 9a ) t -NR 10 -(CR 9 R 9a ) t -U-(CR 9 R 9a ) r O-(CR 9 R 9a ) r R 12 .
  • each of Y and Y' is independently -U-(CR 9 R 9a ) r O-(CR 9 R 9a ) t -R 12 .
  • each R 13 and R 13a is independently H, deuterium, Ci_6 alkyl, C 2 _6 heteroalkyl, C340 cycloalkyl, C 2 _io heterocyclyl, C 6 _io aryl, Ci_ 9 heteroaryl, or C 6 _io aryl-Ci_ 6 -alkyl; with the proviso that where R 13 and R 13a are bonded to the same nitrogen atom, R 13 and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, or a substituted or unsubstituted spiro bicyclic ring or fused bicyclic ring;
  • each R and R a is independently H, deuterium, methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl.
  • the compound may have formula (XI):
  • each of R and R a is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, Ce-io ary Ci_g heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, Ce-io aryl-Ci_6-alkyl, Ci_g heteroaryl-Ci_ 6 -alkyl, C 2 _io heterocyclyl-Ci_ 6 -alkyl, or C 3 _ 8 cycloalkyl-Ci_ 6 -alkyl.
  • the compound may have formula (XII):
  • each of R 14 and R 14a is independently H, deuterium, Ci_3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, -NR 13 R 13a , benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl, or Ci_9 heteroaryl.
  • the compound may have formula (XIII): (R 5a ')f
  • each of R and R a is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, Ce-io heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, Ce-io aryl-Ci_6-alkyl, heteroaryl-Ci_ 6 -alkyl, C 2 _io heterocyclyl-Ci_ 6 -alkyl or C 3 _ 8 cycloalkyl-Ci_ 6 -alkyl; and each n 2 is independently 1, 2, 3 or 4.
  • the compound may have formula (IX'):
  • each of R and R a is independently H, deuterium, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, C2-6 heteroalkyl, Ce-io heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, Ce-io aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl; and each n ! is independently 1, 2, 3 or 4.
  • R 1 , R 2 and N-CH together fonn one of the following divalent groups:
  • the compound may have formula ( ⁇ ):
  • R 1 , R 2 and N-CH together form one of the following divalent groups:
  • R , R and N-CH together form one of the following divalent groups:
  • the compound may have formula ( ⁇ ):
  • R 1 , R 2 and N-CH together form one of the following divalent groups:
  • R , R and N-CH together form one of the following divalent groups:
  • R 1 , R 2 and N-CH together form one of the following divalent groups:
  • R , R and N-CH together form one of the following divalent groups:
  • the present disclosure provides a pharmaceutical composition comprising any one of the above compounds.
  • the pharmaceutical composition also 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, ribavirin, bavituximab, human hepatitis C immune globulin (CIVACIRTM), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-58
  • the interferon is interferon a-2b, pegylated interferon a, interferon a-2a, pegylated interferon a-2a, consensus interferon-a, interferon ⁇ or a combination thereof.
  • the pharmaceutical composition disclosed herein further comprises at least one HCV inhibitor.
  • the HCV inhibitor inhibits at least one of HCV replication process and HCV viral protein function.
  • the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress.
  • the HCV viral protein is metalloproteinase, non- structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5 '-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • IMPDH inosine-5 '-monophosphate dehydrogenase
  • the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress.
  • the HCV viral protein is metalloproteinase, non- structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5 '-monophosphate dehydrogenase (IMPDH) required in HCV viral replication,
  • use of the compound or the pharmaceutical composition disclosed herein for preventing, managing, treating or lessening the severity of HCV infection and a HCV disorder in a patient comprises administering a therapeutically effective amount of the (a) compound or pharmaceutical composition disclosed herein to the patient.
  • the compound or the pharmaceutical composition disclosed herein for use in inhibiting at least one of HCV replication process and HCV viral protein function is provided.
  • the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress;
  • the HCV viral protein is metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5 '-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • IVS internal ribosome entry site
  • IMPDH inosine-5 '-monophosphate dehydrogenase
  • 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 is provided.
  • the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress;
  • the HCV viral protein is metalloproteinase, non- structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) or inosine-5 '-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • a method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient comprises administering a therapeutically effective amount of the (a) compound or pharmaceutical composition disclosed herein to the patient.
  • provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), ( ⁇ '), ( ⁇ '), ( ⁇ '), ( ⁇ '), or ( ⁇ ).
  • 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 whether preceded by the term “optionally” or not, 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.
  • aliphatic refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, the aliphatic group contains 1-20 carbon atoms. In some embodiments, the aliphatic group contains 1-10 carbon atoms. In other embodiments, the aliphatic group contains 1-8 carbon atoms. In still other embodiments, the aliphatic group contains 1-6 carbon atoms, and in yet other embodiments, the aliphatic group contains 1-4 carbon atoms. In other embodiments, the aliphatic group contains 1-3 carbon atoms.
  • aliphatic group examples include linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups, as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl, sec-butyl, vinyl, and the like.
  • haloaliphatic refers to an aliphatic group substituted with one or more of the same or different halogen atoms (i.e., F, CI, Br or I,), wherein the aliphatic group is as defined herein.
  • halogen atoms i.e., F, CI, Br or I,
  • Some non-limiting examples of the haloaliphatic group include trifluoromethyl, trifluoroethyl, chloromethyl, 2-chlorovinyl, and the like.
  • hydroxyaliphatic refers to an aliphatic group substituted with one or more hydroxy groups, wherein the aliphatic group is as defined herein.
  • aliphatic group include hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.
  • aminoaliphatic refers to an aliphatic group substituted with one or more amino groups, wherein the aliphatic group is as defined herein.
  • aminoaliphatic group include aminomethyl, 2-aminoethyl, 2-amino isopropyl, and the like.
  • alkyl refers to a saturated linear or branched chain monovalent hydrocarbon radical of one to twenty carbon atoms, or one to ten carbon atoms, or one to eight carbon atoms, or one to six carbon atoms, or one to four carbon atoms, or one to three carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described below.
  • alkyl group examples include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), «-propyl ( «-Pr, -CH 2 CH 2 CH 3 ), /-propyl (z-Pr, -CH(CH 3 ) 2 ), «-butyl ( «-Bu, -CH 2 CH 2 CH 2 CH 3 ), /-butyl (/-Bu, -CH 2 CH(CH 3 ) 2 ), s-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), /-butyl (/-Bu, -C(CH 3 ) 3 ), «-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 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2
  • alk- refers to inclusive of both straight chain and branched saturated carbon chain.
  • alkylene refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like.
  • alkenyl refers to a linear or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms, or two to eight carbon atoms, or two to six carbon atoms, or two to four carbon atoms, with at least one site of unsaturation, i.e., a carbon-carbon, sp double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alkynyl refers to a linear or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms, or two to eight carbon atoms, or two to six carbon atoms, or two to four carbon atoms, with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • alkynyl group include ethynyl (-C ⁇ CH), propynyl (propargyl, -CH 2 C ⁇ CH), and the like.
  • 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 the hydroxy-substituted alkyl group include hydroxymethyl, hydroxy ethyl, 1,2-dihydroxyethyl, and the like.
  • haloalkyl refers to an alkyl group substituted with one or more of the same or different halogen atoms, wherein the alkyl group is as defined herein.
  • Some non-limiting examples of the haloalkyl group include trifluoromethyl, trifluoroethyl, chloromethyl, fluoromethyl, and the like.
  • hydroxyalkyl 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 the hydroxyalkyl group include hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.
  • aminoalkyl refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is as defined herein.
  • the aminoalkyl group include aminomethyl, 2-aminoethyl, 2-amino isopropyl, and the like.
