WO2004072243A2 - Inhibiteurs macrocycliques de la serine protease de l'hepatite c - Google Patents

Inhibiteurs macrocycliques de la serine protease de l'hepatite c Download PDF

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WO2004072243A2
WO2004072243A2 PCT/US2004/003479 US2004003479W WO2004072243A2 WO 2004072243 A2 WO2004072243 A2 WO 2004072243A2 US 2004003479 W US2004003479 W US 2004003479W WO 2004072243 A2 WO2004072243 A2 WO 2004072243A2
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substituted
aryl
heteroaryl
group
heterocycloalkyl
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PCT/US2004/003479
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English (en)
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WO2004072243A3 (fr
Inventor
Zenwei Miao
Ying Sun
Frank Wu
Suanne Nakajima
Guoyou Xu
Yat Sun Or
Zhe Wang
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Enanta Pharmaceuticals, Inc.
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Priority claimed from US10/384,120 external-priority patent/US20040180815A1/en
Application filed by Enanta Pharmaceuticals, Inc. filed Critical Enanta Pharmaceuticals, Inc.
Priority to AU2004211637A priority Critical patent/AU2004211637C1/en
Priority to JP2006503381A priority patent/JP2007524576A/ja
Priority to CNA2004800092686A priority patent/CN1771050A/zh
Priority to CA002515216A priority patent/CA2515216A1/fr
Priority to EP04709020A priority patent/EP1590442A4/fr
Publication of WO2004072243A2 publication Critical patent/WO2004072243A2/fr
Publication of WO2004072243A3 publication Critical patent/WO2004072243A3/fr

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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
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • 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
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel macrocycles having activity against hepatitis C virus (HCV) and useful in the treatment of HCV infections. More particularly, the invention relates to macrocyclic compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
  • HCV hepatitis C virus
  • HCV BACKGROUND OF THE INVENTION
  • HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world. , _ .
  • anti-HCV therapeutics There are considerable barriers to the development of anti-HCV therapeutics, which include, but are not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, the high incident rate of the virus developing drug-resistant mutants, and the lack of reproducible infectious culture systems and small-animal models for HCV replication and pathogenesis. In a majority of cases, given the mild course of the infection and the complex biology of the liver, careful consideration must be given to antiviral drugs, which are likely to have significant side effects.
  • NS3 hepatitis C non-structural protein-3
  • HCV is a flaviridae type RNA virus.
  • the HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids.
  • the HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions.
  • the P7 protein is of unknown function and is comprised of a highly variable sequence.
  • NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase- dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • the NS3.4A protease is responsible for cleaving four sites on the viral polyprotein.
  • the NS3-NS4A cleavage is autocatalytic, occurring in cis.
  • the remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans.
  • NS3 is a serine protease which is structurally classified as a chymotrypsin-like protease. While the NS serine protease possesses proteolytic activity by Itself, the HCV protease enzyme is not an efficient enzyme in terms of catalyzing polyprotein cleavage.
  • a general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus.
  • Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002). More relevant patent disclosures describing the synthesis of HCV protease inhibitors are: WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999); US5861297 (1999).
  • the present invention relates to novel macrocyclic compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said macrocyclic compounds.
  • the present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • R 1 is selected form the group consisting of H, C ⁇ -C 6 alkyl, C3-C12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
  • R 2 is selected from the group consisting of H, Ci-C ⁇ alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamlno, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; . " L-.. l .-J . l l--. ..-horizon ... I .1 ,1' _ -. __ - - . -
  • R 3 and R 4 are each Independently selected from the group consisting of hydrogen, OH, CH 3 , CN, SH, halogen, N0 , NH 2 , amide, methoxy, trifluoromethoxy, and trifluoromethyl;
  • E represents either a single bond or a double bond between the two carbon atoms attached thereto;
  • W is a substituted or unsubstituted heterocyclic ring system.
  • E represents a double bond, resulting in Formula 11 or pharmaceutically acceptable salts, esters, or prodrugs thereof:
  • E represents a single bond, resulting in Formula III or pharmaceutically acceptable salts, esters, or prodrugs thereof:
  • W is selected from the group consisting of:
  • Q' Is selected from the group consisting of: absent, -CH2-, and -NH-;
  • Y is ) selected from the group consisting of: H, C ⁇ -C 6 alkyl, ary substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
  • W is selected from the group consisting of: and --L ;
  • X, Y, and Z are independently selected from the group consisting of H, N 3 , halogen, C ⁇ C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, Ci-C ⁇ alkynyl, substituted alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl
  • R 6 is NH-C(0)-OR 8 where R 8 is C C 6 alkyl or C 3 -C 6 cycloalkyl; (c) N(R 5 ) 2 , NH-C(0)-R 5 , or NH-C(0)-NH-R 5 where R 5 is independently H, C ⁇ -C 6 alkyl or C 3 -C 6 cycloalkyl, C 6 or C 10 aryl, C 7 -C 14 aralkyl, heterocyclo or (lower alkyl)- heterocyclo;
  • each R 11 is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl,- heterocycloalkylalkyl aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyi; dlarylaminoalkyl, wherein any of the foregoing can be .
  • each R 12 is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylamlnoalkyl, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl;
  • an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having from five to sixteen ring atoms and up to four ring hetero atoms selected from O, N and S, wherein said ring system is optionally substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl, and R 10 ;
  • each R 10 is independently alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heretoaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylamlnoalkyl,
  • each R 12 is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylamlnoalkyl, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl;
  • W is an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having from five to sixteen ring atoms and up to four ring hetero atoms selected from O, N and S, wherein said ring system is optionally substituted with up to three ring substituents selected from
  • W is an aliphatic heteromonocyclic jing system having from five to seven ring atoms and up to four ring hetero atoms selected from O, N and S, wherein said ring system is optionally
  • the compound of any of the formulae herein wherein said optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of pyrrolidines, pyrazolidines, pyrrolines, tetrahydrothiophenes, dihydrothiophenes,
  • the compound of any of the formulae herein wherein said optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of pyridines, piperidines, dihydropyridines, tetrahydropyridines, dihydropyrans, tetrahydropyrans, dioxanes, piperazines, dihydropyrimidines, tetrahydropyrimidines,
  • W is an aliphatic heterobicyclic ring system having from five to sixteen ring atoms and up to four ring hetero atoms selected from O, N and S, wherein said ring system is optionally substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl and R 10 .
