WO2004072243A2 - Macrocyclic hepatitis c serine protease inhibitors - Google Patents

Macrocyclic hepatitis c serine protease inhibitors Download PDF

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Publication number
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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Prior art keywords
substituted
aryl
heteroaryl
group
heterocycloalkyl
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PCT/US2004/003479
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French (fr)
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WO2004072243A3 (en
Inventor
Zenwei Miao
Ying Sun
Frank Wu
Suanne Nakajima
Guoyou Xu
Yat Sun Or
Zhe Wang
Original Assignee
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 CNA2004800092686A priority Critical patent/CN1771050A/en
Priority to JP2006503381A priority patent/JP2007524576A/en
Priority to EP04709020A priority patent/EP1590442A4/en
Priority to CA002515216A priority patent/CA2515216A1/en
Priority to AU2004211637A priority patent/AU2004211637C1/en
Publication of WO2004072243A2 publication Critical patent/WO2004072243A2/en
Publication of WO2004072243A3 publication Critical patent/WO2004072243A3/en

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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

The present invention relates to compounds of Formula (I, II or III), or a pharmaceutically acceptable salt, ester, or prodrug, thereof: (I), (II), (III), wherein W is a substituted or unsubstituted heterocyclic ring system. The compounds inhibit serine protease activity, particularly the activity of hepatitis c virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis c virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Description

MACROCYCLIC HEPATITIS C SERINE PROTEASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit to US provisional serial nos.
(conversion of US 10/365,854), filed February 13, 2003; (conversion of
US 10/360,947), filed February 7, 2003; and (conversion of US
10/384,120), filed March 7, 2003, each of which is hereby incorporated by reference in its entirety for any purpose. TECHNICAL FIELD
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.
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. , _ .
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.
Only two approved therapies for HCV infection are currently available. The original treatment regimen generally involves a 3-12 month course of intravenous interferon-α (IFN-α), while a new approved second-generation treatment involves co- treatment with IFN-α and the general antiviral nucleoside mimics like ribavirin. Both of these treatments sjjffer from interferon-related side effects -as well as low efficacy against HCV infections. There exists a need for the development of effective antiviral agents for treatment of HCV infection due to the poor tolerability and disappointing efficacy of existing therapies.
In a patient population where the majority of individuals are chronically infected and asymptomatic and the prognoses are unknown, an effective drug must possess significantly fewer side effects than the currently available treatments. The hepatitis C non-structural protein-3 (NS3) is a proteolytic enzyme required for processing of the viral polyprotein and consequently viral replication. Despite the huge number of viral variants associated with HCV infection, the active site of the NS3 protease remains highly conserved thus making its inhibition an attractive mode of intervention. Recent success in the treatment of HIV with protease inhibitors supports the concept that the inhibition of NS3 is a key target in the battle against HCV.
HCV is a flaviridae type RNA virus. The HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids.
The HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions. There are three structural proteins, C, E1 and E2. The P7 protein is of unknown function and is comprised of a highly variable sequence. There are six non-structural proteins. 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. It has been shown that a, central hydrophobic region of the NS4A >rotein is required for this enhancement. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficacy at all of the sites.
A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus. Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002). 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).
SUMMARY OF THE INVENTION
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. A compound having the Formula I or a pharmaceutically acceptable salt, ester or prodrug thereof:
W
Figure imgf000006_0001
I wherein: - ^.
A is selected from the group consisting of H, - (C=0)-R2, -(C=0)-0-R1 , -C(=0)- NH-R2, -C(=S)-NH-R2, -S(O)2-R2, -(C=NR1)-R1, and -(C=NR1)-NH-R1;
G is selected from the group consisting of -OH, -0-(C Cι2 alkyl), -NHS(0)2 -R1, ■ (C=0)-R1, -(C=0)-R2, -(C=0)-0-R1, -<C=0)-NH-R1, and -(C=0)-NH-R2 ;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, - S(0)2-, -S(0)2CH2CH2-, -S(θy, -S(0)CH2CH2-, -0-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, CH(CH3)CH2-, -CFHCH2-, -CF2CH2-, and -CRX=CRX- where Rx = H or halogen; j is O, 1, 2, 3, or 4; m is 0, 1 , or 2; s is 0, 1 or 2;
R1 is selected form the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 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--. ..- „ ... I .1 ,1' _ -. __ - - . -
R3 and R4 are each Independently selected from the group consisting of hydrogen, OH, CH3, CN, SH, halogen, N0 , NH2, amide, methoxy, trifluoromethoxy, and trifluoromethyl;
E represents either a single bond or a double bond between the two carbon atoms attached thereto; and
W is a substituted or unsubstituted heterocyclic ring system.
In one embodiment of the present invention E represents a double bond, resulting in Formula 11 or pharmaceutically acceptable salts, esters, or prodrugs thereof:
Figure imgf000007_0001
(H ) wherein the remaining substitutents are as described above.
In one embodiment of the present invention E represents a single bond, resulting in Formula III or pharmaceutically acceptable salts, esters, or prodrugs thereof:
Figure imgf000007_0002
(III) wherein the remaining substituents are as described above. In one embodiment of the present invention there are djsclosed compounds represented by Formulas II and III, or pharmaceutically acceptable salts, esters, or prodrugs thereof: wherein
W is selected from the group consisting of:
Figure imgf000008_0001
Figure imgf000008_0002
Q is selected from the group consisting of: absent, -CH2-, -O-, -NH-, -N(R1)-- -S-, -S(0)z-, and -(C=0)-;
Q' Is selected from the group consisting of: absent, -CH2-, and -NH-; Y is ) selected from the group consisting of: H, Cι-C6 alkyl, ary substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
All other substituents are as defined above.
In one. embodiment of the present invention there are disclosed compounds represented by Formulas II and III, or pharmaceutically acceptable salts, esters, or prodrugs thereof wherein
W is selected from the group consisting of:
Figure imgf000008_0003
and --L ; X and Y are independently selected from the group consisting of: H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH2-dialkylam.no, -CH2-arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
All other substituents are as defined above.
In one embodiment of the present invention there are disclosed compounds represented by Formulas II and III, or pharmaceutically acceptable salts, esters, or prodrugs thereof wherein:
W is
Figure imgf000009_0001
and
X, Y, and Z are independently selected from the group consisting of H, N3, halogen, Cι~C6 alkyl, C3-C12 cycloalkyl, alkylamino, dialkylamino, Ci-Cβ 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, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or, in the alternative, X and Y or Y and Z taken together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl cyclic moiety.
Other aspects of the invention are:
A compound according to any of the formulae herein wherein W is substituted with one or more substituents, each of said substituents being independently selected from any of (a), (b), (c), (d) and (e):
(a) alkenyl; alkoxy; alkoxyalkyl; alkyl; alkylamino; alkylaryl; alkylsulfonyl; alkynyl; amide; amido optionally mono-substituted with C C6 alkyl; aryl; arylalkanoylalkyl; arylalkyl; arylaminoalkyl; aryloxyalkyl; arylsulfonyl; cycloalkoxy; cycloalkyl; dialkylamino; dialkylaminoalkyl; diarylaminoalkyl; haloalkyl; heteroaryl; heteroarylalkyl; heterocyclo; ,„ .. - . „ --- heterocycloalkyl; heterocycloalkylalkyl; thioalkyl; monoalkylaminoalkyl; sulfonyl; (lower alkyl)sulfonyl; haloalkyl; carboxyl; amide; (lower alkyl)amide; heterocyclo optionally substituted with C C6 alkyl; perhaloalkyl; sulfonyl; thioalkyl; urea, C(=0)-R11; OC(=0)R11; C(=0)0-R11; C(=0)N(R11)z; C(=S)N(R11)z; S02R11; NHS(02)R11; ^(R12 ; N(R12)C(=0)R11; wherein each of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy, perhaloalkyl; (b) C7-C14 aralkyl; C∑-Cycycloalkyl; C6-Cιo aryl; heterocyclo; (lower alkyl)- heterocyclo; wherein each aralkyl, cycloalkyl, aryl, heterocyclo or (lower alkyl)-heterocyclo may be optionally substituted with R6, where R6 js halogen, C C 6 alkyl, C3-C β cycloalkyl, d-C 6 alkoxy, C3-C 6 cycloalkoxy, N02, N(R7)z, NH-C(0)-R7 or NH-C(O)- NHR7; where R7 is. H, C C6 alkyl or C3-C6 cycloalkyl; or R6 is NH-C(0)-OR8 where R8 is C C 6 alkyl or C3-C 6 cycloalkyl; (c) N(R5)2, NH-C(0)-R5, or NH-C(0)-NH-R5 where R5 is independently H, Cι-C6 alkyl or C3-C6 cycloalkyl, C6 or C10 aryl, C7-C 14 aralkyl, heterocyclo or (lower alkyl)- heterocyclo;
(d) NH-0(O)-OR8 where R8 is C1-C 6 alkyl or C3-C 6 cycloalkyl;
(e) formyl; halogen;, hydroxy; N02; OH; SH; halo; CN; wherein each R11 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 . optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl; and each R12 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;
The compound of any of the formulae herein wherein W is selected from the > group consisting of:
(a) 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 the group consisting of OH, CN, halogen, formyl, R10 and
) R11; and
(b) 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 R10;
5 wherein: each R10 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,
3 heteroaryl or urea, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl; C(=0)-R11, OC(=0)R11, C(=0)0-R11, C(=0)N(R11)2, C(=S)N(R11)2, S02R11, NHS(02)R11, N(R12>2, and N(R1 )C(=0)R11; each R11 is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy,
5 aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylamlnoalkyl, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl;
0 each R12 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;
The compound of any of the formulae herein wherein 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
. the group consisting of OH, CN, halogen, formyl, R10 and Rn;
The compound of any of the formulae herein wherein 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
> substituted with up to three ring substituents selected from the group consisting of OH,
CN, halogen, formyl, R10 and R11;
The compound of any of the formulae wherein said optionally substituted aliphatic heteromonocyclic ring system has five ring atoms and 1 or 2 ring hetero atoms ) selected from O, N and S;
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,
5 tetrahydrofurans, dlhydrofurans, imidazollnes, tetrahydroimldazoles, dlhydropyrazoles, tetrahydropyrazoles, and oxazolines;
The compound of any of the formulae herein wherein said optionally substituted aliphatic heteromonocyclic ring system has six ring atoms and 1 or 2 ring hetero atoms 0 selected from O, N and S; . -. „„„- ,- .„ .,„ _
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,
> perhydro pyrimidine, moφholine, thioxane, and thiomorpholine;
The compound of any of the formulae herein wherein said optionally substituted aliphatic heteromonocyclic ring system has seven ring atoms and 1 or 2 ring hetero atoms selected from O, N and S; )
The compound of any of the formulae herein wherein said optionally substituted aliphatic heteromonocyclic ring system Is selected from the group consisting of hexamethyleneimine, and hexamethylenesulfide;
> The compound of any of the formulae herein wherein 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 R10.
