US20100099695A1 - HCV NS3 Protease Inhibitors - Google Patents

HCV NS3 Protease Inhibitors Download PDF

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US20100099695A1
US20100099695A1 US12/447,342 US44734207A US2010099695A1 US 20100099695 A1 US20100099695 A1 US 20100099695A1 US 44734207 A US44734207 A US 44734207A US 2010099695 A1 US2010099695 A1 US 2010099695A1
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alkyl
group
independently selected
heteroaryl
heterocyclyl
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Nigel J. Liverton
Vincenzo Summa
Maria Emilia Di Francesco
Marco Ferrara
Kevin F. Gilbert
Steven Harper
John A. McCauley
Charles A. McIntyre
Alessia Petrocchi
Marco Pompei
Joseph J. Romano
Michael T. Rudd
John W. Butcher
M. Katharine Holloway
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MSD Italia SRL
Merck Sharp and Dohme LLC
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Assigned to MERCK & CO., INC. reassignment MERCK & CO., INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BUTCHER, JOHN W.
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    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/41—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
    • A61K31/4192—1,2,3-Triazoles
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    • 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
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
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    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • 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
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • 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
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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    • 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
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Definitions

  • the present invention relates to macrocyclic compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, the synthesis of such compounds, and the use of such compounds for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • HCV hepatitis C virus
  • HCV infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population.
  • HCV human immunodeficiency virus
  • WHO World Health Organization
  • NS3 protease is located in the N-terminal domain of the NS3 protein. Because it is responsible for an intramolecular cleavage at the NS3/4A site and for downstream intermolecular processing at the NS4A/4B, NS4B/5A and NS5A/5B junctions, the NS3 protease is considered a prime drug target.
  • the present invention relates to novel macrocyclic compounds of formula (I) and/or pharmaceutically acceptable salts or hydrates thereof. These compounds are useful in the inhibition of HCV (hepatitis C virus) NS3 (non-structural 3) protease, the prevention or treatment of one or more of the symptoms of HCV infection, either as compounds or their pharmaceutically acceptable salts or hydrates (when appropriate), or as pharmaceutical composition ingredients.
  • these compounds, salts and hydrates may be the primary active therapeutic agent, and, when appropriate, may be combined with other therapeutic agents including but not limited to other HCV antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention relates to a compound of formula (I) and/or a pharmaceutically acceptable salt or hydrate thereof:
  • heterocyclic rings in which the heterocyclic ring system attaches to Z and X at points that are two independently selected ring atoms that are either two acarbon ring atoms or one carbon ring atom and one nitrogen ring atom, and the heterocyclic ring system is selected from the group consisting of:
  • R 1 is selected from the group consisting of —CO 2 R 10 , —CONR 10 SO 2 R 6 , —CONR 10 SO 2 NR 8 R 9 , tetrazolyl, —CONHP(O)R 11 R 12 , and —P(O)R 11 R 12 ;
  • R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 3 -C 8 cycloalkyl, wherein said R 2 are substituted with 0 to 3 independently selected halogen atoms;
  • R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 )alkyl, phenyl(C 1 -C 8 )alkyl, naphthyl(C 1 -C 8 )alkyl, and Het groups, wherein when R 3 is not H, said R 3 is substituted with 0 to 3 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl
  • Het is selected from the group consisting of substituted and unsubstituted 5- and 6-membered saturated heterocyclic rings having 1 or 2 heteroatoms independently selected from N, O and S, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO
  • R 5 is selected from the group consisting of H, halogen atoms, —OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CN, —CF 3 , —OCF 3 , —C(O)OH, —C(O)CH 3 , —SR 10 , —SO 2 (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 7 ) 2 , phenyl, naphthyl, —O-phenyl, —O-naphthyl, heteroaryl and heterocyclyl groups; wherein:
  • R 5 heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 5 heteroaryl is attached through a ring atom selected from C or N,
  • R 5 heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 5 heterocyclyl is attached through a ring atom selected from C or N, and
  • R 5 heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4 substituents independently selected from the group consisting of halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo(C 1 -C 6 alkoxy), —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , —C(O)R 10
  • R 6 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
  • R 6 are substituted with 0 to 2 independently selected W substituents
  • each R 6 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 6 heteroaryl is attached through a ring atom selected from C or N, and
  • each R 6 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 6 heterocyclyl is attached through a ring atom selected from C or N;
  • Y is selected from the group consisting of —C(O)—, —SO 2 —, —OC(O)—, —C(O)N(D)L- and -LN(D)C(O)—. and -LN(D)C(O)—, where
  • D is selected from the group consisting of H, C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups,
  • L is selected from the group consisting of a direct bond, -G-(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-G-, -G-(C 1 -C 6 alkenylene)-, and —(C 1 -C 6 alkenylene)-G-, groups, where said G is selected from the group consisting of a direct bond, —O—, —N— and —S—, said alkylene and alkenylene groups are substituted with 0 to 4 substituents E independently selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkenyl groups, and
  • said D and E may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from N, O and S;
  • Z is selected from the group consisting of —C(O)— and a direct bond
  • M is selected from the group consisting of C 1 -C 12 alkylenes and C 2 -C 12 alkenylenes, wherein said M is substituted with 0 to 2 substituents F independently selected from the group consisting of C 1 -C 8 alkyl, ⁇ CH 2 , C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), and aryl(C 1 -C 8 alkyl), and 2 adjacent substituents F may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and one or more adjacent substituents F may be taken together and/or with an adjacent D or E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
  • X is selected from the group consisting of —O—, —CH 2 O—, —NHC(O)O—, —CH 2 NHC(O)O—, —C ⁇ CCH 2 O—, —C(O)O—, —(CH 2 ) 3 O—, —OC(O)NH—, —(CH 2 ) 2 C(O)NH—, —C(O)NH— and a direct bond;
  • each R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 5 )alkyl, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
  • R 7 when R 7 is not H, said R 7 are substituted with 0 to 2 W substituents,
  • each R 7 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 7 heteroaryl is attached through a ring atom selected from C or N, and
  • each R 7 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 7 heterocyclyl is attached through a ring atom selected from C or N, and
  • R 7 may be taken together with the atom to which it is attached and a second R 7 substituent to form a 4- to 7-membered heterocyclic ring;
  • each W is independently selected from the group consisting of halogen atoms, —OR 10 , C 1 -C 6 alkyl, —CN, —CF 3 , —NO 2 , —SR 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —C(O)R 10 , —N(R 10 )C(O)R 10 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 1 -C 6 haloalkyl, —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), halo(C 1 -C 6 alkoxy), —NR 10 SO 2 R 10 , —SO 2 N(R 10 ) 2 , —NHCOOR 10 ,
  • said W heteroaryl is selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said W heteroaryl is attached through a ring atom selected from C or N,
  • said W heterocyclyl is selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said W heterocyclyl is attached through a ring atom selected from C or N;
  • R 8 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclic, heteroaryl(C 1 -C 4 alkyl), and heterocyclyl(C 1 -C 8 alkyl) groups, wherein
  • R 8 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 ,
  • each R 8 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 8 heteroaryl is attached through a ring atom selected from C or N,
  • each R 8 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 8 heterocyclyl is attached through a ring atom selected from C or N, and
  • R 8 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
  • R 9 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 8 alkyl), C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, phenyl, naphthyl, phenyl(C 1 -C 4 )alkyl, naphthyl(C 1 -C 4 )alkyl, heteroaryl, heterocyclyl, heteroaryl(C 1 -C 4 alkyl), or heterocyclyl(C 1 -C 8 alkyl) groups, wherein
  • R 9 are substituted with 0 to 4 substituents selected from the group consisting of phenyl, naphthyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, C 1 -C 6 alkyl, halo(C 1 -C 6 alkoxy), halogen atoms, —OR 10 , —SR 10 , —N(R 10 ) 2 , —N(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, —C(O)R 10 , C 1 -C 6 haloalkyl, —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 ,
  • each R 9 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 9 heteroaryl is attached through a ring atom selected from C or N,
  • each R 9 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 9 heterocyclyl is attached through a ring atom selected from C or N, and
  • R 9 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S, and
  • R 8 and R 9 may be taken together, with the N to which they are attached, to form a 4- to 8-membered monocyclic ring containing 0 to 2 additional heteroatoms independently selected from N, O and S;
  • each R 10 is independently selected from the group consisting of H and C 1 -C 6 alkyl
  • each R 11 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 alkenyl, —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , —N(R 10 )(R 13 ), —R 14 , and —N(R 10 SO 2 R 6 ;
  • each R 12 is independently selected from the group consisting of —OR 13 , —N(R 10 )—V—CO 2 R 10 , —O—V—CO 2 R 10 , —S—V—CO 2 R 10 , and —N(R 10 )(R 13 );
  • R 11 and R 12 may be taken together, with the phosphorus atom to which they are attached, to form a 5- to 7-membered monocyclic ring;
  • each V is independently selected from the group consisting of —CH(R 15 )— and —(C 1 -C 4 alkylene)-CH(R 15 )—;
  • each R 13 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein
  • R 13 when R 13 is not H, said R 13 is substituted with 0 to 2 substituents independently selected from the group consisting of phenyl, naphthyl, phenyl(C 1 -C 4 alkyl), naphthyl(C 1 -C 4 alkyl), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 4 alkyl), heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl, heterocyclyl(C 1 -C 4 alkyl), C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)
  • each R 13 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 13 heteroaryl is attached through a ring atom selected from C or N,
  • each R 13 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 13 heterocyclyl is attached through a ring atom selected from C or N, and
  • R 13 may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S;
  • R 14 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
  • each R 14 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 14 heteroaryl is attached through a ring atom selected from C or N, and
  • R 14 phenyl, naphthyl or heteroaryl may be substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ; and
  • each R 15 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenyl, naphthyl, heteroaryl, and heterocyclyl groups, wherein
  • R 15 are substituted with 0 to 2 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen atoms, —OC(O)OR 6 , —OC(O)R 6 , —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —NO 2 , —CN, —CF 3 , —SO 2 (C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —NR 10 SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NHCOOR 6 , —NHCOR 6 , —NHCONHR 6 , —CO 2 R 10 , and —C(O)N(R 10 ) 2 ,
  • each R 15 heteroaryl is independently selected from the group consisting of 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, and said R 15 heteroaryl is attached through a ring atom selected from C or N,
  • each R 15 heterocyclyl is independently selected from the group consisting of 5- to 7-membered saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and said R 15 heterocyclyl is attached through a ring atom selected from C or N, and
  • R 15 2 adjacent substituents of said R 15 are optionally taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S.
  • the present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions.
  • the present invention further includes methods of treating or reducing the likelihood or severity of one or more symptoms of HCV infection.
  • the present invention includes compounds of formula (I) above, and pharmaceutically acceptable salts and/or hydrates thereof. These compounds and their pharmaceutically acceptable salts and/or hydrates are HCV protease inhibitors (e.g., HCV NS3 protease inhibitors).
  • heterocyclic rings in which the heterocyclic ring system attaches to Z and X at points that are two independently selected ring atoms that are either two acarbon ring atoms or one carbon ring atom and one nitrogen ring atom, and the heterocyclic ring system is selected from the group consisting of:
  • W, R 5 or oxo is substituted with 0 to 4 independently selected substituents W, R 5 or oxo; wherein for stable heterocyclic rings containing S or N, the heterocyclic ring is unsubstituted at the S or N atom or is substituted at the S or N atom by oxo; wherein said W and R 5 substitutions are located on one or more ring atoms selected from C and N; and provided that the 10-membered unsaturated bicyclic ring is not quinoline, quinazoline or isoquinoline.
  • a moiety selected from the group consisting of —Br, —Cl, —CN, phenyl, —O-phenyl, —OCF 3 , —OCH 3 , —C(O)OH, —CH 3 and —C(O)CH 3 .
