WO2006000085A1 - Hepatitis c inhibitor peptide analogs - Google Patents
Hepatitis c inhibitor peptide analogs Download PDFInfo
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- WO2006000085A1 WO2006000085A1 PCT/CA2005/000967 CA2005000967W WO2006000085A1 WO 2006000085 A1 WO2006000085 A1 WO 2006000085A1 CA 2005000967 W CA2005000967 W CA 2005000967W WO 2006000085 A1 WO2006000085 A1 WO 2006000085A1
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- Prior art keywords
- alkyl
- cycloalkyl
- aryl
- independently selected
- substituents
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- 0 C*C1c(cccc2)c2N=CC1 Chemical compound C*C1c(cccc2)c2N=CC1 0.000 description 11
- BRIBSXILDZYWGO-UHFFFAOYSA-N CC(C)N(C)OC Chemical compound CC(C)N(C)OC BRIBSXILDZYWGO-UHFFFAOYSA-N 0.000 description 2
- UMPRRBSYZVDQTH-UHFFFAOYSA-N CC(C)N1CCC1 Chemical compound CC(C)N1CCC1 UMPRRBSYZVDQTH-UHFFFAOYSA-N 0.000 description 2
- YQOPNAOQGQSUHF-UHFFFAOYSA-N CC(C)N1CCCC1 Chemical compound CC(C)N1CCCC1 YQOPNAOQGQSUHF-UHFFFAOYSA-N 0.000 description 2
- KXIXHISTUVHOCY-UHFFFAOYSA-N CC(C)N1CCCCC1 Chemical compound CC(C)N1CCCCC1 KXIXHISTUVHOCY-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N CCN(C(C)C)C(C)C Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MTPJEFOSTIKRSS-UHFFFAOYSA-N CN(C)CCC#N Chemical compound CN(C)CCC#N MTPJEFOSTIKRSS-UHFFFAOYSA-N 0.000 description 2
- SLYPSCGYLBSAFG-OEYCXGITSA-N CC(C)(C)[C@@H](C(N(C[C@@H](C1)OCc2ccccc2)[C@@H]1C(N[C@](C1)([C@@H]1C(C)=C)C(NS(N(C)c1ccccc1)(=O)=O)=O)=O)=O)NC(OC1CCCC1)=O Chemical compound CC(C)(C)[C@@H](C(N(C[C@@H](C1)OCc2ccccc2)[C@@H]1C(N[C@](C1)([C@@H]1C(C)=C)C(NS(N(C)c1ccccc1)(=O)=O)=O)=O)=O)NC(OC1CCCC1)=O SLYPSCGYLBSAFG-OEYCXGITSA-N 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N CC(C)(OC(C1)=O)OC1=O Chemical compound CC(C)(OC(C1)=O)OC1=O GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- JKRDXRQPIMCMIM-UHFFFAOYSA-N CC(C)(OC(C1=CNc(cccc2)c2Cl)=O)OC1=O Chemical compound CC(C)(OC(C1=CNc(cccc2)c2Cl)=O)OC1=O JKRDXRQPIMCMIM-UHFFFAOYSA-N 0.000 description 1
- VDGUNAHQVGBBFW-UHFFFAOYSA-N CC(C)(c1cc(N(C)C)ccc1)NCc1ccccc1 Chemical compound CC(C)(c1cc(N(C)C)ccc1)NCc1ccccc1 VDGUNAHQVGBBFW-UHFFFAOYSA-N 0.000 description 1
- OKVCJTAEKCLWKS-UHFFFAOYSA-N CC(C)N(C)CC#N Chemical compound CC(C)N(C)CC#N OKVCJTAEKCLWKS-UHFFFAOYSA-N 0.000 description 1
- WFMUJLWWGDJDBF-UHFFFAOYSA-N CC(C)N(C)Cc1ccccc1 Chemical compound CC(C)N(C)Cc1ccccc1 WFMUJLWWGDJDBF-UHFFFAOYSA-N 0.000 description 1
- CQESJDGMFKMMRE-UHFFFAOYSA-N CC(C)N(CC1)CC1N(C)C Chemical compound CC(C)N(CC1)CC1N(C)C CQESJDGMFKMMRE-UHFFFAOYSA-N 0.000 description 1
- KCEUHHADZBJSHN-UHFFFAOYSA-N CC(C)N(CCC#N)C1CC1 Chemical compound CC(C)N(CCC#N)C1CC1 KCEUHHADZBJSHN-UHFFFAOYSA-N 0.000 description 1
- ODIQTOYGORNLPE-UHFFFAOYSA-N CC(C)N1CCN(C)CC1 Chemical compound CC(C)N1CCN(C)CC1 ODIQTOYGORNLPE-UHFFFAOYSA-N 0.000 description 1
- XTRCSOBLUQUDPM-UHFFFAOYSA-N CC(C)N1OCCCC1 Chemical compound CC(C)N1OCCCC1 XTRCSOBLUQUDPM-UHFFFAOYSA-N 0.000 description 1
- OBUILYJKCCEQEW-UHFFFAOYSA-N CC(C)NCCNC Chemical compound CC(C)NCCNC OBUILYJKCCEQEW-UHFFFAOYSA-N 0.000 description 1
- AVNJENBDIXGLCF-UHFFFAOYSA-N CC(C)c1c2[o]ncc2ncc1 Chemical compound CC(C)c1c2[o]ncc2ncc1 AVNJENBDIXGLCF-UHFFFAOYSA-N 0.000 description 1
- RZKXHLCTCHVMRN-UHFFFAOYSA-N CC(C)c1nncc2c1cccc2 Chemical compound CC(C)c1nncc2c1cccc2 RZKXHLCTCHVMRN-UHFFFAOYSA-N 0.000 description 1
- YFPCLQKFNXUAAK-UHFFFAOYSA-N CC(OC1CCCC1)=O Chemical compound CC(OC1CCCC1)=O YFPCLQKFNXUAAK-UHFFFAOYSA-N 0.000 description 1
- CGZINHNFJOCWFB-UHFFFAOYSA-N CC1(C(C)=CC=N2)C2=NC=CC1 Chemical compound CC1(C(C)=CC=N2)C2=NC=CC1 CGZINHNFJOCWFB-UHFFFAOYSA-N 0.000 description 1
- UWKDZWSATBBGBN-UHFFFAOYSA-N CCN(C)CCO Chemical compound CCN(C)CCO UWKDZWSATBBGBN-UHFFFAOYSA-N 0.000 description 1
- XNXJABVNPPCROA-UHFFFAOYSA-N CCN(C)c(cc1)ccc1Cl Chemical compound CCN(C)c(cc1)ccc1Cl XNXJABVNPPCROA-UHFFFAOYSA-N 0.000 description 1
- CITMHNZVCVJAQH-SQFISAMPSA-N CCO/C(/CC(OCC)=O)=N\c(cccc1)c1OC Chemical compound CCO/C(/CC(OCC)=O)=N\c(cccc1)c1OC CITMHNZVCVJAQH-SQFISAMPSA-N 0.000 description 1
- ZAKAONRTRWRIJT-UHFFFAOYSA-N CCOC(CC(OCC)=O)=N Chemical compound CCOC(CC(OCC)=O)=N ZAKAONRTRWRIJT-UHFFFAOYSA-N 0.000 description 1
- NRATWMRHIQSBKP-UHFFFAOYSA-N CCOc1cc(O)c(cccc2OC)c2n1 Chemical compound CCOc1cc(O)c(cccc2OC)c2n1 NRATWMRHIQSBKP-UHFFFAOYSA-N 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N CN(C)Cc1ccccc1 Chemical compound CN(C)Cc1ccccc1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N CN(C)c1ccccc1 Chemical compound CN(C)c1ccccc1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- FLVFPAIGVBQGET-UHFFFAOYSA-N CN(CC1)CC1O Chemical compound CN(CC1)CC1O FLVFPAIGVBQGET-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N CN1CC=CC1 Chemical compound CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N COc(cccc1)c1N Chemical compound COc(cccc1)c1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N Cc1ccc(cccc2)c2n1 Chemical compound Cc1ccc(cccc2)c2n1 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 1
- AKCRQHGQIJBRMN-UHFFFAOYSA-N Nc(cccc1)c1Cl Chemical compound Nc(cccc1)c1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 1
- SUZPLFOSYVTCLE-UHFFFAOYSA-N Oc1c(cccc2Cl)c2ncc1 Chemical compound Oc1c(cccc2Cl)c2ncc1 SUZPLFOSYVTCLE-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0819—Tripeptides with the first amino acid being acidic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
Definitions
- the present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection.
- HCV hepatitis C virus
- the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection.
- Hepatitis C virus is the major etiological agent of post-transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 200 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious, liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death.
- HCV The mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver disease has not been thoroughly elucidated. It is not known how HCV interacts with and evades the host immune system. In addition, the roles of cellular and humoral immune responses in protection against HCV infection and disease have yet to be established. Immunoglobulins have been reported for prophylaxis of transfusion-associated viral hepatitis, however, the Center for Disease Control does not presently recommend immunoglobulin treatment for this purpose. The lack of an effective protective immune response is hampering the development of a vaccine or adequate post-exposure prophylaxis measures, so in the near-term, hopes are firmly pinned on antiviral interventions.
- Interferon in combination with ribavirin has been approved for the treatment of patients with chronic hepatitis C.
- side effects caused by IFN such as retinopathy, thyroiditis, acute pancreatitis, depression
- Pegylated forms of interferons such as PEG-lntron® and Pegasys® can apparently partially address these deleterious side effects but antiviral drugs still remain the avenue of choice for oral treatment of HCV.
- HCV is an enveloped positive strand RNA virus in the Flaviviridae family.
- the single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins.
- NS structural and non-structural
- the generation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases.
- the first (generally referred to as the NS2/3 protease) cleaves at the NS2-NS3 junction;
- the second (the NS3 protease) is a serine protease contained within the N-terminal region of NS3 and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
- the NS4A protein appears to serve multiple functions, acting as a cofactorfor the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
- NS3 protease The complex formation of the NS3 protease with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites.
- the NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities.
- NS5B is a RNA-dependent RNA polymerase that is involved in the replication of HCV.
- a general strategy for the development of antiviral agents is to inactivate virally encoded enzymes that are essential for the replication of the virus.
- HCV NS3 protease inhibitor BILN 2061 is effective in rapidly reducing viral loads in patients infected with the hepatitis C virus (Gastroenterology (2004) 127(5): 1347-1355), thus providing proof of principle of the clinical antiviral activity of HCV NS3 protease inhibitors.
- the NS3 protease has been found to potentially have an additional impact by blocking the IFN-mediated cellular antiviral activity in the infected cell (Foy et al., Science, 17 April 2003). This lends credence to a hypothesis that the NS3/NS4A protease may represent a dual therapeutic target, the inhibition of which may both block viral replication and restore Interferon response of HCV infected cells.
- Inhibitors of the HCV NS3 protease have been described in WO 00/09543 (Boehringer Ingelheim), WO 03/064456 (Boehringer Ingelheim), WO 03/064416 (Boehringer Ingelheim), WO 02/060926 (Bristol-Myers Squibb), WO 03/053349 (Bristol-Myers Squibb), WO 03/099316 (Bristol-Myers Squibb), WO 03/099274 (Bristol-Myers Squibb), WO 2004/032827 (Bristol-Myers Squibb), and .
- WO 2004/043339 (Bristol-Myers Squibb).
- the present invention now provides novel compounds that are inhibitory to the NS3 protease. Furthermore, compounds being active in cell culture are provided.
- An advantage of one aspect of the present invention resides in the fact that compounds according to this invention specifically inhibit the NS3 protease and do not show significant inhibitory activity against other serine proteases such as human leukocyte elastase (HLE), or cysteine proteases such as human liver cathepsin B (Cat B).
- HLE human leukocyte elastase
- Cat B human liver cathepsin B
- R 2 is selected from -CH 2 -R 20 , -NH-R 20 , -O-R 20 , -S-R 20 , -SO-R 20 , -SO 2 -R 20 , -CH 2 O-R 20 , and -O-X-R 20 , wherein X is (C 2-3 )alkenyl, (C 2-3 )alkynyl, or (C 1-3 )alkyl; and R 20 is (C 6 or Cio)aryl or Het, wherein said (C
- R 30 is H, (C 1-6 )alkyl, aryl, or aryl(C 1-6 )alkyl-;
- R 4 and R 6 are each independently selected from H, (C 1-6 )alkyl, -O-(Ci -6 )alkyl, (C 3 - 7 )cycloalkyl, (C 3-7 )cycloalkyl-(C- ⁇ .
- R 200a is H, halogen, (C 1-4 )alkyl, -OH, -O-(C 1-4 )alkyl, -NH 2 , -NH(Ci. 4 )alkyl or -N((C 1-4 )alkyl) 2 ;
- R 200b , R 200c are each independently halogen, cyano, (C 1-4 )alkyl, -O-(C 1-4 )alkyl, -S-(C 1-4 )alkyl, -SO-(C 1-4 )alkyl, or -S0 2 -(C 1-4 )alkyl, wherein each of said alkyl groups is optionally substituted with from one to three halogen atoms; and either R 200b or R 200c (but not both at the same time) may also be H; or R 200a and R 200b or R 200a and R 200c may be covalently bonded to form, together with the two C- atoms to which they are
- One aspect of the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier medium or auxiliary agent.
- the pharmaceutical composition according to this invention additionally comprises a therapeutically effective amount of at least one other antiviral agent.
- Another important aspect of the invention involves a method of treating or preventing a hepatitis C viral infection in a mammal by administering to the mammal an anti-hepatitis C virally effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
- a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof for the treatment or prevention of hepatitis C viral infection in a mammal.
