WO2009053828A2 - Inhibiteurs p3-hydroxyamino macrocycliques des sérine protéases de l'hépatite c - Google Patents

Inhibiteurs p3-hydroxyamino macrocycliques des sérine protéases de l'hépatite c Download PDF

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Publication number
WO2009053828A2
WO2009053828A2 PCT/IB2008/002839 IB2008002839W WO2009053828A2 WO 2009053828 A2 WO2009053828 A2 WO 2009053828A2 IB 2008002839 W IB2008002839 W IB 2008002839W WO 2009053828 A2 WO2009053828 A2 WO 2009053828A2
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Prior art keywords
substituted
compound
aryl
heteroaryl
cycloalkyl
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PCT/IB2008/002839
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WO2009053828A3 (fr
Inventor
Deqiang Niu
Dong Liu
Yonghua Gai
Yat Sun Or
Zhe Wang
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Enanta Pharmaceuticals, Inc.
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Publication of WO2009053828A2 publication Critical patent/WO2009053828A2/fr
Publication of WO2009053828A3 publication Critical patent/WO2009053828A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic

Definitions

  • the present invention relates to novel macrocycles having activity against the hepatitis C virus (HCV) and useful in the treatment of HCV infections. More particularly, the invention relates to N-hydroxyl macrocyclic compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
  • HCV hepatitis C virus
  • HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world.
  • HIV human immunodeficiency virus
  • anti-HCV therapeutics There are considerable barriers to the development of anti-HCV therapeutics, which include, but are not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, the high incident rate of the virus developing drug -resistant mutants, and the lack of reproducible infectious culture systems and small-animal models for HCV replication and pathogenesis. In a majority of cases, given the mild course of the infection and the complex biology of the liver, careful consideration must be given to antiviral drugs, which are likely to have significant side effects.
  • NS3 hepatitis C non- structural protein-3
  • HCV is a flaviridae type RNA virus.
  • the HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids.
  • the HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions. There are three structural proteins, C, El and E2.
  • the P7 protein is of unknown function and is comprised of a highly variable sequence.
  • NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • the NS3-NS4A protease is responsible for cleaving four sites on the viral polyprotein.
  • the NS3-NS4A cleavage is autocatalytic, occurring in cis.
  • the remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans.
  • NS3 is a serine protease which is structurally classified as a chymotrypsin-like protease. While the NS serine protease possesses proteolytic activity by itself, the HCV protease enzyme is not an efficient enzyme in terms of catalyzing polyprotein cleavage. It has been shown that a central hydrophobic region of the NS4A protein is required for this enhancement. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficacy at all of the sites.
  • a general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus.
  • Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002).
  • Other patent disclosures describing the synthesis of HCV protease inhibitors are: WO 2006/007700; US 2005/0261200; WO 2004/113365; WO 03/099274 (2003); US 2003/0008828;
  • the present invention relates to novel N-hydroxyl macrocyclic compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, methods of using the same to treat hepatitis C infection in a subject in need of such therapy .
  • Macrocyclic compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
  • the present invention further relates to pharmaceutical compositions comprising the aforementioned compounds, salts, esters or prodrugs for administration to a subject suffering from HCV infection.
  • the present invention further features pharmaceutical compositions comprising a compound of the present invention (or a pharmaceutically acceptable salt, ester or prodrug thereof) and another anti-HCV agent, such as interferon (e.g., alpha-interferon, beta-interferon, consensus interferon, pegylated interferon, or albumin or other conjugated interferon), ribavirin, amantadine, another HCV protease inhibitor, or an HCV polymerase, helicase or internal ribosome entry site inhibitor.
  • interferon e.g., alpha-interferon, beta-interferon, consensus interferon, pegylated interferon, or albumin or other conjugated interferon
  • ribavirin e.g., amantadine
  • another HCV protease inhibitor e.g., alpha-interferon, beta-interferon, consensus interferon, pegylated interferon, or albumin or other conjugated interferon
  • the present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient in one embodiment of the present invention there are disclosed compounds represented by Formulas I, or pharmaceutically acceptable salts, esters, or prodrugs thereof:
  • each Ri is independently selected from the group consisting of: (i) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
  • heterocycloalkyl or substituted heterocycloalkyl (ii) heterocycloalkyl or substituted heterocycloalkyl; (iii) -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, or -C 2 -C 8 alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing O, 1 , 2, or 3 heteroatoms selected from O, S or N; -C 3 -C) 2 cycloalkyl, or substituted -C 3 -
  • Ci 2 cycloalkyl -C 3 -Ci 2 cycloalkenyl, or substituted -C 3 -Ci 2 cycloalkenyl;
  • Each R 2 is independently selected from the group consisting of: (i) hydrogen; (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
  • heterocycloalkyl or substituted heterocycloalkyl (iii) heterocycloalkyl or substituted heterocycloalkyl; (iv) -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, or -C 2 -C 8 alkynyl containing O, 1 , 2, or 3 heteroatoms selected from O, S, or N; substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing O, 1 , 2, or 3 heteroatoms selected from O, S or N; -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -
  • Ci 2 cycloalkyl -C 3 -Ci 2 cycloalkenyl, or substituted -C 3 -Ci 2 cycloalkenyl;
  • G is selected from the group consisting of -OH, -NH-S(O) 2 -R 3 , -NH-S(O) 2 NR 4 R 5 ;
  • Each R 3 is independently selected from the group consisting of :
  • heterocycloalkyl or substituted heterocycloalkyl (ii) heterocycloalkyl or substituted heterocycloalkyl; (iii) -C)-C 8 alkyl, -C 2 -C 8 alkenyl, or -C 2 -C 8 alkynyl containing O, 1 , 2, or 3 heteroatoms selected from O, S or N, substituted -C 1 -C 8 alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing O, 1 , 2, or 3 heteroatoms selected from O, S or N; -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - C 12 cycloalkyl; -C 3 -C 12 cycloalkenyl, or substituted -C 3 -C )2 cycloalkenyl;
  • each R 4 and R 5 are independently selected from the group consisting of :
  • heterocycloalkyl or substituted heterocycloalkyl (iii) heterocycloalkyl or substituted heterocycloalkyl; (iv) -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, or -C 2 -C 8 alkynyl containing O, 1 , 2, or 3 heteroatoms selected from O, S, or N; substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S or N; -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkyl; -C 3 -Cj 2 cycloalkenyl, or substituted -C 3 -Ci 2 cycloalkenyl;
  • L is selected from the group consisting of -CH 2 -, -0-, -S-, or -S(O) 2 -;
  • X is absent or is selected from the group consisting of: (1) oxygen; (2) sulfur;
  • Y is absent or is selected from the group consisting of:
  • Z is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, Heterocycloalkyl, substituted heterocycloalkyl;
  • each Zi, Z 2 are independently selected from the group consisting of: i) hydrogen; ii) aryl; iii) substituted aryl; iv) heteroaryl; v) substituted heteroaryl; vi) heterocyclic or substituted heterocyclic; vii)-Ci-C 8 alkyl, -C 2 -C 8 alkenyl, or -C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; viii) substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; ix) -C 3 -Ci 2 cycloalkyl; x) substituted -C 3 -Ci 2 cycloalkyl; xi)
  • a cyclic moiety selected from the group consisting of : substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocylic; substituted or unsubstituted cycloalkyl, cycloalkenyl, and heterocyclic fused with one or more aryl, substituted aryl, heteroaryl; substituted heteroaryl, heterocyclic or substituted heterocyclic;
  • a first embodiment of the invention is a compound represented by Formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment of the invention is a compound represented by Formula II:
  • R 6 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; J is absent or is selected from the group consisting of O, S, NR 5 , CO, (CO)NR 5 , (CO)O, NR 5 (CO), NH(CO)NH, NR 5 SO 2 ; wherein R 5 are as defined in the first embodiment;
  • Each R 7 i, R 72 , R 73 and R 74 is independently selected from the group consisting of : (i) hydrogen;
  • G can be -NH-SO 2 -NR 4 R 5 or -NHSO 2 - R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl, and R 4 and R 5 are each independently selected from hydrogen, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Cj-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, aryl, substituted aryl, heteroaryl, substituted
  • Each R 7J , R 72 , R 73 and R 74 is independently selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -M-R 4 ; wherein M is absent, or O, S, NH, NR 5 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl, wherein R 4 , R 5 are as defined previously.
  • a and B are independently selected from the group consisting of H, R 1 , where Ri is selected from -Ci-C 8 alkyl, -C 2 -Cg alkenyl, or -C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkyl; -C 3 -Ci 2 cycloalkenyl, or substituted -C 3 -Cj 2 cycloalkenyl; wherein R 6 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Cj 2 cycloalkenyl.
  • R 7 i, R 72 , R 73 and R 74 is independently selected from the group consisting of hydrogen, halogen, -NO 2 , -CN.
  • A is H.
  • B is selected from the group consisting of -Ci-C 8 alkyl, substituted -Ci-C 8 alkyl, -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkyl; wherein R 6 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl. J is absent, j is 1 or 2.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 - Ci 2 cycloalkyl.
  • each R 6 , R 7 i, R 72 , R 73 , R 74 and J are as defined previously in Formulae III; and A, B, G, j are as defined in the first embodiment.
  • R 6 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl. J is absent, j is 1 or 2.
  • G can be -NH-SO 2 -NR 4 R 5 or -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Cj 2 cycloalkenyl, substituted -C 3 -Cj 2 cycloalkyl, or substituted -C 3 -Cj 2 cycloalkenyl, and R 4 and R 5 are each independently selected from hydrogen, -Cj-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Cj-C 8 alkyl, substituted -C 2 -C 8 alkeny
  • Each R 7J , R 72 , R 73 and R 74 is independently selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -M-R 4 , wherein M is absent, or O, S, NH, NR 5 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl, wherein R 4 , R 5 are as defined previously.
  • a and B are independently selected from the group consisting of H, Rj, where Ri is selected from -Cj-C 8 alkyl, -C 2 -C 8 alkenyl, or -C 2 -C 8 alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing O, 1, 2, or 3 heteroatoms selected from O, S or N; -C 3 -Cj 2 cycloalkyl, or substituted -C 3 -Cj 2 cycloalkyl; -C 3 -Ci 2 cycloalkenyl, or substituted -C 3 -Cj 2 cycloalkenyl.
  • R 6 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl. J is absent, j is 1 or 2.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Cj 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Cj 2 cycloalkyl, or substituted -C 3 -Cj 2 cycloalkenyl.
  • Each R 71 , R 7 2, R 73 and R 74 is independently selected from the group consisting of hydrogen, halogen, - NO 2 , -CN.
  • A is H.