  • heteromonocyclic, heterobicyclic or heterotricyclic ring system having from five to sixteen ring atoms and up to four ring hetero atoms selected from O, N and S, wherein said ring system is optionally substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl and R 10 ;
  • W is an aromatic heteromonocyclic ring system having from five to seven ring atoms and up to four ring hetero atoms selected from O, N and S, wherein said ring system is optionally substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl and R-io;
  • aromatic heteromonocyclic ring system is selected from the group consisting of pyrroles, pyrazoles, porphyrins, furans, thiophenes, pyrazoles, imidazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, and isothiazoles;
  • the compound of any of the formulae herein wherein said optionally substituted ) aromatic heteromonocyclic ring system has six ring atoms and 1, 2 or 3 ring hetero atoms selected from O, N and S;
  • W is an aromatic i heterobicyclic ring system having from eight to twelve ring atoms and up to four ring hetero atoms selected from O, N and S, wherein said ring system is optionally substituted with up to three ring substituents selected from the group consisting of OH,
  • indazoles indoles, isoindoles, isoquinolines, phthalazines, purines, pyrrolo pyridines, quinazolines, quinolines, quinoxalines, thianaphthenes, and xanthines;
  • W is an aromatic heterotricyclic ring system having from ten to sixteen ring atoms and up to four ring
  • ⁇ hetero atoms selected from O, N and S, wherein said ring system is optionally substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl, R 10 and R ⁇ ; and
  • aromatic heterotricyclic ring system is selected from the group consisting of carbazoles, bibenzofurans, psoralens, dibenzoth ⁇ ophenes, phenazines, thianthrenes, phenanthrolines, phenanthridines.
  • W is selected from the group consisting of
  • Q' is selected from the group consisting of absent, -CH 2 -, and -NH-;
  • R 1 is selected from the group consisting of H, -C 6 alkyl, C3-C12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
  • R 2 is selected from the group consisting of H, C C ⁇ alkyl, C3-C12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl
  • R 3 and R 4 are hydrogen.
  • W is selected from the group consisting of
  • Q' is selected from the group consisting of absent, -CH 2 -, and -NH-;
  • R 1 is selected from the group consisting of H, Q-C ⁇ alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
  • R 2 is selected from the group consisting of H, Ci-C ⁇ alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl
  • G is hydroxyl
  • R 3 and R 4 are hydrogen
  • R 3 and R 4 are hydrogen
  • R 1 is selected from the group consisting of H, -C ⁇ alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
  • R 2 is selected from the group consisting of H, Q-C ⁇ alkyl, C 3 -C1 2 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl; ⁇
  • R 3 and R 4 are hydrogen
  • R 3 and R 4 are hydrogen
  • R 3 and R 4 are hydrogen
  • R 3 and R 4 are hydrogen.
  • R 1 is selected from the group consisting of H, alkyl, C3-C12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
  • R 2 is selected from the group consisting of H, C
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl
  • R 3 and R 4 are hydrogen
  • R 3 and R 4 are hydrogen
  • R 3 and R 4 are hydrogen
  • X, Y, and Z are independently selected from the group consisting of hydrogen, N 3 , halogen, Ci-C ⁇ alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, Q-C ⁇ alkynyl, substituted alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl
  • R 1 is hydrogen, C
  • R 2 is hydrogen, Ci-C ⁇ alkyl, C 3 -C1 2 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; and
  • R 3 and R 4 are each independently hydrogen or methyl
  • X, Y, and Z are independently selected from the group consisting of hydrogen, N 3 , halogen, C C ⁇ alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, C C ⁇ alkynyl, substituted alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl,
  • R 1 is hydrogen, C C 6 alkyl, C3-C1 2 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;
  • R 2 is hydrogen, C C 6 alkyl, C 3 -C12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; and
  • R 3 and R 4 are each independently hydrogen or methyl
  • R 3 and R 4 are hydrogen
  • L is selected from the group consisting of: absent, -S-, -SCH 2 -, -SCH2CH2-, -S(0)z-, -S(0)2CH2CH2-, -S(O)-, -S(0)CH 2 CH2-, -O-, -OCH2-,
  • Q' is selected from the group consisting of: absent, -CH 2 -, and -NH-;
  • Y is selected from the group consisting of: H, C ⁇ -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
  • j 0, 1, 2, 3, or 4;
  • m 0, 1, or 2;
  • s 0, 1 or 2;
  • R 1 is selected from the group consisting of: H, Ci-C ⁇ alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12
  • Q' is selected from the group consisting of: absent, -CH2-, and -NH-;
  • Q' is selected from the group consisting of: absent, -CH 2 -, and -NH-;
  • Y is selected from the group consisting of: H, Ci-C ⁇ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
  • Compounds of Formula II, wherein A is -(C 0)-0-R 1 , R 1 is selected from the group consisting of H, Ci-C ⁇ alkyl, C 3 -C 12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, substituted
  • R 1 is selected from the group consisting of H, Ci-C ⁇ alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C1 2 cycloalkyl, aryl,
  • Q' is selected from the group consisting of: absent, -CH 2 -, and -NH-;
  • R 1 is selected from the group consisting of H, C ⁇ -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
  • W is Q is selected from the group consisting of: absent, -GH2-,
  • W is selected from the group consisting of:
  • W is selected from the group consisting of: ;
  • W is - ;
  • W is selected from the group consisting of: ;
  • a compound of Formula III wherein A is G is hydroxyl; L is
  • W is wherein V, X, Y, and Z are each independently selected from: a) -Ci-C ⁇ alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; b) -C 2 -C6 alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; c) -C 2 -C 6 alkynyl containing 0, 1 , 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from hal
  • Another aspect is a compound of formula I, wherein W wherein X, Y, and Z are each independently selected from: a) -C ⁇ -C 6 alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; b) -C 2 -C 6 alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; c) -C 2 -C 6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from ⁇ r w
  • Y and Z are taken together with the carbons to which they are attached to for a cyclic moiety selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; All remaining substituents are as listed above.
  • Another aspect is a method for making a compound of Formula I herein, comprising the steps of: (i) reacting a proline derivative of formula VI:
  • P is a nitrogen-protecting group (e.g., BOC);
  • L is a leaving group (e.g., halide, OMs);
  • R is optionally substituted alkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; with a nucleophilic heterocyclic compound; and (ii) converting the resulting compound to a compound of Formula I as delineated herein.
  • Another aspect is a method for making a compound of Formula I herein, comprising the steps of: (i) reacting a compound of formula VII:
  • L is a leaving group (e.g., halide, OMs);
  • A is a nitrogen protecting group (e.g., BOC); and the remaining variables are as defined for formula I; with a nucleophilic heterocyclic compound; and (ii) converting the resulting compound to a compound of Formula I as delineated herein.