- a further aspect of the invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, in combination with at least one other antiviral agent, for the manufacture of a medicament for the treatment or prevention of hepatitis C viral infection.
- Still another aspect of this invention relates to a method of inhibiting the replication of Case 13/128 WO
- hepatitis C virus by exposing the virus to a hepatitis C viral NS3 protease inhibiting amount of the compound of formula (I) according to this invention, or a pharmaceutically acceptable salt thereof.
- An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat an HCV infection or to inhibit the NS3 protease of HCV; and packaging material comprising a label which indicates that the composition can be used to treat infection by the hepatitis C virus; wherein the composition comprises a compound of formula (I) according to this invention or a pharmaceutically acceptable salt thereof.
- R 1 , R 2 , R 3 , R 5 , Y and n are as defined herein, with the amide anion formed in step a).
- R 1 , R 2 , R 3 , R 5 , Y and n are as defined herein.
- a further aspect of this invention is the use of the intermediate azalactone of formula (III) as described hereinbefore in the preparation of an HCV NS3 protease inhibitor peptide analog.
- P3, P2, P1 and P1' refer to the position of the amino acid residues starting from the N-terminus of the peptide analogs and extending towards and beyond the cleavage site, i.e. the bond in a substrate of the protease enzyme which is normally cleaved by the catalytic action of the protease enzyme.
- P3 refers to position 3 from the C-terminal side of the cleavage site
- P2 position 2 from the C-terminal side of the cleavage site
- the bond between the P1 and PV residues corresponds to the cleavage site.
- the PV position corresponds to the first position on the N-terminal side of the cleavage site (see Berger A. & Schechter I., Transactions of the Royal Society London series B257, 249-264 (1970)).
- these positions are as designated in the following formula: Case 13/128 WO
- (C 1-n )alkyl as used herein, wherein n is an integer, either alone or in combination with another substituent, means acyclic, straight or branched chain alkyl substituents containing from 1 to n carbon atoms.
- “(Ci -6 )alkyl” includes, but is not limited to, methyl, ethyl, n-propyl, n-butyl, 1 -methylethyl (/so-propyl), 1-methylpropyl, 2-methylpropyl, 1 ,1-dimethylethyl (terf-butyl), pentyl and hexyl.
- Me denotes a methyl group
- Et denotes an ethyl group.
- (C 2 - n )alkenyl as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight chain radical containing two to n carbon atoms, at least two of which are bonded to each other by a double bond.
- examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl.
- (C 2-n )alkenyl is understood to encompass individual stereoisomers where possible, including but not limited to (E) and (Z) isomers, and mixtures thereof.
- a (C 2-11 ) alkenyl group is substituted, it is understood to be substituted on any carbon atom thereof which would otherwise bear a hydrogen atom, unless specified otherwise.
- (C 2 - n )alkynyl is intended to mean an unsaturated, acyclic straight chain radical containing two to n carbon atoms, at least two of which are bonded to each other by a triple bond.
- examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.
- (C3. m )cycloalkyl-(C 1-n )alkyl- as used herein, wherein n and m are both integers, means an alkyl radical containing from 1 to n carbon atoms to which a cycloalkyl radical containing from 3 to m carbon atoms is directly linked; including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, cyclohexyl methyl, 1-cyclohexylethyl and 2-cyclohexylethyl.
- a (C 3-m )cycloalkyl-(Ci -n )alkyl- group may be substituted on either the cycloalkyl or the alkyl portion thereof, or both.
- aryl as used herein, either alone or in combination with another radical, means either a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated.
- Aryl includes, but is not limited to, phenyl, indanyl, 1-naphthyl and 2-naphthyl.
- aryl-(C 1-n )alkyl- means an alkyl radical containing from 1 to n carbon atoms, wherein n is an integer, to which an aryl is bonded.
- aryl-(C 1-3 )alkyl- include, but are not limited to, benzyl (phenylmethyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl.
- an aryl-(C 1 . ⁇ )alkyl- group may be substituted on either the aryl or the alkyl portion thereof, or both.
- Het defines a 3- to 7-membered heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, which may be saturated, unsaturated or aromatic, and which is optionally fused to at least one other cycle to form a 4- to 14-membered heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, said heteropolycycle being saturated, unsaturated or aromatic, unless specified otherwise.
- heteroatom means O, S or N.
- radical means a monovalent radical derived by removal of a hydrogen from a three- to seven-membered saturated or unsaturated (including aromatic) heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur.
- heterocycles include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, thiazolidine, pyrroline, pyrrole, thiophene, furan, hydantoin, diazepine, 1 H-imidazole, isoxazole, thiazole, tetrazole, piperidine, piperazine, homopiperidine, homopiperazine, 1 ,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide or pyrimidine, or the following heterocycles:
- heteropolycycle either alone or in combination with another radical, means a heterocycle as defined above fused to one or more other cycle, be it a heterocycle or any other cycle.
- heteropolycycles include, but are not limited to, indole, benzimidazole, thiazolo[4,5-b]-pyridine, quinoline, isoquinoline, or coumarin, or the following:
- alkyl radical as defined above containing from 1 to n carbon atoms, and includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1 ,1-dimethylethoxy.
- the latter radical is known commonly as tert-butoxy.
- (C 1-6 )alkylthio refers to a sulfur atom further bonded to an alkyl radical as defined above containing from 1 to n carbon atoms.
- Examples of (C 1-6 )alkylthio include, but are not limited to, methylthio (CH 3 S-), ethylthio (CH 3 CH 2 S-), propylthio (CH 3 CH 2 CH 2 S-), 1-methylethylthio ((CHs) 2 CHS-), 1 ,1-dimethylethylthio ((CHa) 3 CS-), etc..
- halo or halogen as used interchangeably herein means a halogen substituent selected from fluoro, chloro, bromo or iodo.
- salt thereof means any acid and/or base addition salt of a compound according to the invention; preferably a pharmaceutically acceptable salt thereof.
- pharmaceutically acceptable salt means a salt of a compound of formula (I) which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use.
- pharmaceutically-acceptable acid addition salts and pharmaceutically- acceptable base addition salts. Lists of suitable salts are found in, e.g., S. M. Birge et al., J. Pharm. ScL, 1977, 66, pp. 1-19. Case 13/128 WO
- pharmaceutically-acceptable acid addition salt means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid
- pharmaceutically-acceptable base addition salt means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
- Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium
- organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
- mammal as it is used herein is meant to encompass humans, as well as non-human mammals which are susceptible to infection by hepatitis C virus including domestic animals, such as cows, pigs, horses, dogs and cats, and non-domestic animals.
- antiviral agent means an agent (compound or biological) that is effective to inhibit the formation and/or replication of a virus in a mammal. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal. Such agents can be selected from: another anti-HCV agent, HIV inhibitor, HAV inhibitor and HBV inhibitor.
- Antiviral agents include, for example, ribavirin, amantadine, VX-497 (merimepodib, Vertex Pharmaceuticals), Levovirin, Viramidine, XTL-001 and XTL-002 (XTL Biopharmaceuticals).
- other anti-HCV agent means those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms of disease.
- agents can be selected from: immunomodulatory agents, inhibitors of HCV NS3 protease, inhibitors of HCV polymerase or inhibitors of another target in the HCV life cycle.
- Immunomodulatory agent means those agents (compounds or biologicals) that are effective to enhance or potentiate the immune system response in a mammal.
- Immunomodulatory agents include, for example, class I interferons (such as ⁇ -, ⁇ -, ⁇ - and omega interferons, tau-interferons, consensus interferons and asialo-interferons), class Il interferons (such as ⁇ -interferons), pegylated interferons and conjugated interferons, including but not limited to interferons conjugated with other proteins including but not limited to human albumin.
- class I interferons such as ⁇ -, ⁇ -, ⁇ - and omega interferons, tau-interferons, consensus interferons and asialo-interferons
- class Il interferons such as ⁇ -interferons
- pegylated interferons and conjugated interferons including but not limited to interferons conjugated with other
- inhibitor of HCV NS3 protease means an agent (compound Case 13/128 WO
- HCV NS3 protease include, but are not limited to, those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/037855,, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO 2005/028501 and co-pending patent application 11/039,698; herein incorporated by reference in its entirety (all by Boehringer Ingelheim), WO 02/060926, WO 03/053349, WO 03/099274, WO 03/099316, WO 2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712 (all by B
- inhibitor of HCV polymerase means an agent (compound or biological) that is effective to inhibit the function of an HCV polymerase in a mammal. This includes, but is not limited to, non-nucleoside and nucleoside inhibitors of HCV NS5B polymerase.
- inhibitors of HCV polymerase include but are not limited to those compounds described in: WO 02/04425 (Boehringer Ingelheim) WO 03/007945 (Boehringer Ingelheim), WO 03/010140 (Boehringer Ingelheim), WO 03/010141 (Boehringer Ingelheim), WO 2004/064925 (Boehringer Ingelheim), WO 2004/065367 (Boehringer Ingelheim), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO 03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (Japan Tobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidates JTK-003 (Japan Tobacco), HCV 796 (ViroPharma/Wyeth), R-1626 (Roche) and NM 283 (Idenix/Novartis).
- inhibitor of another target in the HCV life cycle means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HCV in a mammal other than by inhibiting the function of the HCV NS3 protease. This includes agents that interfere with either host or HCV viral mechanisms necessary for the formation and/or replication of HCV in a mammal.
- Inhibitors of another target in the HCV life cycle include, for example, agents that inhibit a target selected from a helicase, a NS2/3 protease and an internal ribosome entry site (IRES) and agents that interfere with the function of other viral targets including but not Case 13/128 WO
- NS5A protein is not limited to an NS5A protein.
- HIV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HIV in a mammal. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HIV in a mammal. HIV inhibitors include, for example, nucleoside inhibitors, non-nucleoside inhibitors, protease inhibitors, fusion inhibitors and integrase inhibitors.
- HAV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HAV in a mammal. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HAV in a mammal.
- HAV inhibitors include Hepatitis A vaccines, for example, Havrix ® (GlaxoSmithKline), VAQTA ® (Merck) and Avaxim ® (Aventis Pasteur).
- HBV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HBV in a mammal. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HBV in a mammal.
- HBV inhibitors include, for example, agents that inhibit HBV viral DNA polymerase or HBV vaccines.
- HBV inhibitors include Lamivudine (Epivir-HBV ® ), Adefovir Dipivoxil, Entecavir, FTC (Coviracil ® ), DAPD (DXG), L-FMAU (Clevudine ® ), AM365 (Amrad), Ldt (Telbivudine), monoval-LdC (Valtorcitabine), ACH-126,443 (L-Fd4C) (Achillion), MCC478 (Eli Lilly), Racivir (RCV), Fluoro-L and D nucleosides, Robustaflavone, ICN 2001-3 (ICN), Bam 205 (Novelos), XTL-001 (XTL), Imino-Sugars (Nonyl-DNJ) (Synergy), HepBzyme; and immunomodulator products such as: interferon alpha 2b, HE2000 (Hollis-Eden), Theradigm (E
- class I interferon as used herein means an interferon selected from a Case 13/128 WO
- interferons that all bind to receptor type I. This includes both naturally and synthetically produced class I interferons.
- class I interferons include ⁇ -, ⁇ -, ⁇ -, ⁇ - interferons, ⁇ -interferons, consensus interferons, asialo-interferons and pegylated forms thereof.
- class Il interferon as used herein means an interferon selected from a group of interferons that all bind to receptor type II. Examples of class Il interferons include ⁇ -interferons. ,
- ⁇ antiviral agents ribavirin and amantadine
- ⁇ immunomodulatory agents class I interferons, class Il interferons, pegylated interferons and conjugated interferons
- ⁇ HCV polymerase inhibitors nucleoside analogs and non-nucleosides
- ⁇ inhibitor of another target in the HCV life cycle agents that inhibit a target selected from a helicase, a NS2/3 protease and an internal ribosome entry site (IRES) and agents that interfere with the function of other viral targets including but not limited to an NS5A protein
- ⁇ HIV inhibitors nucleoside inhibitors, non-nucleoside inhibitors, protease inhibitors, fusion inhibitors and integrase inhibitors
- ⁇ HBV inhibitors agents that inhibit viral DNA polymerase or is an HBV vaccine.
- combination therapy is contemplated wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with at least one additional agent selected from: an antiviral agent, an immunomodulatory agent, another inhibitor of HCV NS3 protease, an inhibitor of HCV polymerase, an inhibitor of another target in the HCV. life cycle, an HIV inhibitor, an HAV inhibitor and an HBV inhibitor. Examples of such agents are provided in the Definitions section above.
- additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form. Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof.
- treatment means the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of the hepatitis C disease and/or to reduce viral load in a patient.
- prevention means the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood.
- One preferred embodiment of the invention provides a compound of formula (I): Case 13/128 WO
- R 4 and R 6 are each independently selected from H, (C 1-6 )alkyl, -O-(Ci -6 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(Ci -6 )alkyl-, aryl, Het, and aryl-(C 1-s )alkyl-; wherein said (C 1-6 )alkyl, -O-(C 1-6 )alkyl, (C 3 - 7 )cycloalkyl, (C3_7)cycloalkyl-(Ci-6)alkyl-, aryl and aryl-(C 1-6 )alkyl- are each optionally substituted with one or more substituents each independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, O-(Ci.
- R 4 and R 6 are linked, together with the nitrogen to which they are bonded, to form a 3- to 7-membered monocyclic saturated or unsaturated heterocycle optionally fused to at least one other cycle to form a heteropolycycle, each of said heterocycle and heteropolycycle optionally containing from one to three additional heteroatoms each independently selected from N, S and O 1 and each of said heterocycle and heteropolycycle being optionally substituted with one or more substituents each independently selected from halogen, (Ci -6 )alkyl, hydroxy, cyano, O-(d.