  • R 5 is independently selected from the group consisting of H, —Br, —Cl, —CN, phenyl, —O-phenyl, —OCF 3 , —OCH 3 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, —CF 3 , —C(O)OH, and —C(O)CH 3 .
  • R 1 is —CO 2 R 10 or —CONR 10 SO 2 R 6 .
  • R 1 is —C(O)OH or —C(O)NHSO 2 cyclopropyl.
  • R 2 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl. In a preferred group of this embodiment, R 2 is —CH ⁇ CH 2 , —CH 2 CH 3 , or —CH 2 CH ⁇ CH 2 .
  • R 3 is H, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
  • R 3 is H, —C(CH 3 ) 3 , —(CH 2 ) 3 CH 3 , cyclohexyl, or —CH(CH 3 ) 2 .
  • M is C 1 -C 12 alkylene or C 2 -C 12 alkenylene, wherein said M is substituted with 0 to 2 substituents F selected from the group consisting of C 1 -C 8 alkyl, and ⁇ CH 2 .
  • M is selected from the group consisting of —CH ⁇ CH(CH 2 ) 5 , —(CH 2 ) 7 —, —CH 2 CH ⁇ CH(CH 2 ) 4 —, —(CH 2 ) 6 —, —CH ⁇ CH(CH 2 ) 4 —, —CH ⁇ CH(CH 2 ) 3 C(CH 3 ) 2 CH 2 —, —CH ⁇ CH(CH 2 ) 3 —, —(CH 2 ) 5 —, —CH ⁇ CH(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 3 —, —CH ⁇ CH(CH 2 ) 2 C(CH 3 ) 2 CH 2 —, —(CH 2 ) 4 C(CH 3 ) 2 CH 2 —, —C( ⁇ CH 2 )(CH 2 ) 5 —, —C( ⁇ CH 2 )(CH 2 ) 3 —, —CH 2 CH ⁇ CH(CH
  • Y is selected from —C(O)N(D)L- and -LN(D)C(O)—.
  • one or more substituents F are taken together and/or with one or more substituents chosen from substituents D and E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O and S. That is, two adjacent substituents F may be taken together to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S, or one substituent F may be taken together with an adjacent D or E to form a 3- to 6-membered ring containing 0 to 3 heteroatoms independently selected from the group consisting of N, O and S.
  • the compound of the invention is selected from the exemplary species depicted in Examples 1 through 109 shown below.
  • composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • a pharmaceutical combination which is (i) a compound of formula (I) and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of formula (I) and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV NS3 protease, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • (j) A method of inhibiting HCV NS3 protease in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • (k) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • the present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV NS3 protease, or (b) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
  • alkyl refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range.
  • C 1-6 alkyl refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • C 1-4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. Alkyl groups may be substituted as indicated.
  • halogenated refers to a group or molecule in which a hydrogen atom has been replaced by a halogen.
  • haloalkyl refers to a halogenated alkyl group.
  • halogen refers to atoms of fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • alkoxy refers to an “alkyl-O—” group. Alkoxy groups may be substituted as indicated.
  • alkylene refers to any linear or branched chain alkylene group (or alternatively “alkanediyl”) having a number of carbon atoms in the specified range.
  • —C 1-6 alkylene- refers to any of the C 1 to C 6 linear or branched alkylenes.
  • a class of alkylenes of particular interest with respect to the invention is —(CH 2 ) 1-6 —, and sub-classes of particular interest include —(CH 2 ) 1-4 —, —(CH 2 ) 1-3 —, —(CH 2 ) 1-2 —, and —CH 2 —.
  • alkylene —CH(CH 3 )— is also of interest.
  • Alkylene groups may be substituted as indicated.
  • cycloalkyl refers to any cyclic ring of an alkane or alkene having a number of carbon atoms in the specified range.
  • C 3-8 cycloalkyl (or “C 3 -C 8 cycloalkyl”) refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkoxy refers to a “cycloalkyl-O—” group. Cycloalkyl groups may be substituted as indicated.
  • Carbocycle (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C 3 to C 8 monocyclic, saturated or unsaturated ring or (ii) a C 7 to C 12 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. Carbocycle groups may be substituted as indicated, for example with C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, halogen, —NH 2 or —OH.
  • the carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
  • the fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term “fused bicyclic carbocycle” generally refers to a C 7 to C 10 bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system.
  • a fused bicyclic carbocycle in which both rings are saturated is a saturated bicyclic ring system.
  • Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
  • a fused bicyclic carbocycle in which one or both rings are unsaturated is an unsaturated bicyclic ring system.
  • a subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include
  • Depicted ring systems include, where appropriate, an indication of the variable to which a particular ring atom is attached.
  • the indole structure For example, the indole structure
  • variable X shows ring atom 2 is directly attached to variable X and ring atom 4 is directly attached to variable Z.
  • Variable R 5 is shown as a floating variable which can be attached to any ring atom, provided that such attachment results in formation of a stable ring.
  • aryl refers to aromatic mono- and poly-carbocyclic ring systems, also referred to as “arenes,” wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond.
  • Suitable aryl groups include phenyl, naphthyl, and biphenylenyl. Aryl groups may be substituted as indicated.
  • heterocycle broadly refers to (i) a stable 4- to 8-membered, saturated or unsaturated monocyclic ring, (ii) a stable 7- to 12-membered bicyclic ring system, or (iii) a stable 11- to 15-membered tricyclic ring system, wherein each ring in (ii) and (iii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring, bicyclic ring system or tricyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) independently selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the bicyclic and tricyclic ring systems typically contain at least two carbon atoms
  • heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
  • Heterocycle groups may be substituted as indicated, and unless otherwise specified, the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • saturated heterocyclics form a subset of the heterocycles.
  • saturated heterocyclic generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated.
  • saturated heterocyclic ring refers to a 4- to 8-membered saturated monocyclic ring, a stable 7- to 12-membered bicyclic ring system, or a stable 11- to 15-membered tricyclic ring system, which consists of carbon atoms and one or more heteroatoms independently selected from N, O and S.
  • Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).
  • unsaturated heterocyclics form another subset of the heterocycles.
  • the term “unsaturated heterocyclic” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is not saturated, i.e., such rings are either unsaturated or partially unsaturated.
  • the term “heteroaromatic ring” refers a stable 5- or 6-membered monocyclic aromatic ring, a stable 7- to 12-membered bicyclic ring system, or a stable 11- to 15-membered tricyclic ring system, which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • heteroaromatic rings containing at least one nitrogen atom e.g., pyridine
  • substitutions can be those resulting in N-oxide formation.
  • Representative examples of heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl
  • phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.
  • alkyl, cycloalkyl, aryl and heterocycle groups are unsubstituted or substituted.
  • the substituents are selected from the group which includes, but is not limited to, halo, C 1 -C 20 alkyl, —CF 3 , —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NO 2 , oxo, —CN, —N 3 , —OH, —O(C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 0 -C 6 alkyl) S(O) 0-2 —, aryl-S(O) 0-2 —, (C 0 -C 6 alkyl)S(O) 0-2 (C 0 -C -C
  • heteroaryl ring described as containing from “1 to 3 heteroatoms” means the ring can contain 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. The oxidized forms of the heteroatoms N and S are also included within the scope of the present invention.
  • any variable e.g., R 7 and R 10
  • its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaromatic ring, or a saturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound.
  • a “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).
  • certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
  • a reference to a compound of formula (I) is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.
  • the compounds of the present inventions are useful in the inhibition of HCV protease (e.g., HCV NS3 protease) and the treatment of HCV infection and/or reduction of the likelihood or severity of symptoms of HCV infection.
  • HCV protease e.g., HCV NS3 protease
  • the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds.
  • the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HCV protease, e.g., by competitive inhibition.
  • the compounds of this invention may be commercial products to be sold for these purposes.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
  • Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
  • suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • suitable pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention mean providing the compound or a prodrug of the compound to the individual in need of treatment.
  • administration and its variants are each understood to include concurrent and sequential provision of the compound or salt (or hydrate) and other agents.
  • prodrug is intended to encompass an inactive drug form or compound that is converted into an active drug form or compound by the action of enzymes, chemicals or metabolic processes in the body of an individual to whom it is administered.
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
  • pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the term “effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the effective amount is a “therapeutically effective amount” for the alleviation of one or more symptoms of the disease or condition being treated.
  • the effective amount is a “prophylactically effective amount” for reduction of the severity or likelihood of one or more symptoms of the disease or condition.
  • the term also includes herein the amount of active compound sufficient to inhibit HCV NS3 protease and thereby elicit the response being sought (i.e., an “inhibition effective amount”).
  • the compounds of the present invention can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation (such as in a spray form), or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
  • Liquid preparations suitable for oral administration e.g., suspensions, syrups, elixirs and the like
  • Solid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.
  • Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids.
  • injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 th edition (ed. A. R. Gennaro, Mack Publishing Co., 1990).
  • the compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
  • mammal e.g., human
  • One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses.
  • Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses.
  • the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the present invention also relates to a method of inhibiting HCV NS3 protease, inhibiting HCV replication, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent.
  • Such therapeutic agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha-1, R7025 (an enhanced interferon (Roche)), interferon- ⁇ , interferon- ⁇ , pegylated interferon- ⁇ (peginterferon- ⁇ ), a combination of interferon- ⁇ and ribavirin, a combination of peginterferon- ⁇ and ribavirin, a combination of interferon- ⁇ and levovirin, and a combination of peginterferon- ⁇ and levovirin.
  • Interferon- ⁇ includes, but is not limited to, recombinant interferon- ⁇ 2a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, N.J.), pegylated interferon- ⁇ 2a (PegasysTM), interferon- ⁇ 2b (such as Intron-A interferon available from Schering Corp., Kenilworth, N.J.), pegylated interferon- ⁇ 2b (PegIntronTM), a recombinant consensus interferon (such as interferon alphacon-1), albuferon (interferon- ⁇ bound to human serum albumin (Human Genome Sciences)), and a purified interferon- ⁇ product.
  • interferon- ⁇ 2a such as Roferon interferon available from Hoffmann-LaRoche, Nutley, N.J.
  • Pegylated interferon- ⁇ 2a such as Intron-A interferon available from Schering Corp., Kenilworth, N.J
  • Amgen's recombinant consensus interferon has the brand name Infergen®.
  • Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin.
  • Viramidine represents an analog of ribavirin disclosed in International Patent Application Publication WO 01/60379.
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease.
  • HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication.
  • Both substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in International Patent Application Publications WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888,
  • Ribavirin, levovirin, and viramidine may exert their anti-HCV effects by modulating intracellular pools of guanine nucleotides via inhibition of the intracellular enzyme inosine monophosphate dehydrogenase (IMPDH).
  • IMPDH inosine monophosphate dehydrogenase
  • Ribavirin is readily phosphorylated intracellularly and the monophosphate derivative is an inhibitor of IMPDH.
  • inhibition of IMPDH represents another useful target for the discovery of inhibitors of HCV replication.
  • the compounds of the present invention may also be administered in combination with an inhibitor of IMPDH, such as VX-497, which is disclosed in International Patent Application Publications WO 97/41211 and WO 01/00622; another IMPDH inhibitor, such as that disclosed in WO 00/25780; or mycophenolate mofetil. See A. C. Allison and E. M. Eugui, 44 (Suppl.) Agents Action 165 (1993).
  • an inhibitor of IMPDH such as VX-497, which is disclosed in International Patent Application Publications WO 97/41211 and WO 01/00622
  • another IMPDH inhibitor such as that disclosed in WO 00/25780
  • mycophenolate mofetil See A. C. Allison and E. M. Eugui, 44 (Suppl.) Agents Action 165 (1993).