)
The compound of any of the formulae herein wherein said optionally substituted aliphatic heterobicyclic ring system has eight to twelve ring atoms and 1 to 4 ring hetero atoms selected from O, N and S;
> The compound of any of the formulae herein wherein said optionally substituted aliphatic heterobicyclic ring system eight to twelve ring atoms and 1 or 2 ring hetero atoms selected from O and N;
The compound of any of the formulae herein wherein W is 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 R10;
The compound of any of the formulae herein wherein 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;
I The compound of any of the formulae herein wherein said optionally substituted aromatic heteromonocyclic ring system has five ring atoms and 1 or 2 ring hetero atoms selected from O, N and S;
The compound of any of the formulae herein wherein said optionally substituted
> 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;
The compound of any of the formulae herein wherein said optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of
> pyridines, pyrimidines, pyrazines, pyrans, and triazines;
The compound of any of the formulae herein wherein said optionally substituted aromatic heteromonocyclic ring system has five ring atoms and 3 or 4 ring hetero atoms selected from O, N and S; ) The compound of any of the formulae herein wherein said optionally substituted aromatic heteromonocyclic ring system is triazolyl or tetrazolyl;
The compound of any of the formulae herein wherein 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,
CN, halogen, formyl and R10;
I The compound of any of the formulae herein wherein said optionally substituted aromatic heterobicyclic ring system is selected from the group consisting of adenines, azabenzimidazoles, azaindoles, benzimidazoles, benzo isothiazoles, benzofurans, benzoisoxazoles, - benzooxazoles, benzothiadiazoles, benzothiazoles, benzothienes, benzothiophenes, benzoxazoles, carbazoles, cinnolines, guanines, imidazopyridines,
» indazoles, indoles, isoindoles, isoquinolines, phthalazines, purines, pyrrolo pyridines, quinazolines, quinolines, quinoxalines, thianaphthenes, and xanthines;
The compound of any of the formulae herein wherein 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, R10 and R^; and
The compound of any of the formulae herein wherein said optionally substituted
> aromatic heterotricyclic ring system is selected from the group consisting of carbazoles, bibenzofurans, psoralens, dibenzothϊophenes, phenazines, thianthrenes, phenanthrolines, phenanthridines.
Other embodiments are a compound of Formula II
Figure imgf000016_0001
Formula II Wherein:
A is selected from the group consisting of H, -(C=0)-R2, -(C=0)-0-R', - C(=0)-NH-R1, -C(=S)-NH-R2 , -S(0)2-R2, -(C=NR1)-R1, and -(C=NR1)-NH-R1;
G is selected from the group consisting of -OH, -0-(C1-C12 alkyl), - NHSfOfe-R1,
Figure imgf000016_0002
-(C=0)-0-Rl, and -(C=0)-NH-R2; *
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, -S(0) , -S(0)2CH2CH2-, -S(O)-, -S(0)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=θyCH2-t -CH(CH3)CH2-, -CFHCH2-, -CF2CH2-, and -CRX=CRX- where Rx = H or halogen;
W is selected from the group consisting
Figure imgf000016_0003
Figure imgf000016_0004
Q is selected from the group consisting of absent, -CH2-, -0-, -NH-, - N(R1K -S-, -S(0)2-, and -(C=OH
Q' is selected from the group consisting of absent, -CH2-, and -NH-;
Y is selected from the group consisting of H, -Ce 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;
R1 is selected from the group consisting of H, -C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, C Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen and methyl;
A compound of theabove formula II, wherein: A is -(C=0)-0-R1; G is hydroxyl; L is absent; j = 3; m = s = 1; and R3 and R4 are hydrogen;
A compound of theabove formula II, wherein:
Figure imgf000017_0001
G is hydroxyl; L is absent; j = 3; m = s = 1; and R3 and R4 are hydrogen;
A compound of theabove formula II, wherein: A is -(C=0)-0-R1, G is hydroxyl; L is absent;
Figure imgf000018_0001
j = 3; m = s = 1; and R3 and R4 are hydrogen; and
A compound of theabove formula II, wherein:
Figure imgf000018_0002
G is hydroxyl; L is absent;
Figure imgf000018_0003
j = 3; m = s = 1; and
R3 and R4 are hydrogen.
Other embodiments are: A compound of Formula III:
Figure imgf000018_0004
Formula III wherein
A is selected from the group consisting of H, -(C=0)-R2, -(C=0)-0-R1, - C(=0)-NH-R2, -C(=S)-NH-R2 , -S(0)2-R2, -(C=NR1)-R1, and -(C=NR1)-NH-R1;
G is selected from the group consisting of -OH, -0-(C Ci2 alkyl), - NHS(0)2-R1, -(C=0)-R2, -(C=0)-0-R,, and -(C=0)-NH-R2;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, -S(0)2-, -S(0)2CH2CH2-, -S(θy, -S(0)CH2CH2-, -0-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2- , -CF2CH2-, and -CRX=CRX- where Rx = H or halogen;
W is selected from the group consisting of
Figure imgf000019_0001
Figure imgf000019_0002
Q is selected from the group consisting of absent, -CH2-, -0-, -NH-, - N(R1)-, -S-, -S(0)2-, and -(C=0)-;
Q' is selected from the group consisting of absent, -CH2-, and -NH-;
Y is selected from the group consisting of H, Ci-Cβ 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, or2; s = 0,1 or 2;
R1 is selected from the group consisting of H, Q-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen and methyl;
A compound according to formula HI above, wherein: A is -(C=0)-0-R1; G is hydroxyl; . L is absent; j = 3; m = s = 1; and R3 and R4 are hydrogen;
> A compound according to formula III above, wherein:
Figure imgf000020_0001
G is hydroxyl;
L is absent; j = 3; . m = s = 1; and
R3 and R4 are hydrogen;
A compound according to formula III above, wherein: A is -(C=0)-0-R1; . G is hydroxyl;
L is absent;
Figure imgf000020_0002
j = 3; m = s = 1; and R3 and R4 are hydrogen;
A compound according to formula III above, wherein:
Figure imgf000021_0001
G is hydroxyl; L is absent;
Figure imgf000021_0002
j = 3; m = s = 1 ; and
R3 and R4 are hydrogen;
A compound of Formula II:
Figure imgf000021_0003
Formula II wherein
A is selected from the group consisting of H, -(C=0)-R2, -(C^J-O-R1, -C(=0)-NH-R2, -C(=S)-NH-R2 , -S(0)2-R2, -(C=NR1>R1, and -(C=NR1)-NH-R1; G is selected from the group consisting of -OH, -0-(C Ci2 alkyl), -NHS ^R1, -(C=0)-R2, -(C=0)-0-R', and -(C=0)-NH-R2;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, -S(0)2-, -S(0)2CH2CH2-, -S(O)-, -S(0)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2-, -CF2CH2-, and where Rx = H or halogen;
W is selected from the group cons ϊiissttiinngg ooff
Figure imgf000022_0001
and
Figure imgf000022_0002
where X and Y are independently selected from the group consisting of H, halogen, Ci- Cβ alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH2-dialkylamino, -CH2-arylamino, -CH2- diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)- diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternativer X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, for a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j = 0, 1, 2, 3, or 4; m = 0, 1, or 2; s = 0, 1 or 2;
R1 is selected from the group consisting of H, -Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, Q-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen and methyl; ι
A compound according to formula II above, wherein: A is -(C=0)-0-R1; G is hydroxyl; L is absent;
J = 3; m=s=1 ; and
R3 and R4 are hydrogen;
A compound according to formula II above, wherein: A is -(C=0)-0-terf-butyl; G is hydroxyl; L is absent;
1 = 3;- m = s = 1; and
R3 and R4 are hydrogen;
A compound according to formula II above, wherein: A is -(C=0)-0-R1, G is hydroxyl; L Is absent;
W is
Figure imgf000023_0001
j = 3; m = s = 1; and
R3 and R4 are hydrogen;
A compound according to formula II above, wherein:
Figure imgf000023_0002
G is hydroxyl; _ _ __ _
L is absent;
W is
Figure imgf000024_0001
J = 3;
M = s = 1; and
R3 and R4 are hydrogen.
Other embodiments are a compound of Formula III:
Figure imgf000024_0002
wherein
A is selected from the group consisting of H, -(C=0)-R2, -(C=0)-0-R1, -C(=0)-NH-R2, -C(=S)-NH-R2 , -S(0)2-R2, -(C=NR R1, and -(C=NR1)-NH-R1;
G is selected from the group consisting of -OH, -0-(C Ci2 alkyl), -NHSfO^R1, -(C=0)-R2, -(C=0)-0-R,, and -(C^O)-NH-R2;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, - S(0)2-, -S(0)zCH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2- , -CF2CH2-, and -CRX=CRX- where Rx = H or halogen; from the group consis ttiinngg ooff
Figure imgf000025_0001
and
Figure imgf000025_0002
where X arid Y are independently selected from the group consisting of H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -CH alkylamino, -CH2-dialkylamino, -CHrarylamino, -CH2-diarylamino, - (C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, for a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; "*"" j = 0, 1, 2, 3, or 4; m = 0, 1 , or 2; s = 0, 1 or 2;
R1 is selected from the group consisting of H,
Figure imgf000025_0003
alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, C|-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen and methyl;
A compound according to formula III above, wherein: is -^OJ-O-R1; G is hydroxyl; L is absent; j = 3; m = s = 1 ; and
R3 and R4 are hydrogen;
A compound according to formula III above, wherein:
Figure imgf000026_0001
G is hydroxyl; L is absent; j = 3; m = s = 1; and R3 and R4 are hydrogen;
A compound according to formula III above, wherein: A is ■(C=0)-0-Rl, G is hydroxyl; L is absent;
Figure imgf000026_0002
j = 3; m - s = I; and
R3 and R4 are hydrogen;
A compound according to formula III above, wherein: A is -(C=0)-0-fert-butyl; G is hydroxyl; L is absent;
Figure imgf000027_0001
j = 3; m = s = 1; and
R3 and R4 are hydrogen;
A compound of Formula IV:
Figure imgf000027_0002
( IV )
wherein ) A is hydrogen, -(C=0)-R1 , -(C=0)-0-R1, -C(=0)-NH-R2 , -C(=S>NH-R2, -
S(0)2-R2, -(C=NR1)-R1, or-(C=NR1)-NH-R1;
G is -OH, -0-(Cι-C12 alkyl), -NHS(0)2-R', -(C=0)-R2, -(OOJ-O-R1, or -(C=0)-NH-R2;
L is -S-, -SCHz-, -SCH2CH2-, -S(O)2-, -S(0)2CH2CH2-, -S(O)-, 5 -S(0)CH2CH2-, -0-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2- - CF2CH2-, or -CRx=CRx- where Rx = H or halogen; _ r - _
X, Y, and Z are independently selected from the group consisting of hydrogen, N3, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, alkylamino, dialkylamino, Q-Cβ 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, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or, in the alternative, X and Y or Y and Z taken together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl cyclic moiety; j = 0, 1, 2, 3, or 4; m = 0y 1, or2; s = 0, 1 or 2;
R1 is hydrogen, C|-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;
R2 is hydrogen, Ci-Cβ alkyl, C3-C12 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
R3 and R4 are each independently hydrogen or methyl;
A compound according to formula IV above, wherein: A is -(C=0)-0-R1; G is hydroxyl; L is absent; j = 3; m = s = 1; and R3 and R4 are hydrogen; A compound according to formula IV above, wherein: A is -(C=0)-0-tert-butyl; G is hydroxyl; L is absent; j = 3; m = s = 1 ; and R3 and R4 are hydrogen;
A compound of Formula V:
Figure imgf000029_0001
( V )
wherein
A is hydrogen, -(C=0)-R1 , -(C^J-O-R1, -C(=0)-NH-R2 , -C(=S)-NH-R2 , or -S(0)2-R2, -(C=NR1)-R1, or -(C=NR1)-NH-R1;
G is -OH, -0-(C Ci2 alkyl), -NHS(0)2-R,, -(C=0)-R2, -(C=0)-0-R,, or -(C=0)-NH-R2; L is absent, -S-, -SCH2-, -SCH2CH2-, -S(0)2-, -S(0)2CH2CH2-, -S(O)-, -S(0)CH2CH2-, -0-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2-, - CF2CH2-, or-CRx=CRx- where Rx = H or halogen -;
X, Y, and Z are independently selected from the group consisting of hydrogen, N3, halogen, C Cβ alkyl, C3-C12 cycloalkyl, alkylamino, dialkylamino, C Cβ 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, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or, in the. alternative, X and Y or Y and Z taken together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, and substituted heteroaryl cyclic moiety; j = 0, 1, 2, 3, or 4; m = 0, 1, or 2; s = 0, 1 or2;
R1 is hydrogen, C C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;
R2 is hydrogen, C C6 alkyl, C3-C12 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
R3 and R4 are each independently hydrogen or methyl;
A compound according to formula V above, wherein: A is -(C=0 0-R1; G is hydroxyl; L is absent; j = 3; m = s = 1 ; and
R3 and R4 are hydrogen; and
A compound according to formula V above, wherein:
Figure imgf000031_0001
G is hydroxyl; L is absent; j = 3; m = s = 1; and R3 and R4 are hydrogen.