- R 200a is H, halogen, (C 1-4 )alkyl, -OH, -O-(C 1-4 )alkyl, -NH 2 , -NH(C 1-4 )alkyl or -N((C 1-4 )alkyl) 2 ;
- R 200b , R 200c are each independently halogen, cyano, (C 1-4 )alkyl, -O-(C 1-4 )alkyl, -S-CC ⁇ alkyl, -SO-(C 1-4 )alkyl, or -SO 2 -(C 1-4 )alkyl, wherein each of said alkyl groups is optionally substituted with from one to three halogen atoms; and either R 200b or R 200c (but not both at the same time) may also be H; or R 200a and R 200b or R 200a and R 200c may be covalently bonded to form, together with the two C- atoms to which they are linked, a 5- or
- R 2002 COOR 2 ° 03 , -N(R 2 ° 02 )(R 20 ° 4 ), or -N(R 2002 )CON(R 2002 )(R 2004 ), wherein R 2002 is H or methyl;
- R 2 is not selected from:
- Het as used in the above definitions unless otherwise stated is defined as a 3- to 7-membered heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, which may be saturated, unsaturated or aromatic, and which is optionally fused to at least one other cycle to form a 4- to 14-membered heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, said heteropolycycle being saturated, unsaturated or aromatic; or a diastereomer thereof or a salt thereof.
- B is selected from: (i) (C 1-10 )alkyl optionally substituted with one or more substituents each selected independently from -COO(Ci -6 )alkyl, -OH, -O(Ci -6 )alkyl, and halogen; ( ⁇ ) (C 3-7 )cycloalkyl, or (C 3-7 )cycloalkyl-(Ct- 4 )alkyl-, each optionally substituted with one or more substituents each selected independently from (C 1-6 )alkyl, -OH and -O(C 1-6 )alkyl; (iii) aryl(C 1-6 )alkyl-; and (iv) Het.
- B is selected from: (i) (C 1-7 )alkyl optionally substituted with one or two or three substituents each independently selected from fluoro, chloro, bromo, hydroxy, methoxy and ethoxy; or optionally substituted with -COOCH 3 ; (ii) (C 3-7 )cycloalkyl, or (Cs ⁇ cycloalkyl-methyl-, each optionally substituted with one or two substituents each independently selected from methyl, ethyl, hydroxy, methoxy and ethoxy; (iii) benzyl; and (iv) Het, wherein Het comprises a 3-, A-, 5-, 6-, or 7-membered heterocyle having one to four heteroatoms each independently selected from O, N, and S, which may be saturated or unsaturated or aromatic.
- B is selected from 1 ,1-dimethylethyl optionally substituted with 1 , 2, or 3 halogen substituents, cyclopropyl-CH 2 -, benzyl, 2,2-dimethylpropyl, cyclopentyl, cyclobutyl, tetrahydrofuranyl, 1 ,1-dimethylpropyl,
- R 5 any and each individual definition of R 5 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 3 , R 4 , R 6 , Y, n, and m as set out herein.
- Y is H. Case 13/128 WO
- Any and each individual definition of Y as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, and m as set out herein.
- R 3 is selected from 1 ,1-dimethylethyl, 1-methylethyl, 1- methylpropyl, 1-hydroxy-1-methylethyl, 1-methoxyethyl,1-ifert-butoxyethyl, 1-
- R 3 is 1 ,1-dimethylethyl or cyclopentyl.
- R 3 is 1,1-dimethylethyl.
- R 3 any and each individual definition of R 3 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 4 , R 5 , R 6 , Y, n, and m as set out herein.
- R 2 is not selected from:
- the group -N(R 4 )R b is selected from:
- R 2 is not selected from:
- R 2 is not selected from:
- R 2 is -O-R 20 , wherein R 20 is Het selected from
- R 2 is not selected from:
- R 200 is one to four substituents each independently selected from H, halogen, cyano, (C 1 . 6 )alkyl; (C 3-7 )cycloalkyl; aryl, Het, -OR 201 , -SR 201 , and -SO 2 R 201 ; wherein each said alkyl, cycloalkyl, aryl and Het is optionally further substituted with R 2000 ; R 201 is in each case independently selected from H, (C 1-6 )alkyl and (C 2-6 )alkenyl, wherein (C 1-6 )alkyl is optionally further substituted with R 2000 is in each case one to three substituents each independently selected from halogen, (Cs ⁇ cycloalkyl, aryl, -OR 2001 , cyano, and -N(R 2002 )R 2001 ; R 2001 is in each case independently selected from H and and R 2002 is in each case independently selected from H and (C 1-6 )alkyl.
- R is -0-R , R is
- R 200d is -OR 201 , wherein R 201 is (C 1-6 )alkyl; R 200e is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl; and R 200 Ms (C 1-6 )alkyl, halogen, -SR 201 , -SO 2 R 201 , or -OR 201 , wherein R 201 is (C 1-6 )alkyl optionally further substituted with (C 3-7 )cycloalkyl or phenyl.
- R 2 is -O-R ⁇ ° and R ⁇ u is
- R 200d is -OR 201 , wherein R 201 is ethyl; R 200e is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl; and R 200f is (C 1-6 )alkyl, halogen, -SR 201 , -SO 2 R 201 , or -OR 201 , wherein R 201 is (Ci -6 )alkyl optionally further substituted with (C 3-7 )cycloalkyl or phenyl.
- A, D, and E represents a S atom and the other two of A, D, and E represent C atoms;
- — represents a single bond between a C atom and an S atom, and represents a single bond or a double bond between two C atoms; provided that each C atom is bonded by one double bond;
- R 200g is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl or (C 2 . 6 )alkenyl; and Case 13/128 WO
- R is one or two substituents each independently selected from H, cyano, (Ci -6 )alkyl and -SO 2 -(C 1-6 )alkyl; wherein each R 200h is bonded to a C atom which would otherwise bear a hydrogen atom.
- R zo is
- R 200g is H or -OR 201 , wherein R 201 is (Ci -6 )alkyl or (C 2-6 )alkenyl; R 200j is H, (C 1-6 )alkyl or -SO 2 -(C 1-6 )alkyl; and R 200i is H or (C 1-6 )alkyl.
- R 2 is -O-R 20
- R* 0 is
- R 200g is -OR 201 , wherein R 201 is (C 1-6 )alkyl; and R 200k is cyano.
- R 2 is selected from:
- Case 13/128 WO Case 13/128 WO or R 2 is -O-R 20 wherein R 20 is selected from: More preferably, R 2 is -O-R 20 wherein R 20 is selected from: Case 13/128 WO
- R 2 any and each individual definition of R 2 as set out herein may be combined with any and each individual definition of R 1 , R 3 , R 4 , R 5 , R 6 , Y, n, and m as set out herein.
- n 1
- n as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y and m as set out herein.
- R 1 is (C 1-6 )alkyl, (C 2-6 )alkenyl, or (C 2-6 )alkynyl; each of which are optionally substituted with from one to three halogen atoms. More preferably, R 1 is (C 2- 6)alkenyl or (C 2- 6)alkyl. Even more preferably, R 1 is ethyl or ethenyl.
- R 1 is ethenyl
- the asymmetric carbon atoms in the cyclopropyl group take the R, S configuration according to the subformula:
- the compounds of the present invention have Case 13/128 WO
- compounds of formula (I) are those wherein n is 1 and R 1 is ethenyl.
- R 1 any and each individual definition of R 1 as set out herein may be combined with any and each individual definition of R 2 , R 3 , R 4 , R 5 , R 6 , Y, n, and m as set out herein.
- n 1
- m 2
- R 1 is ethyl or ethenyl.
- R 4 and R 6 are each independently selected from H, (Ci -6 )alkyl, -O-(C 1-6 )alkyl, . (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl and aryl-(C 1-6 )alkyl-; wherein said (C 1-6 )alkyl, -O-(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(Ci -6 )alkyl-, aryl and aryl-(Ci -6 )alkyl- are each optionally substituted with one to three substituents each independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, O-(C 1-6 )alkyl, -COOH, and -COO(C 1-6 )
- substituents each independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, O-(Ci -6 )alkyl, -NH 2 , -NH(Ci -4 )alkyl, -N((C 1-4 )alkyl) 2 , -COOH, and -COO(C 1-6 )alkyl.
- R 4 and R 6 are each independently selected from H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 3 - 7 )cycloalkyl-(Ci -6 )alkyl-, aryl and aryl-(Ci -6 )alkyl-; wherein said (Ci -6 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(Ci -6 )alkyl-, aryl and aryl-(C 1-6 )alkyl- are each optionally substituted with one to three substituents each independently selected from halogen, (Ci -6 )alkyl, hydroxy, cyano, O-(C 1-6 )alkyl, -COOH, and -COO(C 1-6 )alkyl; or (ii) R 4 and R 6 are linked, together with the nitrogen to which they are bonded, to form a
- R 4 and R 6 are each independently selected from H, (Ci -6 )alkyl, -O-(C-
- R 4 and R 6 are each independently selected from H, (Ci -6 )alkyl : (C 3-7 )cycloalkyl, aryl and aryl-(C 1-6 )alkyl-; wherein said (Ci -6 )alkyl, aryl and aryl-(C 1-6 )alkyl- are each optionally substituted with one to three substituents independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, and -COOH; or (ii) R 4 and R 6 are linked, together with the nitrogen to which they are bonded, to form a 3- to 7-membered monocyclic saturated or unsaturated heterocycle, said heterocycle optionally containing from one to three additional heteroatoms each independently selected from N and O, and said 3- to 7-membered monocyclic saturated or unsaturated heterocycle being optionally substituted with one to three substituents each independently selected from (C 1-6 )alkyl, hydroxy
- R 4 and R 6 are each independently selected from H, methyl, ethyl, propyl, 1-methylethyl, methoxy, ethoxy, propoxy, cyclopropyl, phenyl, and benzyl, the methyl, ethyl, propyl, 1-methylethyl, phenyl and benzyl each being optionally substituted with chloro, hydroxy, cyano, or -COOH; or (ii) R 4 and R 6 are linked, together with the nitrogen to which they are bonded, to form a A-, 5- or 6-membered monocyclic saturated or unsaturated heterocycle, optionally containing from one to three additional heteroatoms each independently selected from N and O, and optionally substituted with from one to three substituents each independently selected from (C 1-6 )alkyl, hydroxy, -N((C 1-4 )alkyl) 2 , and -COOH.
- R 4 and R 6 are each independently selected from H, methyl, ethyl, propyl, 1-methylethyl, cyclopropyl, phenyl, and benzyl, the methyl, ethyl, propyl, 1- methylethyl, phenyl and benzyl each being optionally substituted with chloro, hydroxy, cyano, or -COOH; or (ii) R 4 and R 6 are linked, together with the nitrogen to which they are bonded, to form a 4-, 5- or 6-membered monocyclic saturated or unsaturated heterocycle, optionally containing from one to three additional heteroatoms each independently selected from N and O, and optionally substituted with from one Case 13/128 WO
- R 4 and R 6 are each independently selected from methoxy, methyl and ethyl; or R 4 and R 6 are linked, together with the nitrogen to which they are bonded, to form a 5-membered monocyclic saturated or unsaturated heterocycle.
- R 4 and R 6 are each independently selected from methyl and ethyl; or R 4 and R 6 are linked, together with the nitrogen to which they are bonded, to form a 5-membered monocyclic saturated or unsaturated heterocycle.
- the group -N(R 4 )R 6 is selected from:
- the group -N(R 4 )R 6 is selected from:
- the group -N(R )R is selected from: , Me I / 9 ⁇ I / ⁇ / " >,
- the group -N(R 4 )R 6 is selected from:
- R 4 and R 6 are both methyl.
- R 1 is H, (Ci -6 )alkyl, (C 2-6 )alkenyl, or (C 2-6 )alkynyl, wherein said (C 1-6 )alkyl, (C 2-6 )alkenyl, or (C 2-6 )alkynyl are optionally substituted with from one to three halogen atoms;
- R 2 is selected from -CH 2 -R 20 , -NH-R 20 , -O-R 20 , -S-R 20 , -SO-R 20 , -SO 2 -R 20 , -CH 2 O- R 20 , and -O-X-R 20 , wherein X is (C 2-3 )alkenyl, (C 2-3 )alkynyl, or (Ci -3 )alkyl; and R 20 is (C 6 or Cio)aryl or Het, wherein said (C 6 or C 10 )aryl or Het is optionally mono-,
- R 30 is H, (C 1-6 )alkyl, aryl, or aryl(C-
- heteropolycycle fused to at least one other cycle to form a heteropolycycle
- said heterocycle and heteropolycycle optionally containing from one to three further heteroatoms independently selected from N, S and O
- R 200a is H, halogen, (C 1-4 )alkyl, -OH, -O-(C 1-4 )alkyl, -NH 2 , -NH(C 1-4 )alkyl or -N((C 1-4 )alkyl) 2 ; • .
- R 200b , R 200c are each independently halogen, cyano, (C 1-4 )alkyl, -O-(Ci -4 )alkyl, wO .
- R 200a and R 200b or R 200a and R 200c may be covalently bonded to form, together with the two C- atoms to which they are linked, a 5- or 6-membered carbocyclic ring wherein one or two -CH 2 -groups not being directly linked to each other may be replaced each independently by -O- or NR a wherein R a is H or (Ci- 4 )alkyl, and wherein said carbo- or heterocyclic ring is optionally mono- or di-substituted with and , R 2000a is R 2003 , -N(R 2002 )COR 2003
- R 200d is -OR 201 , wherein R 201 is (C 1-6 )alkyl; R 200e is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl; and R 200f is (C 1-6 )alkyl, halogen, -SR 201 , -SO 2 R 201 , or -OR 201 , wherein R 201 is (Ci -6 )alkyl optionally further substituted with (C 3-7 )cycloalkyl or phenyl; or R 20 is
- R 200g is H or.