  • the compounds of the present invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane).
  • amantadine 1-aminoadamantane
  • the compounds of the present invention may also be administered in combination with the antiviral agent polymerase inhibitor R7128 (Roche).
  • the compounds of the present invention may also be combined for the treatment of HCV infection with antiviral 2′-C-branched ribonucleosides disclosed in R. E. Harry-O'Kuru et al., 62 J. Org. Chem. 1754-59 (1997); M. S. Wolfe et al., 36 Tet. Lett. 7611-14 (1995); U.S. Pat. No. 3,480,613; and International Patent Application Publications WO 01/90121, WO 01/92282, WO 02/32920, WO 04/002999, WO 04/003000 and WO 04/002422; the contents of each of which are incorporated by reference in their entirety.
  • Such 2′-C-branched ribonucleosides include, but are not limited to, 2′-C-methyl-cytidine, 2′-C-methyl-uridine, 2′-C-methyl-adenosine, 2′-C-methyl-guanosine, and 9-(2-C-methyl- ⁇ -D-ribofuranosyl)-2,6-diaminopurine, and the corresponding amino acid ester of the ribose C-2′, C-3′, and C-5′ hydroxyls and the corresponding optionally substituted cyclic 1,3-propanediol esters of the 5′-phosphate derivatives.
  • the compounds of the present invention may also be combined for the treatment of HCV infection with other nucleosides having anti-HCV properties, such as those disclosed in International Patent Application Publications WO 02/51425, assigned to Mitsubishi Pharma Corp.; WO 01/79246, WO 02/32920, WO 02/48165 and WO2005/003147 (including R1656, (2′R)-2′-deoxy-2′-fluoro-2′-C-methylcytidine, shown as compounds 3-6 on page 77); WO 01/68663; WO 99/43691; WO 02/18404 and WO2006/021341, and U.S.
  • nucleosides having anti-HCV properties such as those disclosed in International Patent Application Publications WO 02/51425, assigned to Mitsubishi Pharma Corp.; WO 01/79246, WO 02/32920, WO 02/48165 and WO2005/003147 (including R1656, (2′R)-2′-deoxy-2′-fluoro-2′-C-methylcytidine, shown as
  • Patent Application Publication US2005/0038240 including 4′-azido nucleosides such as R1626, 4′-azidocytidine; U.S. Patent Application Publications US2002/0019363, US2003/0236216, US2004/0006007 and US2004/0063658; and International Patent Application Publications WO 02/100415, WO 03/026589, WO 03/026675, WO 03/093290, WO 04/011478, WO 04/013300 and WO 04/028481; the content of each is incorporated herein by reference in its entirety.
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase.
  • HCV NS5B polymerase inhibitors that may be used as combination therapy include, but are not limited to, those disclosed in International Patent Application Publications WO 02/057287, WO 02/057425, WO 03/068244, WO 2004/000858, WO 04/003138 and WO 2004/007512; U.S. Pat. No. 6,777,392 and U.S. Patent Application Publication US2004/0067901; the content of each is incorporated herein by reference in its entirety.
  • Other such HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2′-F-2′-beta-methylcytidine (see also WO 2005/003147).
  • nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS3 protease inhibitors are selected from the following compounds: 4-amino-7-(2-C-methyl- ⁇ -D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine; 4-amino-7-(2-C-methyl- ⁇ -D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidine; 4-methylamino-7-(2-C-methyl- ⁇ -D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidine; 4-dimethylamino-7-(2-C-methyl- ⁇ -D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidine; 4-cyclopropylamino-7-(2-C-methyl- ⁇ -D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine; 4-amino-7-
  • the compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in International Patent Application Publications WO 01/77091; WO 01/47883; WO 02/04425; WO 02/06246; WO 02/20497; WO 2005/016927 (in particular JTK003); the content of each is incorporated herein by reference in its entirety; and HCV-796 (Viropharma Inc.).
  • non-nucleoside inhibitors of HCV polymerase such as those disclosed in International Patent Application Publications WO 01/77091; WO 01/47883; WO 02/04425; WO 02/06246; WO 02/20497; WO 2005/016927 (in particular JTK003); the content of each is incorporated herein by reference in its entirety; and HCV-796 (Viropharma Inc.).
  • non-nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS3 protease inhibitors are selected from the following compounds: 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid; 14-cyclohexyl-6-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid; 14-cyclohexyl
  • HCV NS3 protease inhibitory activity of the present compounds may be tested using assays known in the art.
  • One such assay is HCV NS3 protease time-resolved fluorescence (TRF) assay as described below and in International Patent Application Publication WO2006/102087.
  • TRF time-resolved fluorescence
  • Other examples of such assays are described in e.g., International Patent Application Publication WO2005/046712.
  • HCV NS3 protease inhibitors, such as those described herein have a Ki less than 50 ⁇ M, such as less than 10 ⁇ M, and less than 100 nM. Ki is determined by an NS3 protease assay.
  • the assay is performed in a final volume of 100 ⁇ l in assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15% glycerol, 0.15% Triton X-100, 10 mM DTT, and 0.1% PEG 8000.
  • NS3 protease is pre-incubated with various concentrations of inhibitors in DMSO for 30 minutes. The reaction is initiated by adding the TRF peptide substrate (final concentration 100 nM).
  • NS3 mediated hydrolysis of the substrate is quenched after 1 hour at room temperature with 100 ⁇ l of 500 mM MES, pH 5.5.
  • Product fluorescence is detected using either a VICTOR V2 or F USION fluorophotometer (Perkin Elmer Life and Analytical Sciences) with excitation at 340 nm and emission at 615 nm with a 400 ⁇ s delay. Testing concentrations of different enzyme forms are selected to result in a signal to background ratio (SB) of 10-30.
  • SB signal to background ratio
  • IC 50 values are derived using a standard four-parameter fit to the data.
  • K values are derived from IC 50 values using the following formula,
  • [S] is the concentration of substrate peptide in the reaction and K M is the Michaelis constant. See P. Gallinari et al., 38 B IOCHEM. 5620-32 (1999); P. Gallinari et al., 72 J. V IROL. 6758-69 (1998); M. Taliani et al., 240 A NAL . B IOCHEM. 60-67 (1996).
  • the present invention also includes processes for making compounds of formula (I).
  • the compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. The following reaction schemes and examples serve only to illustrate the invention and its practice.
  • Olefin metathesis catalysts include the following Ruthenium based species: F. Miller et al., 118 J. A M . C HEM . S OC. 9606 (1996); G. Kingsbury et al., 121 J. Am. Chem. Soc. 791 (1999); H. Scholl et al., 1 O RG . L ETT. 953 (1999); U.S. Patent Application Publication US2002/0107138; K. Furstner et al., 64 J. O RG . C HEM. 8275 (1999).
  • the utility of these catalysts in ring closing metathesis is well known in the literature (e.g. Trnka and Grubbs, 34 A CC . C HEM . R ES. 18 (2001).
  • Step 1 t-Butyl ((1R,2R)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-ethylcyclopropyl)carbamate
  • a hydrogenation vessel was charged with a MeOH (1000 mL) slurry of t-butyl ((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)carbamate (164 g, 0.50 mol) (U.S. Pat. No. 6,995,174) and 5% Ru/C (dry, 7.5 wt %, 12.4 g) and stirred.
  • the vessel was placed under N 2 (20 psi) and vented to atmospheric pressure (3 ⁇ ) to remove residual oxygen.
  • the vessel was then placed under H 2 (50 psi). After 20 hours, the vessel was vented to atmospheric pressure.
  • the reaction slurry was then transferred out of the reaction vessel and filtered through SOLKA FLOK (34 g, wetted with 100 mL MeOH) to yield a clear, light brown solution.
  • the SOLKA FLOK was rinsed with MeOH (200 mL ⁇ 2).
  • the combined MeOH solutions were concentrated under reduced pressure to yield crude product as a white solid (153 g).
  • the crude product was slurried in EtOAc (800 mL), warmed to 40° C. and aged 30 minutes.
  • the solution was then seeded, aged 30 minutes, and heptane (500 mL) was added via addition funnel over 30 minutes.
  • the partially crystallized solid was cooled to RT and aged overnight, after which additional heptane (500 mL) was added.
  • Step 2 (1R,2R)-1-Amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamide hydrochloride (Intermediate A3)
  • AMANO LIPASE PS (7.0 g, 64.7 mmol) was added to a solution of trans-2-pent-4-en-1-ylcyclopentanol (10.0 g, 64.7 mmol) and vinyl acetate (19.5 g, 129.4 mmol) in Et 2 O (275 mL). The mixture was stirred for 16 hours, then filtered through CELITE. The filtrate was concentrated to afford a residue that was purified by column chromatography on SiO 2 (gradient elution, 0-100% Et 2 O/petroleum ether) to afford in the first fractions the title compound (5.43 g, 43%).
  • DIPEA 9.85 g, 76.2 mmol
  • 4-penten-1-ol 7.22 g, 83.9 mmol
  • triphosgene 11.3 g, 38.1 mmol
  • the resulting white suspension was stirred for 5 minutes at 0° C., then allowed to warm to 25° C. over 1 hour.
  • the suspension was cooled to 0° C. with an ice bath, and 1N NaOH (76.2 mL) and L-t-butylglycine (10.0 g, 76.2 mmol) were added.
  • the reaction mixture was warmed to 25° C. and stirred for 18 hours.
  • Step 2 N- ⁇ [(1,1-Dimethylpent-4-en-1-yl)amino]carbonyl ⁇ -L-valine (Intermediate B20)
  • Step 3 (2S)-Cyclopentyl[( ⁇ [(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy ⁇ carbonyl)amino]acetic acid
  • Step 2 Trimethyl ⁇ [(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy ⁇ silane
  • Step 4 Methyl 3-methyl-N-( ⁇ [(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy ⁇ carbonyl)-L-valinate and methyl 3-methyl-N-( ⁇ [(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy ⁇ carbonyl)-L-valinate
  • Step 5 3-Methyl-N-( ⁇ [(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy ⁇ carbonyl)-L-valine or 3-methyl-N-( ⁇ [(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy ⁇ carbonyl)-L-valine
  • Dess-Martin periodinane (6.27 g, 14.78 mmol) was added to a stirred solution of Intermediate A7 (2.00 g, 12.97 mmol) in DCM (120 ml). The mixture was stirred RT for 1 hour, and then diluted with DCM and washed several times with a 1:1 mixture of saturated NaHCO 3(aq.) and Na 2 S 2 O 3(aq.) (1 M). The mixture was then with H 2 O and brine. The organics were dried over Na 2 SO 4 and concentrated to give a residue that was dissolved in pentane, filtered, and concentrated. The resulting oil was used directly in the subsequent reaction.
  • Step 3 (2S)-cyclopentyl[( ⁇ [(1R,2R)-1-methyl-2-pent-4-en-1-ylcyclopentyl]oxy ⁇ carbonyl)amino]acetic acid
  • Step 4 Methyl(2S)-( ⁇ [(3R)(3S)-3-(allyloxy)piperidin-1-yl]carbonyl ⁇ amino)(cyclohexyl)acetate
  • Step 5 (2)-( ⁇ [(3R)(3S)-3-(Allyloxy)piperidin-1-yl]carbonyl ⁇ amino)(cyclohexyl)acetic acid (Intermediate B29)
  • Step 6 (2S)-( ⁇ [(3S) or (3R)-3-(Allyloxy)piperidin-1-yl]carbonyl ⁇ amino)(cyclohexyl)acetic acid (Intermediate B29a) (2S)-( ⁇ [(3R) and (3S)-3-(allyloxy)piperidin-1-yl]carbonyl ⁇ amino)(cyclohexyl)acetic acid (Intermediate B29b)
  • the title compound is commercially available.