  • B is selected from the group consisting of -Ci-C 8 alkyl, substituted -Ci-C 8 alkyl, -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • J is absent, j is 1 or 2.
  • G is -NHSO 2 -R 3 , where R 3 is selected from - C 3 -Cj 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • each R 71 , R 72 , R 73 , R 74 are as defined previously in Formulae III; and A, B, GJ are as defined in the first embodiment.
  • G can be -NH-SO 2 -NR 4 R 5 or -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl, and R 4 and R 5 are each independently selected from hydrogen, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 - Cg alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
  • Each R 7 i, R 72 , R 73 and R 74 is independently selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -M-R 4 , wherein M is absent, or O, S, NH, NR 5 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl, wherein R 4 , R 5 are as defined previously.
  • a and B are independently selected from the group consisting of H, Ri, where Ri is selected from -Cj-C 8 alkyl, -C 2 -C 8 alkenyl, or -C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted -Cj-C 8 alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing 0, 1 , 2, or 3 heteroatoms selected from O, S or N; -C 3 -Cj 2 cycloalkyl, or substituted -C 3 -Cn cycloalkyl; -C 3 -Cj 2 cycloalkenyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Cj 2 cycloalkenyl, substituted -C 3 -Cj 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • R 7J , R 72 , R 73 and R 74 is independently selected from the group consisting of hydrogen, halogen, -NO 2 , -CN.
  • A is H.
  • B is selected from the group consisting of -Cj-C 8 alkyl, substituted -Cj-C 8 alkyl, -C 3 -Cj 2 cycloalkyl, or substituted -C 3 -Cj 2 cycloalkyl.
  • j is 1 or 2.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Cj 2 cycloalkyl.
  • Each R 7J , R 72 , R 73 and R 74 is independently selected from the group consisting of hydrogen, halogen.
  • Zl, Z2 and A, B, G, j are as defined in the first embodiment.
  • Zl and Z2 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or Z 1 and Z 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from the group consisting of substituted or unsubstiruted cycloalkyl, cycloalkenyl, or heterocylic, substituted or unsubstituted cycloalkyl, cycloalkenyl, and heterocyclic fused with one or more aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • a and B are independently selected from the group consisting of H, Ri, where Ri is selected from -Ci- C 8 alkyl, -C 2 -C 8 alkenyl, or -C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted -Ci-Cg alkyl, substituted -C 2 -C 8 alkenyl, or substituted -C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; -C 3 -Cj 2 cycloalkyl, or substituted -C 3 -C 12 cycloalkyl; -C 3 -Ci 2 cycloalkenyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • a and B are selected from the group consisting of hydrogen, -Ci-C 8 alkyl, substituted -Ci-C 8 alkyl, -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkyl.
  • j is 1 or 2.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 - Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • Representative compounds of the invention include, but are not limited to, the following compounds (Table 1) according to Formula VII, wherein A, B, Q and G are delineated in Table 1 below for each example:
  • the present invention also features pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • Compounds of the present invention can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection.
  • Other agents to be administered in combination with a compound or combination of compounds of the invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms. These include agents such as host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like), or antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like).
  • host immune modulators for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like
  • cytokines that modulate immune function.
  • vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV.
  • agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of HCV by targeting proteins of the viral genome involved in the viral replication.
  • These agents include but are not limited to other inhibitors of HCV RNA dependent RNA polymerase such as, for example, nucleoside type polymerase inhibitors described in WOOl 90121(A2), or U.S. Pat. No. 6,348,587Bl or WO0160315 or WOO 132153 or non-nucleoside inhibitors such as, for example, benzimidazole polymerase inhibitors described in EP 1162196Al or WO0204425 or inhibitors of HCV protease such as, for example, peptidomimetic type inhibitors such as BILN2061 and the like or inhibitors of HCV helicase.
  • inhibitors of HCV RNA dependent RNA polymerase such as, for example, nucleoside type polymerase inhibitors described in WOOl 90121(A2), or U.S. Pat. No. 6,348,587Bl or WO0160315 or WOO 132153
  • non-nucleoside inhibitors such as, for example,
  • agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of other viruses for co-infected individuals.
  • agents include but are not limited to therapies for disease caused by hepatitis B (HBV) infection such as, for example, adefovir, lamivudine, and tenofovir or therapies for disease caused by human immunodeficiency virus (HIV) infection such as, for example, protease inhibitors: ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir; reverse transcriptase inhibitors: zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125;
  • one aspect of the invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof.
  • Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • Further aspect of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof.
  • Yet another aspect of the invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof.
  • An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L- deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.
  • Example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV).
  • Another aspect of the invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof.
  • HIV human immunodeficiency virus
  • the agent that treats patients for disease caused by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-1 14, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof.
  • HIV human immunodeficiency virus
  • Example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV).
  • HCV hepatitis C virus
  • the present invention provides the use of a compound or a combination of compounds of the invention, or a therapeutically acceptable salt form, stereoisomer, or tautomer, prodrug, salt of a prodrug, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, particularly hepatitis C virus.
  • HCV hepatitis C virus
  • Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated- interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • combination of compound or compounds of the invention, together with one or more agents as defined herein above can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form, prodrug, salt of a prodrug, or combination thereof.
  • combination of therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt form, prodrugs, or salts of the prodrug, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be used for inhibiting the replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition.
  • such compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).
  • further aspect of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt, stereoisomer, or tautomer, prodrug, salt of a prodrug, or combination thereof, one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.