- R 201 is (C 1-6 )alkyl or (C 2-6 )alkenyl
- R 200h is one or two substituents each independently selected from H, cyano, (C 1-6 )alkyl and -SO 2 -(Ci -6 )alkyl; wherein each R 200h is bonded to a C atom which would otherwise bear a hydrogen atom
- R 1 is (C 2-6 )alkenyl or (C 2 - 6 )alkyl
- n is 1
- m is 2
- R 4 and R 6 are each independently selected from H, (Ci -6 )alkyl, -O-(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(Ci -6 )alkyl-, aryl and aryl-(C 1-6 )alkyl-; wherein said (C 1-6 )alkyl, (C 3-7 )
- R 2OOd is -OR 201 , wherein R 201 is (C 1-6 )alkyl; R 2OOe is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl; and R 200f is (C 1-6 )alkyl, halogen, -SR 201 , -SO 2 R 201 , or -OR 201 , wherein R 201 is (Ci -6 )alkyl optionally further substituted with (C 3-7 )cycloalkyl or phenyl; or R 20 is
- R 200g is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl or (C 2-6 )alkenyl; and R 200h is one or two substituents each independently selected from H, cyano, (Ci -6 )alkyl and -SO 2 -(C 1-6 )alkyl; wherein each R 2OOh is bonded to a C atom which would otherwise bear a hydrogen atom; R 1 is (C 2-6 )alkenyl or (C 2-6 )alkyl; n is 1 ; m is 2; and R 4 and R 6 are each independently selected from H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(C
- R 3 is selected from 1 ,1-dimethylethyl, 1-methylethyl, 1-methylpropyl, 1-hydroxy-1- methylethyl, 1-methoxyethyl,1-fert-butoxyethyl, 1-ethoxyethyl, cyclopentyl,
- R 2 is -O-X-R 20 , wherein X is -CH 2 C ⁇ C-; and R 20 is phenyl; or R 2 is -O-R 20 wherein R 20 is
- R 200d is -OR 201 , wherein R 201 is ethyl; R 200e is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl; and R 200f is (C 1-6 )alkyl, halogen, -SR 201 , -SO 2 R 201 , or -OR 201 , wherein R 201 is (C 1-6 )alkyl optionally further substituted with (C 3 - 7 )cycloalkyl or phenyl; or R 20 is
- R 200g is H or -OR 201 , wherein R 201 is (C,. 6 )alkyl or (C 2 . 6 )alkenyl; R 200j is H, (C 1-6 )alkyl or -SO 2 -(Ci -6 )alkyl; and R 200i is H or (C 1-6 )alkyl; or R zu is
- p200g is -OR 201 , wherein R 201 is (C i -6 )alkyl; and p200k is cyano; R 1 is ethenyl or ethyl; n is 1; m is 2; and the group -N(R 4 )R 6 is selected from:
- B is selected from 1 ,1-dimethylethyl optionally substituted with 1 , 2, or 3 halogen substituents, cyclopropyl-CH 2 -, benzyl, 2,2-dimethylpropyl, cyclopentyl, cyclobutyl, tetrahydrofuranyl, 1 ,1 ,-dimethylpropyl,
- R 3 is selected from 1 ,1-dimethylethyl, 1-methylethyl, 1-methylpropyl, 1-hydroxy-1- methylethyl, 1-methoxyethyl,1-tert-butoxyethyl, 1-ethoxyethyl, cyclopentyl, Case 13/128 WO
- R 200d is -OR 201 , wherein R 201 is ethyl; R 200e is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl; and R 200f is (Ci -6 )alkyl, halogen, -SR 201 , -SO 2 R 201 , or -OR 201 , wherein R 201 is (C 1-6 )alkyl optionally further substituted with (C 3-7 )cycloalkyl or phenyl; or R 20 is
- R 200g is H or -OR 201 , wherein R 201 is (C 1-6 )alkyl or (C 2-6 )alkenyl; R 200j is H, (Ci -6 )alkyl or -SO 2 -(C 1-6 )alkyl; and R 200i is H or (C 1-6 )alkyl; or R zo is
- R 2009 is -OR 201 , wherein R 201 is (C 1-6 )alkyl; and R 200k is cyano; R 1 is ethenyl or ethyl; n is 1; m is 2; and the group -N(R 4 )R 6 is selected from: Case 13/128 WO
- R 1 is ethenyl or ethyl; n is 1 ; Case 13/128 WO
- n 2; and the group -N(R 4 )R 6 is selected from:
- R 1 is ethenyl or ethyl; n is 1 ; m is 2; and the group -N(R 4 )R 6 is selected from Me ⁇ — N Me ⁇ O and hO ; or a diastereomer thereof or a salt thereof.
- preferred compounds of formula (I) are those wherein Case 13/128 wo
- R 4 and R 6 are linked, together with the nitrogen to which they are bonded, to form a 3- to 7-membered monocyclic saturated or unsaturated heterocycle optionally fused to at least one other cycle to form a heteropolycycle, said heterocycle and heteropolycycle optionally containing from one to three further heteroatoms each independently selected from N, S and O, and said 3- to 7-membered monocyclic saturated or unsaturated heterocycle being optionally substituted with one to three substituents each independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, O-(Ci -6 )alkyl, -NH 2 , -NH(C 1-4 )alkyl, -N((C 1-4 )alkyl) 2 , -CO-NH 2 , -CO-NH(C 1-4 )alkyl, -CO-N((C 1-4 )alkyl) 2 , -COOH, and -COO(C 1-6 )alky
- R 200a is H, halogen, (C 1-4 )alkyl, -OH, -O-(C 1-4 )alkyl, -NH 2 , -NH(Ci -4 )alkyl or -N((C 1-4 )alkyl) 2 ;
- R 200b , R 2OOc are each independently halogen, cyano, (Ci -4 )alkyl, -O-(C 1-4 )alkyl, -S-(C 1-4 )alkyl, -SO-(Ci -4 )alkyl, or -S0 2 -(C 1-4 )alkyl, wherein each of said alkyl groups is optionally substituted with from one to three halogen atoms; and either R 200b or R 200c (but not both at the same time) may also be H; or R 200a and R 200b or R 200a and R 200c may be covalently bonded to form, together with the two C- atoms to
- Examples of preferred compounds according to this invention are each single compound listed in Tables 1 to 6.
- the pharmaceutical composition of this invention may additionally comprise at least one other anti-HCV agent.
- anti-HCV agents include, but are not limited to, ⁇ - (alpha), ⁇ - (beta), ⁇ - (delta), ⁇ - (gamma), ⁇ - (omega) and tau-interferon, pegylated ⁇ -interferon, ribavirin and amantadine.
- the pharmaceutical composition of this invention may additionally comprise at least one other inhibitor of HCV NS3 protease.
- the pharmaceutical composition of this invention may additionally comprise at least one inhibitor of HCV polymerase.
- the pharmaceutical composition of this invention may additionally comprise at least one inhibitor of other targets in the HCV life cycle, including but not limited to, an agent that inhibits a target selected from a helicase, an NS2/3 protease and an internal ribosome entry site (IRES) and an agent that interferes with the function of an NS5A protein.
- at least one inhibitor of other targets in the HCV life cycle including but not limited to, an agent that inhibits a target selected from a helicase, an NS2/3 protease and an internal ribosome entry site (IRES) and an agent that interferes with the function of an NS5A protein.
- the pharmaceutical composition of this invention may be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection is preferred.
- the pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
- parenteral as used herein Case 13/128 WO
- the pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example Tween 80) and suspending agents.
- the pharmaceutical composition of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
- carriers which are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried corn starch.
- aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
- Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.01 and about 50 mg/kg body weight per day of the protease inhibitor compound described herein are useful in a monotherapy for the prevention and treatment of HCV mediated disease.
- the pharmaceutical composition of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will Case 13/128 WO
- Such preparations contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound.
- composition of this invention comprises a combination of a compound of formula (I), including a pharmaceutically acceptable salt thereof, and one or more additional therapeutic or prophylactic agent
- both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
- the resulting composition may be administered in vivo to mammals, such as man, to inhibit HCV NS3 protease or to treat or prevent HCV virus infection. Such treatment may also be achieved using a compound of this invention in combination with another antiviral agent.
- Preferred other antiviral agents are described within the Definitions section and the section of preferred pharmaceutical compositions according to this invention and include, but are not limited to: ⁇ -, ⁇ -, ⁇ -, ⁇ -, ⁇ -and tau-interferon, ribavirin, amantadine; other inhibitors of HCV NS3 protease; inhibitors of HCV polymerase; inhibitors of other targets in the HCV life cycle, which include but are not limited to, agents that inhibit a target selected from a helicase, an NS2/3 protease and an internal ribosome entry site Case 13/128 WO
- IVS INFRAS
- NS5A protein agents that interfere with the function of an NS5A protein
- the additional agents may be combined with compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form.
- another embodiment of this invention provides a method of inhibiting HCV NS3 protease activity in a mammal by administering a compound of the formula (I), including a pharmaceutically acceptable salt thereof.
- this method is useful in decreasing the NS3 protease activity of the hepatitis C virus infecting a mammal.
- combination therapy is contemplated wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with at least one additional antiviral agent.
- additional antiviral agents are described hereinbefore and examples of such agents are provided in the Definitions section.
- These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form. Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
- a compound of formula (I), or a pharmaceutically acceptable salt thereof, set forth herein may also be used as a laboratory reagent.
- a compound of this invention, including a pharmaceutically acceptable salt thereof may also be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of laboratory or medical personnel or patients who come in contact with such materials (e.g. blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection apparatuses and materials).
- a compound of formula (I), including a pharmaceutically acceptable salt thereof, set forth herein may also be used as a research reagent.
- a compound of formula (I), including a pharmaceutically acceptable salt thereof, may also be used as positive Case 13/128 WO
- the strong base referred to in step a) is well known to one skilled in the art and includes, but is not limited to, an alkyllithium reagent (including, but not limited to, butyllithium, terf-butyllithium and the like) and the alkali metal salt of a secondary amine or silyl analog thereof (including, but not limited to, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, lithium N-isopropylcyclohexylamide, lithium tetramethylpiperidide, potassium diisopropylamide, and the like).
- an alkyllithium reagent including, but not limited to, butyllithium, terf-butyllithium and the like
- the alkali metal salt of a secondary amine or silyl analog thereof including, but not limited to, lithium hexamethyldisilazide
- R 1 , R 2 , R 3 , R 5 , Y and n are as defined herein.
- a further aspect of this invention is the use of the intermediate azalactone of formula (111) as described hereinbefore in the preparation of an HCV NS3 protease inhibitor peptide analog.
- the compounds of the present invention are synthesized according to a general process wherein the P3, P2, P1 , and P1' fragments can be linked by well known peptide coupling techniques.
- the P3, P2, P1 , and PV fragments may be linked together in any order as long as the final compound corresponds to compounds of formula (I), wherein Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m and n are as defined herein.
- P3 can be linked to P2-P1-P1 1 , or P1-P1' linked to P3-P2.
- This process is illustrated in Scheme I (wherein CPG is a carboxyl protecting group and APG is an amino protecting group). Case 13/128 WO
- the P2 fragment is generally formed by attaching the R 2 moiety to the proline fragment using methodology described in the examples below. This attachment may take place at any stage in this synthetic scheme, i.e., when P2 is an isolated fragment or when it has already been coupled to P3 and/or P1 or P1-P1'. In cases where the R 2 moiety is to be added at an intermediate stage after coupling to the P3 and/or P1 or P1-P1 1 fragments, the P2 fragment shown above is replaced with a suitable precursor fragment for the purposes of this scheme.
- peptides are elongated by deprotecting the ⁇ -amino group of the N-terminal residue and coupling the unprotected carboxyl group of the next suitably N-protected amino acid through a peptide linkage using well known methods. This deprotection and coupling procedure is repeated until the desired sequence is obtained.
- This coupling can be performed with the constituent amino acid fragments in stepwise fashion or by solid phase peptide synthesis according to the method originally described in Merrifield, J. Am. Chem. Soc, (1963), 85, 2149-2154.
- Coupling between two amino acids, an amino acid and a peptide, or two peptide fragments can be carried out using standard coupling procedures such as the azide method, mixed carbonic-carboxylic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide) method, active ester (p-nitrophenyl ester, N-hydroxysuccinic imido Case 13/128 WO
- the coupling step involves the dehydrative coupling of a free carboxyl of one reactant with the free amino group of the other reactant in the presence of a coupling agent to form a linking amide bond.
- a coupling agent to form a linking amide bond.
- suitable coupling agents are N,N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole in the presence of N,N'-dicyclohexylcarbodiimide or N-ethyl-N'-[(3-dimethylamino)propyl]carbodiimide.
- a practical and useful coupling agent is the commercially available (benzotriazol-i-yloxy)tris-(dimethylamino)- phosphonium hexafluorophosphate, either by itself or in the presence of 1-hydroxybenzotriazole.
- Another practical and useful coupling agent is commercially available 2-(1 H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate. Still another practical and useful coupling agent is commercially available O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
- the coupling reaction is conducted in an inert solvent, e.g. dichloromethane, acetonitrile or dimethylformamide.
- An excess of a tertiary amine e.g. diisopropylethylamine, N-methylmorpholine or N-methylpyrrolidine, is added to maintain the reaction mixture at a pH of about 8.
- the reaction temperature usually ranges between 0°C and 50 0 C and the reaction time usually ranges between 15 min and 24 h.
- the C-terminal carboxylic acid is attached to an insoluble carrier (usually polystyrene).
- insoluble carriers usually contain a group that will react with the carboxylic group to form a bond that is stable to the elongation conditions but readily cleaved later. Examples of which are: chloro- or bromomethyl resin, hydroxymethyl resin, trityl resin and 2-methoxy- 4-alkoxy-benzylalcohol resin.