  • alkylene refers to a saturated divalent hydrocarbon group derived from a straight or branched- chain saturated hydrocarbon by the removal of two hydrogen 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.
  • alkylene group examples include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), isopropylidene (-CH 2 -CH(CH 3 )-), ethylidene, 2-methoxy-l,l-propylidene, 2-hydroxy-l,l-propylidene, 2-methyl-2-hydroxy-l,l-propylidene, and the like.
  • alkenylene refers to an unsaturated divalent hydrocarbon group derived from a straight or branched-chain unsaturated hydrocarbon alkene 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.
  • 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 of the cycloalkylene group include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, 1-cyclopent-l-enylene, l-cyclopent-2-enylene, and the like.
  • heterocyclylene refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has two points of attachment to the rest of the molecule, wherein the heterocyclyl group is as defined herein.
  • heterocyclylene group examples include piperidin-l,4-ylene, piperazin-l,4-ylene, tetrahydrofuran-2,4-ylene, tetrahydrofuran-3,4-ylene, azetidin-l,3-ylene, pyrrolidin-l,3-ylene, and the like.
  • heterocyclylalkylene refers to a divalent group derived from a heterocyclylalkyl by the removal of two hydrogen atoms, wherein the heterocyclylalkyl group is as defined herein.
  • Some non-limiting examples of the heterocyclylalkylene group include mo holin-4-methylmethylene, piperidin-N-methylmethylene, piperazin-4-ethyl-l-yl, piperidin-4-ethyl-l-yl, pyrrolidon-2-methyl-l-yl, and the like.
  • haloalkylene refers to haloalkyl system having two points connected to the rest of the molecule, wherein the haloalkyl group is as defined herein.
  • haloalkylene group include difluoromethylene (-CF 2 -), and the like.
  • arylene refers to aryl system having two connection points connected to the rest of the molecule, wherein the aryl radical is as defined herein.
  • arylene group include phenylene, 7-fluorophenylene, and the like.
  • aralkylene refers to aralkyl system having two connection points connected to the rest of the molecule, wherein the aralkyl radical is as defined herein.
  • aralkylene group include benzylene, phenylethylene, and the like.
  • heteroarylene refers to heteroaryl system having two connection points connected to the rest of the molecule, wherein the heteroaryl radical is as defined herein.
  • Some non-limiting examples of the tieteroarylene group include pyridylene, pyrrylene, thiazolylene, imidazolylene, and the like.
  • heteroarylalkyl ene refers to heteroarylalkyl system having two connection points connected to the rest of the molecule, wherein the heteroarylalkyl group is as defined herein.
  • heteroarylalkylene group include pyridine-2-ethylene, thiazole-2-methylene, imidazole-2-ethylene, pyrimidine-2-methylene, and the like.
  • fused bicyclylene refers to fused bicyclyl system having two connection points connected to the rest of the molecule, wherein the fused bicyclyl group is as defined herein.
  • fused bicyclylene group include bicyclo[3.1.0]hexane-3,6-ylene.
  • fused heterobicyclyl ene refers to fused heterobicyclyl system having two connection points connected to the rest of the molecule, wherein the fused heterobicyclyl group is as defined herein.
  • fused heterobicyclylene group include 3-azabicyclo[3.1.0]hexane-3,6-ylene.
  • fused bicyclylalkylene refers to fused bicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the fused bicyclylalkyl group is as defined herein.
  • fused heterobicyclylalkylene refers to fused heterobicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the fused heterobicyclylalkyl group is as defined herein.
  • spiro bicyclylene refers to spiro bicyclyl system having two connection points connected to the rest of the molecule, wherein the fused spiro bicyclyl group is as defined herein.
  • Some non-limiting examples of the spiro bicyclylene group include 5-spiro[2,4]heptane-5,7-ylene, spiro [4,4]nonane-2,7-yl ene, and the like.
  • spiro heterobicyclylene refers to spiro heterobicyclyl system having two connection points connected to the rest of the molecule, wherein the fused spiro heterobicyclyl group is as defined herein.
  • Some non-limiting examples of the spiro heterobicyclylene group include 5-azaspiro[2,4]heptane-5,7-ylene, 2-azaspiro[4,4]nonane-2,7-ylene, and the like.
  • spiro bicyclylalkylene refers to spiro bicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the fused spiro bicyclylalkyl group is as defined herein.
  • spiro heterobicyclylalkylene refers to spiro heterobicyclylalkyl system having two connection points connected to the rest of the molecule, wherein the fused spiro heterobicyclylalkyl group is as defined herein.
  • heteroalkyl refers to hydrocarbon chain, inserted with one or more heteroatoms. Unless otherwise specified, the heteroalkyl group contains 1-10 carbon atoms. In other embodiments, the heteroalkyl group contains 1-8 carbon atoms. In still other embodiments, the heteroalkyl group contains 1-6 carbon atoms, and in yet other embodiments, the heteroalkyl group contains 1-4 carbon atoms. In other embodiments, the heteroalkyl group contains 1-3 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.
  • cycloaliphatic refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated ring exclusive of heteroatoms, having 3 to 12 carbon atoms as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.
  • Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system.
  • cycloaliphatic group examples include cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examples of the cycloaliphatic group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-l-enyl, l-cyclopentyl-2-enyl, l-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-l-enyl, l-cyclohexyl-2-enyl, l-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • cycloalkyloxy refers to an optionally substituted cycloalkyl or carbocyclyl radical, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • cycloalkyloxy group include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.
  • cycloalkylamino refers to an amino group substituted with one or two cycloalkyl radicals, wherein the cycloalkyl group is as defined herein.
  • Some non-limiting examples of the cycloalkylamino group include cyclopropylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino, and the like.
  • carbocyclyloxyalkoxy refers to an alkoxy group substituted with one or more carbocyclyloxy groups, wherein the alkoxy group and carbocyclyloxy group are as defined herein.
  • carbocyclyloxyalkoxy group include cyclopropyloxymethoxy, cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy, cyclohexenyl-3-oxyethoxy, and the like.
  • cycloalkyloxyaliphatic refers to an aliphatic group substituted with one or more cycloalkyloxy groups, wherein the aliphatic group and cycloalkyloxy group are as defined herein.
  • Some non-limiting examples of the cycloalkyloxyaliphatic group include cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, halocyclopropyloxyethyl, and the like.
  • cycloalkylaminoaliphatic refers to an aliphatic group substituted with one or more cycloalkylamino groups, wherein the aliphatic group and cycloalkylamino group are as defined herein.
  • Some non-limiting examples of the cycloalkylaminoaliphatic group include cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminoethyl, halocyclopropylaminoethyl, and the like.
  • cycloalkylaliphatic refers to an aliphatic group substituted with one or more cycloalkyl groups, wherein the cycloalkyl group and aliphatic group are as defined herein.
  • Some non-limiting examples of the cycloalkylaliphatic group include cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl, and the like.
  • cycloalkylalkoxy refers to an alkoxy group substituted with one or more cycloalkyl groups or carbocyclyl groups, wherein the carbocyclyl group, cycloalkyl group and alkoxy group are as defined herein.
  • Some non-limiting examples of the cycloalkylalkoxy group include cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, and the like.
  • heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but not aromatic having a single point of attachment to the rest of the molecule.
  • One or more ring atoms are optionally substituted independently with one or more substituents described herein.
  • the "heterocycle”, “heterocyclyl”, “heterocycloaliphatic” or “heterocyclic” group is a monocycle having 3 to 7 ring members (e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S0 2 , PO or PO 2 , with the proviso that when the ring is a 3-membered ring, there is only one heteroatom) or a bicycle having 7 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S0 2 , PO or P0 2 ).