  • HCV hepatitis C virus
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
  • agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.
  • Other anti-HCV agents include those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms or disease.
  • Such agents include but are not limited to immunomodulatory agents, inhibitors of HCV NS3 protease, other inhibitors of HCV polymerase, inhibitors of another target in the HCV life cycle and other anti-HCV agents, including but not limited to ribavirin, amantadine, levovirin and viramidine.
  • Immunomodulatory agents include those agents (compounds or biologicals) that are effective to enhance or potentiate the immune system response in a mammal.
  • Immunomodulatory agents include, but are not limited to, inosine monophosphate dehydrogenase inhibitors such as VX-497 (merimepodib, Vertex Pharmaceuticals), class I interferons, class II interferons, consensus interferons, asialo-interferons pegylated interferons and conjugated interferons, including but not limited to interferons conjugated with other proteins including but not limited to human albumin.
  • Class I interferons are a group of interferons that all bind to receptor type I, including both naturally and synthetically produced class I interferons, while class II interferons all bind to receptor type II.
  • Examples of class I interferons include, but are not limited to, [alpha]-, [beta]-, [delta]-, [omega]-, and [tau] -interferons, while examples of class II interferons include, but are not limited to, [gamma] -interferons.
  • Inhibitors of HCV NS3 protease include agents (compounds or biologicals) that are effective to inhibit the function of HCV NS3 protease in a mammal.
  • Inhibitors of HCV NS3 protease include, but are not limited to, those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO 2005/028501 , WO 2005/070955, WO 2006/000085, WO 2006/007700 and WO 2006/007708 (all by Boehringer Ingelheim), WO 02/060926, WO 03/053349, WO03/099274, WO
  • Inhibitors of HCV polymerase include agents (compounds or biologicals) that are effective to inhibit the function of an HCV polymerase.
  • Such inhibitors include, but are not limited to, non-nucleoside and nucleoside inhibitors of HCV NS5B polymerase.
  • inhibitors of HCV polymerase include but are not limited to those compounds described in: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141 , WO 2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (all by Boehringer Ingelheim), WO 2005/049622 (Japan Tobacco), WO 2005/014543 (Japan Tobacco),WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO 03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (Japan Tobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidates XTL-2125, HCV 796, R-1626 and NM 283.
  • Inhibitors of another target in the HCV life cycle include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of HCV other than by inhibiting the function of the HCV NS3 protease. Such agents may interfere with either host or HCV viral mechanisms necessary for the formation and/or replication of HCV.
  • Inhibitors of another target in the HCV life cycle include, but are not limited to, entry inhibitors, agents that inhibit a target selected from a helicase, a NS2/3 protease and an internal ribosome entry site (IRES) and agents that interfere with the function of other viral targets including but not limited to an NS5A protein and an NS4B protein.
  • a patient may be co-infected with hepatitis C virus and one or more other viruses, including but not limited to human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV).
  • HAV human immunodeficiency virus
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • combination therapy to treat such co-infections by co-administering a compound according to the present invention with at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • the pharmaceutical compositions of the present invention may further comprise another anti-viral, anti-bacterial, anti-fungal or anti-cancer agent, or an immune modulator, or another thearapeutic agent.
  • the present invention includes methods of treating viral infection such as, but not limited to, hepatitis C infections in a subject in need of such treatment by administering to said subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • the present invention includes methods of treating hepatitis C infections in a subject in need of such treatment by administering to said subject an anti-HCV virally effective amount or an inhibitory amount of a pharmaceutical composition of the present invention.
  • An additional embodiment of the present invention includes methods of treating biological samples by contacting the biological samples with the compounds of the present invention.
  • Yet a further aspect of the present invention is a process of making any of the compounds delineated herein employing any of the synthetic means delineated herein.
  • viral infection refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication. Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.
  • HCV hepatitis C virus
  • anti-cancer agent refers to a compound or drug capable of preventing or inhibiting the advancement of cancer.
  • agents include cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines or thioxantheres.
  • anti-fungal agent shall used to describe a compound which may be used to treat a fungus infection other than 3-AP, 3-AMP or prodrugs of 3-AP and 3-AMP according to the present invention.
  • Anti-fungal agents according to the present invention include, for example, terbinafine, fluconazole, itraconazole, posaconazole, clotrimazole, griseofulvin, nystatin, tolnaftate, caspofungin, amphotericin B, liposomal amphotericin B, and amphotericin B lipid complex.
  • antibacterial agent refers to both naturally occurring antibiotics produced by microorganisms to suppress the growth of other microorganisms, and agents synthesized or modified in the laboratory which have either bactericidal or bacteriostatic activity, e.g., ⁇ -lactam antibacterial agents, glycopeptides, macrolides, quinolones, tetracyclines, and aminoglycosides.
  • bacteriostatic it means that the agent essentially stops bacterial cell growth (but does not kill the bacteria); if the agent is bacteriocidal, it means that the agent kills the bacterial cells (and may stop growth before killing the bacteria).
  • immune modulator refers to any substance meant to alter the working of the humoral or cellular immune system of a subject.
  • immune modulators include inhibitors of mast cell-mediated inflammation, interferons, interleukins, prostaglandins, steroids, corticosteroids, colony-stimulating factors, chemotactic factors, etc.
  • compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • inhibitor(s) of other targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • IRS internal ribosome entry site
  • Ci-C 6 alkyl or “Ci-C 8 alkyl,” as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and six, or one and eight carbon atoms, respectively.