Other embodiments are: compounds of formulae II or III as delineated herein, wherein: A is selected from the group consisting of: H, -(C=0)-R2, -(C=0)-0-R1, -C(=0)-NH-R2, -C(=S)-NH-R2, and -S(0)2-R2; G is selected from the group consisting of: -OH, -O-fd-C^ alkyl), -NHS(0)2-R1, -{C=0)-R1, -(C=0)-0-R1, and -(C=0}-NH-R1; L is selected from the group consisting of: absent, -S-, -SCH2-, -SCH2CH2-, -S(0)z-, -S(0)2CH2CH2-, -S(O)-, -S(0)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2-, and -CF2CH2-; W is selected
from the group consisting of:
Figure imgf000031_0002
and
Figure imgf000031_0003
Q is selected from the group consisting of: absent, -CH2-, -0-, -NH-, -N(R1)-. -S-- -S(0)2-, and -(C=0)-; Q' is selected from the group consisting of: absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Cι-C6 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; R1 is selected from the group consisting of: H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, _ ι _
arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; R2 is selected from the group consisting of: H, Cι-C6 alkyl, C3-C 2 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and R3 and R4 are each Independently selected from the group consisting of hydrogen and methyl; compounds of formula II, wherein A Is -(C=0)-0-R1, R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
N N
N N II || :N
1 I N-«'^Λ-'Y 1 — 11 y heterocycloalkyl; G is hydroxyl; L is "absent; W is \ V u — N
and -i~ ; Q is selected from the group consisting of: absent, -CH2-, -O- -NH-, -N(R1)-. -S-, -S(0)2-, and -(C=0)-; Q' is selected from the group consisting of: absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Cι-C6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1; and R3 and R4 are hydrogen;
Compounds of formula II wherein A is -(C=0)-0-fert-butyl; G is hydroxyl; L is
Figure imgf000032_0001
group consisting of: absent, -CH2-, -O-, -NH-, -N(R1)-- -S-, S(0)z-, and -(C=0)-;
Q' is selected from the group consisting of: absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1 ; and R3 and R4 are hydrogen; Compounds of Formula II, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, substituted
Figure imgf000033_0001
is selected from the group consisting of: absent, -CH2-, -0-, -NH-, -N(R1)-. -S- -S(0)2-, and -(C=0)-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
Compounds of Formula II, wherein A is
Figure imgf000033_0002
G is hydroxyl; L is N — N absent; W is * ; Q is selected from the group consisting of: absent, -CHz-,
-0-, -NH-, -N(R1)-» -S-, -S(0)2-, and -JC=0)-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1; and R3 and R4 are hydrogen;
Compounds of Formula III, wherein A is -(C=0>-0-R1, R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl,
Figure imgf000033_0003
-N(R1)-» -S-, -S(0)2-, and -(C=0)-; Q' is selected from the group consisting of: absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1; and R3 and R4 are hydrogen;
Compounds of Formula III, wherein A is -(C=0)-0-fe/f-butyl; G is hydroxyl; L is
Figure imgf000034_0001
is selected from the group consisting of: absent, -CH2-, -0-, -NH-, -N(R1)-. -S-, -S(0)2-, and -(C=0)-; Q' is selected from the group consisting of: absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Cι-C6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1; and R3 and R4 are hydrogen;
Compounds of Formula III, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
heterocycloalkyl; G is hydroxyl; L is absent; W is * ; Q is selected from the group consisting of: absent, -CH2-, -0-, -NH-, -N(R1)-. -S-, -S(0)2-, and -(C=0)-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted ary), arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1; and R3 and R4 are hydrogen; and
Compounds of Formula III, wherein A is
Figure imgf000034_0002
G is hydroxyl; L is
absent; W is
Figure imgf000034_0003
Q is selected from the group consisting of: absent, -GH2-,
-0-, -NH-, -N(R1)-. -S-, -S(0)2-, and -(C=0)-; Y is selected from the group consisting of: H, Cι-C6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1; and R3 and R4 are hydrogen.
Other embodiments are: Compounds of formulae II or III wherein wherein A is selected from the group consisting of: H, -(C=0)-R2, -(C=0)-0-R1, -C(=0)-NH-R2, -C(=S)-NH-R2, and -S(0)2-R2; G is selected from the group consisting of: -OH, -0-(Cι-Cι2 alkyl), -NHS(0)z-R\ -<C=0)-R2 -(C=0>-0-R1, and -(C=0)-NH-R2; L is selected from the group consisting of: absent, -S-, -SCH2-, -SCH2CH2-, -S(0)2-, -S(0)2CH2CH2-, -S(O)-, -S(0)CH2CH2-, -0-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-,
-CFHCH2- and -CF2CH2-; W is selected from the group consisting of:
Figure imgf000035_0001
and
Figure imgf000035_0002
« - ; X and Y are independently selected from the group consisting of: H, halogen, Cι-C6 alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH2-djalkylamino, -CHrarylamino, -CHrdiarylamlno, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j = 0, 1 , 2, 3, or 4; m = 0, 1 , or 2; s = 0, 1 , or 2; R1 is selected from the group consisting of: H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; R2 is selected from the group consisting of: H, Cι-C6 alkyl, C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and R3 and R4 are each independently selected from the group consisting of hydrogen and methyl;
A compound of Formula II, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is selected from the group consisting
Figure imgf000036_0001
; X and Y are independently selected from the group cbhsisting of: H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl; -CHralkylamino, -CH2-dialkylamlno, -CH2- arylamino, -CH∑-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)- arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are-attached, form a -yclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
A compound of Formula II, wherein A is -(C=0)-0-te-rf-butyl; G is hydroxyl; L is
absent; W is selected from the group consisting of:
Figure imgf000036_0002
; X and Y are independently selected' from the group consisting of: H, halogen, Cι-C6 alkyl, C3-C12 cycloalkyl, -CH2-alky!amino, -CH2-dialkylamino, -CH2-arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen; A compound of Formula II, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Cι-C6 alkyl, C3-Cι2 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
heterocycloalkyl; G is hydroxyl; L is absent; W is
Figure imgf000037_0001
X and Y are independently selected from the group consisting of: H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -CH2- alkylamino, -CH2-dialkylamino, -CH2-arylam.no, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together vvith the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
A compound of Formula II, wherein A is -(C=0)-0-fe-rf-butyl; G is hydroxyl; L is
Figure imgf000037_0002
absent; W is - ; X and Y are independently selected from the group consisting of: H, halogen, Cι-C6 alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH2-dialkylamino, -CH2- arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -<C=0)- arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen; A compound of Formula III, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
Figure imgf000038_0001
H, halogen, Cι-C6 alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH2-dialkylamino, -CH2- arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)- arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
A compound of Formula III, wherein A is -(C=0)-0-fetf-butyl; G is hydroxyl; L is
absent; W is selected from the group consisting of:
Figure imgf000038_0002
; X and Y are independently selected from the group consisting of: H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH^-dialkylamino, -CH2-arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -{C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen; A compound of Formula III, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
heterocycloalkyl; G is hydroxyl; L is absent; W
Figure imgf000039_0001
X and Y are independently selected from the group consisting of: H, halogen, Cι-C6 alkyl, C3-C12 cycloalkyl, -CH2- alkylamino, -CH2-dialkylamino, -CH2-arylamino, -CH2-diaryIamino, ~(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1 ; and R3 and R4 are hydrogen; and
A compound of Formula III, wherein A is
Figure imgf000039_0002
G is hydroxyl; L is
absent; W is
Figure imgf000039_0003
X and Y are independently selected from the group consisting of: H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH2-dialkyIamino, -CH2- arylamlno, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)- arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen. Other embodiments are compounds of formulae IV or V:
Figure imgf000040_0001
(IV) (V)
wherein A is H, -(C=0)-R2, -(C=0)-0-R1, -C(=0)-NH-R2, -C(=S)-NH-R2, or -S(0)2-R2; G is -OH, -0-(Cι-Ci2 alkyl), -NHS(0)2-R1, -(C=0)-R2 -(C=0)-0-R1, or -(C=0)-NH-R2; L is absent, -S-, -SCH2-, -SCH2CH2-, -S(0)2-, -S(0)2CH2CH2-, ~S(θy, -S(0)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2- or -CF2CH2-; X, Y, and Z are independently selected from the group consisting of H, N3, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, alkylamino, dialkylamino, Ci-Cβ 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 aryjalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or, in the alternative, X and Y or Y and Z taken together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl cyclic moiety; j = 0, 1, 2, 3, or 4; m = 0, 1, or 2; s = 0, 1, or 2; R1 is H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; R2 is H, Cι-C6 alkyl, C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted 5 heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; and R3 and R4 are each independently hydrogen or methyl;
A compound of Formula IV, wherein A is -(C=0)-0-R1 ; G is hydroxyl; L Is absent; ; j=3; m=s=1; and R3 and R4 are hydrogen; )
A compound of Formula IV, wherein A is
Figure imgf000041_0001
G is hydroxyl; L is absent; j=3; m=s=1; and R3 and R4 are hydrogen;
A, compound of Formula V, wherein A is -(C=0)-0-R1; L is absent; j=3; m=s=1; 5 and R3 and R4 are hydrogen; and
A compound of Formula V, wherein A is
Figure imgf000041_0002
G is hydroxyl; L is absent; j=3; m=s=1 ; and R3 and R4 are hydrogen.