  • the foam was dissolved in THF (230 mL) and treated with 1N NaOH (170 mL, 0.170 mol) at 40° C. for 2 hours.
  • the mixture was cooled to 0° C., aged for 30 minutes and filtered.
  • the cake was washed with H 2 O (40 mL) and dried under vacuum to give 7.94 g. LRMS (M+H)+ 241.
  • the reaction mixture was quenched by pouring into 300 mL of 1N HCl and 200 mL of EtOAc/Et 2 O while stirring. The mixture was extracted with EtOAc (2 ⁇ ), and the organics were combined washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified on SiO 2 (gradient elution, 0-25% EtOAc/hexanes) to yield the di-ester as a clear oil. To a solution of the di-ester (3.4 g, 9.97 mmol) in MeOH (25 mL), 3N NaOH (16.6 mL, 49.8 mmol) was added, and the mixture was warmed to 50° C. for 4 hours.
  • Step 3 1-t-Butyl 2-methyl(2S,4R)-4-[(3-bromo-7-methoxyquinolin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
  • Step 4 1-t-Butyl 2-methyl(2S,4R)-4-[(7-methoxy-3-vinylquinolin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
  • Intermediate C12 can be prepared according to the procedure described for Intermediate C11 using 3-bromoquinoline instead of 3-bromo-7-methoxyquinoline in Step 1.
  • 6-Methoxyquinolin-2(1H)-one (6.81 g, 38.9 mmol) was carefully added to POBr 3 (18.9 g, 66.1 mmol) at 60° C. and the resulting solution was stirred at 140° C. for 2.5 hours. The reaction mixture was cooled and poured onto crushed ice, and the solid was collected by filtration. Purification of this material on SiO 2 (gradient elution, 5-12% EtOAc/petroleum ether) afforded the title compound (4.57 g, 49.3%) as a solid. LCMS (ES+) m/z 238, 240 (M+H) + .
  • n-BuLi (1.6 N in hexanes, 14.4 mL, 23.0 mmol) was added at ⁇ 78° C. to a solution of 2,2,6,6-tetramethylpiperidine (3.11 g, 22.05 mmol) in anhydrous THF (59 mL), and the mixture was then warmed to 0° C. for 30 minutes. The mixture was cooled back to ⁇ 78° C. and treated with a solution of 2-bromo-6-methoxyquinoline (4.57 g, 19.17 mmol) in THF (14 mL).
  • Step 4 1-t-Butyl 2-methyl(2S,4R)-4-[(2-bromo-6-methoxyquinolin-3-yl)oxy]pyrrolidine-1,2-dicarboxylate
  • Step 5 (2S,4R)-4-[(2-bromo-6-methoxyquinolin-3-yl)oxy]-2-(methoxycarbonyl)pyrrolidinium chloride
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4-[(3-chloroquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4-[(3-but-3-en-1-yl-7-methoxyquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
  • Intermediate C19 can be prepared according to the procedure described for Intermediate C14, Steps 4-5, using 3-bromo-2-naphthol instead of 2-bromo-6-methoxyquinolin-3-ol.
  • Step 4 (2S,4R)-4-[(3-Bromo-1,8-naphthyridin-2-yl)oxy]-2-(methoxycarbonyl)pyrrolidinium chloride
  • Intermediate C20 can be prepared according to the procedure described for Intermediate C14, Steps 4-5, using 3-bromo-1,8-naphthyridin-2-ol instead of 2-bromo-6-methoxyquinolin-3-ol.
  • Intermediate C21 can be prepared according to the procedure described for Intermediate C20, using 4-aminonicotinaldehyde instead of 2-aminonicotinaldehyde.
  • LCMS (ES) m/z 353.5 (M+H) + .
  • Intermediate C22 can be prepared according to the procedure described for Intermediate C20, using 5-aminonicotinaldehyde instead of 2-aminonicotinaldehyde.
  • Intermediate C22 can be prepared according to the procedure described for Intermediate C20, using 3-aminonicotinaldehyde instead of 2-aminonicotinaldehyde.
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4-[(3-bromopyridin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
  • Step 4 Methyl N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-[(3-vinylpyridin-2-yl)oxy]-L-prolinate
  • Step 5 Methyl (2R,4S,7S,16E)-7-t-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxylate
  • Step 6 (2R,4S,7S,16E)-7-t-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxylic acid
  • Step 7 (2R,4S,7S,16E)-7-t-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxamide
  • Step 1 Methyl (2R,4S,7S)-7-t-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxylate
  • Step 2 (2R,4S,7S)-7-t-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxylic acid
  • Step 3 (2R,4S,7S)-7-t-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxamide
  • Step 2 To a solution of a portion of the product from Example 3, Step 2 (95 mg, 0.206 mmol) in DMF (2.2 mL), Intermediate A3 (66 mg, 0.247 mmol), DIEA (0.144 mL, 0.82 mmol), and HATU (102 mg, 0.268 mmol) were added. After 1 hour, the mixture was partitioned between EtOAc and 1N HCl. The organic layer was separated, dried over MgSO 4 , and the solvent was removed in vacuo. The crude product was purified on SiO 2 (gradient elution, 0-70% EtOAc/hexanes) to yield 106 mg of the title compound. LRMS ESI + (M+H) + 676.4.
  • Step 3 Methyl N-[(hex-5-en-1-yloxy)carbonyl]-L-norleucyl-(4R)-4-(2-allylphenoxy)-L-prolinate
  • Step 4 Methyl (2R,4S,7S,15E/Z)-7-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,17-decahydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxylate
  • Step 5 Methyl (2R,4S,7S)-7-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxylate
  • Step 6 (2R,4S,7S)-7-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxylic acid
  • Step 7 (1R,2S)-1-( ⁇ [(2R,4S,7S)-7-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecin-4-yl]carbonyl ⁇ amino)-2-vinylcyclopropanecarboxylic acid
  • 2,548,704 B1 14 (2R,4S,7S)-7-butyl-N- ((1R,2S)-1- ⁇ [(cyclopropylsulfonyl) amino]carbonyl ⁇ -2- vinylcyclopropyl)-6,9- dioxo-19-phenyl- 3,4,6,7,8,9,11,12,13,14,15, 16-dodecahydro-2H-2,5- methano-1,10,5,8- benzodioxadiaza cyclooctadecine-4- carboxamide 735.5 See Example 6 2-allyl-5- phenyl- phenol. Ref: U.S. Pat. No.
  • 2,548,704 B1 16 (8R,10S,13S,22E)-13-t- butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl) amino]carbonyl ⁇ -2- vinylcyclopropyl)-12,15- dioxo-9,10,12,13,14,15, 18,19,20,21-decahydro- 8H,17H,8,11- methanonaphtho[2,1-k] [1,10,3,6] dioxadiaza cyclononadecine-10- carboxamide 721.4 See Example 1 1-bromo- 2- naphthol B11 17 (2R,4S,7S,16E)-7-t-butyl- N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl) amino]carbonyl ⁇ -2- vinylcyclopropyl)-6,9- dioxo-3,4,6,7,8,9,12, 13,14,15
  • Step 1 14-Butyl 2-methyl(2S,4R)-4-[(3-iodobenzyl)oxy]pyrrolidine-1,2-dicarboxylate
  • Step 4 Methyl N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucyl-(4R)-4-[(3-vinylbenzyl)oxy]-L-prolinate
  • Step 5 Methyl (4R,6S,9S,16E)-9-butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),16,18,20-tetraene-6-carboxylate
  • Step 6 (4R,6S,9S,16E)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]-tricosa-1(22),16,18,20-tetraene-6-carboxylic acid
  • Step 7 (1R,2S)-1-( ⁇ [(4R,6S,9S,16E)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),16,18,20-tetraen-6-yl]carbonyl ⁇ amino)-2-vinylcyclopropanecarboxylic acid
  • Step 2 2-(Trimethylsilyl)ethyl N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucyl-(4R)-4-[(3-vinylbenzyl)oxy]-L-prolinate
  • Step 3 2-(Trimethylsilyl)ethyl (4R,6S,9S,16E)-9-butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),16,18,20-tetraene-6-carboxylate
  • Step 4 2-(Trimethylsilyl)ethyl (4R,6S,9S)-9-butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),18,20-triene-6-carboxylate
  • Step 5 (4R,6S,9S)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),18,20-triene-6-carboxylic acid
  • Step 6 (1R,2S)-1-( ⁇ [(4R,6S,9S)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),18,20-trien-6-yl]carbonyl ⁇ amino)-2-vinylcyclopropanecarboxylic acid
  • Step 1 Methyl (4R,6S,9S,16E)-9-isopropyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),16,18,20-tetraene-6-carboxylate
  • Step 2 Methyl (4R,6S,9S)-9-isopropyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),18,20-triene-6-carboxylate
  • Step 3 (4R,6S,9S)—N-((1R,2S)-1- ⁇ [(Cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-9-isopropyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),18,20-triene-6-carboxamide
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4-( ⁇ [(3-bromophenyl)amino]carbonyl ⁇ oxy)pyrrolidine-1,2-dicarboxylate
  • Step 2 (5R,7S,10S)-10-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-3,9,12-trioxo-4,13-dioxa-2,8,11-triazatricyclo[17.3.1.1 5,8 ]tetracosa-1(23),19,21-triene-7-carboxamide
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4-( ⁇ [(3-bromobenzyl)amino]carbonyl ⁇ oxy)pyrrolidine-1,2-dicarboxylate
  • Step 2 (6R,8S,11S,18E)-N-((1R,2S)-1- ⁇ [(Cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-11-isopropyl-4,10,13-trioxo-5,14-dioxa-3,9,12-triazatricyclo[18.3.1.1 6,9 ]pentacosa-1(24),18,20,22-tetraene-8-carboxamide
  • Step 2 1-t-Butyl 2-[2-(trimethylsilyl)ethyl](2S,4R)-4- ⁇ [(4-bromo-1-methyl-1H-indol-2-yl)carbonyl]oxy ⁇ pyrrolidine-1,2-dicarboxylate
  • Step 3 2-[2-(Trimethylsilyl)ethyl](2S,4R)-4- ⁇ [(4-bromo-1-methyl-1H-indol-2-yl)carbonyl]oxy ⁇ pyrrolidine-2-carboxylate
  • Step 4 2-(Trimethylsilyl)ethyl N- ⁇ [(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl ⁇ -3-methyl-L-valyl-(4R)-4- ⁇ [(4-bromo-1-methyl-1H-indol-2-yl)carbonyl]oxy ⁇ -L-prolinate
  • Step 5 2-(Trimethylsilyl)ethyl N- ⁇ [(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl ⁇ -3-methyl-L-valyl-(4R)-4- ⁇ [(1-methyl-4-vinyl-1H-indol-2-yl)carbonyl]oxy ⁇ -L-prolinate
  • N 2 was bubbled through a solution of the compound from Step 4 (400 mg, 0.54 mmol) in PhMe (8 mL) for 30 minutes, and then tributyl(vinyl)tin (0.19 mL, 0.65 mmol) and tetrakistriphenylphosphine palladium (63 mg, 0.05 mmol) were added.
  • the reaction solution was heated to reflux for 2 hours, concentrated, and purified the resulting residue on SiO 2 (gradient elution, 0-1.5% acetone/DCM) to yield the title compound as a yellow oil (320 mg).
  • LRMS (M+H) + Calcd. 682; found 682.