  • Ci-C 6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, «-butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of Ci-C 8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, «-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.
  • C 2 -C 6 alkenyl or "C 2 -C 8 alkenyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety has at least one carbon-carbon double bond and contains from two to six, or two to eight carbon atoms, respectively.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1 -methyl -2 -buten-1-yl, heptenyl, octenyl and the like.
  • C 2 -C 6 alkynyl or "C 2 -C 8 alkynyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety has at least one carbon-carbon triple bond and contains from two to six, or two to eight carbon atoms, respectively.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • C 3 -Cg-cycloalkyl or "C 3 -Ci 2 -cycloalkyl,” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom where the saturated carbocyclic ring compound has from 3 ot 8, or from 3 to 12, ring atoms, respectively.
  • C 3 -C 8 - cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C 3 -Ci 2 -cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • C 3 -C 8 -cycloalkenyl or "C 3 -Ci 2 -cycloalkenyl” as used herein, denote a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond by the removal of a single hydrogen atom where the carbocyclic ring compound has from 3 to 8, or from 3 to 12, ring atoms, respectively.
  • C 3 -C 8 -cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C 3 -Ci 2 -cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
  • arylalkyl refers to a Ci-C 3 alkyl or Ci-C 6 alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • heteroaryl refers to a mono-, bi-, or tri-cyclic aromatic radical or ring having from five to ten ring atoms of which at least one ring atom is selected from S, O and N; wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • heteroarylalkyl refers to a Ci-C 3 alkyl or Ci-C 6 alkyl residue residue attached to a heteroaryl ring.
  • heterocycloalkyl refers to a non-aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- or tri-cyclic group fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above rings may be fused to a benzene ring.
  • heterocycloalkyl groups include, but are not limited to, [l,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • substituted refers to independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, -NH 2 , protected amino, -NH -d-C ⁇ -alkyl, -NH -C 2 -C 12 -alkenyl, -NH -C 2 -C 12 -alkenyl, -NH -C 3 -C 12 -cycloalkyl, -NH - aryl, -NH -heteroaryl, -NH -heterocycloalkyl, -dialkylamino, -diarylamino, - diheteroarylamino, -O-Ci-Ci 2 -alkyl, -O-C 2 -Ci 2 -alkeny
  • each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from -F, -Cl, -Br, -I, -OH, -NO 2 , -CN, or -NH 2 .
  • any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group.
  • Aromatic groups can be substituted or unsubstituted.
  • any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can also be an aliphatic group, an alicyclic group or a heterocyclic group.
  • An "aliphatic group” is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
  • alicyclic denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom.
  • Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.
  • heterocyclic refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tri-cyclic group fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above rings may be fused to a benzene ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, [l,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl.
  • Such heterocyclic groups may be further substituted to give substituted heterocyclic.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are intended to be monovalent or divalent.
  • alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene, cycloalkynylene, arylalkylene, hetoerarylalkylene and heterocycloalkylene groups are to be included in the above definitions, and are applicable to provide the formulas herein with proper valency.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxy group so that it will depart during synthetic procedures such as in a substitution or elimination reactions.
  • hydroxy activating group include, but not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
  • activated hydroxy refers to a hydroxy group activated with a hydroxy activating group, as defined above, including mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate groups, for example.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, and methoxymethyl groups.
  • halo and halogen, as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- , or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques, which are known to those skilled in the art.
  • subject refers to a mammal.
  • a subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like.
  • the subject is a human.
  • the subject may be referred to herein as a patient.
  • the term "pharmaceutically acceptable salt” refers to those salts of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the are described generally in T.H. Greene and P. G., S. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert- butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1- dimethyl-2-propenyl, 3-methyl- 3 -butenyl, allyl, benzyl, para- methoxybenzyl
  • Preferred hydroxy protecting groups for the present invention are acetyl (Ac or -C(O)CH 3 ), benzoyl (Bz or -C(O)C 6 H 5 ), and trimethylsilyl (TMS or-Si(CH 3 ) 3 ).Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • salts include, but are not limited to, nontoxic acid addition salts e.g., 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, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • nontoxic acid addition salts e.g., 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, 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, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • 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, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the are described generally in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9- fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
  • ester refers to esters of the compounds formed by the process of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound, which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant invention.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • acyl includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates. Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et al, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
  • protogenic organic solvent or “protic solvent” as used herein, refer to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al, Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art.
  • the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired bridged macrocyclic products of the present invention.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations. VCH Publishers (1989); T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).
  • the compounds of this invention may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
  • the pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra- articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • an inhibitory amount or dose of the compounds of the present invention may range from about 0.1 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • viral infections are treated or prevented in a subject such as a human or lower mammal by administering to the subject an anti-hepatitis C virally effective amount or an inhibitory amount of a compound of the present invention, in such amounts and for such time as is necessary to achieve the desired result.
  • An additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of composition of the present invention in such amounts and for such time as is necessary to achieve the desired result.
  • anti-hepatitis C virally effective amount of a compound of the invention, as used herein, mean a sufficient amount of the compound so as to decrease the viral load in a biological sample or in a subject.
  • an anti-hepatitis C virally effective amount of a compound of this invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.
  • inhibitory amount of a compound of the present invention means a sufficient amount to decrease the hepatitis C viral load in a biological sample or a subject. It is understood that when said inhibitory amount of a compound of the present invention is administered to a subject it will be at a reasonable benefit/risk ratio applicable to any medical treatment as determined by a physician.