  • BOC nitrogen protecting group
  • the invention relates to a method for making a compound of any of the formulae delineated herein (e.g., Formulae I to VII with substituent variables as defined anywhere herein) or a pharmaceutically acceptable salt, ester or prodrug thereof, comprising the steps of: (i) reacting a proline derivative described herein (including that having a mesylate substituent) with a nucleophilic form (e.g., protonated or corresponding metal salt form) of a heterocyclic compound; and (ii) converting the resulting compound to a compound of any of the formulae delineated herein.
  • the method includes reacting any one or more intermediate compounds as described herein, or includes any one or more steps or reagents or combination of transformations as specifically delineated in the examples and schemes herein.
  • the invention in another aspect, relates to a method of making a pharmceutical composition
  • a method of making a pharmceutical composition comprising combining a compound of any of the formulae herein or a pharmaceutically acceptable salt, ester or prodrug thereof, with a pharmaceutically acceptable earner.
  • Another aspect is a compound of formulae VI or VII wherein L is OMs and A and the remaining variables are as defined for any of the formulae (e.g., I, II, III) herein.
  • a first embodiment of the invention is a compound represented by Formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable earner or excipient.
  • the compounds may be of any of the formulae delineated herein (including any substituent variables as defined anywhere delineated herein) wherein W is selected from the following aromatics, which may optionally be substituted:
  • the compounds may be of any of the formulae delineated herein (including any substituent variables as defined anywhere delineated herein) wherein W is selected from the following non-aromatics, which may be optionally substituted:
  • Another embodiment of the invention is a compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, represented by Formula II as described above where W is a tetrazole or derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment of the invention is a compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, represented by Formula III as described above wherein W is a tetrazole, or derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • Exemplary tetrazolyl macrocyclic compounds and associated methods of the invention are disclosed in US Provisional Patent application no. (conversion of US 10/365,854), filed February 13, 2003.
  • Representative subgenera of the invention include, but are not limited to:
  • R 1 is selected from the group consisting of H, C ⁇ -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
  • Q is selected from the group consisting of: absent, ⁇ CF- 2 -, -O-, -NH-,
  • Q' is selected from the group consisting of: absent, -CH 2 -, and -NH-;
  • Q' is selected from the group consisting of: absent, -CH 2 -, and -NH-;
  • R 1 is selected from the group consisting of H, C ⁇ -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
  • R 1 is selected from the group consisting of H, Ci-C ⁇ alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
  • Q' is selected from the group consisting of: . -
  • Q' is selected from the group consisting of: absent, -CH 2 -, and -NH-;
  • R 1 is selected from the group consisting of H, C ⁇ -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
  • W is Q is selected from the group consisting of: absent, -CH 2 -,
  • Representative compounds of the invention include, but are not limited to, the following compounds:
  • Another embodiment of the invention is a compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, represented by Formula II as described above where W is a triazole or derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment of the invention is a compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, represented by Formula III as described above _
  • W is a triazole or derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • Exemplary triazole macrocyclic compounds and associated methods of the invention are disclosed in US Provisional Patent application no. (conversion of US 10/360,947), filed February 7, 2003.
  • Representative subgenera of the invention include, but are not limited to:
  • X and Y are independently selected from the group consisting of:
  • a compound of Formula II, wherein A is -(C O)-0-R 1 , R 1 is selected from the group consisting of H, Ci-C ⁇ alkyl, C 3 -C12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
  • X and Y are independently selected from the group consisting of:
  • W is selected from the group consisting of: X or -i ;
  • N N
  • N N
  • Another embodiment of the invention is a compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, represented by Formula II as described above where W is a pyridazinone or derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment of the invention is a compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, represented by Formula III as described above where W is a pyridazinone or derivative thereof, in combination with a pharmaceutically acceptable earner or excipient.
  • Exemplary pyridazinone macrocyclic compounds and associated methods of the invention are disclosed in US Provisional Patent application no. (conversion of US 10/384,120), filed March 7, 2003.
  • Representative subgenera of the invention include, but are not limited to:
  • W -J- , and R 3 and R 4 are hydrogen;
  • Representative compounds of the invention include, but are not limited to, the following compounds:
  • Additional compounds of the invention are those of formula I, II or II, wherein W is a substituted benzimidazolyl, including those wherein the benzimidazolyl is substituted with 1 or 2 heteroaryl groups, each of which may be independently substituted. Examples of such compounds include:
  • compositions of the present invention may further contain other anti-HCV agents.
  • anti-HCV agents include, but are not limited to, or-interferon, yff-interferon, ribavirin, and amantadine.
  • compositions of the present invention may further contain other HCV protease inhibitors.
  • compositions of the present invention may further comprise inhibitors) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • inhibitors of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • the present invention includes methods of treating hepatitis C infections in a subject in need of such treatment by administering to said subject an anti-HCV virally effective amount of the pharmaceutical compounds or compositions of the present invention.
  • the methods can further include administration of an additional therapeutic agent, including another antiviral agent or an anti-HCV agent.
  • the additional agent can be co-administered, concurrently administered or _
  • the methods herein can further include the step of identifying that the subject is in need of treatment for hepatitis C infection.
  • the identification can be by subjective (e.g., health care provider determination) or objective (e.g., diagnostic test) means.
  • C x -C y is used in conjunction with the name of a carbon-containing group to indicate that the group contains from x to y carbon atoms where x and y are whole numbers.
  • halo and "halogen,” as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals. Examples include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, octyl, decyl, dodecyl radicals.
  • substituted alkyl refers to an "alkyl” group substituted by independent replacement of one or more (e.g., 1 , 2, or 3) of the hydrogen atoms thereon with F, CI, Br, I, OH, N0 2 , CN, C,-C 6 -alkyl-OH, C(0)-CrC 6 -alkyl, OCH 2 -(C 3 -Ci 2 - cycloalkyl), C(0)-aryl, C(0)-heteroaryl, COralkyl, C0 2 -aryl, C0 2 -heteroaryl, CONH 2 , CONH-(CrC6-alkyl), CONH-aryl, CONH-heteroaryl, OC(OHd-C 6 -alkyl), OC(0)-aryl, OC(0)-heteroaryl, OC ⁇ 2 -alkyl, OCO ⁇ -aryl, OC ⁇ 2-hetero
  • cycloalkyl CF 3 , CH CF 3 , CHC1 2 , CH 2 NH2,CH 2 SO2CH 3 H, C,-C 6 alkyl, halo alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C ⁇ 2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, Q-Ce- alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C
  • haloalkyl refers to an acyclic, straight or branched chain alkyl substituent having one or more hydrogen substituted for a halogen selected from bromo, chloro, fluoro, or iodo.