  • Step 6 2-(Trimethylsilyl)ethyl(5R,7S)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclohenicosine-7-carboxylate
  • Step 7 (5R,7S)—N-((1R,2S)-1- ⁇ [(Cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclohenicosine-7-carboxamide
  • Step 1 2-(Trimethylsilyl)ethyl (5R,7S)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclohenicosine-7-carboxylate
  • Step 2 (5R,7S)—N-((1R,2S)-1- ⁇ [(Cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclohenicosine-7-carboxamide
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4-[(1-bromo-2-naphthyl)oxy]pyrrolidine-1,2-dicarboxylate
  • Step 3 Methyl (4R)-4-[(1-bromo-2-naphthyl)oxy]-1-((2S)-2-cyclohexyl-2- ⁇ [(hept-6-en-1-yloxy)carbonyl]amino ⁇ acetyl)-L-prolinate
  • Step 4 Methyl (10S,13S,15R)-10-cyclohexyl-1-methylene-8,11-dioxo-1,2,3,4,5,6,8,9,10,11,14,15-dodecahydro-13H-12,15-methanonaphtho[2,1-k][ 1 , 10 , 3 , 6 ]dioxadiazacyclooctadecine-13-carboxylate
  • Step 5 (10S,13S,15R)-10-Cyclohexyl-1-methylene-8,11-dioxo-1,2,3,4,5,6,8,9,10,11,14,15-dodecahydro-13H-12,15-methanonaphtho[2,1-k][1,10,3,6]dioxadiazacyclooctadecine-13-carboxylic acid
  • Step 6 (10S,13S,15R)-10-Cyclohexyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-1-methylene-8,11-dioxo-1,2,3,4,5,6,8,9,10,11,14,15-dodecahydro-13H-12,15-methanonaphtho[2,1-k][1,10,3,6]dioxadiazacyclooctadecine-13-carboxamide
  • Step 1 Methyl N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucyl-(4R)-4-[(3,5-dibromobenzyl)oxy]-L-prolinate
  • Step 2 Methyl (4R,6S,9S)-19-bromo-9-butyl-16-methylene-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[15.3.1.1 4,7 ]docosa-1(21),17,19-triene-6-carboxylate.
  • Step 3 (4R,6S,9S)-19-Bromo-9-butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-16-methylene-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[15.3.1.1 4,7 ]docosa-1(21),17,19-triene-6-carboxamide
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4-(prop-2-yn-1-yloxy)pyrrolidine-1,2-dicarboxylate
  • Step 2 1-t-Butyl 2-methyl(2S,4R)-4- ⁇ [3-(2-bromophenyl)prop-2-yn-1-yl]oxy ⁇ pyrrolidine-1,2-dicarboxylate
  • Step 4 Methyl N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4- ⁇ [3-(2-bromophenyl) prop-2-yn-1-yl]oxy ⁇ -L-prolinate
  • Step 5 Methyl N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4- ⁇ [3-(2-vinylphenyl) prop-2-yn-1-yl]oxy ⁇ -L-prolinate
  • Step 6 Methyl N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4- ⁇ [3-(2-vinylphenyl) prop-2-yn-1-yl]oxy ⁇ -L-prolinate-dicobalt hexacarbonyl complex
  • Step 7 Methyl (5R,7S,10S,19E)-10-t-butyl-9,12-dioxo-1,2-didehydro-3,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosine-7-carboxylate-dicobalt hexacarbonyl complex
  • Step 8 Methyl (5R,7S,10S,19E)-10-t-butyl-9,12-dioxo-1,2-didehydro-3,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosine-7-carboxylate
  • Step 9 ((5R,7S,10S,19E)-10-t-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-9,12-dioxo-1,2-didehydro-3,6,7,9,10,11,12,14,15,16,17,18-dodecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosine-7-carboxamide
  • Step 1 Methyl (5R,7S,10S)-10-t-butyl-9,12-dioxo-1,2,3,6,7,9,10,11,12,14,15,16,17,18,19,20-hexadecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosine-7-carboxylate
  • Step 2 (5R,7S,10S)-10-t-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-9,12-dioxo-1,2,3,6,7,9,10,11,12,14,15,16,17,18,19,20-hexadecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosine-7-carboxamide
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4-( ⁇ 1-[5-(acetyloxy)pentyl]-1H-1,2,3-triazol-4-yl ⁇ methoxy)pyrrolidine-1,2-dicarboxylate
  • Step 2 1-t-Butyl 2-methyl(2S,4R)-4-[(1- ⁇ 5-[( ⁇ [(1S)-1-(t-butoxycarbonyl)-2-methylpropyl]amino ⁇ carbonyl)oxy]pentyl ⁇ -1H-1,2,3-triazol-4-yl)methoxy]pyrrolidine-1,2-dicarboxylate
  • Step 3 Methyl (1R,16S,19S)-16-isopropyl-14,17-dioxo-2,13-dioxa-5,6,7,15,18-pentaazatricyclo[16.2.1.1 4,7 ]docosa-4(22),5-diene-19-carboxylate
  • Step 4 (1R,2S)-1-( ⁇ [(1R,16S,19S)-16-Isopropyl-14,17-dioxo-2,13-dioxa-5,6,7,15,18-pentaazatricyclo[16.2.1.1 4,7 ]docosa-4(22),5-dien-19-yl]carbonyl ⁇ amino)-2-vinylcyclopropanecarboxylic acid
  • Step 1 Methyl (4R,6S,9S,16E)-9-t-butyl-8,11-dioxo-3,12-dioxa-7,10,22-triazatricyclo[16.3.1.1 4,7 ]tricosa-1(22),16,18,20-tetraene-6-carboxylate
  • Step 2 Methyl (4R,6S,9S)-9-t-butyl-8,11-dioxo-3,12-dioxa-7,10,22-triazatricyclo[16.3.1.1 4,7 ]tricosane-6-carboxylate
  • Step 3 (4R,6S,9S)-9-t-Butyl-6- ⁇ [((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)amino]carbonyl ⁇ -8,11-dioxo-3,12-dioxa-7,10-diaza-22-azoniatricyclo[16.3.1.1 4,7 ]tricosane trifluoroacetate
  • Step 2 Methyl N-[(hex-5-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-( ⁇ [(2-allylcyclohexyl)oxy]carbonyl ⁇ amino)-L-prolinate
  • Step 3 Methyl (4R,6S,9S,17E/Z)-9-t-butyl-2,8,11-trioxo-3,4,5,6,8,9,10,11,14,15,16,19,19a,20,21,22,23,23a-octadecahydro-2H,13H-4,7-methano-1,12,3,7,10-benzodioxatriazacyclohenicosine-6-carboxylate
  • Step 4 Methyl (4R,6S,9S)-9-t-butyl-2,8,11-trioxoicosahydro-2H,13H-4,7-methano-1,12,3,7,10-benzodioxatriazacyclohenicosine-6-carboxylate
  • Step 5 (4R,6S,9S,19aS,23aS)-9-t-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-2,8,11-trioxoicosahydro-2H,13H-4,7-methano-1,12,3,7,10-benzodioxatriazacyclohenicosine-6-carboxamide
  • Step 3 t-Butyl N-( ⁇ [5-(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentyl]oxy ⁇ carbonyl)-L-valinate
  • Step 4 Methyl (4R)-4-[(2- ⁇ 5-[( ⁇ [(1S)-1-(t-butoxycarbonyl)-2-methylpropyl]amino ⁇ carbonyl) oxy]pentanoyl ⁇ -1,2,3,4-tetrahydroisoquinolin-8-yl)oxy]-L-prolinate hydrochloride
  • Step 5 (2R,4S,7S)-7-Isopropyl-6,9,15-trioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H,17H-16,18-ethano-2,5-methano-1,10,5,8,16-benzodioxatriazacyclononadecine-4-carboxylic acid
  • Step 6 (1R,2S)-1-( ⁇ [(2R,4S,7S)-7-Isopropyl-6,9,15-trioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H,17H-16,18-ethano-2,5-methano-1,10,5,8,16-benzodioxatriazacyclononadecin-4-yl]carbonyl ⁇ amino)-2-vinylcyclopropanecarboxylic acid
  • Step 1 N- ⁇ [(5- ⁇ 1-[(3R,5S)-14-Butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl]-1H-1,2,3-triazol-4-yl]pentyl)oxy ⁇ carbonyl ⁇ -3-methyl-L-valine
  • Step 2 N- ⁇ [(5- ⁇ 1-[(3R,5S)-5-(Methoxycarbonyl)pyrrolidin-3-yl]-1H-1,2,3-triazol-4-yl ⁇ pentyl)oxy]carbonyl ⁇ -3-methyl-L-valine hydrochloride
  • Step 3 Methyl (2R,4S,7S)-7-t-butyl-6,9-dioxo-10-oxa-1,5,8,17,18-pentaazatricyclo[14.2.1.1 2,5 ]icosa-16(19),17-diene-4-carboxylate
  • Step 4 (2R,4S,7S)-7-t-Butyl-N-((1R,2R)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-ethylcyclopropyl)-6,9-dioxo-10-oxa-1,5,8,17,18-pentaazatricyclo[14.2.1.1 2,5 ]icosa-16(19),17-diene-4-carboxamide
  • Step 3 1-t-Butyl 2-[2-(trimethylsilyl)ethyl](2S,4R)-4- ⁇ [(1-allyl-1H-indol-2-yl)carbonyl]oxy ⁇ pyrrolidine-1,2-dicarboxylate
  • Step 4 2-(Trimethylsilyl)ethyl N-[(pent-4-en-1-yloxy)carbonyl]-L-valyl-(4R)-4- ⁇ [(1-allyl-1H-indol-2-yl)carbonyl]oxy ⁇ -L-prolinate
  • Step 5 2-(Trimethylsilyl)ethyl (3R,5S,8S,15E)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,17-decahydro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]indole-5-carboxylate
  • Step 6 (3R,5S,8S)—N-((1R,2S)-1- ⁇ [(Cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,17-decahydro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]indole-5-carboxamide
  • Step 1 2-(Trimethylsilyl)ethyl (3R,5S,8S)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,15,16,17-dodecahydro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]indole-5-carboxylate
  • Step 2 (3R,5S,8S)—N-((1R,2S)-1- ⁇ [(Cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,15,16,17-dodecahydro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]indole-5-carboxamide
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4- ⁇ [3-(2-bromophenyl)propanoyl]amino ⁇ pyrrolidine-1,2-dicarboxylate
  • Step 2 (5R,7S,10S,19E)-10-t-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-3,9,12-trioxo-1,2,3,4,5,6,7,9,10,11,12,14,15,16,17,18-hexadecahydro-5,8-methano-13,4,8,11-benzoxatriazacyclodocosine-7-carboxamide
  • Step 1 1-t-Butyl 2-methyl(2S,4R)-4- ⁇ [(4-bromo-1H-indol-2-yl)carbonyl]amino ⁇ pyrrolidine-1,2-dicarboxylate
  • Step 2 1-t-Butyl 2-methyl(2S,4R)-4- ⁇ [(4-bromo-1-methyl-1H-indol-2-yl)carbonyl]amino ⁇ pyrrolidine-1,2-dicarboxylate
  • Step 3 Methyl (4R)-4- ⁇ [(4-bromo-1-methyl-1H-indol-2-yl)carbonyl]amino ⁇ -L-prolinate trifluoro acetate
  • Step 4 Methyl N- ⁇ [(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl ⁇ -3-methyl-L-valyl-(4R)-4- ⁇ [(4-bromo-1-methyl-1H-indol-2-yl)carbonyl]amino ⁇ -L-prolinate
  • Step 5 Methyl N- ⁇ [(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl ⁇ -3-methyl-L-valyl-(4R)-4- ⁇ [(1-methyl-4-vinyl-1H-indol-2-yl)carbonyl]amino ⁇ -L-prolinate
  • Step 6 (5R,7S,10S,18E)-10-t-Butyl-N-((1R,2R)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-ethylcyclopropyl)-15,15,24-trimethyl-3,9,12-trioxo-4,5,6,7,9,10,11,12,14,15,16,17-dodecahydro-3H-2,23-epimino-5,8-methano-13,4,8,11-benzoxatriazacyclohenicosine-7-carboxamide
  • Step 4 Ethyl N- ⁇ [(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl ⁇ -3-methyl-L-valyl-(4R)-4-[(8-bromoimidazo[1,2-a]pyridin-2-yl)methoxy]-L-prolinate
  • Step 5 Ethyl N- ⁇ [(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl ⁇ -3-methyl-L-valyl-(4R)-4-[(8-vinylimidazo[1,2-a]pyridin-2-yl)methoxy]-L-prolinate
  • Step 6 5R,7S,10S)-10-t-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-15,15-dimethyl-9,12-dioxo-6,7,9,10,11,12,14,15,16,17,18,19-dodecahydro-5H-5,8-methano-23,2-(metheno)pyrido[2,3-n][1,10,3,6,13]dioxatriazacyclohenicosine-7-carboxamide
  • Step 1 Methyl (4R)-4-[(2-chloroquinolin-3-yl)oxy]-1- ⁇ (2S)-2-cyclopentyl-2-[( ⁇ [(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy ⁇ carbonyl)amino]acetyl ⁇ -L-prolinate
  • Step 2 Methyl (4R)-1- ⁇ (2S)-2-cyclopentyl-2-[( ⁇ [(trans)-2-pent-4-en-1-ylcyclopentyl]oxy ⁇ carbonyl)amino]acetyl ⁇ -4-[(2-vinylquinolin-3-yl)oxy]-L-prolinate
  • Step 3 Methyl (3aR,7S,10S,12R,20E,24aR)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,22,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate and methyl (3aS,7S,10S,12R,20E,24aS)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,22,23,24,24a-tetradecahydro-10H-9,12-methano cyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate
  • Step 4 Methyl (3aR,7S,10S,12R,24aR)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate
  • Step 5 (3aR,7S,10S,12R,24aR)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylic acid
  • Step 6 (1R,18R,22R,26S,29S)-26-cyclopentyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-24,27-dioxo-2,23-dioxa-11,25,28-triazapentacyclo[26.2.1.0 3,12 .0 5,10 .0 18,22 ]hentriaconta-3(12),4,5,7,9,10-hexaene-29-carboxamide
  • Step 1 Methyl 3-methyl-N-( ⁇ [(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy ⁇ carbonyl)-L-valyl-(4R)-4-[(6-methoxy-2-vinylquinolin-3-yl)oxy]-L-prolinate
  • Step 2 Methyl (3aR,7S,10S,12R,20E,24aR)-7-t-butyl-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,22,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate
  • Step 3 (3aR,7S,10S,12R,24aR)-7-t-Butyl-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylic acid
  • Step 4 (3aR,7S,10S,12R,24aR)-7-t-Butyl-N-((1R,2S)-1- ⁇ [(cyclopropylsulfonyl)amino]carbonyl ⁇ -2-vinylcyclopropyl)-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxamide
  • Step 3 The product of Step 3 was treated as described in Example 94 Step 6 to afford a residue that was purified by automated mass-triggered HPLC (FractionLynx) to furnish, after freeze drying, the title compound (112 mg, 68%) as a white solid.