- MeOH methanol; MS: mass spectrometry; NaHMDS: sodium hexamethyldisilazide; NMO: N-methylmorpholine-N-oxide; NMP: N-methylpyrrolidone; Ph: Phenyl Pr: propyl; t R : retention time; TBAF: tetra-n-butylammonium fluoride; TBDMSCI: te/f-butyldimethylsilyl chloride; TBTU: 2-(1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TPAP: tetra-n-propylammonium perruthenate; Tris/HCI: tris(hydroxymethyl)aminomethane hydrochloride; Ts: tosyl (p-
- the P3 carbamate fragment 1a was prepared as described in WO 03/064416.
- THF 35OmL
- carbonic acid cyclopentyl ester 2,5-dioxo- pyrrolidin-1-yl ester (9.0Og; 39.6mmol)
- terf-butyl glycine (6.24g; 47.5mmol) resulting in a suspension.
- Distilled water (10OmL) was added with vigorous stirring. A small amount of solid remained undissolved.
- Triethylamine (16.6mL; 119mmol) was then added resulting in a homogenous solution which was stirred at RT.
- analogous P3 carbamate fragments in which the cyclopentyloxycarbonyl group has been replaced by another R 5 substituent as defined herein and/or the te/f-butyl group has been replaced by another R 3 substituent as defined herein may be prepared using an analogous procedure.
- the reaction mixture was diluted with EtOAc, washed with 10% citric acid (2x) water (2x) saturated NaHCO 3 (2x), water (2x) and brine (1x), dried (MgSO4), filtered and evaporated to obtain the crude compound as a nearly colorless oil (3.73g ; >100%; assume 9.89mmol).
- the crude product (1.01g; 2.97mmol) was dissolved in DMSO (6.5mL) and cyclopentylamine was added dropwise. The reaction mixture was stirred at RT. for 45 min and then diluted with EtOAc.
- P2 moieties of compounds of Formula (I) can be prepared using the protocols outlined in WO 00/59929, WO 00/09543, WO 03/064456 and WO 03/064416.
- R 2 moieties of compounds of formula 1 are either commercially available or have been described previously in the literature. General methods for the synthesis of some of these fragments are described in WO 00/59929, WO 00/09543, WO 03/064456 and WO 03/064416 and more specific and pertinent examples are provided below.
- P2 aniline moieties are commercially available or may require some well known chemical transformation.
- the nitro is commercially available and is then converted to the corresponding amine by using a reducing agent.
- the carboxylic acid is commercially available, it can be transformed into the corresponding amine via a Curtius rearrangement.
- Step A 2-Amino-3-nitrophenol 2b1 (5 g; 32.4 mmol) was dissolved in H 2 O ( 29.5 mL) and 1 ,4-dioxane (14.7 mL ). The mixture was heated to reflux and hydrobromic acid (48%; 16.7 mL; 147 mmol ) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 0 0 C ( ice bath ), and sodium nitrite (2.23 g; 32.3 mmol ) in H 2 O Case 13/128 WO
- Step B The nitrophenol starting material 2b2 (3.1 g; 14.2 mmol ) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1 mmol) followed by MeI ( 2.6 mL; 42.5 mmol ). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1 X 200 mL ), washed with water (1 X 200 mL ), brine ( 4 X 100 mL ), dried ( MgSO 4 ), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole 2b3 ( 94%; 3.1 g) as an orange solid. MS 234 (M+2H) + ; Homogeneity by HPLC (TFA) @ 220nm: 98%
- Step C 2-Bromo-3-nitroanisole 2b3 (1.00 g; 4.31 mmol ) was dissolved in glacial acetic acid (11.0 mL )/ethanol (11.0 mL ) and to the solution was added iron powder (0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water ( 35 mL ), neutralized with solid Na 2 CO 3 and the product extracted with CH 2 CI 2 ( 3X 50 mL ). The extracts were dried ( Na 2 SO 4 ), filtered and concentrated in vacuo to afford the crude product, 2-bromo-3 methoxyaniline 2b4 ( 91%; 0.79 g ) as a pale yellow oil. MS 201.8 (MH) + ; Homogeneity by HPLC (TFA) @ 220nm: 95% Case 13/128 WO
- Step A 2-Amino-3-nitrophenol 2b1 (5 g; 32.4 mmol) was dissolved in concentrated HCI (75 ml_) and 1 ,4-dioxane (14.7 ml_). The mixture was heated to 70 0 C until most of the solids were in solution. The reaction mixture was cooled to 0 0 C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H 2 O (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained below 10 0 C during the addition and the stirring was continued for an additional 15 min. at 0 0 C.
- This diazonium intermediate was poured into a solution of Cu(I)CI (3.8 g; 38.9 mmol) in H 2 O (18.5 mL) and cone. HCI (18.5 mL) at 0 0 C. The reaction was stirred for 15 min. at O 0 C, warmed to 6O 0 C, and stirred for an additional 15 min. The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3 X 150 mL). The organic layers were combined, washed with brine (1 X), dried (Na 2 SO 4 ), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil.
- Step B The nitrophenol starting material 2c1 (1.3 g; 7.49 mmol) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 mmol), followed by MeI (1.4 mL; 22.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated in vacuo and the residue taken up in ether (150 mL), washed with water (150 mL), brine (4 X 100 mL), and then dried over (MgSO 4 ). The organic phase was filtered and evaporated to afford the crude 2- chloro-3-nitroanisole 2c2 (98%; 1.38 g) as an orange solid. Homogeneity by HPLC (TFA) @ 220nm: 93%. Case 13/128 WO
- Step C 2-Chloro-3-nitroanisole 2c2 (1.38 g; 7.36 mmol ) was dissolved in a mixture of glacial acetic acid (19 ml_ )/ethanol (19 ml_ ). To this solution was added iron powder (1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (70 ml_), neutralized with solid Na 2 CO 3 and the product extracted with CH 2 CI 2 ( 3X 150 mL ). The extracts were combined and washed with sat.
- R 201 when R 201 is Et in the above scheme, ethyl cyanoacetate and ethanol are used as reagents.
- R 201 is Me in the above scheme, methyl cyanoacetate and methanol are used as reagents.
- appropriately substituted ⁇ -ketoesters are condensed with substituted anilines and subsequently thermally cyclized to afford the corresponding 2-alkyl substituted hydroxyquinolines.
- step A when the initial condensation reaction with the aniline (step A) is performed with the corresponding methyl ketone, a methyl group is incorporated in the 2-position of the resulting hydroxyquinoline.
- Step C The condensation product 2g4(1.73g, 6.41 mmol) was dissolved in diphenyl ether (10 mL) and placed in a sand bath (300 0 C). The internal temperature was monitored and allowed to stay between 240-250 0 C for 8 minutes. The mixture was cooled and then directly loaded on a silica gel column and eluted first with hexanes, then with 30% EtOAc/Hexanes and finally 50% EtOAc/hexanes. The product was concentrated and dried in vacuo to give the corresponding 4-hydroxyquinoline derivative 2g5 as a beige crystalline solid (0.76g, 53%). MS electrospray: (M + H)+; 224 and (M - H)-; 222.
- Step B In a pre-heated sand bath (300-350 0 C) 1 diphenyl ether (6 mL) was heated until the internal temperature reached 220 0 C.
- Adduct 2h2 (981 mg, 3.48mmol) was added portionwise over ca. 4 min period (gas evolution) to the heated solvent. The temperature (220 0 C) was maintained for another 5 min. after which the solution was allowed to cool. Upon cooling, the product crashed out of solution and was filtered and washed with diethyl ether. After drying in vacuo (16h), product 2h3 was obtained as a beige solid (417mg, 67%). MS: (M + H)+; 180.
- Step B In a pre-heated sand bath (300-350 0 C), compound 2i2 (730mg, 3.0mmol) in diphenyl ether (8 mL) was heated until the internal temperature reached 220 0 C and that temperature was maintained for 7 minutes after which the solution was allowed to Case 13/128 WO
- Step A To THF (30 mL) was added sodium hydride (60% in oil, 920mg, 23mmol, 1.2eq) before being cooled to O 0 C. Diethyl malonate (2.91ml_, 19.15mmol, 1.0eq) was then added dropwise (gas evolution) and this solution was allowed to warm to RT. and was stirred for 1 hr. This mixture was cooled down to O 0 C before the addition of 2- chlorophenyl isothiocyanate 2j1 (2.5ml_, 19.15mmol, 1.0eq). The resulting mixture was again allowed to warm to RT. for 3 hrs until the SM was consumed. The orange solution was concentrated down and dried in vacuo to afford the sodium salt adduct 2j2 (6.73g, 100%) as an orange crystalline solid. This material was used as is for subsequent steps.
- Step B A solution of adduct 2j2 (6.Og, 17.06mmol, 1eq) in DMF (50 mL) was cooled down to -45 0 C. Ethyl iodide (1.64mL, 20.5mmol, 1.2eq) was then slowly added and the solution was stirred at -45 0 C for 2 hrs and then at RT. (16hrs). Water was added Case 13/128 WO
- Step C In a pre-heated sand bath (350 0 C) a solution of compounds 2j3 and 2j4 (6.1g, 17.05mmol, 1 eq.) in diphenyl ether (60 ml_) was heated until the internal temperature reached 220 0 C, which was maintained for 7 minutes. The solution was cooled to R.T. and the mixture loaded directly on a silica gel column, being eluted first with hexanes (1 L) to remove the diphenyl ether, and then 3% EtOAc/hexanes to afford the desired quinoline 2j5 (2.76g, 52%) as a pale yellow solid.
- Step D To a solution of quinoline 2j5 (2.76g crude; 8.85mmol; 1eq) in THF (10 ml_) and methanol (10 ml.) at R.T. was added 1N NaOH (45 ml_; 45mmol; 5.1eq). The reaction was allowed to stir at reflux (85 0 C) for 24 hrs (monitored by HPLC). The mixture was acidified using 4N HCI and extracted using methylene chloride (3X). The organic fractions were dried over MgSO 4 , filtered and concentrated to afford the quinoline acid 2j6 (2.43g, 97%) as a pale yellow solid. MS: (M + H)+; 284. This material was used as is for the following reaction.
- Step A To 3-amino-2-chloro-pyridine 2k1 (964mg, 7.5mmol, 1eq) was added imidate 2g2 (1.47g, 7.5mmol, 1eq) in ethanol (15 ml_) under a N 2 atmosphere. The mixture was stirred at RT. for 24 hrs at which point the reaction was concentrated and purified directly on a silica gel column (eluent: EtOAc/Hexanes (1 :9)) to afford adduct 2k2 (1.54g, 76%) as a clear oil.
- Step A The imidate salt 2g2(1.4g, 7.2mmol, 1 eq.) was combined with 2-(methylthio)- aniline 211 (0.96g, 7.50mmol, 1 eq.) in ethanol (15 mL) under an N 2 atmosphere. The reaction mixture was stirred at RT. (1 h) and monitored by HPLC. The reaction mixture was concentrated and then ether was added and the mixture filtered. The solids were washed with ether and the combined ether washes concentrated in vacuo. The resulting adduct 2I2 was obtained as a yellow oil (1.66g, 82%) and used as is in Case 13/128 WO
- Step B The condensation product 212 (1.66g, 5.90mmol) was dissolved in diphenyl ether (10 mL) and placed in a sand bath (300 0 C). The internal temperature was monitored and allowed to stay between 240-250 0 C for 10 minutes. The mixture was cooled and then directly loaded on a silica gel column and eluted first with hexanes, then with 30% EtOAc/Hexanes and finally 50% EtOAc/hexanes. The product was concentrated and dried in vacuo to give the corresponding 4-hydroxyquinoline derivative 2I3 as a yellow solid (0.735g, 53%). MS electrospray: (M + H)+; 236 and (M - H)-; 234.
- Step A The imidate salt 2g2 (1.5g, 7.65mmol) was combined with 2-methyl-3- aminoanisole 2a2 (1.05g, 7.65mmol, 1 eq.) in ethanol (15 mL) under an N 2 atmosphere. The reaction mixture was stirred at RT. (24 h) and monitored by HPLC. The reaction mixture was concentrated and then ether was added and the mixture filtered. The solids were washed with ether and the combined ether washes concentrated in vacuo. The resulting adduct 2m1 was purified by chromatography (SiO 2 , 15% EtOAc/hexanes) to obtain as a yellow oil (2.11g, 99%). MS electrospray: (M + H)+; 280 and (M - H)-; 278.
- Step B The condensation product 2m1 (2.1g, 7.52mmol) was dissolved in diphenyl ether (10 mL) and placed in a sand bath (300°C). The internal temperature was monitored and allowed to stay between 240-250 0 C for 10 minutes. The mixture was cooled and then directly loaded on a silica gel column and eluted first with hexanes, then with 30% EtOAc/Hexanes and finally 50% EtOAc/hexanes. The product was concentrated and dried in vacuo to give the corresponding 4-hydroxyquinoline derivative 2m2 as a yellow oil which solidified upon standing to a yellow solid (1.09g, Case 13/128 WO
- Step A and B Beginning with ortho-anisidine 2n1 and following the same protocol as outlined in previous examples, the desired 8-methoxyquinoline derivative 2n3 was obtained in 38% overall yield as a pale yellow solid. MS: 220 (M +H)+.
- Step A To 2-bromo-3-aminoanisole 2b4 (750mg, 3.7mmol, 1eq) was added imidate 2g2 (0.73g, 3.7mmol, 1eq) in ethanol (7 mL) under a N 2 atmosphere. The mixture was stirred at RT. for 24 hrs at which point the reaction was concentrated and purified directly on a silica gel column (eluent: EtOAc/Hexanes (1 :9)) to afford adduct 2o1 (1.12g, 88%) as a pale yellow oil. MS: 344 (M + H)+ and 346 (MH + 2)+.