Another aspect is a compound of formula I, wherein W is
Figure imgf000041_0003
wherein V, X, Y, and Z are each independently selected from: a) -Ci-Cβ 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) -C2-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) -C2-C6 alkynyl 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; d) aryl; e) substituted aryl; f) heteroaryl; g) substituted heteroaryl; h) heterocycloalkyl; or i) substituted heterocycloalkyl; or in the attemative, V and X, X and Y, or 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;
Another aspect is a compound of formula I, wherein W
Figure imgf000042_0001
wherein X, Y, and Z are each independently selected from: a) -Cι-C6 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) -C2-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) -C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from ιr w
halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; d) aryl; e) substituted aryl; f) heteroaryl; g) substituted heteroaryl; h) heterocycloalkyl; or i) substituted heterocycloalkyl; or in the alternative, 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:
Figure imgf000043_0001
VI
wherein,
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:
Figure imgf000044_0001
Formula VII
wherein,
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.
In other aspects, 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. In other aspects 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.
In another aspect, the invention relates to 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.
DETAILED DESCRIPTION OF THE INVENTION 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.
In some embodiments , 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:
Aromatic
Figure imgf000046_0001
Figure imgf000046_0002
WPyrrole iH- e Isothiazole
Figure imgf000046_0003
Figure imgf000046_0004
P Gyridine Py Crfdazsine Py Orimidine P 0yrazine Phlhalazine Quinoxaline Qumazoline Quino|jne
Figure imgf000046_0005
Figure imgf000046_0006
Figure imgf000046_0007
1H-lmidazo[4,5-jb]pyridine
Figure imgf000046_0008
Benzothiazole Benzooxazole lH-lmidazo[4,5-φyridine 1,3-D-hydro-benzoiπ.idazo--2-or.e
Figure imgf000046_0009
Figure imgf000046_0011
2,3-Dihydro-1H-indole 1W-Indole-2,3-dione
Figure imgf000046_0012
1,3-Dihydro-ber-zoimidazole-2-thione
Figure imgf000046_0013
1,3-Di ydro-benzoimidazol-
1,3-Dihydro-indol-2-one 2-one } <
1H-Pyrτolo[2.3.c]pyridine Benzofuran Benzo[b]lhiophene Benzorøisoxazole BenzoMisolhiazo,e
1
Figure imgf000046_0014
IH-Quinolin-4-one 1H-Quinazolin-4-one
Figure imgf000046_0015
OG H A
1 H-Quinazolin-2-one
In other embodiments, 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:
Non-Aromatic
Figure imgf000047_0001
Figure imgf000047_0002
Pyrazolidine
Figure imgf000047_0003
lmidazolidin-2-one |mid--zoHdine-2--hione Pyrrolidin-2-one Pyrro.idir.e-2,5-dioι.e piperidine-2,6<lione
Figure imgf000047_0004
Thiomorpholine 1,1-dioxide
Figure imgf000047_0005
Figure imgf000047_0006
etra y ro- uran Tetrahydro-pyran p^ oxane 1,2,3,6-Tetrahydro-pyridine
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. a-
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:
Compounds of Formula II, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
heterocycloalkyl; G is hydroxyl; L is absent; W is / γ ,
Figure imgf000048_0001
Figure imgf000048_0002
Q is selected from the group consisting of: absent, τCF-2-, -O-, -NH-,
-N(R1)-, -S-, -S(0)2-, and -(C=0)-; Q' is selected from the group consisting of: absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1; and R3 and R4 are hydrogen;
Compounds of Formula II, wherein A is -(C=0)-0-tetf-butyl; G is hydroxyl; L is
absent; W is
Figure imgf000048_0003
group consisting of: absent, -CH2-, -O-, -NH-, -N(R1)-. -S-, -S(0)2-, and -(C=0)-; Q' is selected from the group consisting of: absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
Compounds of Formula II, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
N — N heterocycloalkyl; G is hydroxyl; L is absent; W is ; Q is selected from the group consisting of: absent, -CH2-, -0-, -NH-, -N(R1)-. -S-, -S(0)2-, and -(C=0)-;
Y is selected from the group consisting of: H, Cι-C6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
Compounds of Formula II, wherein A is -(C=0)-0-tert-butyl; G is hydroxyl; L is rzrN absent; W is *^ * Y ; Q is selected from the group consisting of: absent, -CH2-,
-O- -NH-, -N(R1)-» -S-, -S(0)2-, and -(C=0)-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
Compounds of Formula III, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
heterocycloalkyl; G is hydroxyl; L is absent; W is
Figure imgf000049_0001
N=N
and -I ; Q is selected from the group consisting of: absent, -CH2-, -0-, -NH-, -N(R1)-, -S-, -S(0)2-, and -(C=0)-; Q' is selected from the group consisting of: . -
absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Cι-C6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
Compounds of Formula III, wherein A is -(C=0)-0-fe-rf-butyl; G is hydroxyl; L is
absent; W is
Figure imgf000050_0001
Q is selected from the group consisting of: absent, -CH?-, -0-, -NH-, -N(R1)-. -S-, -S(0)2-, and -(C=0>-;
Q' is selected from the group consisting of: absent, -CH2-, and -NH-; Y is selected from the group consisting of: H, Ci-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
Compounds of Formula III, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
heterocycloalkyl; G is hydroxyl; L is absent; W is
Figure imgf000050_0002
Q is selected from the group consisting of: absent, -CH2-, -O-, -NH-, -N(R1)-- -S-, -S(0)2-, and -(C=0)-; Y is selected from the group consisting of: H, Cι-C6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; rn=s:=1; and R3 and R4 are hydrogen; and
Compounds of Formula III, wherein A is -(C=0)-0-ferf-butyl; G is hydroxyl; L is
absent; W is
Figure imgf000050_0003
Q is selected from the group consisting of: absent, -CH2-,
-0-, -NH-, -N(RV. -S-, -S(0)2-, and -(C=0)-; Y is selected from the group consisting of: H, C -Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1; and R 3 „ a„nd J D R4 are hydrogen.
Representative compounds of the invention include, but are not limited to, the following compounds:
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0003
The following additional tetrazolyl macrocyclic molecules of the invention were made by the methods and procedures described herein. While stereochemistry is shown, the invention is not limited to the stereochemistry depicted. Those of ordinary skill in the art will readily appreciate that other isomers of these compounds are also within the scope of the invention.
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
Figure imgf000058_0004
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0003
Figure imgf000059_0004
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000060_0003
Figure imgf000060_0004
58
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0003
Figure imgf000061_0004
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0003
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 _
where 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:
A compound of Formula Ir, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is selected from the group consisting
Figure imgf000063_0001
; X and Y are independently selected from the group consisting of:
H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -dialkylamino, -CH2-dialkylamino, -CH2- arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=O)-dialkylamino, -(C=O)- arylamino, -(C=O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1 ; and R3 and R4 are hydrogen;
A compound of Formula II, wherein A is is hydroxyl; L is
absent; W is selected from the group consisting
Figure imgf000063_0002
X and Y are independently selected from the group consisting of: H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -CHralkylamino, -CH2-dialkylamino, -CH∑-arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)-diarylamino, aiyl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen;
A compound of Formula II, wherein A is -(C=O)-0-R1, R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
heterocycloalkyl; G is hydroxyl; L is absent; W is and Y are independently selected from the group consisting of: H, haloge
Figure imgf000064_0001
alkyl, C3-C12 cycloalkyl, -CH2- alkylamino, -CH2-dialkylamino, -CH∑-arylamino, -CH2-diarylamino, -(C=0)-alkylamino,
-(C=0)-dialkylamino, -(C=0)-arylamino, -(C=0)-dia-rylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; ]=3; m=s=1; and R3 and R4 are hydrogen;
A compound of Formula II, wherein A is
Figure imgf000064_0002
G is hydroxyl; L is
Figure imgf000064_0003
H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -CHralkylamino, -CH2-dialkylamino, -CH2- arylamino, -Chfe-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)- arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen;
A compound of Formula III, wherein A is ~(C=0)-0-R1, R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryli substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is selected from the group consisting
Figure imgf000065_0001
and
Figure imgf000065_0002
X and Y are independently selected from the group consisting of:
H, halogen, Cι-C6 alkyl, C3-C12 cycloalkyl, -CHralkylamino, -CH2-dialkylamino, -CH2- arylamino, -CH∑-diarylamino, -(C=Q)-alkylamino, -(C=0)-dialkylamino, -(C=O)- arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; J 3; m=s=1 ; and R3 and R4 are hydrogen; L is
Figure imgf000065_0003
absent; W is selected from the group consisting of: X or -i ; X and Y are independently selected from the group consisting of: H, halogen, Ci-Cβ alkyl, C3-C12 cycloalkyl, -CH2-alkylam.no, -CH2-dialkylamino, -CH2-arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, - C=O)-arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form __
a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen;
A compound of Formula II, wherein A is -(C=0)-0-R1, R1 is selected from the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted
N„ ,N N heterocycloalkyl; G is hydroxyl; L is absent; W is ; X and Y are independently selected from the group consisting of: H, halogen, Cι-C6 alkyl, C3-C12 cycloalkyl, -CH2- alkylamino, -CHrdialkylamino, -CHrarylamino, -Chb-diarylamino, -(C=0)-alkylamino,
-(C=O)-dialkylamino, -(C=0)-arylamino, -(C=O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen; and
A compound of Formula II, wherein A is
Figure imgf000066_0001
G is hydroxyl; L is
Figure imgf000066_0002
absent; W is ; X and Y are independently selected from the group consisting of: H, halogen, Cι-C6 alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH2-dialkylamino, -CH2- arylamino, -CH2-diarylamino, -(C=0)-alkylamino, -(C=0)-dialkylamino, -(C=0)- arylamino, -(C=0)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylajkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R3 and R4 are hydrogen. Representative compounds of the invention include, but are not limited to, the following compounds:
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
The following additional triazole macrocyclic molecules of the invention were made by the methods and procedures described herein. While stereochemistry is shown, the invention is not limited to the stereochemistry depicted. Those of ordinary skill in the art will readily appreciate that other isomers of these compounds are also within the scope of the invention.