  • Step 1 Methyl (3aS,7S,10S,12R,24aS)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100029666A1 (en) * 2008-07-22 2010-02-04 Steven Harper Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
US20100144608A1 (en) * 2008-09-11 2010-06-10 Yiyin Ku Macrocyclic hepatitis C serine protease inhibitors
US20100168384A1 (en) * 2009-06-30 2010-07-01 Abbott Laboratories Anti-viral compounds
US20110002884A1 (en) * 2008-02-25 2011-01-06 Mccauley John A Therapeutic compounds
US20110046161A1 (en) * 2008-04-28 2011-02-24 Liverton Nigel J Hcv ns3 protease inhibitors
WO2012040040A1 (en) * 2010-09-21 2012-03-29 Merck Sharp & Dohme Corp. Hcv ns3 protease inhibitors
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8828930B2 (en) 2009-07-30 2014-09-09 Merck Sharp & Dohme Corp. Hepatitis C virus NS3 protease inhibitors
WO2014145095A1 (en) 2013-03-15 2014-09-18 Gilead Sciences, Inc. Macrocyclic and bicyclic inhibitors of hepatitis c virus
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
US8937041B2 (en) 2010-12-30 2015-01-20 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US8951964B2 (en) 2010-12-30 2015-02-10 Abbvie Inc. Phenanthridine macrocyclic hepatitis C serine protease inhibitors
US9296782B2 (en) 2012-07-03 2016-03-29 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
US9333204B2 (en) 2014-01-03 2016-05-10 Abbvie Inc. Solid antiviral dosage forms
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

Families Citing this family (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY140680A (en) 2002-05-20 2010-01-15 Bristol Myers Squibb Co Hepatitis c virus inhibitors
US7879797B2 (en) 2005-05-02 2011-02-01 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
KR20080036598A (ko) 2005-08-01 2008-04-28 머크 앤드 캄파니 인코포레이티드 Ｈｃｖ ｎｓ３ 프로테아제 억제제로서의 마크로사이클릭펩티드
GB0609492D0 (en) 2006-05-15 2006-06-21 Angeletti P Ist Richerche Bio Therapeutic agents
GB0612423D0 (en) 2006-06-23 2006-08-02 Angeletti P Ist Richerche Bio Therapeutic agents
WO2008051514A2 (en) 2006-10-24 2008-05-02 Merck & Co., Inc. Hcv ns3 protease inhibitors
US8138164B2 (en) 2006-10-24 2012-03-20 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
AU2007309546A1 (en) 2006-10-24 2008-05-02 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. HCV NS3 protease inhibitors
CN101568346B (zh) 2006-10-27 2015-11-25 默沙东公司 Hcv ns3蛋白酶抑制剂
CA2667031C (en) 2006-10-27 2013-01-22 Merck & Co., Inc. Hcv ns3 protease inhibitors
AU2007335962B2 (en) 2006-12-20 2012-09-06 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Antiviral indoles
GB0625349D0 (en) 2006-12-20 2007-01-31 Angeletti P Ist Richerche Bio Therapeutic compounds
GB0625345D0 (en) 2006-12-20 2007-01-31 Angeletti P Ist Richerche Bio Therapeutic compounds
EP2178885A1 (en) 2007-07-17 2010-04-28 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Macrocyclic indole derivatives for the treatment of hepatitis c infections
WO2009010804A1 (en) * 2007-07-19 2009-01-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Macrocyclic compounds as antiviral agents
US8383583B2 (en) 2007-10-26 2013-02-26 Enanta Pharmaceuticals, Inc. Macrocyclic, pyridazinone-containing hepatitis C serine protease inhibitors
CL2008003384A1 (es) 2007-11-14 2009-12-11 Enanta Pharm Inc Compuestos derivados de quinoxalina macrocíclica, inhibidores de serina proteasa; composicion farmaceutica que los comprende; y su uso en el tratamiento de la hepatitis c.
WO2009064955A1 (en) 2007-11-14 2009-05-22 Enanta Pharmaceuticals, Inc. Macrocyclic tetrazolyl hepatitis c serine protease inhibitors
WO2009079353A1 (en) 2007-12-14 2009-06-25 Enanta Pharmaceuticals, Inc. Triazole-containing macrocyclic hcv serine protease inhibitors
MX2010006518A (es) 2007-12-14 2010-08-10 Enanta Pharm Inc Inhibidores de serina proteasa de hepatitis c de oximil macrociclica.
US8283309B2 (en) 2007-12-20 2012-10-09 Enanta Pharmaceuticals, Inc. Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors
US8293705B2 (en) 2007-12-21 2012-10-23 Avila Therapeutics, Inc. HCV protease inhibitors and uses thereof
US8309685B2 (en) 2007-12-21 2012-11-13 Celgene Avilomics Research, Inc. HCV protease inhibitors and uses thereof
WO2009082701A1 (en) 2007-12-21 2009-07-02 Avila Therapeutics, Inc. Hcv protease inhibitors and uses thereof
CA2709535A1 (en) 2007-12-21 2009-07-02 Avila Therapeutics, Inc. Hcv protease inhibitors and uses thereof
CN102015652A (zh) 2008-03-20 2011-04-13 益安药业 作为丙型肝炎病毒抑制剂的氟化大环化合物
US8207341B2 (en) 2008-09-04 2012-06-26 Bristol-Myers Squibb Company Process or synthesizing substituted isoquinolines
US20100080770A1 (en) * 2008-09-29 2010-04-01 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US8563505B2 (en) * 2008-09-29 2013-10-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8044087B2 (en) * 2008-09-29 2011-10-25 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2379579A1 (en) * 2008-12-19 2011-10-26 Gilead Sciences, Inc. Hcv ns3 protease inhibitors
WO2010082050A1 (en) 2009-01-16 2010-07-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Macrocyclic and 7-aminoalkyl-substituted benzoxazocines for treatment of hepatitis c infections
US8377962B2 (en) 2009-04-08 2013-02-19 Idenix Pharmaceuticals, Inc. Macrocyclic serine protease inhibitors
EP2429568B1 (en) * 2009-05-13 2016-08-17 Enanta Pharmaceuticals, Inc. Macrocyclic compounds as hepatitis c virus inhibitors
US8703700B2 (en) * 2009-05-22 2014-04-22 Sequoia Pharmaceuticals, Inc. Bimacrocylic HCV NS3 protease inhibitors
AR077712A1 (es) 2009-08-05 2011-09-14 Idenix Pharmaceuticals Inc Inhibidores de serina proteasa macrociclica
US8445490B2 (en) 2009-10-14 2013-05-21 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
JP2013508285A (ja) 2009-10-14 2013-03-07 ブリストル−マイヤーズ スクイブ カンパニー Ｃ型肝炎の処置のための組成物
WO2011049908A2 (en) 2009-10-19 2011-04-28 Enanta Pharmaceuticals, Inc. Bismacrokyclic compounds as hepatitis c virus inhibitors
AU2011209051B2 (en) 2010-01-27 2015-01-15 AB Pharma Ltd. Polyheterocyclic compounds highly potent as HCV inhibitors
WO2011139513A1 (en) * 2010-05-04 2011-11-10 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis c
US8765944B2 (en) 2010-08-19 2014-07-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
PE20140015A1 (es) 2010-09-21 2014-02-16 Enanta Pharm Inc Inhibidores de las proteasas de serina del vhc derivados de prolinas macrociclicas
EP2621501A4 (en) * 2010-09-29 2014-04-09 Merck Sharp & Dohme POLYCYCLIC HETEROCYCLIC DERIVATIVES AND METHODS FOR THEIR USE IN THE TREATMENT OF VIRAL DISEASES
EP2651884A2 (en) * 2010-12-14 2013-10-23 Merck Sharp & Dohme Corp. Process and intermediates for preparing macrolactams
WO2012109398A1 (en) 2011-02-10 2012-08-16 Idenix Pharmaceuticals, Inc. Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating hcv infections
US8933066B2 (en) 2011-04-14 2015-01-13 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8957203B2 (en) 2011-05-05 2015-02-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8691757B2 (en) 2011-06-15 2014-04-08 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2012171332A1 (zh) 2011-06-16 2012-12-20 爱博新药研发(上海)有限公司 抑制丙型肝炎病毒的大环状杂环化合物及其制备和应用
KR20140059236A (ko) 2011-08-19 2014-05-15 머크 샤프 앤드 돔 코포레이션 Hcv 프로테아제 억제제의 결정 형태
US8629150B2 (en) * 2011-09-28 2014-01-14 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8697706B2 (en) 2011-10-14 2014-04-15 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
EP2780026B1 (en) * 2011-11-15 2019-10-23 Merck Sharp & Dohme Corp. Hcv ns3 protease inhibitors
US8916702B2 (en) 2012-02-06 2014-12-23 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
EP2917222A1 (en) 2012-10-18 2015-09-16 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis c
MX360452B (es) 2012-10-19 2018-11-01 Bristol Myers Squibb Co Inhibidores del virus de la hepatitis c.