  • thioalkyl refers to an acyclic, stright or branched chain alkyl substituent containing a thiol group, such as, for example and not limitation, thiopropyl.
  • alkoxy refers to an alkykjroup, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert- butoxy, neopentoxy and n-hexoxy.
  • alkenyl denotes a monovalent group derived by the removal of a single hydrogen atom from a hydrocarbon moiety having at least one carbon-carbon double bond.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • substituted alkenyl refers to an "alkenyl” group substituted by independent replacement of one or more of the hydrogen atoms thereon with F, CI, Br, I, OH, N0 2 , CN, C r C 6 -alkyl-OH, C(OMC.-C 6 -alkyl), OCH2-(C 3 -C 12 - cycloalkyl), C(0)-aryl, C(0)-heteroaryl, CO2-alkyl, C0 2 -aryl, COrheteroaryl, CONH 2 , CONH-C,-C 6 -alkyl, CONH-aryl, CONH-heteroaryl, OC(OMC C 6 -alkyl), OC(0)-aryl, OC(0)-heteroaryl, OC ⁇ 2 -alkyl, OCO aryl, OC02-heteroaryl,OCONH 2 , OCONH- -Ce-
  • cycloalkyl substituted C 3 -Ci 2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C
  • alkynyl denotes a monovalent group derived by the removal of a single hydrogen atom from a hydrocarbon moiety having at least one carbon-carbon triple bond.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1 -propynyl, 1 -butynyl, and the like.
  • substituted alkynyl refers to an "alkynyl” group substituted by independent replacement of one or more of the hydrogen atoms thereon with F, CI, Br, I, OH, N0 2 , CN, C-C ⁇ -alkyl-OH, C(O)-(C r C 6 -alkyl), OCH 2 -(C 3 -C 12 - cycloalkyl), C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, C0 2 -aryI, C0 2 -heteroaryl, CONH 2 , CONH-(C,-C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC(O)-(C C 6 -alkyl), OC(0)-aryl, OC(O)-heteroaryl, OCO alkyl, OC0 2 -aryl, OCO 2 -heteroaryl,
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetra hyd rona phthyl, indanyl, idenyl and the like.
  • substituted aryl refers to an aryl group, as defined herein, substituted by Independent replacement of one or more of the hydrogen atoms thereon with F, CI, Br, I, OH, N0 2 , CN, d-Ce-alkyl-OH, C(0)-(C,-C 6 -alkyl), OCH 2 -(C 3 - - -
  • Circycloalkyl C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, COraryl, C0 2 -heteroaryl, CONH 2 , CONH-(C,-C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC(0)-(C ⁇ -C 6 -aIkyl), OC(0)-aryl, OC(O)-heteroaryl, OCOralkyl, OCOraryl, OCOrheteroaryl, OCONH 2 , OCONH-(C,-C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC(OMC,-C6-alkyl), NHC(O)- aryl, NHC(0)-heteroaryl, NHC0 2 -alkyl, NHC0 2 -aryl, NHCOrheteroaryl, NHCONH 2 , NHCONH-(C,
  • arylalkyl refers to a CI-C3 alkyl or CI-C6 alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • substituted arylalkyl refers to an arylalkyl group, as previously defined, substituted by independent replacement of one or more of the hydrogen atoms thereon with F, CI, Br, I, OH, NO 2 , CN, Q-Ce-alkyl-OH, C(Oj-C C 6 - alkyl, OCHH rCircycloalkyl), C(0)-aryl, C(0)-heteroaryl, COralkyl, COraryl, COr heteroaryl, CONH 2 , CONH-C,-C 6 -alkyl, CONH-aryl, CONH-heteroaryl, OC(OMC C 6 - alkyl), OC(0)-aryl, OC(0)-heteroaryl, OCOralkyl, OCOraryl, OCOrheteroaryl, OCONH 2 , OCONH-(C,-C 6 -alkyl), OCONH-ary
  • cycloalkyl denotes a monovalent group derived by the removal of a single hydrogen atom from a monocyclic or bicyclic saturated carbocyclic ring , compound. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • substituted cycloalkyl refers to a cycloalkyl group as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with F, CI, Br, I, OH, N0 2 , CN, C r C 6 -alkyl-OH, CfOM -Ce- alkyl), OCHHCrCircycloalkyl), C(0)-aryl, C(O)-heteroaryl, C0 2 -alkyl, C0 2 -aryl, COr heteroaryl, CONH 2 , CONH-(C r C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC(0)-(C ⁇ -C ⁇ -- alkyl), OC(0)-aryl, OC(0)-heteroaryl, OCOralkyl, OCOraryl, OC02-heteroaryl, OCONH2, OCONH-CI-
  • heterocyclo and “heterocyclic” as used herein, refer to a monovalent substituent derived by removal of a hydrogen from a three to seven-membered saturated or unsaturated (including aromatic) cycle having 1 to 4 non-carbon ring atoms selected from the heteroatoms consisting of N, O, and S.
  • suitable heterocycles include but are not limited to tetrahydrofuran, thiophene, diazepine, isoxazole, piperidine, dioxane, morpholine, and pyrimidine.
  • the term also includes a heterocycle as defined herein fused to one or more other cycles whether hetero or carbocyclic.
  • One example is thiazolo[4,5-b]-pyridine.
  • heterocycloalkyl aliphatic heteromonocyclic ring system
  • aliphatic heterobicyclic ring system aliphatic heterotricyclic ring system
  • heteroaryl aliphatic heteromonocyclic ring system
  • aromatic heterobicyclic ring system aromatic heterotricyclic ring system
  • heterocycloalkyl refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6- membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quatemized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring.
  • heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, mo ⁇ holinyl, thiazolidinyl, isothiazolidinyl, and tetra hydrofuryl.
  • substituted heterocycloalkyl refers to a heterocycloalkyl group, as previously defined, substituted by independent replacement of one or more of the hydrogen atoms thereon with F, CI, Br, I, OH, NO 2 , CN, C 1 -C.
  • aliphatic heteromonocyclic ring system is intended to mean a ring system containing a non-aromatic ring that includes at least one ring hetero (i.e., non-carbon) atom selected from O, N and S.
  • aliphatic heterobicyclic ring system is intended to mean a ring system containing a two fused rings, at least one of which is a non-aromatic ring that includes at least one ring hetero (i.e., non- carbon) atom selected from O, N and S.
  • aliphatic heterotricyclic ring system is intended to mean a ring system containing three fused rings, at least one of which is a non-aromatic ring that includes at least one ring hetero (i.e., non-carbon) atom selected from O, N and S.