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000074_0003
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000076_0003
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000077_0003
Figure imgf000078_0001
Figure imgf000078_0002
Figure imgf000078_0003
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000079_0003
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000080_0003
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:
A compound of Formula II, wherein A is -(C=0)-0-R1 ; G is hydroxyl; L is absent;
; j=3; m=s=1; W= * X , and R3 and R4 are hydrogen;
A compound of Formula II, wherein A is -(C=0)-0-ferf-butyl; G is hydroxyl; L is
absent; j=3; m=s=1 ; W= -J-- , and R and R are hydrogen;
A compound of Formula III, wherein A is -(C=0)-0-R1; L is absent; j=3; m=s=1;
W= -J- , and R3 and R4 are hydrogen; and
A compound of Formula III, wherein A is -(C=0)-0-fetf-butyl; G is hydroxyl; L is
Representative compounds of the invention include, but are not limited to, the following compounds:
Figure imgf000081_0002
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
The following additional pyridazinone macrocyclic molecules of the invention were made by the methods and procedures described herein. While stereochemistry is shown, the invention is not limited to the stereochemistry depicted. Those of ordinary skill in the art will readily appreciate that other isomers of these compounds are also within the scope of the invention.
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000086_0003
M
Figure imgf000087_0001
Figure imgf000087_0002
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:
Figure imgf000088_0001
According to an alternate embodiment, the pharmaceutical compositions of the present invention may further contain other anti-HCV agents. Examples of anti-HCV agents include, but are not limited to, or-interferon, yff-interferon, ribavirin, and amantadine.
According to an additional alternate embodiment, the pharmaceutical compositions of the present invention may further contain other HCV protease inhibitors.
According to yet another alternate embodiment, the pharmaceutical 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).
According to a further embodiment, 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 _
sequentially administered with the compound or composition delineated herein. 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.
All references, including patents, patent publications, articles, texts, etc. disclosed throughout this specification are hereby incorporated by reference in their entirety.
Definitions
The following definitions of various terms and phrases used to describe the invention are consistent with their normal use in the art and apply to the terms as they are used throughout this specification and claims unless otherwise limited in specific instances, either individually or as part of a larger group. ~
The term "Cx-Cy," as used herein, 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.
The term "halo" and "halogen," as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term "alkyl," as used herein, 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.
The term "substituted alkyl," as used herein, 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, N02, CN, C,-C6-alkyl-OH, C(0)-CrC6-alkyl, OCH2-(C3-Ci2- cycloalkyl), C(0)-aryl, C(0)-heteroaryl, COralkyl, C02-aryl, C02-heteroaryl, CONH2, CONH-(CrC6-alkyl), CONH-aryl, CONH-heteroaryl, OC(OHd-C6-alkyl), OC(0)-aryl, OC(0)-heteroaryl, OCθ2-alkyl, OCO∑-aryl, OCθ2-heteroaryl, OCONH2, OCONH-(CrC6- alkyl), OCONH-aryl, OCONH-heteroaryl, NHC(OHCrC6-alkyl), NHC(0)-aryl, NHC(O)- heteroaryl, NHC02-alkyl, NHC02-aryl, NHCOa-heteroaryl, NHCONH2, NHCONH-(C,-C<r alkyl), NHCONH-aryl, NHCONH-heteroaryl, Sθ2-C C6 alkyl, Sθ2-aryl, SOrheteroaryl, S02NH2, S02NH-CrC6-alkyl, S02NH-aryl, S02NH-heteroaryl, CrCe-alkyl, Cs- r „ „ w _ _
cycloalkyl, CF3, CH CF3, CHC12, CH2NH2,CH2SO2CH3H, C,-C6 alkyl, halo alkyl, C3-C12 cycloalkyl, substituted C3-Cι2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, Q-Ce- alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C|-C3-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, Q-Ce-alkyl- thio, or methylthiomethyl.
The term "haloalkyl," as used herein, 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.
The term "thioalkyl," as used herein, refers to an acyclic, stright or branched chain alkyl substituent containing a thiol group, such as, for example and not limitation, thiopropyl.
The term "alkoxy," as used herein, refers to an alkykjroup, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert- butoxy, neopentoxy and n-hexoxy.
The term "alkenyl," as used herein, 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.
The term "substituted alkenyl," as used herein, refers to an "alkenyl" group substituted by independent replacement of one or more of the hydrogen atoms thereon with F, CI, Br, I, OH, N02, CN, CrC6-alkyl-OH, C(OMC.-C6-alkyl), OCH2-(C3-C12- cycloalkyl), C(0)-aryl, C(0)-heteroaryl, CO2-alkyl, C02-aryl, COrheteroaryl, CONH2, CONH-C,-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(OMC C6-alkyl), OC(0)-aryl, OC(0)-heteroaryl, OCθ2-alkyl, OCO aryl, OC02-heteroaryl,OCONH2, OCONH- -Ce- alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O>CrC6-alkyl,NHC(0)-aryl, NHC(O)- heteroaryl, NHC02-alkyl, NHC02-aryl, NHCOa-heteroaryl, NHCONH2, NHCONH-(C,-C6- alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO2-(CrC6-alkyl), S02-aryl, SOrheteroaryl, SO2NH2, S02NH-(CrC6-alkyl), S02NH-aryl, SO2NH-heteroaryl, C,-C6-alkyl, C3-C(r cycloalkyl, CF3, CH2CF3, CHC12, CH2NH2, CH∑SOzCHsH, C,-C6 alkyl, halo alkyl, C3-Cι2 r t , _
cycloalkyl, substituted C3-Ci2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C|-C6- alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, Q-Ca-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, Ci-Cβ-alkyl- thio, or methylthiomethyl.
The term "alkynyl," as used herein, 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.
The term "substituted alkynyl," as used herein, refers to an "alkynyl" group substituted by independent replacement of one or more of the hydrogen atoms thereon with F, CI, Br, I, OH, N02, CN, C-Cβ-alkyl-OH, C(O)-(CrC6-alkyl), OCH2-(C3-C12- cycloalkyl), C(0)-aryl, C(0)-heteroaryl, C02-alkyl, C02-aryI, C02-heteroaryl, CONH2, CONH-(C,-C6-alkyl), CONH-aryl, CONH-heteroaryl, OC(O)-(C C6-alkyl), OC(0)-aryl, OC(O)-heteroaryl, OCO alkyl, OC02-aryl, OCO2-heteroaryl, OCONH2, OCONH-(C|-C6- alkyl), OCONH-aryl, OCONH-heteroaryl, NHC(OHC|-C6-alkyl), NHC(O)-aryl, NHC(O)- heteroaryl, NHCO2-alkyl, NHC02-aryl, NHCO2-heteroaryl, NHCONH2, NHCONH-(C,-C6- alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO2-( -C6-alkyl), Sθ2-aryl, SOrheteroaryl, S02NH2, SO2NH-(CrC6-alkyl), S02NH-aryl, SO2NH-heteroaryl, C,-C6-alkyl, C3-C6- cycloalkyl, CF3, CH2CF3, CHC12, CH2NH2, CH2SO2CH3H, CrC6 alkyl, halo alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C Cβ- alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, CrC-ralkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, CrCβ-alkyl- thio, or methylthiomethyl.
The term "aryl," as used herein, 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.
The term "substituted aryl," as used herein, 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, N02, CN, d-Ce-alkyl-OH, C(0)-(C,-C6-alkyl), OCH2-(C3- - -
Circycloalkyl), C(0)-aryl, C(0)-heteroaryl, C02-alkyl, COraryl, C02-heteroaryl, CONH2, CONH-(C,-C6-alkyl), CONH-aryl, CONH-heteroaryl, OC(0)-(Cι-C6-aIkyl), OC(0)-aryl, OC(O)-heteroaryl, OCOralkyl, OCOraryl, OCOrheteroaryl, OCONH2, OCONH-(C,-C6-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC(OMC,-C6-alkyl), NHC(O)- aryl, NHC(0)-heteroaryl, NHC02-alkyl, NHC02-aryl, NHCOrheteroaryl, NHCONH2, NHCONH-(C,-C6-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SOr( -C6-alkyl), SCV aryl, SOrheteroaryl, S02NH2, S02NH-(C|-CValkyl), S02NH-aryl, S02NH-heteroaryl, C Cβ-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CHC12, CH2NH2, CH2S02CH3H, C,-C6 alkyl, halo alkyl, C3-Cι2 cycloalkyl, substituted C3-Cι2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, CrCβ-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C|-C3-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, Ci-Cβ-alkyl-thio, or -methylthiomethyl.
The term "arylalkyl," as used herein, 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.
The term "substituted arylalkyl," as used herein, 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, NO2, CN, Q-Ce-alkyl-OH, C(Oj-C C6- alkyl, OCHH rCircycloalkyl), C(0)-aryl, C(0)-heteroaryl, COralkyl, COraryl, COr heteroaryl, CONH2, CONH-C,-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(OMC C6- alkyl), OC(0)-aryl, OC(0)-heteroaryl, OCOralkyl, OCOraryl, OCOrheteroaryl, OCONH2, OCONH-(C,-C6-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC(0)-(C,-C6- alkyl), NHC(0)-aryl, NHC(0)-heteroaryl, NHCOralkyl, NHCOraryl, NHCOrheteroaryl, NHCONH2, NHCONH-(CrC6-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SOHC Cβ- alkyl), SOraryl, S02-heteroaryl, S02NH2, S02NH-(C,-C6-alkyl), S02NH-aryl, S02NH- heteroaryl, CrC6-alkyl, C3-CVcycloalkyl, CF3, CH2CF3, CHC12, CH2NH2, CH∑SO∑CHsH, -Cβ alkyl, halo alkyl, C3-Cι2 cycloalkyl, substituted C3-Cι2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, Q-Cβ-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, -C3-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, Cι-C6-alkyl-thio, or methylthiomethyl.
The term "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.
The term "substituted cycloalkyl," as used herein, 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, N02, CN, CrC6-alkyl-OH, CfOM -Ce- alkyl), OCHHCrCircycloalkyl), C(0)-aryl, C(O)-heteroaryl, C02-alkyl, C02-aryl, COr heteroaryl, CONH2, CONH-(CrC6-alkyl), CONH-aryl, CONH-heteroaryl, OC(0)-(Cι-C<-- alkyl), OC(0)-aryl, OC(0)-heteroaryl, OCOralkyl, OCOraryl, OC02-heteroaryl, OCONH2, OCONH-CI-C6-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(0)-(C|-C6-alkyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHCOralkyl, NHCOraryl, NHCOrheteroaryl, NHCONH2, NHCONH-(C,-C6-alkyl), NHCONH-aryl, NHCONH-heteroaryl, S02-(C,-C6- alkyl), SO2-aryl, SOrheteroaryl, SO2NH2, S02NH-(C,-C6-alkyl), S02NH-aryl, S02NH- heteroaryl, Ci-Cg-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CHC12, CH2NH2, CH2S02CH3H, -C6 alkyl, halo alkyl, C3-Cι2 cycloalkyl, substituted C3-Cι2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, Q-Cβ-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, Cι-C3-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, d-Cβ-alkyl-thio, or methylthiomethyl.