  • biological sample(s), means a substance of biological origin intended for administration to a subject. Examples of biological samples include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, and the like; sperm and ova; bone marrow and components thereof; or stem cells.
  • another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease.
  • the subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daily inhibitory dose of the compounds of this invention administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. All publications, patents, published patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety.
  • BME for 2-mercaptoethanol
  • BOP for benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate ;
  • DIBAL-H for diisobutylaluminum hydride
  • DIEA for diisopropyl ethylamine
  • DMAP for N,N-dimethylaminopyridine
  • DME for ethylene glycol dimethyl ether
  • DMEM Dulbecco's Modified Eagles Media
  • DMF for N,N-dimethyl formamide
  • DMSO for dimethylsulfoxide
  • KHMDS potassium bis(trimethylsilyl) amide
  • Ph for phenyl
  • RCM for ring-closing metathesis
  • TFA for trifluoroacetic acid
  • THF for tetrahydrofuran
  • TPP or PPh 3 for triphenylphosphine
  • tBOC or Boc for tert-butyloxy carbonyl
  • the quinoxaline and quinoline analogs of the present invention were prepared via several different synthetic routes.
  • the simplest method, shown in Scheme 2, was to condense lH-quinoxalin-2-one analogs (2-2), or Hydroxyquinolines (2-3), where R6, R71, R72, R73, R74 and J are as defined previously, with key intermediate ⁇ -l by using Mitsunobu conditions to give compound 2-1.
  • Mitsunobu conditions see O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React. 29, 1-162 (1983); D. L. Hughes, Organic Preparations and Procedures Int. 28, 127-164 (1996); and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1, 273-283 (1997).
  • the macrocyclic starting material 3-1 was prepared following Scheme- 1 by starting with the commercially available trans-Boc-hydroxyproline.
  • Compounds of Formula 3-3 (the carbamates) were prepared by reacting 3-1 with CDI and isoindoline derivatives 3-2.
  • Scheme 3 R71, R72, R73 and R74 are as previously defined in Formula I.
  • Scheme 4 illustrates the general synthetic method of the Oximyl macrocyclics 4-3.
  • a suitable leaving group such as, but not limited to OMs, OTs, OTf, bromide, or iodide.
  • Compound (4-1) was subsequently treated with an aryl Oxime (i.e. compound 4-2) at the presence of a base such as, but not limited to K 2 CO 3 , Pyridine, TEA, DBU in a suitable solvent like DMF, DMSO, THF etc. to provide compound 4-3.
  • a base such as, but not limited to K 2 CO 3 , Pyridine, TEA, DBU in a suitable solvent like DMF, DMSO, THF etc.
  • Scheme 5 illustrates the oxidation of the p3 nitrogen.
  • Compound 5-1 was subjected to the Boc deprotection procedure, such as, but not limited to hydrochloric acid, to provide the free amino compound, which reacted with aryl aldehyde under reductive amination condition to give compound 5-2.
  • the p3 nitrogen of formula (5-2) was oxidized with H2O2 using Na2WO4 as catalyst.
  • the resulting compound was hydrolyzed to give free amino alcohol 5-3.
  • Alkylated or acylated with appropriate alkyl halide or activated acyl groups (A-X) followed by hydrolysis to give compounds of formula (5-4).
  • the carboxylic acid was treated with sulfonamide to provide compounds of formula (5-5).
  • Scheme 6 illustrates a method to prepare compounds with substitution groups on the hydroxyl group (i.e. compounds 6-3).
  • Compound 6-1 was prepared by treating the ⁇ - bromocarboxylic acid with the hydroxylamine following the procedure described in the literature (J. Org. Chem. 2000, 65(9), 2684-2695).
  • Compound 6-2 was made by: 1) introducing the Q group into hydroxyl proline following the procedure described in schemes 2-4; 2) hydrolysis of the resulting ester followed by coupling with the Pl aminoacid piece; 3) hydrolysis of the resulting ester followed by coupling with the sulfonamide following the procedures described in schemes 1 and 5.
  • Compounds 6-3 was then made by coupling 6-1 and 6-2 followed by metathesis as described in scheme- 1.
  • MS Found 516.28, M+Na + .
  • Step 2B The title compound of Step 2A (200 mg, 0.28 mmol) was treated with HCl (4 M in dioxane, 3 mL, 12 mmol). The reaction mixture was stirred at room temperature for 1 h until LCMS showed the complete consumption of starting material. The solvent was removed in vacuo. The residue was dissolved in DCM (3 ml). The solvent was removed in vacuo and the residue was used directly in next step.
  • Step 2D To a solution of compound E-2-4 (13 mg) in 3 ml dry DCM was treated with cyclopentyl chloroformate (3 eqiv.) at the presence of /Pr 2 NEt (5 eqiv.). The reaction mixture is stirred for 2 hours. The reaction mixture was diluted with 20 mL EtOAc, and washed with NaHCO 3 aq. (10 ml) and brine (10 ml). The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and then concentrated in vacuo. The residue was dissolved in 3 mL of dioxane and 1 mL of 1 N LiOH aqueous solution, and the resulting mixture was stirred at room temperature for 20 hours.
  • Step 3A Cyclopropylsulfonyl chloride (1.4g, 10 mmol) was dissolved in 0.5 M ammonia in dioxane (50 ml, 25 mmol) at RT. The reaction was kept at RT for 3 days. The large amount of precipitation was filtered and discarded. The clear filtrate was evaporated in vacuo and the white residue was dried on vacuum for 24 hours to give the cyclopropylsulfonamide (0.88 g, 74%).