- Step A To available thiophen-3-ylamine 2p1 (0.50 g, 5.04 mmol) was added imidate 2g2 (1.08g, 5.5mmol) in ethanol (10 mL) under a N 2 atmosphere. The mixture was stirred at RT. for 3 h at which point the reaction was concentrated. To the residue was added ether, and the suspension filtered and washed with ether to afford adduct 2p2(1.0g, 82%). This material was sufficiently clean to be used in the subsequent step. MS: 242.1 (MH)+.
- Step B Adduct 2p2 (1.0g, 4.14mmol) was dissolved in diphenyl ether (5 mL) and placed in a pre-heated sand bath (300 0 C). The internal temperature was monitored and allowed to stay between 210°C-225°C for 7 minutes. The mixture was directly loaded on a silica gel column and eluted with hexanes to remove diphenyl ether, followed by a gradient of 30% EtOAc/hexane to neat EtOAc. Concentration and drying in vacuo afforded the desired thieno[3.2-b]pyridinol 2p3 (200mg, 25%) as a brown solid. MS: 196 (MH)+.
- 6-substituted isoquinolones can be made from 3-substituted cinnamic acid derivatives by first activation with a chloroformate in base followed by treatment with an azide source. The resulting acyl azide can undergo a Curtius rearrangement followed by thermal cyclization to afford the appropriately substituted isoquinolones. As described here, the cinnamic acid can be differentially substituted. Case 13/128 WO
- isoquinolines were prepared according to the following reference; Tetrahedron, 2002, 58, 5761-5766.
- Step A The 3-methoxycinnamic acid 2r1 (2.5 g, 14.03 mmol) was dissolved in acetone (40 ml_) and treated with triethylamine (3.94 mL, 28.06 mmol). The solution was cooled to 0 0 C and then treated dropwise with ethyl chloroformate (2.0 mL, 21 mmol). A white precipitate immediately formed upon addition of each drop. The solution was stirred for 1h (with a suspension) before being treated with sodium azide (0.91 g, 14.03 mmol) in 10 mL of H 2 O dropwise over 30 min.
- Step B The diphenyl ether (10 mL) and tributylamine (7 mL) were heated in a sand bath to 190 0 C before the dropwise addition of the acyl azide 2r2 (behind an explosion shield) in toluene (5 mL) over several minutes. The toluene distilled off and the temperature was raised to 21O 0 C for 2h. After cooling, the precipitated product was collected by filtration and washed with hexanes to give the desired isoquinoline 2r3 (0.47 g, 19%). MS (electrospray); (M+H) + ; 176 and (M-H) " ; 174.
- Step B NaH was added (96 mg, 3.79 mmol) to commercially available Boc-4R- hydroxy-proline (350 mg, 1.51 mmol) at r.t. and stirred for 1h followed by the addition of the bromide 2s1 (325 mg, 1.67 mmol). The resulting solution was heated at reflux for 16 h, cooled to r.t., diluted with EtOAc and washed successively with 1M HCI, water and brine to yield the desired product 2s3 (520 mg, 99%).
- P1' sulfamide fragments are commercially available (for example, N 1 N- dimethylsulfamide [available from TCI America]) or may be prepared by methods similar to those described in Examples 3A, 3B or 3C below. Case 13/128 WO
- Step 1 Reagent 3a1 (0.3g, 0.99 mmol) [prepared according to Winum, J-Y; Toupet, L; Barragan, V; Dewynter, G; Montero, J-L., Org. Lett., 14(3), 2241-2243 (2001)] was suspended in CH 2 CI 2 before morpholine (0.086 mL, 0.99 mmol) was added and stirred for 5h. The reaction was followed by TLC. On completion the reaction mixture was directly adsorbed on the silica gel and eluted the product with 6% MeOH in CHCI 3 to afford 0.258g (98%) of compound 3a2 as a white solid.
- Step 2 Compound 3a2 (0.150 g, 0.56 mmol) was dissolved in CH 2 CI 2 (5 mL) and treated with TFA (1 mL). The reaction was stirred for 4h and monitored by TLC. Upon completion, the solvent was evaporated and the residue directly adsorbed on the silica gel and eluted with 5% MeOH in CHCI 3 to afford 0.075g (80.2%) of compound 3a3 as a white solid.
- Step A Reagent 3a1 (1.5g, 4.98 mmol) was suspended in 12 mL of CH 2 CI 2 before the pyrroline (0.40 mL, 5.22 mmol, 1.05 equiv.) was added and stirred overnight. On completion, the reaction mixture was directly adsorbed on the silica gel and eluted the product with 1 % AcOEt in CH 2 CI 2 to afford 0.919g (74%) of compound 3b1 as a white Case 13/128 WO
- Step B Compound 3b1 (0.919 g, 3.70 mmol) was dissolved in 10 ml_ of CH 2 CI 2 and treated with TFA (2 ml_). The reaction was stirred at room temperature for 4h. The solvent was then evaporated in vacuo, the residue was dried under vacuum to afford 0.565g (quantitative) of compound 3b2 as a beige solid.
- Step A Note: the reaction was performed on a solid phase synthesizer (Advanced Chemtech ACT 396), using the 96-wells block.
- the starting material 3a1 (45.2 mg, 0.15 mmol) was weighed in 96 Eppendorf vials and 96 different amines (0.18 mmol, 1.2 equiv.) were weighed and placed in separate Eppendorf vials.
- Each well of the reaction block were filled with 1.2 ml_ of 1 ,2-dichloroethane and the starting material 3a1 and the various amines were added.
- the reaction mixtures were shaken for 12 h in the case of aliphatic amines and for 36 h in the case of anilines derivatives.
- PS-trisamine resin was added to each well (Argonaut Technologies, 3.42 mmol/g loading, 0.63 mmol, 0.184 g, 4.2 equiv.). After shaking for 3 h, the solvent was drained and the resins were washed successively with CH 2 CI 2 (3 x 1mL), MeOH (3 x 1mL) and CH 2 CI 2 (3 x 1mL). In each well was then added CH 2 CI 2 (1.2 mL) and AcOH (100 ⁇ l) and the shaking was maintained for 30 minutes.
- Step B The products 3d in 2-dram vials were dissolved in 1 ,2-dichloroethane (0.5 mL) and TFA (0.5 mL) and the vials were shaken on an orbital shaker for 1.5 h.
- Boc-dipeptide ester 5b1 was obtained as an amorphous white solid after evaporation of the solvents and drying of the residues under high vacuum at 70°C for 1h (108.1g, quantitative).
- a solution of 4N hydrogen chloride in dioxane was added to the Boc-dipeptide ester 5b1 (108g, 243mmol) resulting in a colorless solution.
- the solution was stirred at R.T. for 1h.
- the solvent was evaporated and the residue placed under high vacuum for 3h affording the hydrochloride salt of compound S23 as an amorphous solid.
- the solid was used as such.
- dipeptide S23 wherein B and X are as defined herein is carried out by coupling the P1 residue to the properly protected frans-hydroxy praline under standard conditions as described previously. The stereochemistry of the hydroxyl group is inverted by the well known Mitsunobu reaction using para- nitrobenzoic acid. Coupling of dipeptide S23 with the P3 moiety (prepared using standard methodology and exemplified in the examples section) yielded tripeptide S24.
- the acid can be activated by the formation of an anhydride and undergo an internal cyclization to afford an azalactone as depicted below.
- This azalactone can be isolated and purified by column chromatography. Treatment of the azalactone with lithiated Case 13/128 WO
- sulfamide provides the desired compounds.
- the desired sulfamide wherein R 4 and R 6 are as defined herein can be coupled with the properly protected P1 residue S32.
- the adduct S33 can then be coupled to a preformed P3-P2 residue S35 whereinB, X, R 200g , R 200h and R 200j are each independently selected from R 200 as defined herein to yield the desired S29.
- compounds of formula S29 can also be prepared according to Scheme 4 of Example 6c. Case 13/128 WO
- the brosylate tripeptide methyl ester can be hydrolyzed to the corresponding acid and then coupled with the required sulfonamide.
- Introduction of the aromatic substituent on P2 can then be achieved by displacing the brosylate moiety with the desired hydroxyl aryl or heteroaryl derivative.
- Step A To a solution of the brosylate intermediate 6h1 (50mg, 0.072mmol, 1.0eq.), dissolved in NMP (3 mL) was added the hydroxyquinoline (16.1 mg, 0.072mmol, 1.0eq.) and cesium carbonate (25.7mg, 0.079mmol, 1.1 eq.). The mixture was heated at 70 0 C for 7 hours. After the complete conversion of starting material to products, the reaction mixture was diluted with EtOAc and washed with H 2 O (2x), saturated aq. NaHCO 3 (2x), and brine (1x). The organic layer was dried over anhydrous MgSO 4 , filtered and evaporated to dryness. Product 6j1 (49.3mg, 100%) was sufficiently clean to be used directly in the following step. Case 13/128 WO
- Step B The methyl ester 6j1 (49.3mg, LOmmol) was dissolved in a solution of THF/MeOH/H 2 O(2:1 :1 , 1.2mL) and saponified with 1N NaOH (0.58ml_, 0.58mmol, 8 eq.)- The hydrolysis reaction was carried out over 5h at RT. Thereafter, the solution was evaporated to dryness to give an off-white solid. This material was dissolved in acetic acid and purified by preparative HPLC (ACCN/H 2 O/TFA). Pure fractions were combined, frozen, and lyophilized to afford the tripeptide intermediate as a white solid (29.5mg; 61% yield), 99.8% homogeneity by analytical HPLC.
- Step C The intermediate acid (50 mg, 0.074 mmol), N,N-dimethylsulfamide (36.7 mg, 0.296 mmol), DIPEA (0.065 mL, 0.37 mmol) and DMAP (36.1 mg, 0.296 mmol), were dissolved in DMF (2.5 mL) and to it was added DBU (0.047 mL, 0.33 mmol). Stirred for 5 min, then added HATU (31 mg, 0.081 mmol). The reaction mixture was stirred for 12h.
- reaction mixture was concentrated and the residue was dissolved in AcOH, purified by preparatory HPLC (YMC Combiscreen ODS-AQ, 50 x20mm ID S-5 micron, 120A ; 220nm) using a linear gradient and 0.06% TFA CH3CN / H2O. The pure fractions were combined, concentrated and lyophilized to provide the product, compound 4015, as the TF salt (4 mg, 7%).
- Step A To a solution of the brosylate intermediate 6h1 (50mg, 0.072mmol, 1eq.), dissolved in NMP (2 ml_) was added the hydroxyquinoline 2m2 (20mg, 0.086mmol, 1.2eq.) and cesium carbonate (33mg, O.IOmmol, 1.4eq.). The mixture was heated at 70 0 C for 8 hours. After the complete conversion of starting material to products, the reaction mixture was diluted with EtOAc and washed with H 2 O (2x), saturated aq. NaHCO 3 (2x), and brine (1x). The organic layer was dried over anhydrous MgSO 4 , filtered and evaporated to dryness.
- Step B The methyl ester 6k2 (36mg, 0.052mmol) was dissolved in a solution of THF/MeOH/H 2 O(2: 1:1, 1.5ml_) and . saponified with 1 N NaOH (0.42mL, 0.42mmol, 8 eq.). The hydrolysis reaction was carried out over 16h at RT. Thereafter, the solution was evaporated to dryness to give an off-white solid. This material was dissolved in acetic acid and purified by preparative HPLC (AcCN/H 2 O/TFA). Pure fractions were combined, frozen, and lyophilized to afford 6k3 (compound 4023) as a white solid (16.5mg; 47% yield). Homogeneity by analytical HPLC (100%).
- Step C To a solution of the acid 6k3 (140 mg, 0.206 mmol), in 5 mL of CH 2 CI 2 , was added 0.086 mL of Et 3 N (0.617 mmol, 3.01 equiv.). The resulting solution was cooled to 0 0 C for the addition of the isobutyl chloroformate (0.040 mL, 0.308 mmol, 1.50 equiv.). The ice bath was removed one hour later and the reaction stirred at room temperature for an extra 4 hours. The reaction mixture was concentrated to dryness. The crude material was purified by flash column chromatography with Hexanes/EtOAc; 70:30 to provide 84 mg of the desired compound 6k4 (62% yield). Case 13/128 WO
- Step D A solution of the sulfamide 3b2, in 1.5 mL of THF, was cooled down to -15 0 C for the addition of LiHMDS 1M sln/THF (0.08OmL, 0.080 mmol, 1.26 equiv.). The resulting solution was stirred 5 minutes at this temperature and 20 minutes at room temperature. The reaction was then cooled back to -15°C and a solution of the azalactone 6k4 (42 mg, 0.063 mmol, 1 equiv.), in 1.5 mL of THF, was added drop by drop. The resulting solution was stirred 30 minutes at -15,-10 0 C then overnight at room temperature.
- LiHMDS 1M sln/THF 0.08OmL, 0.080 mmol, 1.26 equiv.
- reaction mixture diluted with AcOH, was purified by preparatory HPLC (YMC Combiscreen ODS-AQ, 50 x20mm ID S-5micron,120A ; 220nm) using a linear gradient and 0.06% TFA CH 3 CN / H 2 O .
- the pure fractions were combined, concentrated and lyophilized to provide the product, compound 4015, as the TF salt (28mg, 54%).
- Steps A and B were carried out as described above in Example 6K but using the 8- bromo-2-ethoxy-7-methoxy-4-quinolinol 2o2 instead of 8-methyl-2-ethoxy-7-methoxy- 4-quinolinol 2m2 in step A.