The terms "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. Examples of 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. Although the terms "heterocycloalkyl," "aliphatic heteromonocyclic ring system," "aliphatic heterobicyclic ring system," "aliphatic heterotricyclic ring system," "heteroaryl," "aromatic heteromonocyclic ring system," "aromatic heterobicyclic ring system," "aromatic heterotricyclic ring system," "heteroarylalkyl," are covered generally by the term "heterocycle," their specific meanings are set forth in further detail below.
The term "heterocycloalkyl," as used herein, 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. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, moφholinyl, thiazolidinyl, isothiazolidinyl, and tetra hydrofuryl.
The term "substituted heterocycloalkyl," as used herein, 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, NO2, CN, C1-C.5- alkyl-OH, C(0)-CrC6-alkyl, OCH∑-fQrdrcycloalkyl), C(O)-aryl, C(0)-heteroaryl, COr alkyl, C02-aryl, COrheteroaryl, CONH2, CONH-C,-C6-alkyl, CONH-aryl, CONH- heteroaryl, OC(O)-C1-C6-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OC02-alkyl, OCOraryl, OCOrheteroaryl, OCONH , OCONH-(C,-C6-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC(OMC.-C6-alkyl), NHC(0)-aryl, NHC(0)-heteroaryl, NHC02-alkyl, NHCO2-aryl, NHCOrheteroaryl, NHCONH2, NHCONH-(C,-C6-alkyl), NHCONH-aryl, NHCONH- heteroaryl, SOr(Cι-C6-alkyl), S02-aryl, SOrheteroaryl, S02NH2, S02NH-(Cι-C6-alkyl), S02NH-aryl, S02NH-heteroaryl, -Cg-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CHC12, CH2NH2, CH2S02CH3H, CrC6 alkyl, halo alkyl, G3-C12 cycloalkyl, substituted Cs-Cι2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, Ci-Cβ-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C|-C3-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, Q-Cβ-alkyl-thio, or methylthiomethyl. As used herein, the term "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. The term "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. The term "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. As will be appreciated, 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. Thus, 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."
As used herein, the term "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. The term "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. The term "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. Thus, 5,6, 7,8 tetrahydroisoquinoline is an example of an aromatic heterobicyclic ring system, whereas 1,2,3,4 tetrahydroisoquinoline is an example of an aliphatic heterobicyclic ring system.
The term "heteroaryl," as used herein, 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.
The term "substituted heteroaryl," as used herein, 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, N02, CN, CrC6-alkyl-OH, C(0)-CrC6- alkyl, OCHr(C3-C1rcycloalkyl), C(0)-aryl, C(0)-heteroaryl, COralkyl, C02-aryl, C02- heteroaryl, CONH2, CONH-(C|-C6-alkyl), CONH-aryl, CONH-heteroaryl, OC(0)-(Cι-C6)- alkyl, OC(0)-aryl, OC(0)-heteroaryl, OCOralkyl, OCOraryl, OC02-heteroaryl, OCONH2, OCONH-(C,-C6-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC(0)-(CrC6- alkyl), NHC(0)-aryl, NHC(0)-heterOaryl, NHCOralkyl, NHCOraryl, NHCOrheteroaryl, NHCONH2, NHCONH-(C,-C6-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SOH -Cβ- alkyl), SOraryl, SOrheteroaryl, S02NH2, S02NH-(C,-C6-alkyl), S02NH-aryl, S02NH- heteroaryl, CrC6-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CHC12, CH2NH2, CH2S02CH3H, C1-C6 alkyl, halo alkyl, C3-Cι2 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C|-C6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, Q-C3-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, Q-Cβ-alkyl-thio, or methylthiomethyl.
The term "heteroarylalkyl," as used herein, refers to a Q-C3 alkyl or Ci-Cβ alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimldinylethyl and the like.
The term "substituted heteroarylalkyl," as used herein, 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, N02, CN, Ci-Ce-alkyl-OH, C(0)- -C6- alkyl, OCHr(C3-drcyclpalkyl), C(0)-aryl, C(0)-heteroaryl, COralkyl, COraryl, COr heteroaryl, CONH2, CONH-CrC6-alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-d-C6- alkyl, OC(0)-aryl, OC(0)-heteroaryl, OCOralkyl, OCOraryl, OCOrheteroaryl, OCONH2, OCONH-(C,-C6-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC(0)-(Cι-C6- alkyl), NHC(0)-aryl, NHC(0)-heteroaryl, NHCOralkyl, NHCOraryl, NHCOrheteroaryl, NHCONH2, NHCONH-(C,-C6-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO (CrC6- alkyl), SOraryl, SOrheteroaryl, S02NH2, S02NH-(C,-Ce-alkyl), SQ2NH-aryl, S02NH- heteroaryl, Q-Cβ-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CHC12, CH2NH2, CH2S02CH3H, CrC6 alkyl, halo alkyl, C Ci2 cycloalkyl, substituted C3-Cι2 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, CrC6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, Ci-Cy-alkylamlno, thio, aryl-thio, heteroarylthio, benzyl-thio, Q-Cβ-alkyl-thio, or methylthiomethyl.
Substituent groups substituted on any group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocyclic) delineated herein also include any of -F, -CI, -Br, -I, -OH, protected hydroxy, aliphatic ethers, aromatic ethers, oxo, -N02, -CN, -d-dralkyl optionally substituted with halogen (such as perhaloalkyls), CrCiralkenyl optionally substituted with halogen, -C2-Cιralkynyl optionally substituted with halogen, -NH2, protected amino, -NH -CrCι2-alkyl, -NH -C2-Cι2-alkenyl, -NH -Cr Ciralkynyl, -NH -ϋ3-C .2-cycloalkylr-NH -aryl, -NH -heteroaryl, -NH -heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -0-C -Cι2-alkyl, -0-C2-Cι2-alkenyl, -0-C2-CιralkynyI, -0-C3-Ci2-cycloalkyl, -O-aryl, -0-heteroaryl, -O-heterocycloalkyl, -C(0 d-C^alkyl, -C(O)- CrCiralkenyl, -C(O)- CrCι2-alkynyI, -C(0)-C3-Cι2- cycloalkyl, -C(0)-aryi, -C(0)-heteroaryl, -C(0)-heterocycloalkyl, -CONH2, -CONH- d- Ciralkyl, -CONH- C2-C12-alkenyl, -CONH- CrCι2-alkynyl, -CONH-C3-Cι2-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -COr d-Cι2-alkyl, -COr CrCiralkenyl, -COr CrC12-alkynyl, -COrC3-Cι2-cycloalkyl, -COraryl, -COr heteroaryl, -C02-heterocycloalkyl, -OCOr CrC^alkyl, -OCOr CrCiralkenyl, -OCOr d-Ciralkynyl, -OCOrC3-Cιrcycloalkyl, -OCOraryl, -OC02-heteroaryl, -OCOrheterocycloalkyl, -OCONH2, -OCONH- d-Cι2-alkyl, -OCONH- d-Ciralkenyl, -OCONH- CrCiralkynyl, -OCONH- C3-dr.cycloalkyl, -OCONH- aryl, -OCONH- heteroaryl, -OCONH- heterocycloalkyl, -NHC(O)- Cι-Ci2-alkyl, -NHC(0)-C2-Cιr alkenyl, -NHC(0)-CrCiralkynyl, -NHC(0)-C3-Circycloalkyl, -NHC(0)-aryl, -NHC(O)- heteroaryl, -NHC(0)-heterocycloalkyl, -NHCOr Ci-Ciralkyl, -NHCOr CrCiralkenyl, -NHCOr CrCiralkynyl, -NHCOr C3-Cιrcycloalkyl, -NHCOr aryl, -NHCOr heteroaryl, -NHCOr heterocycloalkyl, -NHC(0)NH2, NHC(0)NH-
Figure imgf000097_0001
-NHC(0)NH-CrCiralkenyl, -NHC(0)NH-C2-Cιralkynyl, -NHC(0)NH-C3-Cir cycloalkyl, -NHC(0)NH-aryl, -NHC(0)NH-heteroaryl, -NHC(0)NH-heterocycloalkyl, NHC(S)NH2, NHC(S)NH- C C12-alkyl, -NHC(S)NH-C2-C12-alkenyl, -NHC(S)NH-CrC12- alkynyl, -NHC(S)NH-C3-drcycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, NHC(NH)NH- d-Ciralkyl, -NHC(NH)NH-C2-Cιralkenyl, -NHC(NH)NH-CrCι2-alkynyl, -NHC(NH)NH-C3-dr cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH- heterocycloalkyl, NHC(NH)-C1-C12-alkyl, -NHC(NH)-CrCι2-alkenyl, -NHC(NH)-C Cιr alkynyl, -NHC(NH)-C3-C12-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-Cι-Cιralkyl, -C(NH)NH-CrCι2-alkenyl, -C(NH)NH-CrC12-alkynyl, -C(NH)NH-C3-Cιrcycloalkyl, -C(NH)NH-aryl, -C(NH)NH- heteroaryl, -C(NH)NH-heterocycIoalkyl, -S(0)-Cι-Cι2-alkyl, - S(0)-CrC1ralkenyl, - SfO^Crdralkynyl, - S(0)-C3-Ci2-cycloalkyl, - S(0)-aryl, - S(0)-heteroaryl, - S(O)- heterocycloalkyl -S02NH2, -S02NH- d-C12-alkyl, -S02NH- CrCι2-alkenyl, -S02NH- C2-C12-alkynyl, -S02NH- C3-Cι2-cycloalkyl, -S02NH- aryl, -S02NH- heteroaryl, -SO2NH- heterocycloalkyl, -NHS02-Cι-Cι2-alkyl, -NHSOrCrCiralkenyl, - NHS02-Cr Ci2-alkynyl, -NHSOrC3-Cι2-cycloalkyl, -NHSOraryl, -NHSOrheteroaryl, -NHSOr heterocycloalkyl, -CH2NH2, -CH2S02CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-Cι2-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-Cι-Cι2-alkyl, -S-C2-Cιralkenyl, -S-Cr Ciralkynyl, -S-C3-Cιrcycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. It is understood that the aryls, heteroaryls, alkyls and the like can be further substituted.
The term "alkylamino," as used herein, refers to a group having the structure - NH(Cι-Ci2 alkyl) where Q-C12 alkyl is as previously defined. The term "dialkylamino" refers to a group having the structure -N(Cι-Cι2 alkyl^ where CrCι2 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.
The term "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.
The term "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.
The term "hydroxy protecting group," as used herein, 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- methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl, 2-
(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxyl protecting groups for the present invention are acetyl (Ac or -C(0)CH3), benzoyl (Bn or -C(0)C6H5), and trimethylsilyl (TMS or-Si(CH3)3).