  • 3 to 7 ring members e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S
  • the heterocyclyl may be a carbon radical or heteroatom radical.
  • Heterocyclyl also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or heterocyclic ring.
  • Some non-limiting examples of the heterocyclic ring include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidyl, mo holinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl (oxiranyl), azepanyl, oxepanyl, thiepany
  • heterocyclylalkyl refers to heterocyclic-substituted alkyl radical.
  • heterocyclylalkoxy refers to heterocyclic-substituted alkoxy radical wherein oxygen atom serves as the attaching point to the rest of the molecule.
  • heterocyclylalkylamino refers to heterocyclic-substituted alkylamino radical wherein nitrogen atom serves as the attaching point to the rest of the molecule. Wherein the heterocyclyl, alkyl, alkoxy and alkylamino group are as defined herein.
  • heterocyclylalkyl group examples include pyrrol-2-ylmethyl, morpholin-4-ylethyl, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino, and the like.
  • heterocyclylaliphatic refers to heterocyclic-substituted aliphatic group, wherein the heterocyclic radical and aliphatic group are as defined herein.
  • Some non-limiting examples of the heterocyclylaliphatic group include pyrrol-2-ylmethyl, piperidin-2-ylethyl, piperazin-2-ylethyl, piperidin-2-ylmethyl, and the like.
  • heterocyclyloxy refers to optionally substituted heterocyclyl radical, as defined herein, connected to an oxygen atom, and the oxygen atom serves as the attaching point to the rest of the molecule.
  • heterocyclyloxy group examples include pyrrol-2-yloxy, pyrrol-3-yloxy, piperidin-2-yloxy, piperidin-3-yloxy, piperazin-2-yloxy, piperidin-4-yloxy, and the like.
  • heterocyclylamino refers to an amino group substituted with one or two heterocyclyl groups, wherein the heterocyclyl group is as defined herein.
  • the heterocyclylamino group include pyrrol-2-ylamino, pyrrol-3-ylamino, piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperazin-2-ylamino, dipyrrol-2-ylamino, and the like.
  • heterocyclyloxyalkoxy refers to an alkoxy radical substituted with one or more heterocyclyloxy groups, wherein the alkoxy radical and heterocyclyloxy group are as defined herein.
  • the heterocyclyloxyalkoxy group include pyrrol-2-yloxymethoxy, pyrrol-3 -yloxyethoxy, piperidin-2-yloxyethoxy, piperidin-3 -yloxyethoxy, piperazin-2-yloxymethoxy, piperidin-4-yloxyethoxy, and the like.
  • heterocyclyloxyaliphatic refers to an aliphatic group substituted with one or more heterocyclyloxy groups, wherein the aliphatic group and heterocyclyloxy group are as defined herein.
  • heterocyclyloxyaliphatic group include pyrrol-2-yloxymethyl, piperazin-3-yloxy ethyl, piperazin-2-yloxyethyl, morpholin-2-yloxymethyl, piperidin-2-yloxyethyl, and the like.
  • heterocyclylaminoaliphatic refers to an aliphatic group substituted with one or more heterocyclylamino groups, wherein the aliphatic group and heterocyclylamino group are as defined herein.
  • heterocyclylaminoaliphatic group include pyrrol-2-ylaminomethyl, piperazin-3-lyaminoethyl, piperazin-2-lyaminoethyl, piperidin-2-lyaminoethyl, mo holin-2-lyaminomethyl, and the like.
  • 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-2 /-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).
  • halogen refers to F, CI, Br or I.
  • alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy") atom.
  • alkoxy an oxygen
  • Some non-limiting examples of the alkoxy group include methoxy, ethoxy, propoxy, butoxy, and the like.
  • alkoxy defined above may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxy, amino, halo, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, and the like.
  • hydroxy-substituted alkoxy or "hydroxyalkoxy” refers to an alkoxy group substituted with one or more hydroxy groups, wherein the alkoxy group is as defined above.
  • Some non-limiting examples of the hydroxyalkoxy group include hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, and the like.
  • aminoalkoxy refers to an alkoxy group substituted with one or more amino groups, wherein the alkoxy group is as defined above.
  • aminoalkoxy group include aminomethoxy, 2 -amino ethoxy, 2-aminopropoxy, 2-aminoisopropoxy, and the like.
  • azidoalkoxy refers to an alkoxy group substituted with one or more azido groups, wherein the alkoxy group is as defined above.
  • the azidoalkoxy group include 2-azidoethoxy, 3-azidopropoxy, 2-azidopropoxy, and the like.
  • alkoxyalkoxy refers to an alkoxy group substituted with one or more alkoxy groups, wherein the alkoxy group is as defined above.
  • alkoxyalkoxy group include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy, and the like.
  • alkoxyaliphatic refers to an aliphatic group substituted with one or more alkoxy groups, wherein the aliphatic group and alkoxy group are as defined herein.
  • alkoxyaliphatic group include methoxymethyl, ethoxymethyl, ethoxyethyl, ethoxypropenyl, and the like.
  • alkylaminoaliphatic refers to an aliphatic group substituted with one or more alkylamino groups, wherein the aliphatic group and alkylamino group are as defined herein.
  • alkylaminoaliphatic group include dimethylaminoethyl, methylamino ethyl, diethylaminomethyl, diethylaminoethyl, and the like.
  • alkylthioaliphatic refers to an aliphatic group substituted with one or more alkylthio groups, wherein the aliphatic group and alkylthio group are as defined herein.
  • alkylthioaliphatic group include methylthioethyl, methylthiopropyl, ethylthioethyl, methylthiopropenyl, and the like.
  • haloalkyl refers to an alkyl group, alkenyl group or alkoxy group substituted with one or more halogen atoms.
  • haloalkyl group include trifluoromethyl, 2-chloro-ethenyl, trifluoromethoxy, and the like.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “arylalkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of six to fourteen 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 a single point of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term “aryl ring”.
  • Some non-limiting examples of the aryl ring include phenyl, naphthyl, and anthryl.
  • arylaliphatic refers to an aliphatic group substituted with one or more aryl groups, wherein the aliphatic group and the aryl group are as defined herein.
  • arylaliphatic group include phenylethyl, benzyl, (/?-tolyl)ethyl, styryl, and the like.
  • aryloxy refers to optionally substituted aryl radicals, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • the aryl radical is as defined herein.
  • Some non-limiting examples of the aryloxy group include phenyloxy, methylphenyloxy, ethylphenyloxy, and the like.
  • arylamino refers to an amino group substituted with one or two aryl groups, wherein the aryl group is as defined herein.
  • arylamino group include phenylamino, (p-fluorophenyl)amino, diphenylamino, ditolylamino, (di-/?-tolyl)amino, and the like.
  • aryloxyalkoxy refers to an alkoxy group substituted with one or more aryloxy groups, wherein the alkoxy group and the aryloxy group are as defined herein.
  • aryloxyalkoxy group include phenyloxymethoxy, phenyloxyethoxy, phenyloxypropoxy, and the like.
  • aryloxyaliphatic refers to an aliphatic group substituted with one or more aryloxy groups, wherein the aryloxy group and the aliphatic group are as defined herein.
  • aryloxyaliphatic group include phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, and the like.
  • arylaminoaliphatic refers to an aliphatic group substituted with one or more arylamino groups, wherein the arylamino group and the aliphatic group are as defined herein.
  • arylaminoaliphatic group include phenylaminomethyl, phenylaminoethyl, tolylaminoethyl, phenylaminopropyl, phenylaminoallyl, and the like.
  • arylalkoxy refers to an alkoxy group substituted with one or more aryl groups, wherein the aryl group and the alkoxy group are as defined herein.