  • ring hetero i.e., non-carbon
  • the aliphatic heterocyclic ring systems can possess any degree of saturation (i.e., double or triple bonds) provided that none of the heteroatom-containing constituent rings are aromatic.
  • structures such as indoline, which contains a non-aromatic heterocyclic ring (i.e., a pyrroline ring) fused to an aromatic carbocyclic ring (specifically, a phenyl ring), and phthalimide, are examples of an "aliphatic heterobicyclic ring systems.”
  • aromatic heteromonocyclic ring system is intended to mean an aromatic ring that includes at least one ring hetero (i.e., non-carbon) atom selected from O, N and S.
  • aromatic heterobicyclic ring system is intended to mean an aromatic ring system containing two fused rings that includes at least one ring hetero (i.e., non-carbon) atom selected from O, N and S.
  • aromatic heterotricyclic ring system is intended to mean an aromatic ring system containing three fused rings that includes at least one ring hetero (i.e., non-carbon) atom selected from O, N and S.
  • Substituent atoms of the aromatic heterocyclic ring systems can, together with additional atoms, form further fused ring structures that are not aromatic.
  • 5,6, 7,8 tetrahydroisoquinoline is an example of an aromatic heterobicyclic ring system
  • 1,2,3,4 tetrahydroisoquinoline is an example of an aliphatic heterobicyclic ring system.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which at least one ring atom is selected from S, O and Nand the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • substituted heteroaryl refers to a heteroaryl group as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with F, CI, Br, I, OH, N0 2 , CN, C r C 6 -alkyl-OH, C(0)-C r C 6 - alkyl, OCHr(C 3 -C 1 rcycloalkyl), C(0)-aryl, C(0)-heteroaryl, COralkyl, C0 2 -aryl, C0 2 - heteroaryl, CONH 2 , CONH-(C
  • heteroarylalkyl refers to a Q-C 3 alkyl or Ci-C ⁇ alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimldinylethyl and the like.
  • substituted heteroarylalkyl refers to a heteroarylalkyl group, as previously defined, substituted by independent replacement of one or more of the hydrogen atoms thereon with F, CI, Br, I, OH, N0 2 , CN, Ci-Ce-alkyl-OH, C(0)- -C 6 - alkyl, OCHr(C 3 -drcyclpalkyl), C(0)-aryl, C(0)-heteroaryl, COralkyl, COraryl, COr heteroaryl, CONH 2 , CONH-C r C 6 -alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-d-C6- alkyl, OC(0)-aryl, OC(0)-heteroaryl, OCOralkyl, OCOraryl, OCOrheteroaryl, OCONH2, OCONH-(C,-C 6 -alkyl), OCONH-ary
  • Substituent groups substituted on any group also include any of -F, -CI, -Br, -I, -OH, protected hydroxy, aliphatic ethers, aromatic ethers, oxo, -N0 2 , -CN, -d-dralkyl optionally substituted with halogen (such as perhaloalkyls), CrCiralkenyl optionally substituted with halogen, -C 2 -C ⁇ ralkynyl optionally substituted with halogen, -NH 2 , protected amino, -NH -CrC ⁇ 2 -alkyl, -NH -C 2 -C ⁇ 2 -alkenyl, -NH -Cr Ciralkynyl, -NH - ⁇ 3 -C
  • alkylamino refers to a group having the structure - NH(C ⁇ -Ci 2 alkyl) where Q-C 12 alkyl is as previously defined.
  • dialkylamino refers to a group having the structure -N(C ⁇ -C ⁇ 2 alkyl ⁇ where C r C ⁇ 2 alkyl is as previously defined. Examples of dialkylamino are, but not limited to, N,N- dimethylamino, N,N-diethylamino, N,N-methylethylamino, piperidino, and the like.
  • diarylamino refers to a group having the structure -Nfaryl ⁇ or - N(substituted aryl) 2 where substituted aryl is as previously defined. Examples of _
  • diarylamino are, but not limited to, N,N- diphenylamino, N,N-dinapthylamino, N,N- di(toluenyl)amino, and the like.
  • diheteroarylamino refers to a group having the structure - N(heteroaryl) 2 or -N(substituted heteroaryl ⁇ , where heteroaryl and substituted heteroaryl is as previously defined.
  • Examples of diheteroarylamino are, but not limited to, N,N- difuranylamino, N,N-dithiazolidinylamino, N,N-di(imidazole)amino, and the like.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis. 3rd edition, John Wiley & Sons, New York (1999).
  • Examples of -hydroxyl protecting groups include benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1- dimethyl-2-propenyl, 3-methyl- 3 -butenyl, allyl, benzyl, para- methoxy
  • hydroxyl protecting groups for the present invention are acetyl (Ac or -C(0)CH 3 ), benzoyl (Bn or -C(0)C 6 H 5 ), and trimethylsilyl (TMS or-Si(CH 3 ) 3 ).
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • nitrogen (or amino) protecting group refers to a labile chemical moiety which is known in the art to protect a nitrogen group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the nitrogen . , ___ , .
  • Nitrogen protecting groups as described herein may be selectively removed.
  • Nitrogen protecting groups as known in the are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis. 3rd edition, John Wiley & Sons, New York (1999).
  • nitrogen protecting groups include, but are not limited to, t- butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyJ, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • nucleophilic heterocyclic compound refers to a heterocyclic group in a nucleophilic form (e.g., metal salt form, protonated form) such that it is capable of reacting with another molecule resulting in a covalent bond between the two molecules (e.g., a nucleophile in a nucleophilic displacement reaction).
  • nucleophilic heterocyclic compounds are known in the art and delineated herein.
  • leaving group refers to a moiety that can-be detached from a molecule during a reaction, especially nucleophilic displacement reactions.
  • leaving groups include, for example, halides, mesyl groups, tosyl groups, alkoxides, hydroxides, and protonated forms thereof. Examples of such leaving groups are known in the art and delineated herein.
  • acyl includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • protogenic organic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled In the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations. VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2d.
  • subjecf refers to an animal.
  • the animal is a mammal. More preferably the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • subject refers to a mammal. Preferably the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs and the like.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, Q-C ⁇ sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, but are not limited to, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/reward ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association and Pergamon Press, 1987), both of which are incorporated by reference herein.
  • an effective amount or "therapeutically effective amount,” as used herein, means an amount which is capable of inhibiting the HCV NS3 serine protease, therefore interfering with the production of the viral polyprotein essential for viral replication.
  • the HCV serine protease inhibition contemplated by the present method includes both therapeutic and prophylactic treatment, as appropriate for the subject in need of such treatment. Methods of treatment, dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques.