The term "protected hydroxy," as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
The term "nitrogen (or amino) protecting group," as used herein, 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 . , ___, .
protecting group 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). Examples of nitrogen protecting groups include, but are not limited to, t- butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyJ, and the like.
The term "protected amino," as used herein, refers to an amino group protected with an amino protecting group as defined above.
The term "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). Examples of such nucleophilic heterocyclic compounds are known in the art and delineated herein.
The term "leaving group: refers to a moiety that can-be detached from a molecule during a reaction, especially nucleophilic displacement reactions. Examples of 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.
The term "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.
The term "aprotic solvent," as used herein, 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. Such compounds 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. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick ef a/., Vol. II, in the Technigues of Chemistry Series. John Wiley & Sons, NY, 1986.
The term "protogenic organic solvent," as used herein, 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. Such 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. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic- Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick ef al., Vol. II, in the Technigues of Chemistry Series. John Wiley & Sons, NY, 1986.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, 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. As can be appreciated by the skilled artisan, 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. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons (1995), and subsequent editions thereof.
The term "subjecf as used herein refers to an animal. Preferably 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. Such 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.
The term "subject" as used herein 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.
As used herein, 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. Other pharmaceutically acceptable 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, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrale, pivalate, propjonate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, Q-Cβ sulfonate and aryl sulfonate.
As used herein, the term "pharmaceutically acceptable 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. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
The term "pharmaceutically acceptable prodrugs," as used herein, 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. The term "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.
The term "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. For example, 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. Alternatively, 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. For example, 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. As such, 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. Such 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 ___ „ , _.,.
amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. Pharmaceutical Compositions
The pharmaceutical 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. As used herein, the term "pharmaceutically acceptable earner" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some Examples of 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 sulfate and magnesium stearate, as .
well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical 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. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, 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. , , . , , _
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absoφtion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle, injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other 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.
Solid 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. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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. Examples of embedding compositions which can be used 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.
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. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absoφtion 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.
Antiviral Activity
According to the methods of treatment of the present invention, 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. The term "anti-hepatitis C virally effective amount" of a compound of the invention, as used herein, means a sufficient amount of the compound so as to decrease the viral load in a M ,. -, „ „ .,„, , , _
subject, thus decreasing said subject's chronic HCV symptoms. As well understood in the medical arts 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.
Upon improvement of a subject's condition, 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.
It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific 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. In general, 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.
Abbreviations
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are:
ACN for acetonitrile; , , _ _
BME for 2-mercaptoethanol;
BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate;
COD for cyclooctadiene;
DABCYL for 6-(N-4'-carboxy-4-(dimethylamino)azobenzene)- aminohexyl-1-0-(2- cyanoethylHN,N-diisopropyl)-phosphoramidite;
DAST for diethylaminosulfur trifluoride;
DCM for dichloromethane;
DIAD for diisopropyl azodicarboxylate;
DIBAL-H for diisobutylaluminum hydride;
DIEA for diisopropyl ethylamine;
DMAP for N,N-dimethylaminopyridine;
DME for ethylene glycol dimethyl ether;
DMEM for Dulbecco's Modified Eagles Media;
DMF for N,N-dimethyl formamide;
DMSO for dimethylsulfoxide;
DUPHOS
Figure imgf000110_0001
EDANS for 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;
EDCI or EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride; i EtOAc for ethyl acetate;
HATU for O (7-Azabenzotriazole-1 -yl)-N,N,N',N' - tetramethyluronium hexafluorophosphate;
HMBA is 4-Hydroxymethylbenzoic acid AM resin;
Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene) > (tricyclohexylphosphine)ruthenium(ll);
KHMDS is potassium bis(trimethylsilyl) amide;
Ms for mesyl; . ,
NMM for N-4-methylmoφholine
Ph for phenyl;
PuPHOS
PyBrOP for Bromo-tri-pyrolidino-phosphonium hexafluorophosphate;
RCM for ring-closing metathesis;
RT for room temperature;
RT-PCR for reverse transcription-pόlymerase chain reaction; tBOC or Boc for tert-butyloxy carbonyl.
TEA for triethyl amine;
TFA for trifluoroacetic acid;
THF for tetrahydrofuran;
TLC for thin layer chromatography;
TPP or PPb3 for triphenylphosphine; and
Xantphos for4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene.
Certain chemical structures herein having -NH or -OH groups appear without those hydrogen atoms attached to oxygen or nitrogen atoms depicted. Thus, where a nitrogen or oxygen atom in such structure appears to lack proper valency, the presence of those hydrogen atoms are implied.
SYNTHETIC METHODS
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared.
I. Replacement Method Compounds of the present invention can be made via a replacement procedure described generally in the following scheme:
Figure imgf000112_0001
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.
In some embodiments, commercially available Boc-hydroxyproline A
OH y is treated with HCI in dioxane to yield starting material lb.
Synthesis of Cyclic peptide precursor Scheme 1
Figure imgf000113_0001
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. For further details of the synthetic methods employed to produce the cyclic peptide precursor Ig, see U.S. Patent No. 6,608,027, which is herein incoφorated by reference in its entirety.
Synthesis of mesylate of macrocyclic peptide precursor Scheme 2
Figure imgf000113_0002
Ig Ha
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.
I l l Scheme 3
Figure imgf000114_0001
lla ],]
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.
Scheme 4
Figure imgf000114_0002
lla IVa
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.
B. Synthesis of substitutes for W W may be any of the substitutents described previously herein. Synthesis of these various substituents is within the skill of those of ordinary skill in the art. Some exemplary syntheses are presented herein by way of example and not of limitation. Other substituents are either commercially available or readily synthesized by those of ordinary skill in the art.
Synthesis of tetrazoles
Structurally diverse tetrazoles Va-Vq were synthesized from comrhercially available nitrite compounds as described in Scheme 5 below:
Scheme 5
Figure imgf000115_0001
One skilled in the art will recognize that several 5-substituted tetrazole compounds may be produced in this manner with any nitrile-containing compound suitable for the reaction conditions set forth above.
Svnthesis of triazoles
Scheme 6
Figure imgf000115_0002
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. Commercially available alkynes suitable for triazole formation include, but are not limited to:
Figure imgf000116_0001
Synthesis of alkyne Q-
Alkynes useful in the synthesis of triazoles may be made by any appropriate method. Below are some exemplary syntheses. Sonogashira reaction Scheme 7
Pd (H), 5% eq
Oil
TEA,
MeCfi ._■
X H + Y-halide — „ . * x γ reflux, 12 h
V"3 halide = I, Br ™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(PPh3)2 and Cul via the synthetic route described generally in Scheme 7.
Commercially-available aryl halides suitable for the Sonogashira reaction include, but are not limited to:
Figure imgf000116_0002
u _
Commercially-available primary alkynes suitable for the Sonogashira reaction include, but are hot limited to:
Figure imgf000117_0001
Synthesis of alkvnyl amides Scheme 8
Figure imgf000117_0002
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.
Post-Replacement Modification
The resultant macrocyclcic compound may be modified after W is attached. Some exemplary modifications follow.
1.. Synthesis of I 3henolic esters
Scheme 9
Figure imgf000117_0003
ma IXa
R = methyl, ethyl, ally), 2-hydroxyethyl, isopropyl, methiomethyl The post-replacement modification of macrocyclic compound Ilia to obtain various phenolic esters was performed by the synthetic route described generally in Scheme 9.
Hydrolysis of macrocyclic peptide ethyl ester-
Scheme 10
Figure imgf000118_0001
IVa IVa
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.
3. Using Suzuki coupling to generate more bi-aryl compounds Scheme 11
Figure imgf000118_0002
Xlb
XIa
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.
II. 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.
A. Synthesis of proline derivatives.
Scheme 12
Figure imgf000119_0001
Xlla Xllb
Figure imgf000119_0002
B. Synthesis of linear tripeptides.
Scheme 13
Figure imgf000119_0003
The linear tri-peptide containing tetrazole-substituted proline derivatives Xllc were prepared via the synthetic route described generally in Scheme 12.
Synthesis of cyclic peptide via Ring-closing-Metathesis
(RCM). Scheme 14
Figure imgf000120_0001
Formation of macrocyclic compound Xb was performed using linear tripeptide > Xllld via the Ring-Closing Metathesis reaction described generally in Scheme 14.
D. Other derivatives
1. Tetrazole-substituted proline derivatives of the present invention were synthesized by the synthetic route described generally in Scheme 12.
Scheme 15
Figure imgf000121_0001
Additional tetrazole-substituted proline derivatives of the present invention were synthesized by the synthetic route described generally in Scheme 15.
Suzuki coupling
Figure imgf000121_0002
Xlllb- (2-4) XVla XVlb
Further derivatives were prepared using the Suzuki Coupling reaction described generally in Scheme 16.
III. SOLID PHASE SYNTHESIS
Some compounds of the invention are amenable to synthesis by solid phase synthesis. For example, the triazole-substituted proline derivatives (P2) 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. > The following synthetic schemes set forth manners in which the triazole- substituted proline derivatives are made and the solid-phase synthesis of the compounds of the present invention.
A. Synthesis of proline derivatives Two methods were employed to synthesize the triazole-substituted proline ) derivatives which are described generally by the following schemes:
Cyclo-addition method
Scheme 17-
Figure imgf000122_0001
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.
2. Mesylate method Scheme 18
Figure imgf000122_0002
) XVIIlb XVllIc XVUId
Additional proline derivatives were synthesized via the replacement of mesylate XVIIIa with a 4,5-substituted-1H-triazole via the synthetic route described generally in Scheme 18.
B. On-resin assembly and on-resin RCM
Scheme 19
Figure imgf000123_0001
XlXe
On resin assembly
The on-resin assembly of linear peptide XlXd followed by the on-resin RCM to obtain resin-bound cyclic peptide precursor XlXe was performed via steps A-D described generally in Scheme 19.
IV. Other reactions In some embodiments, the substituent W is well-suited to other types of reactions. For example, and not by limitation, when 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. A. Condensation Reactions
Scheme 20
Figure imgf000124_0001
XXa-2 XXa-3 XXa-4
The simplest method, shown in Scheme 20, is to condense commercially available pyridazinones (XXa-1 - XXa-4) with key intermediate If by using Mitsunobu conditions followed by hydrolysis with LiOH. For further details on the Mitsunobu reaction see O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React 29, 1-162 (1983); D. L. Hughes, Organic Preparations and Procedures Int. 28, 127-164 (1996); and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1, 273-283 (1997).
Scheme 21
Figure imgf000125_0001
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.