  • arylalkoxy group include phenylmethoxy, phenylethoxy, (p-tolyl)methoxy, phenylpropoxy, and the like.
  • arylalkylamino refers to an alkylamino group substituted with one or more aryl groups, wherein the aryl group and the alkylamino group are as defined herein.
  • arylalkylamino group include phenylmethylamino, phenylethylamino, phenylpropylamino, (p-tolyl)methylamino, and the like.
  • heteroaryl used alone or as part of a larger moiety as in “heteroarylalkyl” or “ heteroarylalkoxy” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system is inclusive of one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or “heteroaromatic compound”.
  • Suitable heteroaryl ring include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazolyl-5-yl, N-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidine-5-yl, pyridazinyl (e.g., 3 -pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e
  • heteroaryloxy refers to an optionally substituted aryl radical, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • the heteroaryloxy group include pyrid-2-yloxy, thiazol-2-yloxy, imidazol-2-yloxy, pyrimidin-2-yloxy, and the like.
  • heteroaryloxyaliphatic refers to an aliphatic group substituted with one or more heteroaryloxy groups, wherein the aliphatic group and the heteroaryloxy group are as defined herein.
  • heteroaryloxy group include pyrid-2-yloxyethyl, thiazol-2-yloxymethyl, imidazol-2-yloxyethyl, pyrimidin-2-yloxypropyl, and the like.
  • sulfonyl whether used alone or linked to other terms such as “alkylsulfonyl”, refers to respectively divalent radicals -S0 2 -.
  • alkylsulfonyl refers to a sulfonyl radical substituted with an alkyl radical, forming an alkylsulfonyl (-SO 2 CH 3 ).
  • sulfamyl refers to a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO 2 NH 2 ).
  • carboxyalkoxy refers to an alkoxy group substituted with one or more carboxy groups, wherein the alkoxy group and the carboxy group are as defined herein.
  • carboxyalkoxy group include carboxymethoxy, carboxy ethoxy, and the like.
  • aralkyl refers to aryl-substituted alkyl radicals.
  • the aralkyl radical includes "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms.
  • the aralkyl radical is "phenylalkylenyl” attached to alkyl portions having one to three carbon atoms.
  • Some non-limiting examples of such radical include benzyl, diphenylmethyl and phenylethyl.
  • the aryl in said aralkyl can be additionally substituted with halo, alkyl, alkoxy, haloalkyl or haloalkoxy.
  • alkylthio refers to radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
  • the alkylthio radical includes lower alkylthio radicals having one to three carbon atoms.
  • Some non-limiting examples of the "alkylthio” include methylthio (CH 3 S-).
  • haloalkylthio refers to radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
  • the haloalkylthio radical includes lower haloalkylthio radicals having one to three carbon atoms.
  • the haloalkylthio group include trifluoromethylthio.
  • alkylamino refers to "N-alkylamino" and "NN-dialkylamino” wherein amino groups are independently substituted with one alkyl radical or with two alkyl radicals, respectively.
  • the alkylamino radical includes "lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom.
  • the alkylamino radical includes lower alkylamino radicals having one to three carbon atoms.
  • alkylamino radical examples include mono or dialkylamino such as N-methylamino, N-ethylamino, NN-dimethylamino, NN-diethylamino, and the like.
  • alkylaminohaloalkoxy refers to a haloalkoxy group substituted with one or more alkylamino groups, wherein the haloalkoxy group and the alkylamino group are as defined herein.
  • alkylaminohaloalkoxy group include methylaminodifluoromethoxy, ethylaminotrifluoromethoxy, and the like.
  • heteroarylamino refers to amino groups substituted with one or two heteroaryl radicals, wherein the heteroaryl radical is as defined herein. Some non-limiting examples of the heteroarylamino group include N-thienylamino. In other embodiments, the "heteroarylamino" radical includes substituted on the heteroaryl ring portion of the radical.
  • heteroarylaliphatic refers to aliphatic groups substituted with one or more heteroaryl radicals, wherein the heteroaryl radical and the aliphatic group are as defined herein.
  • heteroarylaliphatic group include thiophen-2-ylpropenyl, pyridin-4-ylethyl, imidazol-2-methyl, furan-2-ethyl, indole-3 -methyl, and the like.
  • heteroarylalkyl refers to alkyl groups substituted with one or more heteroaryl radicals, wherein the heteroaryl radical and the alkyl group are as defined herein.
  • heteroarylalkyl group include imidazol-2-methyl, furan-2-ethyl, indol-3 -methyl, and the like.
  • heteroarylalkylamino refers to nitrogen-containing heteroarylalkyl radicals attached through a nitrogen atom to other radicals, wherein the heteroarylalkyl radicals is as defined herein.
  • Some non-limiting examples of the heteroarylalkylamino group include pyridin-2-methylamino, thiazol-2-ethylamino, imidazol-2-ethylamino, pyrimidin-2-propylamino, pyrimidin-2-methylamino, and the like.
  • aminoalkyl refers to a linear or branched-alkyl radical having one to ten carbon atoms, substituted with one or more amino radicals.
  • the aminoalkyl radical includes "lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals.
  • Some non-limiting examples of such radical include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • alkylaminoalkyl refers to alkyl radicals substituted with alkylamino radicals.
  • the alkylaminoalkyl radical includes "lower alkylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms.
  • the alkylaminoalkyl radical includes lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms.
  • the suitable alkylaminoalkyl radical include mono and dialkyl substituted, such as N-methylaminomethyl, NN-dimethyl-aminoethyl, NN-diethylaminomethyl, and the like.
  • carboxyalkyl refers to a linear or branched alkyl radical having one to ten carbon atoms substituted with one or more carboxy radicals. Some non-limiting examples of such radical include carboxymethyl, carboxypropyl, and the like.
  • aryloxy refers to optionally substituted aryl radicals, as defined above, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • aryloxy refers to optionally substituted aryl radicals, as defined above, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the rest of the molecule.
  • heteroarylalkoxy refers to oxy-containing heteroarylalkyl radicals attached through an oxygen atom to other radicals, wherein the heteroarylalkyl radical is as defined herein.
  • Some non-limiting examples of such radical include pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, and the like.
  • cycloalkylalkyl refers to cycloalkyl-substituted alkyl radicals. Some non-limiting examples of such radical include cyclohexylmethyl.
  • the cycloalkyl in the radicals may be additionally substituted with halo, alkyl, alkoxy or hydroxy.
  • fused bicyclic refers to unsaturated or saturated fused cyclic system and bridged ring system that is not aromatic.
  • ring Al and ring A2 share a bond that is a alkyl or heteroalkyl chain, wherein j is 0, 1, 2, 3 or 4.
  • Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon).
  • Each cyclic ring in a fused bicyclyl can be either a carbocyclic or a heteroalicyclic.
  • fused bicyclic ring system or bridged ring system include hexahydro-furo[3,2-Z>]furan, 2,3,3a,4,7,7a-hexahydro-l /-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8iz-octahydro- naphthalene.
  • fused heterobicyclyl refers to unsaturated or saturated fused cyclic system and bridged ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). And at least one ring in the system is inclusive of one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members, e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S(3 ⁇ 4, PO or ⁇ (3 ⁇ 4.
  • fused heterobicyclic ring system include hexahydro-furo[3,2-/j]furan,
  • spirocyclyl refers to a ring originating from a particular annular carbon of another ring.
  • ring A and ring B share a carbon atom between the two saturated ring system, which terms as a "spirocyclyl” or "spiro bicyclyl”.
  • Each cyclic ring in the spirocyclyl or spiro bicyclyl can be either a carbocyclic or a heteroalicyclic.