  • a compound of the present invention may be combined with a pharmaceutically acceptable excipient for administration to a virally-infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection.
  • the compounds of the present invention may be used in vaccines and methods for protecting individuals against HCV viral infection over an extended period of time.
  • the compounds may be employed in a manner consistent with the conventional utilization of protease inhibitors in vaccines.
  • a compound of the present invention may be combined with pharmaceutically acceptable excipients conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against HCV viral infection.
  • the protease inhibitors of the present invention can be administered as agents for treating or preventing HCV viral infection in a subject.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain two or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- , or as (D)- or (L)- for - ⁇ , u ___ Struktur , _ ., .
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers Racemates, and Resolutions (John Wiley & Sons, 1981).
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable earners.
  • pharmaceutically acceptable earner means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil ; com oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non- toxic compatible lubricants such as sodium lauryl
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents, commonly used in the art such as, for example, water or other solvents, solubilizing agents and 30 emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. , , . , , _
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or earners such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or earners such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives., polyethylene glycols, silicones, bentqnites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives., polyethylene glycols, silicones, bentqnites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Abso ⁇ tion enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • viral infections are treated or prevented in a subject, such as a human or lower mammal, by administering to the subject an effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a subject such as a human or lower mammal
  • anti-hepatitis C virally effective amount means a sufficient amount of the compound so as to decrease the viral load in a M ,. - , mecanicept . ,creme, , , , _
  • an anti-hepatitis C virally effective amount of a compound of this invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease.
  • the subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the specific anti-HCV virally effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient In need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • HMBA is 4-Hydroxymethylbenzoic acid AM resin
  • KHMDS is potassium bis(trimethylsilyl) amide
  • RT-PCR for reverse transcription-p ⁇ lymerase chain reaction
  • tBOC or Boc for tert-butyloxy carbonyl.
  • the hydroxyl proline or mesylated proline precursor may be used.
  • This replacement method protocol is suitable for converting any hydroxy (or corresponding mesylate) proline compound or derivative starting compound to a heterocyclic substituted proline derivative.
  • the subsequent synthetic methods set forth the various procedures and intermediate steps that may be used to prepare the compounds disclosed herein.
  • A. Synthesis Of Hydroxyl Proline Cyclic Peptide Precursors A cyclic peptide precursor Tnay be used to synthesize the compounds of the invention. In some embodiments, a mesylated version of the cyclic precursor may be used.
  • the cyclic peptide precursor Ig was synthesized from Boc-L-2-amino-8-nonenoic acid la and c/s-L-hydroxyproline methyl ester lb via steps A-D set forth generally in Scheme 1.
  • steps A-D set forth generally in Scheme 1.
  • the cyclic precursor mesylate was synthesized by forming the mesylate upon the hydroxyl of the hydroxyl proline residue of the cyclic peptide precursor via the synthetic route generally described above in Scheme 2.
  • the compounds of the present invention are made via the replacement of the mesylate of the macrocyclic peptide mesylate lla with a 5-substituted-2 7-tetrazole, Exemplary syntheses of such tetrazoloes as described in Scheme 5, below, via the synthetic route described generally in Scheme 3.
  • the compounds of the present invention are made via the replacement of the mesylate of the macrocyclic peptide mesylate lla with a 4,5-substituted-1 H-triazole via the synthetic route described generally in Scheme 4. Exemplary syntheses of such triazoles are described in scheme 6, below.
  • Triazoles of the present invention are prepared by reacting alkyne compound Via, which is commercially available or made from procedures elucidated infra, and trimethylsilyl azide via the synthetic route described generally in Scheme 6.
  • alkyne compound Via which is commercially available or made from procedures elucidated infra, and trimethylsilyl azide via the synthetic route described generally in Scheme 6.
  • alkynes suitable for triazole formation include, but are not limited to:
  • Alkynes useful in the synthesis of triazoles may be made by any appropriate method. Below are some exemplary syntheses. Sonogashira reaction Scheme 7
  • V" 3 halide I, Br TM h
  • Alkynes used in the present invention can be made by the Sonogashira reaction with primary alkyne compound Vila, an aryl halide (Y-halide), and triethylamine in acetonitrile with PdCl2(PPh 3 )2 and Cul via the synthetic route described generally in Scheme 7.
  • aryl halides suitable for the Sonogashira reaction include, but are not limited to:
  • Additional alkynes used in the present invention can be made by reacting alkynyl acid Va, BOP, and, DIEA in DMF with amine Vlllb via the synthetic route described generally in Scheme 8.
  • the resultant macrocyclcic compound may be modified after W is attached. Some exemplary modifications follow.
  • the hydrolysis of macrocyclic peptide ethyl esters of the present invention is performed by dissolving macrocyclic peptide ethyl ester IV in dioxane and adding 1 M LiOH via the synthetic route described generally in Scheme 10.
  • Compounds of the present invention may be further diversified by performing a Suzuki coupling adding to bromo-substituted triazole macrocyclic ethyl ester (see infra Example 26 for preparation) DME an aromatic boric acid, cesium carbonate and KF via the synthetic route described generally in Scheme 11.
  • Stepwise Synthesis Compounds of the invention may also be prepared though a stepwise synthesis rather than a replacement mechanism. Below is an exemplary synthesis where W is a tetrazole.
  • the triazole-substituted proline derivatives can be synthesized and used in an on-resin assembly of a linear tripeptide chain.
  • the resin- bound tripeptides, containing the triazole-substituted proline derivatives undergo Ring- Closing-Metathesis (RCM) to furnish a cyclic tripeptide that is cleaved from the resin by hydrolysis affording the final product.
  • RCM Ring- Closing-Metathesis
  • the cyclo-addition method to create triazolyl proline derivatives involves the 3+2 > cyclo-addition of azide proline derivative XVllb and alkyne Vllb via the synthetic route described generally In Scheme 17.
  • Exemplary syntheses of alkynes are described in Scheme 7 above.
  • the substituent W is well-suited to other types of reactions.
  • W is a pyridazinone
  • the following reaction schemes are used. These methods may be used for other substituents, but are discussed here in the context of pyridazinones.
  • the second method of preparing pyridazinone ana ogs o t e present invention is to further chemically manipulate di-bromo intermediate XXIa (Scheme 21).
  • the standard Mitsunobu coupling of the commercially available 4,5-dibromopyridazinone with hydroxyl If afforded the desired macrocycle XXIa.
  • Coupling of XXIa with excess 3- thiophene boronic acid, cesium carbonate and potassium fluoride furnished di- thiophene XXIb.