WO2014071007A1 (en) 2012-11-02 2014-05-08 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
US9598433B2 (en) 2012-11-02 2017-03-21 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9643999B2 (en) 2012-11-02 2017-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2014070974A1 (en) 2012-11-05 2014-05-08 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2014123894A1 (en) 2013-02-07 2014-08-14 Bristol-Myers Squibb Company Macrocyclic compounds as hcv entry inhibitors
WO2014121418A1 (en) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
JP2016507559A (ja) 2013-02-07 2016-03-10 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｈｃｖエントリー阻害剤としての大環状分子
WO2014121417A1 (en) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
CN105143233A (zh) 2013-03-07 2015-12-09 百时美施贵宝公司 用于治疗丙型肝炎的化合物
WO2014137869A1 (en) 2013-03-07 2014-09-12 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
US11484534B2 (en) 2013-03-14 2022-11-01 Abbvie Inc. Methods for treating HCV
US9873707B2 (en) 2013-10-18 2018-01-23 Merck Sharp & Dohme Corp. Methods and intermediates for preparing macrolactams
WO2017198102A1 (zh) * 2016-05-16 2017-11-23 深圳市塔吉瑞生物医药有限公司 一种取代的大环喹喔啉化合物及其药物组合物及应用
WO2021162070A1 (ja) * 2020-02-14 2021-08-19 東レ株式会社 核酸製造用モノマーの製造方法

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3480613A (en) * 1967-07-03 1969-11-25 Merck & Co Inc 2-c or 3-c-alkylribofuranosyl - 1-substituted compounds and the nucleosides thereof
US6323180B1 (en) * 1998-08-10 2001-11-27 Boehringer Ingelheim (Canada) Ltd Hepatitis C inhibitor tri-peptides
US20020019363A1 (en) * 2000-02-18 2002-02-14 Ismaili Hicham Moulay Alaoui Method for the treatment or prevention of flavivirus infections using nucleoside analogues
US20020107138A1 (en) * 2000-08-10 2002-08-08 Hoveyda Amir H. Recyclable metathesis catalysts
US6608027B1 (en) * 1999-04-06 2003-08-19 Boehringer Ingelheim (Canada) Ltd Macrocyclic peptides active against the hepatitis C virus
US20030236216A1 (en) * 2001-06-12 2003-12-25 Devos Rene Robert 4'-substituted nucleoside derivatives as inhibitors of HCV RNA replication
US20040006007A1 (en) * 2001-09-28 2004-01-08 Gilles Gosselin Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
US20040063658A1 (en) * 2002-05-06 2004-04-01 Roberts Christopher Don Nucleoside derivatives for treating hepatitis C virus infection
US20040067901A1 (en) * 2001-01-22 2004-04-08 Balkrishen Bhat Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US20040229776A1 (en) * 2003-04-02 2004-11-18 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for hepatitis C viral protease inhibitors
US20040229818A1 (en) * 2003-03-05 2004-11-18 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compound
US20040254159A1 (en) * 2003-02-27 2004-12-16 Hasvold Lisa A. Heterocyclic kinase inhibitors
US20040266668A1 (en) * 2003-04-18 2004-12-30 Suanne Nakajima Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors
US20050020503A1 (en) * 2003-05-21 2005-01-27 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US20050038240A1 (en) * 2003-06-19 2005-02-17 Roche Palo Alto Llc Processes for preparing 4'-azido-nucleoside derivatives
US6955174B2 (en) * 2000-08-18 2005-10-18 Uryovascular Systems, Inc. Cryotherapy method for detecting and treating vulnerable plaque
WO2006119061A2 (en) * 2005-05-02 2006-11-09 Merck & Co., Inc. Hcv ns3 protease inhibitors
US20060257980A1 (en) * 2003-04-16 2006-11-16 Wenying Li Macrocyclic isoquinoline peptide inhibitors of hepatitis C virus
US20070027071A1 (en) * 2005-07-20 2007-02-01 Holloway M K HCV NS3 protease inhibitors
US20100298210A1 (en) * 2006-10-24 2010-11-25 Liverton Nigel J HCV NS3 Protease Inhibitors
US7973040B2 (en) * 2008-07-22 2011-07-05 Merck Sharp & Dohme Corp. Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors

Family Cites Families (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6128582A (en) 1996-04-30 2000-10-03 Vertex Pharmaceuticals Incorporated Molecules comprising an IMPDH-like binding pocket and encoded data storage medium capable of graphically displaying them
GB9623908D0 (en) 1996-11-18 1997-01-08 Hoffmann La Roche Amino acid derivatives
GB9707659D0 (en) 1997-04-16 1997-06-04 Peptide Therapeutics Ltd Hepatitis C NS3 Protease inhibitors
EP1012180B1 (en) 1997-08-11 2004-12-01 Boehringer Ingelheim (Canada) Ltd. Hepatitis c inhibitor peptide analogues
ES2241157T3 (es) 1997-08-11 2005-10-16 Boehringer Ingelheim (Canada) Ltd. Peptidos inhibidores de la hepatitis c.
IT1299134B1 (it) 1998-02-02 2000-02-29 Angeletti P Ist Richerche Bio Procedimento per la produzione di peptidi con proprieta' inibitrici della proteasi ns3 del virus hcv, peptidi cosi' ottenibili e peptidi
ATE344271T1 (de) 1998-02-25 2006-11-15 Univ Emory 2'-fluoronukleoside
GB9806815D0 (en) 1998-03-30 1998-05-27 Hoffmann La Roche Amino acid derivatives
ES2281170T3 (es) 1998-03-31 2007-09-16 Vertex Pharmaceuticals Incorporated Inhibidores de serina proteasas, particularmente proteasa ns3 del virus de la hepatitis c.
GB9812523D0 (en) 1998-06-10 1998-08-05 Angeletti P Ist Richerche Bio Peptide inhibitors of hepatitis c virus ns3 protease
WO2000025780A1 (en) 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Compounds derived from an amine nucleus that are inhibitors of impdh enzyme
UA74546C2 (en) 1999-04-06 2006-01-16 Boehringer Ingelheim Ca Ltd Macrocyclic peptides having activity relative to hepatitis c virus, a pharmaceutical composition and use of the pharmaceutical composition
DE60005017T2 (de) 1999-06-25 2004-06-09 Vertex Pharmaceuticals Inc., Cambridge Prodrugs von impdh-inhibierenden carbamaten
TR200103147T1 (tr) 1999-12-27 2002-06-21 Japan Tobacco Inc. Kaynaşık halkalı bileşikler ve bunların ilaç olarak kullanımı.
US6495677B1 (en) 2000-02-15 2002-12-17 Kanda S. Ramasamy Nucleoside compounds
US6455508B1 (en) 2000-02-15 2002-09-24 Kanda S. Ramasamy Methods for treating diseases with tirazole and pyrrolo-pyrimidine ribofuranosyl nucleosides
AU2001253206A1 (en) 2000-04-05 2001-10-23 Tularik, Inc. Ns5b hcv polymerase inhibitors
AR029903A1 (es) * 2000-04-05 2003-07-23 Schering Corp Inhibidores macrociclicos de la ns3-serina proteasa, del virus de la hepatitis c, que comprenden partes p2 n-ciclicas, composiciones farmaceuticas y utilizacion de los mismos para la manufactura de un medicamento
ES2319732T3 (es) 2000-04-13 2009-05-12 Pharmasset, Inc. Derivados de nucleosido 3'- o 2'-hidroximetilo sustituido para el tratamiento de infecciones virales.
MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
EA200601591A1 (ru) 2000-05-26 2007-02-27 Айденикс (Кайман) Лимитед Применение рибонуклеозидных соединений для лечения флавивирусных и пестивирусных инфекций
US6448281B1 (en) 2000-07-06 2002-09-10 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
GB0017676D0 (en) 2000-07-19 2000-09-06 Angeletti P Ist Richerche Bio Inhibitors of viral polymerase
US20030008841A1 (en) 2000-08-30 2003-01-09 Rene Devos Anti-HCV nucleoside derivatives
WO2002020497A1 (fr) 2000-09-01 2002-03-14 Shionogi & Co., Ltd. Composés ayant une action inhibitrice du virus de l'hépatite c
BR0114837A (pt) 2000-10-18 2006-05-09 Pharmasset Ltd nucleosìdeos modificados para tratamento de infecções viróticas e proliferação celular anormal
MXPA03005219A (es) 2000-12-12 2003-09-25 Schering Corp Peptidos diarilicos como inhibidores de ns3-serina proteasa en hepatitis de virus c.
WO2002048116A2 (en) 2000-12-13 2002-06-20 Bristol-Myers Squibb Pharma Company Inhibitors of hepatitis c virus ns3 protease
KR20030081343A (ko) 2000-12-15 2003-10-17 파마셋, 리미티드 플라비비리다에 감염 치료용 항바이러스제
JPWO2002051425A1 (ja) 2000-12-26 2004-04-22 三菱ウェルファーマ株式会社 Ｃ型肝炎治療剤
US7544374B2 (en) 2001-08-14 2009-06-09 Tel Aviv University Future Technology Development L.P. Lipidated glycosaminoglycan particles and their use in drug and gene delivery for diagnosis and therapy
WO2003026675A1 (en) 2001-09-28 2003-04-03 Idenix (Cayman) Limited Methods and compositions for treating flaviviruses and pestiviruses using 4'-modified nucleoside
EP1465862A1 (en) 2002-01-17 2004-10-13 SmithKline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin k inhibitors
GB0201179D0 (en) 2002-01-18 2002-03-06 Angeletti P Ist Richerche Bio Therapeutic agents
CA2369711A1 (en) 2002-01-30 2003-07-30 Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the hepatitis c virus
CA2474563C (en) 2002-02-13 2010-11-09 Merck & Co., Inc. Methods of inhibiting orthopoxvirus replication with nucleoside compounds
MY140680A (en) 2002-05-20 2010-01-15 Bristol Myers Squibb Co Hepatitis c virus inhibitors
EP1551421A2 (en) 2002-06-21 2005-07-13 Merck & Co. Inc. Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase
CA2488484A1 (en) 2002-06-27 2004-01-08 Merck & Co., Inc. Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase
JP2005533817A (ja) 2002-06-28 2005-11-10 イデニクス（ケイマン）リミテツド フラビウィルス科ウィルス感染治療用の修飾２′および３′−ヌクレオシドプロドラッグ
PL374792A1 (en) 2002-06-28 2005-10-31 Idenix (Cayman) Limited 2' and 3'-nucleoside prodrugs for treating flaviviridae infections
BR0312278A (pt) 2002-06-28 2007-06-19 Idenix Cayman Ltd éster 2'-c-metil-3'-o-l-valina de ribofuranosil citidina para tratamento de infecções por flaviviridae
US20060264389A1 (en) 2002-07-16 2006-11-23 Balkrishen Bhat Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase
CA2492607A1 (en) 2002-07-25 2004-02-05 Micrologix Biotech Inc. Anti-viral 7-deaza d-nucleosides and uses thereof
CA2494340C (en) 2002-08-01 2012-01-24 Pharmasset Inc. Compounds with the bicyclo[4.2.1]nonane system for the treatment of flaviviridae infections
TW200418498A (en) 2002-09-30 2004-10-01 Genelabs Tech Inc Nucleoside derivatives for treating hepatitis C virus infection
KR20050065661A (ko) 2002-11-01 2005-06-29 비로파마 인코포레이티드 벤조푸란 화합물, 조성물 및 ｃ형 간염 바이러스 감염 및관련 질병의 치료 및 예방 방법
GB0307891D0 (en) 2003-04-04 2003-05-14 Angeletti P Ist Richerche Bio Chemical compounds,compositions and uses
ES2726998T3 (es) 2003-05-30 2019-10-11 Gilead Pharmasset Llc Análogos de nucleósidos fluorados modificados
GB0313250D0 (en) 2003-06-09 2003-07-16 Angeletti P Ist Richerche Bio Therapeutic agents
TW200510425A (en) 2003-08-13 2005-03-16 Japan Tobacco Inc Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
GB0321003D0 (en) 2003-09-09 2003-10-08 Angeletti P Ist Richerche Bio Compounds, compositions and uses
GB0323845D0 (en) 2003-10-10 2003-11-12 Angeletti P Ist Richerche Bio Chemical compounds,compositions and uses
US7132504B2 (en) 2003-11-12 2006-11-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
CA2549851C (en) 2004-01-21 2012-09-11 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis c virus
PT1719773E (pt) 2004-02-24 2009-06-03 Japan Tobacco Inc Compostos heterotetracíclicos fundidos e a sua utilização como inibidores da polimerase do hcv
GB0413087D0 (en) 2004-06-11 2004-07-14 Angeletti P Ist Richerche Bio Therapeutic compounds
GB0416396D0 (en) 2004-07-22 2004-08-25 Angeletti P Ist Richerche Bio Therapeutic agents
US7153848B2 (en) 2004-08-09 2006-12-26 Bristol-Myers Squibb Company Inhibitors of HCV replication
ES2327252T3 (es) 2004-08-23 2009-10-27 F. Hoffmann-La Roche Ag 4'-azido nucleosidos antivirales.