- Step C To a mixture of the acid 6m2 (50 mg, 0.067 mmol), N,N-dimethylsulfamide (33.3 mg, 0.268 mmol), DIPEA (0.06 ml_, 0.335 mmol) and DMAP (33 mg, 0.268 mmol) in DMF (2.5 mL) was added DBU (0.04 ml_, 0.301 mmol). The mixture was stirred for 5 min, then HATU (28 mg, 0.074 mmol) was added and the reaction mixture was stirred for 12h.
- reaction mixture was concentrated and the residue was dissolved in AcOH, purified by preparatory HPLC (YMC Combiscreen ODS-AQ, 50 x20mm ID S-5 micron, 120A ; 220nm) using a linear gradient and 0.06% TFA CH 3 CN /H 2 O. The pure fractions were combined, concentrated and lyophilized to provide the product compound 4012 as the TF salt (22 mg, 38%).
- Steps A and B were carried out as described above in example 6K but using 8- methyl-7-methoxy-4-quinolinol instead of 8-methyl-2-ethoxy-7-methoxy-4-quinolinol 2m2 in step A.
- Step C Acid 6n2 (100mg, 0.157mmol), HATU (71 mg, 0.187 mmol), DIPEA (0.07 ml_, 0.40 mmol) were dissolved in DMF (2 mL) and stirred for 1h.
- a solution of sulfamide 3a3 (55 mg, 0.331 mmol), DBU (0.1 mL, 0.71 mmol), DMAP (77mg, 0.63 mmol) and DIPEA (0.07 mL, 0.40 mmol) in DMF (2 mL) was made and added to it. Stirred the reaction mixture for 16h.
- This synthesis uses the intermediate 6n2 from Example 6N as starting material.
- the acid 6n2 50 mg, 0.074 mmol
- N,N-dimethyl sulfamide 39.2 mg, 0.316 mmol
- DIPEA 0.07 mL, 0.395 mmol
- DMAP 40 mg, 0.316 mmol
- DMF 2 mL
- DBU 0.05 mL, 0.356 mmol
- HATU 33 mg, 0.087 mmol
- the reaction mixture was stirred for 12h.
- reaction mixture was concentrated and the residue was dissolved in AcOH, purified by preparatory HPLC (YMC Combiscreen ODS-AQ, 50 x20mm ID S-5 micron, 120A ; 220nm) using a linear gradient and 0.06% TFA CH 3 CN / H 2 O.
- the pure fractions were combined, concentrated and lyophilized to provide the product compound 2002 as the TF salt (16.2 mg, 28%).
- Steps A and B were done as described above in example 6K but using the 8- thiomethoxy-4-quinolinol instead of 8-methyl-2-ethoxy-7-methoxy-4-quinolinol 2m2 in step A.
- Step C The acid 6p2 (72 mg, 0.113 mmol), N,N-dimethyl sulfamide (56 mg, 0.452 mmol), DIPEA (0.1 ml_, 0.565 mmol) and DMAP (55 mg, 0.452 mmol), were dissolved in DMF (5 mL) and to it was added DBU (0.07 mL, 0.508 mmol). Stirred for 5 min, then added HATU (47 mg, 0.124 mmol). The reaction mixture was stirred for 12h.
- reaction mixture was concentrated and the residue was dissolved in AcOH, purified by preparatory HPLC (YMC Combiscreen ODS-AQ, 50 x20mm ID S-5 micron, 120A ; 220nm) using a linear gradient and 0.06% TFA CH 3 CN / H 2 O. The pure fractions were combined, concentrated and lyophilized to provide compound 3001 as the TF salt (42 mg, 50%).
- Step B 1 M NaOH solution (0.8 mL, 0.8 mmol) was added to starting ester (6q2, 50 mg, 0.076 mmol) in a THF/MeOH/water solvent mixture (2:1 :1 ratio, 4 mL total volume) and allowed to stir overnight at rt.
- the reaction mixture was concentrated, diluted with DMSO and purified by prep-HPLC (H 2 O/CH 3 CN/ 0.06% TFA). The pure fractions were combined and the solvents removed by lyophilization to obtain a white solid (6q3, 38 mg, 78 %).
- MS ES+ 643.3.
- Step C HATU (25 mg, 0.066 mmol) was added to a solution of the acid (6q3, 25 mg, 0.039 mmol) and DIPEA (0.035 mL, 0.198 mmol) in DMF (1.4 mL) at rt. The solution immediately changed color from colourless to yellow. Then a solution of N 1 N- Case 13/128 WO
- Compound 6r1 was synthesized by sequential coupling as described, for example, in Example 6D, but using commercially available 4-R-benzyloxy proline instead of 4- hydroxyproline.
- the methyl ester was hydrolyzed under basic conditions as described in example 6K.
- the sulfamide 3c2 in a 2-dram vial was dried under house vacuum in a dessicator containing P 2 O 5 for a few days.
- the vial was fitted with a screw cap and septum.
- Anhydrous THF (0.5 ml_) was added to the vial and 3 vacuum-argon cycles were performed.
- LiHMDS 1.0 M in THF, 1.2 equiv. based on the amount of sulfamide present in each vial
- LiHMDS 1.0 M in THF, 1.2 equiv. based on the amount of sulfamide present in each vial
- LiHMDS 1.0 M in THF, 1.2 equiv. based on the amount of sulfamide present in each vial
- LiHMDS 1.0 M in THF, 1.2 equiv. based on the amount of sulfamide present in each vial
- LiHMDS 1.0 M in THF, 1.2 equiv. based on the amount of s
- Step 5 The acid 6v4 (50 mg, 0.09 mmol) was combined with HATU (65 mg, 0.17 mmol) and DIPEA (0.05 mL, 0.30 mmol) in DMF (0.8 mL) before being stirred at RT for 1h. Next, a solution of DBU (0.025 mL, 0.17 mmol), DMAP (21 mg, 0.17 mmol) and N,N-dimethylsulfamide (20 mg, 0.16 mmol) in DMF (1 mL) was added to the preactivated acid. The reaction mixture was stirred at RT for 48h. The reaction was diluted with DMSO and purified by preparative HPLC to give compound 6003 (9.3 mg, 16%) as a white solid.
- Step 1 To a solution of compound 6m2 (143 mg, 0.192 mmol) in CH 2 CI 2 (5 mL) at 0 0 C was added TEA (80.3 ⁇ L, 0.57 mmol) followed by the dropwise addition of isobutyl chloroformate (33 mL, 0.29 mmol). The reaction mixture was stirred at O 0 C for 30 min, then the ice bath was removed and stirring was continued at rt for 16h. On completion of the reaction as indicated by TLC, the mixture was concentrated to give a brown residue which was purified by flash chromatography (silica gel 40-60 ⁇ ) 1:1 Hex/EtOAc) to give 104 mg of compound 6w1 as a yellow oil (yield 74%).
- EIMS Case 13/128 WO
- reaction mixture was warmed slowly to rt and allowed to stir at that temperature for 12h, then was concentrated to dryness.
- the residue was dissolved in AcOH and purified by prep HPLC (Combiprep ODS-AQ, 20 x 50mm) to give 29 mg of compound 4038 as a white amorphous solid (48%).
- EXAMPLE 7 - NS3-NS4A PROTEASE ASSAY The enzymatic assay used to evaluate the present compounds is described in WO 00/09543 and WO 00/59929.
- EXAMPLE 8 CELL-BASED LUCIFERASE REPORTER HCV RNA REPLICATION ASSAY: The assay used to evaluate the activity of the present compounds in cells expressing a stable subgenomic HCV replicon is described in WO 2005/028501.
- Representative compounds according to this invention were found to be active when evaluated in the preceding enzymatic and cell based assays.
- EXAMPLE 9 - SPECIFICITY ASSAYS The specificity assays used to evaluate the selectivity of compounds according to this invention were performed as described in WO 00/09543 except that the assay buffer for the Elastase assay was comprised of 50 mM Tris-HCI pH 8, 0.25 M NaCitrate, Case 13/128 WO
- n-dodecyl ⁇ -d-maltoside 0.01% n-dodecyl ⁇ -d-maltoside, and 5.25% DMSO.
- Representative compounds according to this invention were found to be selective in that they do not show significant inhibition (no measurable activity at concentrations up to 30 ⁇ M) in the Human Leukocyte Elastase assay or Human Liver Cathepsin B assays.
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US7592336B2 (en) | 2005-05-10 | 2009-09-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7601686B2 (en) | 2005-07-11 | 2009-10-13 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2009140475A1 (en) * | 2008-05-15 | 2009-11-19 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
US7696242B2 (en) | 2004-07-20 | 2010-04-13 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor peptide analogs |
US7741281B2 (en) | 2005-11-03 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2010080874A1 (en) | 2009-01-07 | 2010-07-15 | Scynexis, Inc. | Cyclosporine derivative for use in the treatment of hcv and hiv infection |
US7763584B2 (en) | 2006-11-16 | 2010-07-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7767818B2 (en) | 2004-07-20 | 2010-08-03 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor dipeptide analogs |
US7772183B2 (en) | 2005-10-12 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2010101967A2 (en) | 2009-03-04 | 2010-09-10 | Idenix Pharmaceuticals, Inc. | Phosphothiophene and phosphothiazole hcv polymerase inhibitors |
US7816348B2 (en) | 2006-02-03 | 2010-10-19 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
WO2010132163A1 (en) | 2009-05-13 | 2010-11-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic compounds as hepatitis c virus inhibitors |
WO2011017389A1 (en) | 2009-08-05 | 2011-02-10 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv |
US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7897622B2 (en) | 2006-08-17 | 2011-03-01 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
JP2011509242A (en) * | 2007-12-21 | 2011-03-24 | アビラ セラピューティクス, インコーポレイテッド | HCV protease inhibitors and uses thereof |
US7935670B2 (en) | 2006-07-11 | 2011-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7939667B2 (en) | 2003-05-21 | 2011-05-10 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor compounds |
WO2011063076A1 (en) | 2009-11-19 | 2011-05-26 | Itherx Pharmaceuticals, Inc. | Methods of treating hepatitis c virus with oxoacetamide compounds |
US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2011075615A1 (en) | 2009-12-18 | 2011-06-23 | Idenix Pharmaceuticals, Inc. | 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors |
US8003604B2 (en) | 2006-11-16 | 2011-08-23 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP2364984A1 (en) | 2005-08-26 | 2011-09-14 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
WO2011123586A1 (en) | 2010-04-01 | 2011-10-06 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8044087B2 (en) | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8044023B2 (en) | 2008-05-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP2399575A2 (en) | 2006-08-11 | 2011-12-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods, uses and compositions for treatment of an infection by a virus of the family of flaviviridae through the farnesoid X receptor (FXR) inhibition |
US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8202996B2 (en) | 2007-12-21 | 2012-06-19 | Bristol-Myers Squibb Company | Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N- ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide |
US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
EP2476690A1 (en) | 2008-07-02 | 2012-07-18 | IDENIX Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8242140B2 (en) | 2007-08-03 | 2012-08-14 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
WO2012107589A1 (en) | 2011-02-11 | 2012-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment and prevention of hcv infections |
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 |
WO2012135581A1 (en) | 2011-03-31 | 2012-10-04 | Idenix Pharmaceuticals, Inc. | Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor |
US8283310B2 (en) | 2008-12-15 | 2012-10-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2012154321A1 (en) | 2011-03-31 | 2012-11-15 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8314141B2 (en) | 1996-10-18 | 2012-11-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
US8343477B2 (en) | 2006-11-01 | 2013-01-01 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
WO2013039855A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013039920A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections |
US8420596B2 (en) | 2008-09-11 | 2013-04-16 | Abbott Laboratories | Macrocyclic hepatitis C serine protease inhibitors |
WO2013056046A1 (en) | 2011-10-14 | 2013-04-18 | Idenix Pharmaceuticals, Inc. | Substituted 3',5'-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013133927A1 (en) | 2012-02-13 | 2013-09-12 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions of 2'-c-methyl-guanosine, 5'-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl n-(phenylmethyl)phosphoramidate] |
US8563505B2 (en) | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2013177188A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
WO2013177195A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphate prodrugs for hcv infection |
WO2013177219A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | D-amino acid compounds for liver disease |
US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2014058801A1 (en) | 2012-10-08 | 2014-04-17 | Idenix Pharmaceuticals, Inc. | 2'-chloro nucleoside analogs for hcv infection |
WO2014063019A1 (en) | 2012-10-19 | 2014-04-24 | Idenix Pharmaceuticals, Inc. | Dinucleotide compounds for hcv infection |
WO2014066239A1 (en) | 2012-10-22 | 2014-05-01 | Idenix Pharmaceuticals, Inc. | 2',4'-bridged nucleosides for hcv infection |
WO2014078427A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of rp-nucleoside analog |
WO2014078436A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of sp-nucleoside analog |
US8741837B2 (en) | 2007-12-21 | 2014-06-03 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
WO2014099941A1 (en) | 2012-12-19 | 2014-06-26 | Idenix Pharmaceuticals, Inc. | 4'-fluoro nucleosides for the treatment of hcv |
US8778877B2 (en) | 2007-12-21 | 2014-07-15 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
WO2014137926A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | 3'-deoxy nucleosides for the treatment of hcv |
WO2014137930A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
WO2014197578A1 (en) | 2013-06-05 | 2014-12-11 | Idenix Pharmaceuticals, Inc. | 1',4'-thio nucleosides for the treatment of hcv |
US8937041B2 (en) | 2010-12-30 | 2015-01-20 | Abbvie, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
WO2015017713A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
US8951964B2 (en) | 2010-12-30 | 2015-02-10 | Abbvie Inc. | Phenanthridine macrocyclic hepatitis C serine protease inhibitors |
US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2015042375A1 (en) | 2013-09-20 | 2015-03-26 | Idenix Pharmaceuticals, Inc. | Hepatitis c virus inhibitors |
US8993595B2 (en) | 2009-04-08 | 2015-03-31 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
WO2015061683A1 (en) | 2013-10-25 | 2015-04-30 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate and d-alanine thiophosphoramidate pronucleotides of nucleoside compounds useful for the treatment of hcv |
WO2015066370A1 (en) | 2013-11-01 | 2015-05-07 | Idenix Pharmaceuticals, Inc. | D-alanine phosphoramidate pronucleotides of 2'-methyl 2'-fluoro guanosine nucleoside compounds for the treatment of hcv |