  • 1 H-NMR 500 MHz, CD 3 Cl): ⁇ 4.62 (2H, s), 2.59 (IH, m), 1.20 (2H, m), 1.02 (2H, m).
  • Step 3B The title compound from Example 2 (2.0 mg) and carbonyldiimidazole (1.0 mg) were dissolved in 0.7 ml anhydrous DMF and the resulting solution was heated to 4O 0 C for 1 hour. Cyclopropylsulfonamide (1.0 mg) was added to the reaction followed by DBU (1.0 mg). The reaction mixture was stirred at 4O 0 C for 10 hour. LCMS showed the formation of the desired product. The reaction was cooled down and 10 ml ethyl acetate was added to the solution. The mixture was washed with saturated aqueous NaHCO 3 solution, water and brine. The organic layer was dried over anhydrous sodium sulfate.
  • the title compound is prepared following the procedures described in Example 2 by using appropriate chloroformate reagents.
  • the title compound is made by reacting the title compound of Example 1 with
  • the title compound is prepared following the procedures described in Example 3 by starting with the title compound of Example 2 and 2-thiophenesulfonamide.
  • the mesylate compound from step 14A (1.0 eqiv.), (1.2 eqiv.), and K2CO3 (2 eqiv.) are dissolved in DMF or DMSO.
  • the resulting reaction mixture is stirred at 40-80°C for 10 hours, cooled and extracted with ethyl acetate.
  • the organic extract is washed with water (2x30ml), and the organic solution is concentrated in vacuo, subsequently purified by column chromatography eluting with 50% ethyl acetate in hexanes to give the product.
  • the title compound is prepared following the procedures described in Example 14 by using appropriate chloroformate reagents.
  • the title compound is prepared following the procedures described in Example 14 by using appropriate chloroformate reagents.
  • the title compound 28-3 is made following the procedures described in Example 14 (steps 14A and 14B).
  • Examples 29 to Examples 32 below are made following the procedures described in Examples 28 and 3 by starting with the approporiate materials.
  • Compound 33-4 was prepared from 1.-3 by the standard hydrolysis reaction as described in the PCT WO 2004113365.
  • Compound 33-6 was prepared from the standard coupling reaction of 33-4 and 33-5 as described in the PCT WO 2004113365.
  • oxim core intermediate 33-8 (0.053mmol) and DIPEA (0.09ml, 0.516mmolmmol) in DMF (1.5ml) at 0 0 C was added HATU (26mg, 0.068mmol). The mixture was stirred at room temperature for 18h, diluted with EtOAc and washed with half-sat.-aq. NaCl four times. The organic phase was dried over anhydrous MgSO 4 , filtered, and then concentrated in vacuo.
  • the compounds of the present invention exhibit potent inhibitory properties against the HCV NS3 protease.
  • the following examples elucidate assays in which the compounds of the present invention are tested for anti-HCV effects.
  • HCV protease activity and inhibition is assayed using an internally quenched fluorogenic substrate.
  • a DABCYL and an EDANS group are attached to opposite ends of a short peptide. Quenching of the EDANS fluorescence by the DABCYL group is relieved upon proteolytic cleavage. Fluorescence was measured with a Molecular Devices Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm.
  • the assay is run in Corning white half-area 96-well plates (VWR 29444-312 [Corning 3693]) with full-length NS3 HCV protease Ib tethered with NS4A cofactor (final enzyme concentration 1 to 15 nM).
  • the assay buffer is complemented with 10 ⁇ M NS4A cofactor Pep 4A (Anaspec 25336 or in-house, MW 1424.8).
  • RET S 1 (Ac- Asp-Glu- ASP(EDANS)-GIu-GIu-AbU-[COO]AIa-SCr-LyS-(D ABCYL)- NH 2 , . AnaSpec 22991, MW 1548.6) is used as the fluorogenic peptide substrate.
  • the assay buffer contained 50 mM Hepes at pH 7.5, 30 mM NaCl and 10 mM BME.
  • the enzyme reaction is followed over a 30 minutes time course at room temperature in the absence and presence of inhibitors.
  • the peptide inhibitors HCV Inh 1 (Anaspec 25345, MW 796.8) Ac-Asp-Glu-Met- Glu-Glu-Cys-OH, [-20 0 C] and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac- Asp-Glu-Dif-Cha-Cys-OH, were used as reference compounds.
  • IC50 values were calculated using XLFit in ActivityBase (IDBS) using equation
  • HCV Cell Based Assay Cell lines, including Huh- 11 -7 or Huh 9-13, harboring HCV replicons (Lohmann, et al Science 285:110-113, 1999) are seeded at 5xlO 3 cells/well in 96 well plates and fed media containing DMEM (high glucose), 10% fetal calf serum, penicillin- streptomycin and non-essential amino acids. Cells are incubated in a 5% CO 2 incubator at 37 0 C. At the end of the incubation period, total RNA is extracted and purified from cells using Qiagen Rneasy 96 Kit (Catalog No. 74182). To amplify the
  • HCV RNA so that sufficient material can be detected by an HCV specific probe (below), primers specific for HCV (below) mediate both the reverse transcription of the HCV RNA and the amplification of the cDNA by polymerase chain reaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (Applied Biosystems catalog no. 4309169).