GB0419850D0 (en) 2004-09-07 2004-10-13 Angeletti P Ist Richerche Bio Therapeutic agents
CA2585113A1 (en) 2004-10-26 2006-05-04 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Tetracyclic indole derivatives as antiviral agents
GB0509326D0 (en) 2005-05-09 2005-06-15 Angeletti P Ist Richerche Bio Therapeutic compounds
KR20080036598A (ko) * 2005-08-01 2008-04-28 머크 앤드 캄파니 인코포레이티드 Ｈｃｖ ｎｓ３ 프로테아제 억제제로서의 마크로사이클릭펩티드
WO2007028789A1 (en) 2005-09-07 2007-03-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Quinazoline derivatives as antiviral agents
GB0518390D0 (en) 2005-09-09 2005-10-19 Angeletti P Ist Richerche Bio Therapeutic compounds
GB0519797D0 (en) 2005-09-29 2005-11-09 Istituto Di Ricerche D Biolog Therapeutic agents
GB0609492D0 (en) * 2006-05-15 2006-06-21 Angeletti P Ist Richerche Bio Therapeutic agents
EP2029741A4 (en) 2006-06-08 2011-03-16 Merck Sharp & Dohme QUICK PROCEDURE FOR DETERMINING THE HEMMERSENSITIVITY OF NS3 / 4A PROTEASE SEQUENCES CLONED FROM CLINICAL SAMPLES
GB0612423D0 (en) * 2006-06-23 2006-08-02 Angeletti P Ist Richerche Bio Therapeutic agents
UY30437A1 (es) 2006-06-26 2008-01-31 Enanta Pharm Inc Quinoxalinil macroceclicos inhibidores de serina proteasa del virus de la hepatitis c
WO2008051514A2 (en) 2006-10-24 2008-05-02 Merck & Co., Inc. Hcv ns3 protease inhibitors
US8138164B2 (en) 2006-10-24 2012-03-20 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
CN101568346B (zh) 2006-10-27 2015-11-25 默沙东公司 Hcv ns3蛋白酶抑制剂
CA2667031C (en) 2006-10-27 2013-01-22 Merck & Co., Inc. Hcv ns3 protease inhibitors
CA2705449C (en) 2006-11-09 2017-01-10 Twinblade Technologies Holding Sweden Ab Hub device
US20100143886A1 (en) 2007-03-09 2010-06-10 Ludmerer Steven W In vivo hcv resistance to anti-viral inhibitors
MX2009013832A (es) 2007-06-29 2010-03-10 Gilead Sciences Inc Derivados de purina y su uso como moduladores del receptor 7 similar a un puente.
WO2009010804A1 (en) 2007-07-19 2009-01-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Macrocyclic compounds as antiviral agents
WO2009064955A1 (en) 2007-11-14 2009-05-22 Enanta Pharmaceuticals, Inc. Macrocyclic tetrazolyl hepatitis c serine protease inhibitors
CL2008003384A1 (es) 2007-11-14 2009-12-11 Enanta Pharm Inc Compuestos derivados de quinoxalina macrocíclica, inhibidores de serina proteasa; composicion farmaceutica que los comprende; y su uso en el tratamiento de la hepatitis c.

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3480613A (en) * 1967-07-03 1969-11-25 Merck & Co Inc 2-c or 3-c-alkylribofuranosyl - 1-substituted compounds and the nucleosides thereof
US6323180B1 (en) * 1998-08-10 2001-11-27 Boehringer Ingelheim (Canada) Ltd Hepatitis C inhibitor tri-peptides
US6608027B1 (en) * 1999-04-06 2003-08-19 Boehringer Ingelheim (Canada) Ltd Macrocyclic peptides active against the hepatitis C virus
US20020019363A1 (en) * 2000-02-18 2002-02-14 Ismaili Hicham Moulay Alaoui Method for the treatment or prevention of flavivirus infections using nucleoside analogues
US20020107138A1 (en) * 2000-08-10 2002-08-08 Hoveyda Amir H. Recyclable metathesis catalysts
US6955174B2 (en) * 2000-08-18 2005-10-18 Uryovascular Systems, Inc. Cryotherapy method for detecting and treating vulnerable plaque
US6777395B2 (en) * 2001-01-22 2004-08-17 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase of hepatitis C virus
US20040067901A1 (en) * 2001-01-22 2004-04-08 Balkrishen Bhat Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US20030236216A1 (en) * 2001-06-12 2003-12-25 Devos Rene Robert 4'-substituted nucleoside derivatives as inhibitors of HCV RNA replication
US20040006007A1 (en) * 2001-09-28 2004-01-08 Gilles Gosselin Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
US20040063658A1 (en) * 2002-05-06 2004-04-01 Roberts Christopher Don Nucleoside derivatives for treating hepatitis C virus infection
US20040254159A1 (en) * 2003-02-27 2004-12-16 Hasvold Lisa A. Heterocyclic kinase inhibitors
US20040229818A1 (en) * 2003-03-05 2004-11-18 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compound
US20040229776A1 (en) * 2003-04-02 2004-11-18 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for hepatitis C viral protease inhibitors
US20060257980A1 (en) * 2003-04-16 2006-11-16 Wenying Li Macrocyclic isoquinoline peptide inhibitors of hepatitis C virus
US20040266668A1 (en) * 2003-04-18 2004-12-30 Suanne Nakajima Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors
US20050020503A1 (en) * 2003-05-21 2005-01-27 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US20050038240A1 (en) * 2003-06-19 2005-02-17 Roche Palo Alto Llc Processes for preparing 4'-azido-nucleoside derivatives
WO2006119061A2 (en) * 2005-05-02 2006-11-09 Merck & Co., Inc. Hcv ns3 protease inhibitors
US20070027071A1 (en) * 2005-07-20 2007-02-01 Holloway M K HCV NS3 protease inhibitors
US7470664B2 (en) * 2005-07-20 2008-12-30 Merck & Co., Inc. HCV NS3 protease inhibitors
US20100298210A1 (en) * 2006-10-24 2010-11-25 Liverton Nigel J HCV NS3 Protease Inhibitors
US7973040B2 (en) * 2008-07-22 2011-07-05 Merck Sharp & Dohme Corp. Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Han (Advances in Characterization of Pharmaceutical Hydrates. Trends in Bio/Pharmaceutical Industry, pages 25-29. March, 2006) *
Stella et al (Prodrugs: Challenges and Rewards, Part 1, 2007) *
Vippagunta et al (Adv Drug Deliv Rev 48:3-26, 2001) *

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8591878B2 (en) * 2008-02-25 2013-11-26 Merck Sharp & Dohme Corp. Therapeutic compounds
US20110002884A1 (en) * 2008-02-25 2011-01-06 Mccauley John A Therapeutic compounds
US20110046161A1 (en) * 2008-04-28 2011-02-24 Liverton Nigel J Hcv ns3 protease inhibitors
US8461107B2 (en) 2008-04-28 2013-06-11 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US7973040B2 (en) * 2008-07-22 2011-07-05 Merck Sharp & Dohme Corp. Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors
US20110224134A1 (en) * 2008-07-22 2011-09-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Macrocyclic quinoxaline compounds as hcv ns3 protease inhibitors
US8080654B2 (en) 2008-07-22 2011-12-20 Insituto di Ricerche di Biologia Molecolare P. Angeletti SpA Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors
US20100029666A1 (en) * 2008-07-22 2010-02-04 Steven Harper Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
US20100144608A1 (en) * 2008-09-11 2010-06-10 Yiyin Ku Macrocyclic hepatitis C serine protease inhibitors
US9309279B2 (en) 2008-09-11 2016-04-12 Abbvie Inc. Macrocyclic hepatitis C serine protease inhibitors
US8642538B2 (en) 2008-09-11 2014-02-04 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US8420596B2 (en) 2008-09-11 2013-04-16 Abbott Laboratories Macrocyclic hepatitis C serine protease inhibitors
US8232246B2 (en) 2009-06-30 2012-07-31 Abbott Laboratories Anti-viral compounds
US20100168384A1 (en) * 2009-06-30 2010-07-01 Abbott Laboratories Anti-viral compounds
US8828930B2 (en) 2009-07-30 2014-09-09 Merck Sharp & Dohme Corp. Hepatitis C virus NS3 protease inhibitors
WO2012040040A1 (en) * 2010-09-21 2012-03-29 Merck Sharp & Dohme Corp. Hcv ns3 protease inhibitors
US8937041B2 (en) 2010-12-30 2015-01-20 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US8951964B2 (en) 2010-12-30 2015-02-10 Abbvie Inc. Phenanthridine macrocyclic hepatitis C serine protease inhibitors
US10201541B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US8993578B2 (en) 2011-10-21 2015-03-31 Abbvie Inc. Methods for treating HCV
US9452194B2 (en) 2011-10-21 2016-09-27 Abbvie Inc. Methods for treating HCV
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8969357B2 (en) 2011-10-21 2015-03-03 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8680106B2 (en) 2011-10-21 2014-03-25 AbbVic Inc. Methods for treating HCV
US8685984B2 (en) 2011-10-21 2014-04-01 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
US9296782B2 (en) 2012-07-03 2016-03-29 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
US10335409B2 (en) 2012-07-03 2019-07-02 Gilead Pharmasset Llc Inhibitors of hepatitis C virus
US10603318B2 (en) 2012-07-03 2020-03-31 Gilead Pharmasset Llc Inhibitors of hepatitis C virus
US9617310B2 (en) 2013-03-15 2017-04-11 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
WO2014145095A1 (en) 2013-03-15 2014-09-18 Gilead Sciences, Inc. Macrocyclic and bicyclic inhibitors of hepatitis c virus
US9333204B2 (en) 2014-01-03 2016-05-10 Abbvie Inc. Solid antiviral dosage forms
US9744170B2 (en) 2014-01-03 2017-08-29 Abbvie Inc. Solid antiviral dosage forms
US10105365B2 (en) 2014-01-03 2018-10-23 Abbvie Inc. Solid antiviral dosage forms
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

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