  • Hydrolysis of compound compounds XXIa and XXIb with LiOH gave the desired analogs XXld and XXIc respectively.
  • Many different boronic acids may be used in a similar manner to yield a plethora of di-substituted pyridazinonyl macrocycles.
  • the dipeptide 1c (1.91g) was dissolved in 15 mL of dioxane and 15 mL of 1 N LiOH aqueous solution and the hydrolysis reaction was earned out at RT for 4 hours.
  • the reaction mixture was acidified by 5% citric acid and extracted with 100 mL EtOAc, and followed by washing with water 2x20 ml, 1M NaHC0 3 2x20 ml and brine 2x20 ml, respectively.
  • the organic phase was dried over anhydrous Na 2 SO- 4 and then removed in vacuum, yielding the free carboxylic acid compound 1d (1.79g, 97%), which was used for next step synthesis without need for further purification.
  • MS found 516.28, M+Na + .
  • Structurally diverse tetrazoles llla-lllq, for use in preparing tetrazolyl macrocycles of the invention were synthesized from commercially available nitrile compounds as described below:
  • N-Boc-cis-hydroxyproline methyl ester 4a (10 g, 40.8 mmol) and N,N-Diisopropylethyl amine (DIEA, 12 mL, 60 mmol) in 110 mL of DCM, was added 3.85 mL of mesylate chloride (50 mmol) in a dropwise manner and the resulting reaction mixture was stirred at 0 °C for 3 hours.
  • Boc-cis-Hyp-OMe 4a was totally converted to its mesylate 4b.
  • the dipeptide 4e was prepared by dissolving 0.22 g (0.6 mmol) of N-Boc- trans-4-(3-phenyl tetrazolyl)-proline methyl ester 4c in 6 mL of dioxane and 2 mL of 1 N LiOH aqueous solution. The resulting reaction mixture was stirred at RT for 3-8 hours to allow the for the hydrolysis of the methyl ester. The reaction mixture was acidified by 5% citric acid, extracted with 40 mL EtOAc, and washed with water 2x20 ml, 1M NaHC0 3 2x20 ml and brine 2x10 ml, respectively.
  • the reaction mixture was diluted with 40 L EtOAc, and washed with 5% citric acid 2x 20 ml, water 2x20 ml, 1M NaHC0 3 4x20 ml, and brine 2x10 ml, respectively.
  • Tripeptide 4g was prepared by deprotecting the amine of dipeptide 4e (0.24 g, 0.49 mmol) in 2 mL TFA at 0 °C for 10 min. After removal of TFA in vacuo, the free amine product was subjected to next coupling reaction directly.
  • Boc- 2-amino-8-nonenoic acid 4f (0.136g, 0.50 mmol)
  • DIEA 0.4 ml, 4eq.
  • HATU 0.4g, 2eq
  • the reaction mixture was diluted with 40 mL EtOAc and washed with 5% citric acid 2x 20 ml, water 2x20 ml, 1M NaHC0 3 4x20 ml and brine 2x10 ml, respectively.
  • the title compound was prepared by dissolving compound 4i (20mg) in 2 mL of dioxane and 1 mL of 1 N LiOH aqueous solution. The resulting reaction mixture was stirred at RT for 4-8 hours. The reaction mixture was then acidified with 5% citric acid, extracted with 10 mL EtOAc, and washed with water 2x20 ml. The solvent was , . . .
  • the linear peptide of the present example was prepared via the procedure set forth in Example 4 (II) with the proline derivative prepared in step 5A, D- ⁇ -vinyl " cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
  • the macrocyclic peptide ethyl ester of the present example was prepared with the linear peptide of Step 5B via the procedure set forth in Example 4 (III).
  • W is .
  • Q absent.
  • Y 3-bromophenyl.
  • i 3.
  • the linear peptide of the present example was prepared via the procedure set forth in Example 4 (II) with the proline derivative prepared in step 6A, D- ⁇ -vinyl cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
  • the macrocyclic peptide ethyl ester of the present example was prepared with the linear peptide of Step 6B via the procedure set forth in Example 4 (III).
  • W is ⁇ .
  • Q absent.
  • Y 4-bromophenyl.
  • i 3.
  • the linear peptide of the present example was prepared via the procedure set forth in Example 4 (II) with the proline derivative prepared in step 7A, D- ⁇ -vinyl cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
  • the macrocyclic peptide ethyl ester of the present example was prepared with the linear peptide of Step 7B via the procedure set forth in Example 4 (III).
  • the linear peptide of the present example was prepared via the procedure set forth in Example 4 (II) with the proline derivative prepared in step 8A, D- ⁇ -vinyl cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
  • the macrocyclic peptide ethyl ester of the present example was prepared with the linear peptide of Step 8B via the procedure set forth in Example 4 (III).
  • the linear peptide of the present example was prepared via the procedure set forth in Example 4 (II) with the proline derivative prepared in step 9A, D- ⁇ -vinyl cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
  • the macrocyclic peptide ethyl ester of the present example was prepared with the linear peptide of Step 9B via the procedure set forth in-Example 4 (III).
  • W is N .
  • Q absent.
  • Y 4-biphenyl.
  • i 3.
  • W is .
  • Q absent.
  • Y 3-(p-trifluoromethoxyphenyl)phenyl .
  • i 3.
  • W is y V .
  • Q absent.
  • Y 4-(3-thienyl)phenyl .
  • i 3.
  • W is * .
  • Q absent.
  • Y 4-(p-cvanophenyl)phenyl .
  • i 3.
  • R is
  • ⁇ % Y W is N .
  • Q absent.
  • Y 5-phenyl-2-thienyl.
  • i 3.
  • W is ⁇ .
  • Q absent.
  • Y 3-chloro-4-hvdroxyphenyl.
  • i 3.
  • the title compound was prepared via the replacement of the mesylate 2 and tetrazole 3a.
  • the replacement method is performed by dissolving 0.04 Immol of the macrocyclic peptide precursor mesylate 2 and 0.123mmol of tetrazole 3a in 3ml of DMF and adding 0.246mmol of sodium carbonate (60mg).
  • the resulting reaction mixture is stirred at 60°C for 4-10 hours and subsequently cooled and extracted with ethyl acetate.
  • the organic extract was washed with water (2x30ml), and the organic solution is concentrated in vacuo to be used in crude form for hydrolysis of the ethyl ester.
  • W is .
  • Q absent.