  • the nucleotide sequences of the RT-PCR primers which are located in the NS5B region of the HCV genome, are the following: HCV Forward primer "RBNS5bfor" 5 'GCTGCGGCCTGTCGAGCT: HCV Reverse primer "RBNS5Brev”: 5 'CAAGGTCGTCTCCGCATAC.
  • Detection of the RT-PCR product is accomplished using the Applied Biosystems (ABI) Prism 7700 Sequence Detection System (SDS) that detects the fluorescence that is emitted when the probe, which is labeled with a fluorescence reporter dye and a quencher dye, is processed during the PCR reaction.
  • SDS Sequence Detection System
  • the increase in the amount of fluorescence is measured during each cycle of PCR and reflects the increasing amount of RT-PCR product.
  • quantification is based on the threshold cycle, where the amplification plot crosses a defined fluorescence threshold. Comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples (ABI User Bulletin #2 December 11, 1997).
  • the data is analyzed using the ABI SDS program version 1.7.
  • the relative template concentration can be converted to RNA copy numbers by employing a standard curve of HCV RNA standards with known copy number (ABI User Bulletin #2 December 11, 1997).
  • the RT reaction is performed at 48 0 C for 30 minutes followed by PCR.
  • Thermal cycler parameters used for the PCR reaction on the ABI Prism 7700 Sequence Detection System are: one cycle at 95 0 C, 10 minutes followed by 35 cycles each of which include one incubation at 95 0 C for 15 seconds and a second incubation for 60
  • RT-PCR is performed on the cellular messenger RNA glyceraldehydes-3 -phosphate dehydrogenase (GAPDH).
  • GAPDH messenger RNA glyceraldehydes-3 -phosphate dehydrogenase
  • the GAPDH copy number is very stable in the cell lines used.
  • GAPDH RT-PCR is performed on the same exact RNA sample from which the HCV copy number is determined.
  • the GAPDH primers and probes, as well as the standards with which to determine copy number, are contained in the ABI Pre- Developed TaqMan Assay Kit (catalog no. 4310884E).
  • the ratio of HCV/GAPDH RNA is used to calculate the activity of compounds evaluated for inhibition of HCV
  • HCV replicon RNA levels in Huh- 1 1-7 or 9-13 cells is determined by comparing the amount of HCV RNA normalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposed to compound versus cells exposed to the 0% inhibition and the 100% inhibition controls.
  • cells are seeded at 5x 10 3 cells/well in a 96 well plate and are incubated either with: 1) media containing 1% DMSO (0% inhibition control), 2) 100 international units, IU/ml Interferon-alpha 2b in media/1 %DMSO or 3) media/1 %DMSO containing a fixed concentration of compound.
  • 96 well plates as described above are then incubated at 37 0 C for 3 days (primary screening assay) or 4 days (IC50 determination). Percent inhibition is defined as:
  • C2 the ratio of HCV RNA copy number/GAPDH RNA copy number in the 100% inhibition control ( 100 IU/ml Interferon-alpha 2b).
  • HCV NS3 proteases of different HCV genotypes including genotypes 1, 2, 3 and 4.
  • Representative compounds were tested in the above assays (Example 122 and Example 123).

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Abstract

La présente invention concerne des composés de formule (I), ou un de leurs sels, esters ou prodromédicaments pharmaceutiquement acceptables : qui inhibent l'activité des sérine protéases, en particulier l'activité de la protéase NS3-NS4A du virus de l'hépatite C (VHC). Par conséquent, les composés de la présente invention perturbent le cycle de vie du virus de l'hépatite C et ils sont également utiles comme agents antiviraux. L'invention concerne en outre des compositions pharmaceutiques comprenant les composés précités et destinées à être administrées à un patient souffrant d'une infection par le VHC, ainsi que des procédés de traitement d'une infection par le VHC chez un patient par administration d'une composition pharmaceutique comprenant les composés de la présente invention.
PCT/IB2008/002839 2007-10-22 2008-10-23 Inhibiteurs p3-hydroxyamino macrocycliques des sérine protéases de l'hépatite c WO2009053828A2 (fr)

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WO2011017389A1 (fr) 2009-08-05 2011-02-10 Idenix Pharmaceuticals, Inc. Inhibiteurs macrocycliques de la sérine protéase macrocyclique utiles contre les infections virales, en particulier le virus de l’hépatite c
WO2011075615A1 (fr) 2009-12-18 2011-06-23 Idenix Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c à base de 5,5-arylène ou hétéroarylène condensé
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WO2012109398A1 (fr) 2011-02-10 2012-08-16 Idenix Pharmaceuticals, Inc. Inhibiteurs macrocycliques de sérine protéase, compositions pharmaceutiques les contenant et leur utilisation pour le traitement des infections par le vhc
WO2012135581A1 (fr) 2011-03-31 2012-10-04 Idenix Pharmaceuticals, Inc. Procédés pour traiter une infection par virus de l'hépatite c pharmacorésistant par un inhibiteur de virus de l'hépatite c consistant en arylènes ou hétéroarylènes fusionnés en 5,5
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US8993595B2 (en) 2009-04-08 2015-03-31 Idenix Pharmaceuticals, Inc. Macrocyclic serine protease inhibitors
EP2899207A1 (fr) 2014-01-28 2015-07-29 Amikana.Biologics Nouveau procédé pour tester l'inhibition de la protéase du HCV
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US9598433B2 (en) 2012-11-02 2017-03-21 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
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