  • radicals include 2,7-diaza-spiro[4.4]non-2-yl, 7-oxo-2-azaspiro[4.5]dec-2-yl, 4-azaspiro[2.4]hept-5-yl, 4-oxaspiro[2.4]hept-5-yl, 5-azaspiro[2.4]hept-5-yl, spiro[2.4]heptyl, spiro[4.4]nonyl,
  • spiro bicyclylene refers to spiro bicyclyl system having two connection points connected to the rest of the molecule, wherein spiro bicyclyl radical is as defined herein.
  • spiro heterobicyclyl refers to a ring originating from a particular annular carbon of another ring.
  • ring A and ring B share a carbon atom between the two saturated ring system, which terms as a "spirocyclyl”.
  • at least one ring in the system is inclusive of one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members, e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , PO or PO 2 .
  • Some non-limiting examples of such radicals include
  • the group derived from a-amino acid refers to an a-amino acid radical derived from an a-amino acid by the removal of one hydroxy in carboxy, which attached to X or X', and the group derived from a-amino acid is optionally substituted with one or more substituents, in some embodiments the substituent is deuterium, F, CI, Br, I, hydroxy, cyano alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or heterocycylcarbonyl.
  • the substituent is deuterium, F, CI, Br, I, hydroxy, cyano alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or heterocycylcarbonyl.
  • a bond drawn from a substituent to the center of one ring within a ring system represents substitution of the substituent (R 5a ) f at any substitutable position on the rings to which it is attached.
  • Figure (a) represents possible substitution in any of the positions on the Wl, W2, and W ring.
  • a dot line drawn together with a bond within a ring system represents either a double bond or a single bond.
  • structure in Figure (c) represents any structures selected from Figure (d).
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the present compounds are within the scope disclosed herein.
  • 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 in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C 1 -C24) 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, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
  • phosphates such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
  • a thorough discussion of prodrugs is provided in T. 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, Nat.Rev. 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.
  • 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, enzyme cleavage, and the like, of the administered compound.
  • the invention includes metabolites of compounds disclosed herein, including compounds produced by a process comprising contacting a compound disclosed herein with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • 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 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often 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.
  • the term "racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • a "pharmaceutically acceptable salt” refers to organic or inorganic salts of a compound disclosed herein.
  • the pharmaceutically acceptable salt is well known in the art. For example, Berge et al., describe pharmaceutically acceptable salt in detail in J. Pharmacol Sci, 1977, 66: 1 -19, which is incorporated herein by reference.
  • Some non-limiting examples of the pharmaceutically 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 or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, sodium malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci_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.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, Ci_ 8 sulfonate or aryl sulfonate.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • Some non-limiting examples of the solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • the term "hydrate” refers to the complex where the solvent molecule is water.
  • 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), benzyloxycarbonyl (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 group include acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Some non-limiting examples of the carboxy-protecting group include -CH 2 CH 2 S0 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl) ethoxymethyl, 2-(/?-toluenesulfonyl)ethyl, 2-(/7-nitrophenylsulfonyl)ethyl, 2-(diphenyl phosphino)-ethyl, nitroethyl, and the like.
  • inhibiting HCV viral protein should be broadly understood, 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 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.
  • fused ring compounds and pharmaceutical formulations thereof, that are useful in inhibiting HCV infection, especially inhibiting the activity of the non-structural 5A (“NS5A”) protein
  • each X 1 and X 2 is independently O, S, NR 6 , or CR 7 R 7a ;
  • Wi is a carbocyclyl or heterocyclyl ring
  • W 2 is a carbocyclyl, heterocyclyl, spiro bicyclyl, spiro heterobicyclyl, fused bicyclyl or fused heterobicyclyl each X, X', Y 1 , Y 2 , Y 1 and Y 2' is independently N or CR 7 ;
  • each a, b, n and p is independently 0, 1, 2 or 3;
  • each c and d is independently 1 or 2;
  • each r is independently 0, 1 or 2;
  • R 13 and R 13a are optionally joined to form a 4-7 membered ring; and each R 13 and R 13a is independently H, deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl; with the proviso that where R 13 and R 13a are bonded to the same nitrogen atom, R 13 and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, or a substituted or unsubstituted spiro bicyclic ring or fused bicyclic ring, wherein each of alkylene, alkenylene, cycloalkylene, heterocycloalkylene, -(CR 8 R 8a ) n -0-(CR 8 R 8a ) p -, -(CR 8 R 8a ) n -N(R 5 )-(CR 8 R 8a )
  • Wi is a C3_g carbocyclyl or C 2 _io heterocyclyl ring
  • W 2 is a C3_g carbocyclyl, C 2 _io heterocyclyl, C 5 _i 2 spiro bicyclyl, C 5 _i 2 spiro heterobicyclyl, C 5 _i 2 fused bicyclyl or C 5 _i 2 fused heterobicyclyl ring.
  • each of A and A' is independently a bond, Ci_ 6 alkylene, C 2 _ 6 alkenylene _ 8 cycloalkylene, C 2 0 heterocycloalkylene, -(CR 8 R 8a ) n -0-(CR 8 R 8a ) p -, -(CR 8 R 8a ) n -N(R 5 )-(CR 8 R 8a ) p -
  • each X 1 and X 2 is independently O, S, NR 6 , or CR 7 R 7a ;
  • each e is independently 0, 1, 2, 3 or 4;
  • each Y 1 and Y 2 is independently N or CR 7 ;
  • each R 7 and R 7a is independently H, deuterium, F, CI, Br, I
  • A' is inde endently selected from
  • each of R 1 , R 2 , R 3 and R 4 is independently H, deuterium, Ci_g alkyl, Ci_g
  • R 1 and R 2 together with X-CH they are attached to, or R 3 and R 4 , together with X'-CH they are attached to, optionally form a 3-8 membered heterocycle, C 5 _i2 fused bicycle, C 5 _i2 fused heterobicycle, C5 2 spiro bicycle or C5 2 spiro heterobicycle.
  • R 1 , R 2 and Y-X-CH together form one of the following monovalent roups:
  • R , R and Y' -X'-CH together form one of the following monovalent roups:
  • the compound may have formula (II):
  • a and A' is independently
  • the compound may have formula (III):
  • the compound may have formula (IV):
  • the compound may have formula (V):
  • the compound may have formula (VI):
  • i 0, 1, 2, 3 or 4;
  • W3 is a C3_io carbocyclyl or C2-10 heterocyclyl ring.
  • the com ound may have formula (VII):
  • the compound may have formula (IX):
  • the com ound may have formula (X):
  • each of Y and Y' is independently a monovalent group derived from an a-amino acid.
  • the a-amino acid is isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophane, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, ⁇ , ⁇ -dimethylglycine, homoserine, norvaline, norleucine, ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosine or hydroxyproline.
  • the a-amino acid is in the D configuration.
  • the a-amino acid is in the L configuration.
  • each of Y and Y' is independently
  • each of Y and Y' is independently -U-(CR 9 R 9a ) t -NR u -(CR 9 R 9a ) t -R 12 .
  • each of Y and Y' is independently -U-(CR 9 R 9a ) r R 12 .
  • each of Y and Y' is independently -[U-(CR 9 R 9a ) t -NR 10 -(CR 9 R 9a ) t ] k -U-(CR 9 R 9a ) t -O-(CR 9 R 9a ) t -R 12 .
  • each of Y and Y' is independently -U-(CR 9 R 9a ) t -NR 10 -(CR 9 R 9a ) t -U-(CR 9 R 9a ) r O-(CR 9 R 9a ) r R 12 .
  • each of Y and Y' is independently -U-(CR 9 R 9a ) r O-(CR 9 R 9a ) t -R 12 .