  • the title compound was prepared by dissolving the title compound of Example 4 (20mg) in 2 mL of dioxane and 1 mL of 1 N LiOH aqueous solution. The resulting reaction mixture was stirred at RT for 4-8 hours. The reaction mixture was acidified with 5% citric acid, extracted with 10 mL EtOAc, and washed with water 2x20 ml. The solvent was evaporated and the residue was purified by HPLC on a YMC AQ12S11- 0520WT column with a 30-80% (100% acetonitrile) gradient over a 20 min period. After lyophilization, title compound was obtained as a white amorphous solid.
  • W is ⁇ .
  • i 3.
  • R 3
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3b from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is * .
  • Q absent.
  • Y 2-methyl-4-bromophenyl.
  • i 3.
  • R 3 is
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3c from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3d from Example 3, followed by hydrolysis of the ethyl ester by the procedure of -Example 22.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tejrazole 3e from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3f from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is , * N .
  • Q absent.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3g from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is ⁇ .
  • Q absent.
  • Y 4-butoxyphenyl.
  • i 3.
  • Example 21 with mesylate 2 and tetrazole 31 from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3j from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 21 with mesylate 2 and tetrazole 3k from Example 3, followed by hydrolysis of the ethyl ester by the procedure of -Example 22.
  • N Q --Y W is ⁇ .
  • Q absent.
  • Y 4-methoxy-1 -naphthyl.
  • R 3 R 4
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 31 from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3m from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is .
  • Q absent.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3n from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and tetrazole 3o from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is .
  • Q absent.
  • Y 3-chlorophenyl.
  • i 3.
  • Example 21 with mesylate 2 and 5-(3-fluorophenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is .
  • Q absent.
  • Y 3-phenoxyphenyl.
  • i 3.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3-benzyloxyphenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is .
  • Q absent.
  • Y 3-trifluormethylphenyl.
  • i 3.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3-trifluormethylphenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 21 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(4-bromophenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(4-fluorophenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(4-methoxyphenyl)-1H-tetrazoIe, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is .
  • Q absent.
  • Y 4-ethoxyphenyl.
  • i 3.
  • Example 21 with mesylate 2 and 5-(4-trifluoromethylphenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is .
  • Q absent.
  • W is .
  • Q absent.
  • the title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(4-(N,N-dimethylamino)-3,5- di(trifluoromethyl)phenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(2,4-dichlorophenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3,5-dichlorophenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3,4-dichlorophenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(2-pyridyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • W is ⁇ .
  • Q absent.
  • Y 2-pyridyl.
  • i 3.
  • Y 3-pyridyl.
  • Example 21 with mesylate 2 and 5-(3-pyridyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • Example 21 with mesylate 2 and 5-(4-pyridyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • the tetrazole of the present example was prepared by dissolving 4-hydroxy-3- bromo-4-hydroxy-benzonitrile in DMF and adding methyl iodide and stirring at RT for 3- 12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic phase was then dried over Na 2 S0 4 and concentrated in vacuo to yield the 3-bromo-4-methoxy-benzonitrile. This compound then was used to form the corresponding tetrazole via the method described in Example 3.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3-bromo-4-methoxy-phenyl)-1 H-tetrazole from 57 A, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • the tetrazole of the present example was prepared by dissolving 4-cyano-phenol in DMF and adding (bromomethyl)cyclopropane and stirring at RT for 3-12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic phase was then dried over Na 2 S0 4 and concentrated in vacuo to yield the 4-(methylcyclopropane)benzonitrile. This compound then was used to form the corresponding tetrazole via the method described in Example 3.
  • Example 22 The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(4-(methylcyclopropane)-phenyl)-1 H-tetrazole from 58A, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
  • the tile compound was prepared by using ethyl ester title compound from -Example 21 without workup, adding (bromomethyl)cyclopropane, and stirring at 60°C . . - .. .• - -- .. , - for 3-12 hours.
  • the resulting reaction mixture was cooled to RT, poured into a mixture of 50:50 EtOAc:water, washed with water, and concentrated in vacuo.
  • the resulting crude ethyl ester compound is then hydrolyzed to the free acid by the procedure set forth in Example 22.
  • W is .
  • Q absent.
  • Y 3-chloro-4-methoxyphenyl.
  • i 3.
  • R is
  • Example 21 The title compound was prepared with the title compound of Example 21 and methyl iodide according to the procedure set forth in Example 59.
  • W is .
  • Q absent.
  • Y 3-chloro-4-ethoxyphenyl.
  • i 3.
  • R is

Abstract

L'invention concerne des composés de la formule (I, II ou III), ou un sel, un ester ou un promédicament pharmaceutiquement acceptable de ceux-ci, dans laquelle W représente un système de noyau hétérocyclique substitué ou non substitué. Ces composés inhibent l'activité de la sérine protéase, en particulier celle de la protéase du virus de l'hépatite C (VHC) NS3-NS4A. En conséquence, ces composés, qui interfèrent avec le cycle de vie du virus de l'hépatite C, sont également utiles en tant qu'antiviraux. L'invention concerne également des compositions pharmaceutiques comprenant les composés précités à administrer au patient souffrant d'une infection du VHC. L'invention concerne en outre des procédés de traitement d'une infection du VHC chez un patient par administration d'une composition pharmaceutique comprenant lesdits composés.
PCT/US2004/003479 2003-02-07 2004-02-06 Inhibiteurs macrocycliques de la serine protease de l'hepatite c WO2004072243A2 (fr)

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AU2004211637A AU2004211637C1 (en) 2003-02-07 2004-02-06 Macrocyclic hepatitis C serine protease inhibitors
JP2006503381A JP2007524576A (ja) 2003-02-07 2004-02-06 大環状のｃ型肝炎セリンプロテアーゼ阻害剤
CNA2004800092686A CN1771050A (zh) 2003-02-07 2004-02-06 丙型肝炎丝氨酸蛋白酶的大环抑制剂
CA002515216A CA2515216A1 (fr) 2003-02-07 2004-02-06 Inhibiteurs macrocycliques de la serine protease de l'hepatite c
EP04709020A EP1590442A4 (fr) 2003-02-07 2004-02-06 Inhibiteurs macrocycliques de la serine protease de l'hepatite c

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US36094703A 2003-02-07 2003-02-07
US10/360,947 2003-02-07
US36585403A 2003-02-13 2003-02-13
US10/365,854 2003-02-13
US10/384,120 US20040180815A1 (en) 2003-03-07 2003-03-07 Pyridazinonyl macrocyclic hepatitis C serine protease inhibitors
US10/384,120 2003-03-07

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AU2004211637B2 (en) 2009-08-13
AU2004211637C1 (en) 2010-08-19
AU2004211637A1 (en) 2004-08-26
KR100940619B1 (ko) 2010-02-05
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WO2004072243A3 (fr) 2005-11-03

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