WO2015081297A1 (en) | 2013-11-27 | 2015-06-04 | Idenix Pharmaceuticals, Inc. | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
WO2015095419A1 (en) | 2013-12-18 | 2015-06-25 | Idenix Pharmaceuticals, Inc. | 4'-or nucleosides for the treatment of hcv |
WO2015134780A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Solid prodrug forms of 2'-chloro-2'-methyl uridine for hcv |
WO2015134560A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Solid forms of a flaviviridae virus inhibitor compound and salts thereof |
WO2015134561A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions comprising a 5,5-fused heteroarylene flaviviridae inhibitor and their use for treating or preventing flaviviridae infection |
WO2015161137A1 (en) | 2014-04-16 | 2015-10-22 | Idenix Pharmaceuticals, Inc. | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
US9334279B2 (en) | 2012-11-02 | 2016-05-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP3020723A1 (en) | 2010-09-21 | 2016-05-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic proline derived hcv serine protease inhibitors |
US9409943B2 (en) | 2012-11-05 | 2016-08-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9499550B2 (en) | 2012-10-19 | 2016-11-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9580463B2 (en) | 2013-03-07 | 2017-02-28 | 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 |
US9694086B2 (en) | 2007-12-21 | 2017-07-04 | Celgene Car Llc | HCV protease inhibitors and uses thereof |
WO2017137423A1 (en) * | 2016-02-08 | 2017-08-17 | Synaffix B.V. | Improved sulfamide linkers for use in bioconjugates |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
EP3750544A2 (en) | 2011-11-30 | 2020-12-16 | Emory University | Jak inhibitors for use in the prevention or treatment of viral infection |
US11338043B2 (en) | 2016-02-08 | 2022-05-24 | Synaffix B.V. | Antibody-conjugates with improved therapeutic index for targeting HER2 tumours and method for improving therapeutic index of antibody-conjugates |
US11951175B2 (en) | 2016-02-08 | 2024-04-09 | Synaffix B.V. | Bioconjugates containing sulfamide linkers for use in treatment |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2305697A3 (en) | 2005-07-25 | 2011-07-27 | Intermune, Inc. | Macrocyclic inhibitors of Hepatitis C virus replication |
EP2079480B1 (en) * | 2006-10-24 | 2013-06-05 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
WO2010034105A1 (en) * | 2008-09-23 | 2010-04-01 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor compounds |
MX2011004007A (en) * | 2008-10-15 | 2011-05-19 | Intermune Inc | Therapeutic antiviral peptides. |
US8232246B2 (en) * | 2009-06-30 | 2012-07-31 | Abbott Laboratories | Anti-viral compounds |
TW201116540A (en) * | 2009-10-01 | 2011-05-16 | Intermune Inc | Therapeutic antiviral peptides |
US9957233B1 (en) | 2016-08-05 | 2018-05-01 | Calitor Sciences, Llc | Process for preparing substituted quinolin-4-ol compounds |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2445938A1 (en) * | 1998-08-10 | 2000-02-24 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
US6869964B2 (en) * | 2002-05-20 | 2005-03-22 | Bristol-Myers Squibb Company | Heterocyclicsulfonamide hepatitis C virus inhibitors |
WO2005046712A1 (en) * | 2003-11-12 | 2005-05-26 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2002248147B2 (en) | 2000-11-20 | 2006-04-06 | Bristol-Myers Squibb Company | Hepatitis C tripeptide inhibitors |
US6867185B2 (en) | 2001-12-20 | 2005-03-15 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
CA2369970A1 (en) | 2002-02-01 | 2003-08-01 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
CA2370396A1 (en) | 2002-02-01 | 2003-08-01 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
JP4271148B2 (en) | 2002-05-20 | 2009-06-03 | ブリストル−マイヤーズ スクイブ カンパニー | Substituted cycloalkyl P1 'hepatitis C virus inhibitors |
ATE503764T1 (en) | 2002-05-20 | 2011-04-15 | Bristol Myers Squibb Co | HEPATITIS C VIRUS INHIBITORS |
MY140680A (en) | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
US20050075279A1 (en) * | 2002-10-25 | 2005-04-07 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis C virus |
JP4682140B2 (en) | 2003-03-05 | 2011-05-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Hepatitis C inhibitor peptide analogues |
WO2004101605A1 (en) | 2003-03-05 | 2004-11-25 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibiting compounds |
AU2004240704B9 (en) * | 2003-05-21 | 2009-10-22 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor compounds |
-
2005
- 2005-06-22 WO PCT/CA2005/000967 patent/WO2006000085A1/en not_active Application Discontinuation
- 2005-06-22 EP EP05759498A patent/EP1763531A4/en not_active Withdrawn
- 2005-06-22 US US10/595,108 patent/US7705146B2/en active Active
- 2005-06-22 JP JP2007516924A patent/JP4914348B2/en not_active Expired - Fee Related
- 2005-06-22 CA CA2556669A patent/CA2556669C/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2445938A1 (en) * | 1998-08-10 | 2000-02-24 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
US6869964B2 (en) * | 2002-05-20 | 2005-03-22 | Bristol-Myers Squibb Company | Heterocyclicsulfonamide hepatitis C virus inhibitors |
WO2005046712A1 (en) * | 2003-11-12 | 2005-05-26 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
Non-Patent Citations (1)
Title |
---|
See also references of EP1763531A4 * |
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WO2009099596A2 (en) | 2008-02-04 | 2009-08-13 | Idenix Pharamaceuticals, Inc. | Macrocyclic serine protease inhibitors |
US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2009140475A1 (en) * | 2008-05-15 | 2009-11-19 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
CN102099353A (en) * | 2008-05-15 | 2011-06-15 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
US8044023B2 (en) | 2008-05-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP2476690A1 (en) | 2008-07-02 | 2012-07-18 | IDENIX Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US8357806B2 (en) | 2008-09-04 | 2013-01-22 | Bristol-Myers Squibb Company | Process for synthesizing substituted isoquinolines |
US8877929B2 (en) | 2008-09-04 | 2014-11-04 | Bristol-Myers Squibb Company | Process for synthesizing substituted isoquinolines |
US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
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 |
US9309279B2 (en) | 2008-09-11 | 2016-04-12 | Abbvie Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US8044087B2 (en) | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8563505B2 (en) | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8283310B2 (en) | 2008-12-15 | 2012-10-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2010080874A1 (en) | 2009-01-07 | 2010-07-15 | Scynexis, Inc. | Cyclosporine derivative for use in the treatment of hcv and hiv infection |
WO2010101967A2 (en) | 2009-03-04 | 2010-09-10 | Idenix Pharmaceuticals, Inc. | Phosphothiophene and phosphothiazole hcv polymerase inhibitors |
US8993595B2 (en) | 2009-04-08 | 2015-03-31 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
WO2010132163A1 (en) | 2009-05-13 | 2010-11-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic compounds as hepatitis c virus inhibitors |
US9284307B2 (en) | 2009-08-05 | 2016-03-15 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors |
WO2011017389A1 (en) | 2009-08-05 | 2011-02-10 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv |
WO2011063076A1 (en) | 2009-11-19 | 2011-05-26 | Itherx Pharmaceuticals, Inc. | Methods of treating hepatitis c virus with oxoacetamide compounds |
WO2011075615A1 (en) | 2009-12-18 | 2011-06-23 | Idenix Pharmaceuticals, Inc. | 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors |
WO2011123586A1 (en) | 2010-04-01 | 2011-10-06 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
EP3020723A1 (en) | 2010-09-21 | 2016-05-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic proline derived hcv serine 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 |
US9353100B2 (en) | 2011-02-10 | 2016-05-31 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections |
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 |
WO2012107589A1 (en) | 2011-02-11 | 2012-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment and prevention of hcv infections |
US9243025B2 (en) | 2011-03-31 | 2016-01-26 | Idenix Pharmaceuticals, Llc | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2012135581A1 (en) | 2011-03-31 | 2012-10-04 | Idenix Pharmaceuticals, Inc. | Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor |
WO2012154321A1 (en) | 2011-03-31 | 2012-11-15 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US9527885B2 (en) | 2011-05-05 | 2016-12-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US10201541B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8951985B2 (en) | 2011-09-12 | 2015-02-10 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013039855A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013039920A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013056046A1 (en) | 2011-10-14 | 2013-04-18 | Idenix Pharmaceuticals, Inc. | Substituted 3',5'-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections |
EP3750544A2 (en) | 2011-11-30 | 2020-12-16 | Emory University | Jak inhibitors for use in the prevention or treatment of viral infection |
WO2013133927A1 (en) | 2012-02-13 | 2013-09-12 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions of 2'-c-methyl-guanosine, 5'-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl n-(phenylmethyl)phosphoramidate] |
WO2013177219A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | D-amino acid compounds for liver disease |
WO2013177188A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
WO2013177195A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphate prodrugs for hcv infection |
WO2014058801A1 (en) | 2012-10-08 | 2014-04-17 | Idenix Pharmaceuticals, Inc. | 2'-chloro nucleoside analogs for hcv infection |
US9499550B2 (en) | 2012-10-19 | 2016-11-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2014063019A1 (en) | 2012-10-19 | 2014-04-24 | Idenix Pharmaceuticals, Inc. | Dinucleotide compounds for hcv infection |
WO2014066239A1 (en) | 2012-10-22 | 2014-05-01 | Idenix Pharmaceuticals, Inc. | 2',4'-bridged nucleosides for hcv infection |
US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9334279B2 (en) | 2012-11-02 | 2016-05-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9598433B2 (en) | 2012-11-02 | 2017-03-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9409943B2 (en) | 2012-11-05 | 2016-08-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2014078427A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of rp-nucleoside analog |
WO2014078436A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of sp-nucleoside analog |
WO2014099941A1 (en) | 2012-12-19 | 2014-06-26 | Idenix Pharmaceuticals, Inc. | 4'-fluoro nucleosides for the treatment of hcv |
WO2014137926A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | 3'-deoxy nucleosides for the treatment of hcv |
WO2014137930A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
US9580463B2 (en) | 2013-03-07 | 2017-02-28 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
WO2014197578A1 (en) | 2013-06-05 | 2014-12-11 | Idenix Pharmaceuticals, Inc. | 1',4'-thio nucleosides for the treatment of hcv |
WO2015017713A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
WO2015042375A1 (en) | 2013-09-20 | 2015-03-26 | Idenix Pharmaceuticals, Inc. | Hepatitis c virus inhibitors |
WO2015061683A1 (en) | 2013-10-25 | 2015-04-30 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate and d-alanine thiophosphoramidate pronucleotides of nucleoside compounds useful for the treatment of hcv |
WO2015066370A1 (en) | 2013-11-01 | 2015-05-07 | Idenix Pharmaceuticals, Inc. | D-alanine phosphoramidate pronucleotides of 2'-methyl 2'-fluoro guanosine nucleoside compounds for the treatment of hcv |
WO2015081297A1 (en) | 2013-11-27 | 2015-06-04 | Idenix Pharmaceuticals, Inc. | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
WO2015095419A1 (en) | 2013-12-18 | 2015-06-25 | Idenix Pharmaceuticals, Inc. | 4'-or nucleosides for the treatment of hcv |
US10105365B2 (en) | 2014-01-03 | 2018-10-23 | Abbvie Inc. | Solid antiviral dosage forms |
US9744170B2 (en) | 2014-01-03 | 2017-08-29 | Abbvie Inc. | Solid antiviral dosage forms |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
WO2015134780A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Solid prodrug forms of 2'-chloro-2'-methyl uridine for hcv |
WO2015134561A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Pharmaceutical compositions comprising a 5,5-fused heteroarylene flaviviridae inhibitor and their use for treating or preventing flaviviridae infection |
WO2015134560A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Solid forms of a flaviviridae virus inhibitor compound and salts thereof |
WO2015161137A1 (en) | 2014-04-16 | 2015-10-22 | Idenix Pharmaceuticals, Inc. | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
WO2017137423A1 (en) * | 2016-02-08 | 2017-08-17 | Synaffix B.V. | Improved sulfamide linkers for use in bioconjugates |
US10874746B2 (en) | 2016-02-08 | 2020-12-29 | Synaffix B.V. | Sulfamide linkers for use in bioconjugates |
US11338043B2 (en) | 2016-02-08 | 2022-05-24 | Synaffix B.V. | Antibody-conjugates with improved therapeutic index for targeting HER2 tumours and method for improving therapeutic index of antibody-conjugates |
US11590239B2 (en) | 2016-02-08 | 2023-02-28 | Synaffix B.V. | Antibody-conjugates with improved therapeutic index for targeting CD30 tumours and method for improving therapeutic index of antibody-conjugates |
US11951175B2 (en) | 2016-02-08 | 2024-04-09 | Synaffix B.V. | Bioconjugates containing sulfamide linkers for use in treatment |
US11957763B2 (en) | 2016-02-08 | 2024-04-16 | Synaffix B.V. | Sulfamide linkers for use in bioconjugates |
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US20060258868A1 (en) | 2006-11-16 |
CA2556669A1 (en) | 2006-01-05 |
CA2556669C (en) | 2012-05-01 |
US7705146B2 (en) | 2010-04-27 |
JP2008504240A (en) | 2008-02-14 |
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EP1763531A4 (en) | 2009-07-01 |
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