  • each R 13 and R 13a is independently H, deuterium, Ci_6 alkyl, C 2 _6 heteroalkyl, C340 cycloalkyl, C 2 _io heterocyclyl, C 6 _io aryl, Ci_ 9 heteroaryl, or C 6 _io aryl-Ci_ 6 -alkyl; with the proviso that where R 13 and R 13a are bonded to the same nitrogen atom, R 13 and R 13a , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, or a substituted or unsubstituted spiro bicyclic ring or fused bicyclic ring;
  • each R and R a is independently H, deuterium, methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl.
  • the compound may have formula (XI):
  • each of R and R a is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, Ce-io ary Ci_g heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, Ce-io aryl-Ci_6-alkyl, Ci_g heteroaryl-Ci_ 6 -alkyl, C 2 _io heterocyclyl-Ci_ 6 -alkyl, or C 3 _ 8 cycloalkyl-Ci_ 6 -alkyl.
  • the compound may have formula (XII):
  • each of R 14 and R 14a is independently H, deuterium, Ci_3 hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl, or Ci_9 heteroaryl.
  • the compound may have formula (XIII): (R 5a ')f
  • each of R and R a is independently H, deuterium, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2-6 heteroalkyl, Ce-io heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, Ce-io aryl-Ci_6-alkyl, heteroaryl-Ci_ 6 -alkyl, C 2 _io heterocyclyl-Ci_ 6 -alkyl or C 3 _ 8 cycloalkyl-Ci_ 6 -alkyl; and each n 2 is independently 1, 2, 3 or 4.
  • the compound may have formula (IX'):
  • each of R and R a is independently H, deuterium, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, C2-6 heteroalkyl, Ce-io heteroaryl, C2-10 heterocyclyl, C3_g cycloalkyl, Ce-io aryl-Ci_6-alkyl, heteroaryl-Ci_6-alkyl, C2-10 heterocyclyl-Ci_6-alkyl or C3_g cycloalkyl-Ci_6-alkyl; and each n ! is independently 1, 2, 3 or 4.
  • R 1 , R 2 and N-CH together fonn one of the following divalent groups:
  • R R 4 and N-CH together form one of the following divalent groups:
  • the compound may have formula ( ⁇ ):
  • R 1 , R 2 and N-CH together form one of the following divalent groups:
  • R , R and N-CH together form one of the following divalent groups:
  • the compound may have formula ( ⁇ ):
  • R 1 , R 2 and N-CH together form one of the following divalent groups:
  • R , R and N-CH together form one of the following divalent groups:
  • R 1 , R 2 and N-CH together form one of the following divalent groups:
  • non-limiting examples of compounds disclosed herein, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, are shown in the following:
  • a compound disclosed herein comprises a compound of formula (I), a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate and a pharmaceutically acceptable salt 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 and a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
  • 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.
  • the skills in the art could choose “pharmaceutically acceptable” substance or composition base on the other ingredients and the objects for treatment such as human.
  • the compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be used 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, salicylic acid; a pyranosidyl acid, such as glucuronic acid or galacturonic acid; an alpha hydroxy acid, such as citric acid or tartaric acid; an amino acid, such as aspartic acid or glutamic acid; an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as 7-toluenesulfonic acid or 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, salicylic acid; a pyranosidyl acid, such as glucuronic acid or galacturonic acid
  • 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, 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.
  • 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 great for inhibiting HCV NS5A protein.
  • the pharmaceutical composition disclosed herein further comprises anti-HCV agents.
  • the anti-HCV agent may be any other known anti-HCV agent except the compound described herein, such as 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 inosine5' -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, virazole, bavituximab, CivacirTM, boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP
  • the interferon is interferon a-2b, pegylated interferon a, interferon a-2a, pegylated interferon a-2a, consensus interferon-a, interferon ⁇ or a combination thereof.
  • the pharmaceutical composition disclosed herein further comprises at least one HCV inhibitor.
  • the HCV inhibitor inhibits at least one of HCV replication process and HCV viral protein function.
  • the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress.
  • the HCV viral protein is non- structural protein, or an internal ribosome entry site (IRES) or inosine-5 '-monophosphate dehydrogenase (IMPDH) required in HCV viral replication,.
  • therapeutically effective amounts of a compound of formula(I), as well as pharmaceutically acceptable salts thereof may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical compositions, which include therapeutically effective amounts of compounds of formula(I) or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • 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). When applied to individual active ingredient, administered alone, the term refers to that ingredient alone.
  • 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 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 and 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 of administration by injection are preferred.
  • compositions adapted for oral administration may be presented as discrete units such as capsules of 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, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • Capsules are maded 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 acacia, 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 aliginate, gelating, 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.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, 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 polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • 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 additive such as peppermint oil or natural sweeteners, or 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 of embedding particulate material in polymers, wax, or the like.
  • the compounds of formula(I), and pharmaceutically acceptable salts thereof 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 phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.
  • the compounds of formula(I) and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carriers 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(8-caprolactone), polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly(8-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 Pharmacol. Res., 1986, 3(6), 318.
  • Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • 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, or insufflators.
  • 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 antioxidants, 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 HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress.
  • the HCV viral protein is non- structural protein, or an internal ribosome entry site (IRES) or inosine-5 '-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • IRS internal ribosome entry site
  • IMPDH inosine-5 '-monophosphate dehydrogenase
  • 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 5A (NS5A) protein of HCV.
  • a method which comprises administering the compound or the pharmaceutical composition disclosed herein, further comprising administering to the patient additional anti-HCV agents (combination therapy), wherein the anti-HCV agent is an 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, ribavirin, bavituximab, human hepatitis C immune globulin (CIVACIRTM), boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir
  • the anti-HCV agent is an
  • interferon is interferon a-2b, pegylated interferon a, interferon a-2a, pegylated interferon a-2a, consensus interferon-a, interferon ⁇ or a combination thereof.
  • 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 is administered together with a compound or composition disclosed herein as a single dosage form or separately from the compound or composition as part of a multiple dosage form.
  • the additional anti-HCV agent may be administered at the same time as a 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.
  • a compound or composition can also be administered with one or more other therapeutic agents, as discussed above.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium.
  • Anhydrous dichloromethane and chloroform were obtained by refluxing the solvent with calcium hydride, ethyl acetate, petroleum ether, hexane, NN-dimethylacetamide and NN-dimethylformamide were treated with anhydrous sodium sulfate prior to use.
  • MS data were also determined on an Agilent 6320 series LC-MS spectrometer equipped with G1312A binary pumps, a G1316A TCC (Temperature Control of Column, maintained at 30 °C), a G1329A autosampler and a G1315B DAD detector were used in the analysis.
  • An ESI source was used on the LC-MS spectrometer.
  • MS data were also determined on an Agilent 6120 series LC-MS spectrometer equipped with G1311A Quaternary pump, a G1316A TCC (Temperature Control of Column, maintained at 30 °C), a G1329A autosampler and a G1315D DAD detector were used in the analysis.
  • An ESI source was used on the LC-MS spectrometer.
  • Dess-Martin (Dess-Martin periodinane) ( 1 , 1 , 1 -Triacetoxy)- 1 , 1 -dihydro- l ,2-benziodoxol-3( li/)-one
  • Compound 18 can be prepared by a general synthetic procedure illustrated in Scheme 1, wherein X 5 is F, CI, Br, I or OTf; each of R 5a , R 5a' , f, f , Y 1 , Y 2 , Y 1 ' , Y 2' , Y 4 , Wi, W 2 , R 14 and R 16 is as defined herein; and Pg is an amino -protecting group such as Boc, Fmoc or Cbz.
  • Compound 1 can undergo cyclization to give compound 2 at an elevated temperature in the presence of a base.
  • Compound 2 can react with a reductantto give compound 3.
  • Halogenation of compound 3 with a halogenating agent such as NIS can give compound 4.
  • Compound 11 can be oxidized to give compound 12 with an oxidant such as Dess-Martin Periodinane.
  • Compound 12 can be cyclized in the presence of ammonium hydroxide and glyoxal to give compound 13.
  • Compound 13 can react with NIS to afford di-iodo compound 14.
  • One iodine atom of di-iodo compound 14 can then be removed in the presence of sodium sulfite to provide compound 15.
  • Coupling reaction of compound 15 with compound 9 in the presence of a Pd catalyst can give compound 16.
  • the protecting group Pg of compound 16 can be removed to afford compound 17.
  • Compound 17 can be condensed with compound 17-1 to provide compound 18.
  • Compound 31 can be prepared by a general synthetic procedure illustrated in Scheme 2, wherein each of A 1 , A 2 and A 3 is independently N or CR 7 ; X 5 is F, CI, Br, I or OTf; each of R 5a , R 5a' , f, f , Y 1 , Y 2 , Y 1' , Y 2' , Y 4 , Y 4 , Wi, W 2 , R 14 and R 16 is as defined herein; and Pg is an amino -protecting group such as Boc, Fmoc or Cbz. Condensation of compound 19 with compound 19-1 can give a mixture of compound 20 and compound 21.
  • compound 20 and compound 21 can be cyclized at an elevated temperature in the presence of acetic acid to give compound 22.
  • Compound 22 can further react with Z «s(pinacolato)diboron in the presence of a Pd catalyst to afford compound 23.
  • Compound 5' can react with trifluoromethanesulfonic anhydride to afford compound 24 by base catalysis.
  • Coupling reaction of compound 24 with compound 6 in the presence of a Pd catalyst can give compound 25.
  • Compound 25 can further react with compound 23 in the presence of a Pd catalyst to afford compound 26.
  • Compound 26 can react with trifluoromethanesulfonic anhydride to give compound 27 by base catalysis.
  • Compound 27 can further react with Z «s(pinacolato)diboron in the presence of a Pd catalyst to afford compound 28. Coupling reaction of compound 28 with compound 15 in the presence of a Pd catalyst can give compound 29. The protecting group Pg of compound 29 can be removed to afford compound 30. Compound 30 can be condensed with compound 17-1 to provide compound 31.
  • Compound 35 can be prepared by a general synthetic procedure illustrated in Scheme 3, wherein X' is F, CI, Br, I or OTf; each of R , R , f, f , Y , Y Y , Y , W and Wi is as defined herein.
  • Compound 32 can be transformed to compound 34 by reacting with compound 33 in the presence of an acid. Coupling reaction of compound 34 with compound 6 in the presence of a Pd catalyst can give compound 35.
  • Compound 43 can be prepared by a general synthetic procedure illustrated in Scheme 4, wherein each of R 5a , R 5a' , f, f , Y 1 , Y 2 , Y 1' , Y 2' , Y 4 , W W 2 , R 14 and R 16 is as defined herein; and Pg is an amino -protecting group such as Boc, Fmoc or Cbz.
  • Reaction of compound 36 with TMSA can afford compound 37 by Pd catalysis.
  • Removing TMS from compound 37 can give compound 38 in the presense of a base.
  • Coupling reaction of compound 25 with compound 15 in the presence of a Pd catalyst can give compound 39.
  • Compound 39 can react with trifluoromethanesulfonic anhydride to afford compound 40 by base catalysis. Coupling reaction of compound 40 with compound 38 in the presence of a Pd catalyst can give compound 41. The protecting group Pg of compound 41 can be removed to afford compound 42. Compound 42 can be condensed with compound 17-1 to provide compound 43.
  • Compound 54 can be prepared by the process illustrated in Scheme 5, wherein each of A 1 , A 2 and A 3 is independently N or CR 7 ; each of R 5a , R 5a' , f, f , Y 1 , Y 2 , Y 4 , Y 4 , W 1? R 14 and R 16 is as defined herein; and Pg is an amino-protecting group such as Boc, Fmoc or Cbz.
  • Compound 44 is obtained by Diels-Alder reaction from reacting benzoquinone with a conjugated diene, and then compound 44 is converted to compound 45 by rearrangement in the presence of a base. Compound 45 is reduced under hydrogenation condition in the presence of Pd/C to give compound 46.
  • Compound 46 can react with trifluoromethanesulfonic anhydride to afford compound 47 by base catalysis. Coupling reaction of compound 47 with compound 6 in the presence of a Pd catalyst can give compound 48. Compound 48 can further react with compound 23 in the presence of a Pd catalyst to afford compound 49. Compound 49 can react with trifluoromethanesulfonic anhydride to give compound 50 by base catalysis. Compound 50 can further react with ZHs(pinacolato)diboron in the presence of a Pd catalyst to afford compound 51. Coupling reaction of compound 51 with compound 15 in the presence of a Pd catalyst can give compound 52. The protecting group Pg of compound 52 can be removed to afford compound 53. Compound 53 can be condensed with compound 17-1 to provide compound 54.
  • Compound 61 can be synthesized through the procedure depicted in Scheme 6, wherein each of R , R , f, f, Y , Y and Wi is as defined herein; Pg is an amino-protecting group such as Boc, Fmoc or Cbz.
  • Compound 55 is obtained by Diels-Alder reaction from reacting dimethyl but-2-ynedioate with a conjugated diene.
  • Compound 55 can react with a reducing agent, such as Pd/C through the process of catalytic hydrogenation to afford compound 56.
  • Compound 56 can give compound 57 by base catalysis. Cyclic condensation of compound 57 can yield compound 58 in the presence of a condensation agent.
  • Compound 58 can be transformed to compound 59 by reacting compound 58 with hydrazine hydrate in acetic acid under heating condition.
  • Compound 59 can be converted to compound 60 in the presence of phosphorus oxychloride. Coupling reaction of compound 60 with compound 6 in the presence of a Pd catalyst can give compound 61.
  • Compound 71 can be prepared by a general synthetic procedure illustrated in Scheme 7, wherein X 5 is F, CI, Br, I or OTf; each of w, R 5a , R 5a' , f, f , Y 1 , Y 2 , Y 2' , Y 4 , W, Wi, R 14 and R 16 is as defined herein; and Pg is an amino-protecting group such as Boc, Fmoc or Cbz.
  • Halogenation of compound 62 with a halogenating agent such as NIS can give compound 63. The methyl group of compound 63 can then be removed in the presence of boron tribromide to provide compound 64.
  • Compound 64 can react with trifluoromethanesulfonic anhydride to afford compound 65 by base catalysis. Coupling reaction of compound 6 with compound 65 in the presence of a Pd catalyst can give compound 66. Compound 66 can react with trifluoromethanesulfonic anhydride to afford compound 67 by base catalysis. Compound 67 can further react with ZHs(pinacolato)diboron in the presence of a Pd catalyst to afford compound 68. Coupling reaction of compound 68 with compound 15 in the presence of a Pd catalyst can give compound 69. The protecting group Pg of compound 69 can be removed to afford compound 70. Compound 70 can be condensed with compound 17-1 to provide compound 71.
  • Step 1) the preparation of compound 1-2
  • Step 2) the preparation of compound 1-3
  • Step 5 the preparation of compound 1-6
  • Step 1) the preparation of compound 2-1
  • Step 1) the preparation of compound 3-2
  • Compound 3-5 was dissolved in a solution of NH 3 in MeOH (10 mL, 7 M). The solution was stirred at 0 °C for 0.5 hr and at rt for another 1.0 hr. To the mixture was added glyoxal (1.2 mL, 40%) dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt for 24 hrs and concentrated in vacuo. The residue was dissolved in DCM (100 mL). The solution was washed with water (30 mL x 3) and brine, dried over anhydrous Na 2 S0 4 and concentrated in vacuo.
  • Step 5 the preparation of compound 4-6
  • Step 4 the preparation of compound 5-4 To a solution of compound 5-3 (1.80 g, 4.62 mmol) in DCM (20 mL) was added boron tribromide (2.0 mL, 21.2 mmol) dropwise at -78 °C. At the end of the addition, the mixture was stirred at -78 °C for 10 mins, and then stirred at rt for another 1.0 hr. After the reaction was completed, the mixture was poured slowly into ice water (50 mL).
  • Step 7) the preparation of compound 6-7
  • Step 13) the preparation of compound 6-14
  • diborane 8.3 mL, 1M in THF
  • the mixture was stirred at rt for 2.0 hrs.
  • the mixture was quenched with MeOH (4.0 mL), and concentrated in vacuo.
  • the residue was dissolved in DCM (50 mL).
  • the solution was washed with water (20 mL x 3) and brine, dried over anhydrous Na 2 S0 4 and concentrated in vacuo to give the title compound as colorless slurry (1.01 g, 80%).
  • the compound was characterized by the following spectroscopic data:
  • the compound was characterized by the following spectroscopic data: l n NMR (400 MHz, CDC1 3 ) ⁇ (ppm): 7.64, 7.62 (dd, dd, 1H), 7.56 (s, 1H), 7.54, 7.52 (dd, dd, 1H), 7.48, 7.46 (dd, dd, 1H), 7.43, 7.41 (dd, dd, 1H), 4.85-4.81 (m, 1H), 4.50-4.46 (m, 1H), 3.70-3.65 (m, 4H), 3.08-3.05 (m, 2H), 2.98-2.93 (m, 4H), 2.89-2.86 (m, 2H), 2.54-2.50 (m, 1H), 2.04-1.96 (m, 1H), 1.88-1.79 (m, 5H), 1.73-1.43 (m, 10H), 1.40 (s, 9H), 1.32, 1.29 (q, q, 12H), 1.28-1.19 (m, 2H).
  • Step 22 the preparation of compound 6-24
  • DCM DCM
  • DIPEA DIPEA
  • Step 2 the preparation of compound 7-2
  • TFA 8.0 mL
  • Step 2 the preparation of compound 7-2
  • TFA 8.0 mL
  • the mixture was stirred at 40 °C for 7.0 hrs.
  • the mixture was concentrated in vacuo.
  • the residue was dissolved in EtOAc (50 mL).
  • the resulting mixture was washed with Na 2 C0 3 aqueous solution and brine, dried over anhydrous Na 2 S0 4 and concentrated in vacuo.
  • the compound was characterized by the following spectroscopic data:
  • Step 7) the preparation of compound 7-7
  • pyridine (0.24 mL, 3 mmol) dropwise at 0 °C.
  • trifluoromethanesulfonic anhydride (0.34 mL, 2 mmol) was added.
  • the mixture was stirred at 0 °C for 20 mins and at rt for another 1.0 hrs.
  • the reaction was completed, the mixture was quenched with ice water (10 mL), and then the aqueous layer was extracted with DCM (20 mL x 3).
  • the compound was characterized by the following spectroscopic data: l n NMR (400 MHz, CDC1 3 ) ⁇ (ppm): 7.56 (s, 1H), 7.39, 7.37 (dd, dd, 1H), 7.20, 7.18 (dd, dd, 1H), 7.14, 7.11 (dd, dd, 1H), 6.96, 6.94 (dd, dd, 1H), 4.85-4.81 (m, 1H), 4.50-4.46 (m, 1H), 2.95-2.86 (m, 8H), 2.76-2.68 (m, 2H), 2.55-2.43 (m, 3H), 2.30-2.29 (m, 3H), 2.04-1.83 (m, 7H), 1.74-1.43 (m, 11H), 1.40 (s, 9H).

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Abstract

La présente invention concerne des composés de type noyau spiro, des compositions pharmaceutiques en contenant et leurs utilisations en médecine. Il s'agit de composés de formule (I) ou d'un stéréo-isomère, un isomère géométrique, un tautomère, un N-oxyde, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de ceux-ci. L'invention concerne également des compositions pharmaceutiques contenant lesdits composés de type noyau spiro et l'utilisation desdits composés et/ou des compositions pharmaceutiques en contenant en vue de l'inhibition du processus de réplication du VHC et/ou en vue de l'inhibition de l'action des protéines virales du VHC, ainsi que pour prévenir, prendre en charge, traiter ou atténuer la gravité d'une infection par le VHC ou d'une affection provoquée par le VHC chez un patient. (I)
PCT/CN2013/001466 2012-11-29 2013-11-28 Composés de type noyau spiro utilisables en tant qu'inhibiteurs du virus de l'hépatite c, compositions pharmaceutiques en contenant et leurs utilisations WO2014082381A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104478877A (zh) * 2014-10-31 2015-04-01 广东东阳光药业有限公司 制备雷迪帕韦中间体的方法
JP2017521484A (ja) * 2014-06-06 2017-08-03 愛博新薬研発（上海）有限公司 Ｃ型肝炎を抑制する化合物、医薬組成物及びそれらの応用
US9738629B2 (en) 2014-01-23 2017-08-22 Sunshine Lake Pharma Co., Ltd. Bridged ring compounds as Hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof
US10118920B2 (en) 2015-04-20 2018-11-06 Cellcentric Ltd Isoxazolyl substituted benzimidazoles
US10428065B2 (en) 2015-04-20 2019-10-01 Cellcentric Ltd Isoxazolyl substituted imidazopyridines

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105384792B (zh) * 2014-08-23 2020-12-22 广东东阳光药业有限公司 作为丙型肝炎抑制剂的化合物及其在药物中的应用
CN112843013A (zh) * 2019-11-28 2021-05-28 宜昌东阳光长江药业股份有限公司 治疗丙型肝炎的组合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009047264A1 (fr) * 2007-10-10 2009-04-16 Novartis Ag Composés organiques et leurs utilisations
WO2011079327A1 (fr) * 2009-12-24 2011-06-30 Vertex Pharmaceuticals Incorporated Analogues destinés au traitement ou à la prévention d'infections à flavivirus
WO2012021591A1 (fr) * 2010-08-12 2012-02-16 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101546119B1 (ko) * 2009-05-13 2015-08-20 길리애드 파마셋 엘엘씨 항바이러스 화합물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009047264A1 (fr) * 2007-10-10 2009-04-16 Novartis Ag Composés organiques et leurs utilisations
WO2011079327A1 (fr) * 2009-12-24 2011-06-30 Vertex Pharmaceuticals Incorporated Analogues destinés au traitement ou à la prévention d'infections à flavivirus
WO2012021591A1 (fr) * 2010-08-12 2012-02-16 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9738629B2 (en) 2014-01-23 2017-08-22 Sunshine Lake Pharma Co., Ltd. Bridged ring compounds as Hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof
JP2017521484A (ja) * 2014-06-06 2017-08-03 愛博新薬研発（上海）有限公司 Ｃ型肝炎を抑制する化合物、医薬組成物及びそれらの応用
CN104478877A (zh) * 2014-10-31 2015-04-01 广东东阳光药业有限公司 制备雷迪帕韦中间体的方法
US10118920B2 (en) 2015-04-20 2018-11-06 Cellcentric Ltd Isoxazolyl substituted benzimidazoles
US10428065B2 (en) 2015-04-20 2019-10-01 Cellcentric Ltd Isoxazolyl substituted imidazopyridines

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