B. Bromide differentiation reaction
Scheme 22
Figure imgf000126_0001
Differentiation between the bromides on macrocyclic XXIa is achieved via Michael addition. As shown in Scheme 22, commercially available pyrrolidine is coupled with di-bromide to give compound XXIIa in 87% yield. The bromide moiety D to the carbonyl is then under goes a Suzuki coupling reaction with 3-thiophene boronic acid to produce intermediate XXIIb, which is further treated with LiOH to afford analog XXIIc. For further details concerning the Suzuki coupling reaction see A. Suzuki, Pure Appl. Chem. 63, 419-422 (1991) and A. R. Martin, Y. Yang, Ada Chem. Scand. 47, 221-230 (1993).
Sulfur containing nucleophiles
Scheme 23
Figure imgf000127_0001
XXIII- XXIIId XXIlle
While the secondary amine nucleophile pyrrolidine gave exclusive addition to the 5-bromide position on macrocycle XXIa, sulfur-containing nucleophiles did not exhibit the same selectivity as shown in Scheme 23. With sulfur-containing nucleophiles, addition on both bromines of XXIa is observed together with the mono-coupled product XXI la with only one equivalent of mercaptopyrimidine. The separability of compounds XXIIIa, XXIIIB and starting material XXIa by flash column chromatography allowed for a further Suzuki coupling of the mono-alkylated XXIIIa with 3-thiophene boronic acid followed by hydrolysis of XXIIId with LiOH to fumish analog XXIlle. The di-alkylated product XXIIlb is also hydrolyzed with LiOH to produce analog XXIlle.
D. Suzuki coupling with boronic acid
Scheme 24
Figure imgf000128_0001
XXIa XXIVa
Figure imgf000128_0002
XXlVb XXlVc
With only a limited number of boronic acids available for Suzuki coupling, other coupling methods such as Stille coupling and N-arylation using Buchwald's chemistry were also explored (Scheme 24). Coupling of intermediate XXIa with 2-stannylthiazole with Stille standard conditions followed by hydrolysis afforded analog XXIVa. As for N- arylation, coupling of imidazole to di-bromide 6 proceeded smoothly. Unfortunately, hydrolysis with LiOH resulted in replacement of the imidazole moiety on position 5 with a methoxy (XXIVb. For further details concerning Stille coupling reactions see J. K. Stille, Angew. Chem. Int. Ed. 25, 508-524 (1986); M. Pereyre ef al., Tin in Organic Synthesis (Butterworths, Boston, 1987) pp 185-207 passim., and T. N. Mitchell, Synthesis 1992, 803-815. For further details of the Buchwald reaction see J. F. Hartwig, Angew. Chem. Int. Ed. 37, 2046-2067 (1998).
Other diversified pyridazinone analogs
Scheme 25
Figure imgf000129_0001
Another method for diversifying pyridazinone analogs is outlined in Scheme 25. Michael addition with sodium azide as the nucleophile to di-bromo XXIa yielded, as in the secondary amine case, only the mono-coupled compoundXXVa. Further Suzuki coupling with 3-thiophene boronic acid produced azide XXVb. Compound XXVb is hydrolyzed to give analog XXVc. In addition, the azide moiety of compound XXVb is further converted to tetrazole under standard conditions with sodium cyanide, followed by hydrolysis to provide analog XXVd.
F. Synthesis of 5,6 pyridazinoyl macrocycle
Scheme 26
Figure imgf000129_0002
The synthesis of 5,6 pyridazinonyl macrocycle XXVIb is outlined in Scheme 26. Commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one is condensed with key intermediate If via Mitsunobu conditions to give compound XXVIa. Product XXVIa is further subjected to Suzuki coupling conditions with 3-thiophene boronic acid, followed by hydrolysis to give the desired analog XXVb.
EXAMPLES
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims. -Example 1. Synthesis of the cyclic peptide precursor
Figure imgf000130_0001
1A. To a solution of Boc-L-2-amino-8-nonenoic acid 1a (1.36g, 5 mol) and the commercially available cis-L-hydroxyproline methyl ester 1 (1.09g, 6 mmol) in 15 ml DMF, was added DIEA (4 ml, 4eq.) and HATU (4g, 2eq). The coupling was earned out at 0 °C over a period of 1 hour. The reaction mixture was diluted with 100 mL EtOAc, and followed by washing with 5% citric acid 2x 20 ml, water 2x20 ml, 1M NaHC034x20 ml and brine 2x10 ml, respectively. The organic phase was dried over anhydrous Na2S0 and then was evaporated, affording the dipeptide 1c (1.91g, 95.8%) that was identified by HPLC (Retention time = 8.9 min, 30-70%, 90%B), and MS (found 421.37, M+Na+). 1B. 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 NaHC03 2x20 ml and brine 2x20 ml, respectively. The organic phase was dried over anhydrous Na2SO-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.
1C. To a solution of the free acid obtained above (1.77, 4.64 mmol) in 5 ml DMF, D-β-vinyl cyclopropane amino acid ethyl ester 1e (0.95g, 5 mmol), DIEA (4 ml, 4eq.) and HATU (4g, 2eq) were added. The coupling was carried out at 0 °C over a period of 5 hours. The reaction mixture was diluted with 80 mL EtOAc, and followed by washing with 5% citric acid 2x 20 ml, water 2x20 ml, 1M NaHC03 4x20 ml and brine 2x10 ml, respectively. The organic phase, was dried over anhydrous Na2Sθ4 and then evaporated. The residue was purified by silica gel flash chromatography using different ratios of hexanesiEtOAc as elution phase (5:1-»3:1- 1:1-->1:2-»1:5). The linear tripeptide 1f was isolated as an oil after removal of the elution solvents (1.59g, 65.4%), identified by HPLC (Retention time = 11.43 min) and MS (found 544.84, M+Na+).
1D. Ring Closing Metathesis (RCM). A solution of the linear tripeptide 1f (1.51g, 2.89 mmol) in 200 ml dry DCM was deoxygenated by bubbling N2. Hoveyda's 1st generation catalyst (5 mol% eq.) was then added as solid. The reaction was refluxed under N2 atmosphere 12 hours. The solvent was evaporated and the residue was purified by silica gel flash chromatography using different ratios of hexanesiEtOAc as elution phase (9:1-»5:1- 3:1-»1:1-»1:2→1:5). The cyclic peptide precursor 1 was isolated as a white powder after removal of the elution solvents (1.24g, 87%), identified by HPLC (Retention time = 7.84 min, 30-70%, 90%B), and MS (found 516.28, M+Na+). For further details of the synthetic methods employed to produce the cyclic peptide precursor 1, see U.S. Patent No. 6,608,027, which is herein incorporated by reference in its entirety.
Example 2. Synthesis of the cyclic peptide precursor mesylate I l' mil ' _ jP
Figure imgf000132_0001
1 2
2A. To a solution of the macrocyclic peptide precursor 1 (500mg.--1.01 mmol) and DIEA (0.4 ml, 2 mmol) in 2.0 ml DCM, mesylate chloride (0.1 ml) was added slowly at 0 °C where the reaction was kept for 3 hours. 30 mL EtOAc was then added and followed by washing with 5% citric acid 2x10 ml, water 2x10 ml, 1M NaHC03 2x10 ml and brine 2x10 ml, respectively. The organic phase was dried over anhydrous Na2S0 and evaporated, yielding the title compound mesylate that was used for next step synthesis without need for further purification.
Example 3. Tetrazole Synthesis
Structurally diverse tetrazoles llla-lllq, for use in preparing tetrazolyl macrocycles of the invention were synthesized from commercially available nitrile compounds as described below:
Figure imgf000132_0002
To a sealed tube containing 5 ml xylene, was added 3-CI-4-hydroxy- benzoacetonitile (0.31 g, 5 mol), NaN3 (0.65g, 10 mmol) and the triethylamine hydrochloride (0.52g, 3 mmol). The mixture was stirred vigorously at 140 °C over a period of 20-30 hours. The reaction mixture was then cooled and poured to a mixture of EtOAc (30 ml) and aqueous citric acid solution (20 mL). After washing with water 2x10 ml and brine 2x10 ml, the organic phase was dried over anhydrous Na2S0 and was evaporated to a yellowish solid. After re-crystallization with EtOAc-hexanes, the tetrazole compound 3a was obtained in good yield (0.4g, 86%%), high purity (>90%, by
HPLC), and identified by NMR and MS (found 197.35 and 199.38, M+H+).
Figure imgf000133_0001
PROLINE DERIVATIVE SYNTHESIS
Figure imgf000133_0002
To a solution of 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. TLC (hexanesiethyl acetate = 1:1, v/v) showed that Boc-cis-Hyp-OMe 4a was totally converted to its mesylate 4b. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 100ml EtOAc, washed with 5% citric acid 2x50 ml and brine 2x30 ml, and dried over anhydrous Na2S0 . Removal of solvents gave 13 g (98% yield) N-Boc-cis-4-mesylate-proline methyl ester 4b, which was used in Step B without need for further purification.
To a solution of the mesylate 4b (0.65 g, 2 mmol) in 5 mL DMF, was added 4 mmol of 5-phenyl-1 H-tetrazole and anhydrous sodium carbonate (0.53 g, 5 mmol). The resulting reaction mixture was stirred vigorously at 60°C for 6-12 hours. TLC (hexanes:ethyl acetate = 1:1, v/v) showed the mesylate 4b was completely converted to trans 4-tetrazole-substituted proline derivative 4c. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 30 ml EtOAc and washed with 1 M Na2C03 (3x10 ml), water (3x10 ml), 5% citric acid (3x10 ml) and brine (3x10 ml), respectively. The organic phase was dried over anhydrous Na2S04 and concentrated in vacuo, giving the 5-phenyl tetrazole substituted proline derivative 4c in excellent yield (94%) and high purity (>90%). 4c: 94% yield, [M+Naf = 396.39. SYNTHESIS OF LINEAR TRIPEPTIDES
Figure imgf000134_0001
A. (1) 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 NaHC03 2x20 ml and brine 2x10 ml, respectively. The organic phase was dried over anhydrous Na2S04 and concentrated in vacuo, yielding the free carboxylic acid compound (0.20g, 92%), which was used for next step synthesis without need for further purification. (2) To a cooled (0 °C) solution of the free acid obtained above (0.20g, 0.55 mmol) in 2 ml DMF, was added D-β-vinyl cyclopropane amino acid ethyl ester 4d (0.1 g, 0.52 mmol), DIEA (0.4 ml, 4eq.) and HATU (0.4g, 2eq). The resulting reaction mixture was stirred at 0 °C for 0.5-3 hours. The reaction mixture was diluted with 40 L EtOAc, and washed with 5% citric acid 2x 20 ml, water 2x20 ml, 1M NaHC03 4x20 ml, and brine 2x10 ml, respectively. The organic phase was dried over anhydrous Na2S04 and concentrated in vacuo, affording the dipeptide 4e (0.24g, 94%), identified by HPLC (Retention time = 10.03 min) and MS (found 519.22, M+Na+).
B. (1) 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. (2) To a cooled (0 °C) solution of the free amine compound obtained above in 2 ml DMF, was added Boc- 2-amino-8-nonenoic acid 4f (0.136g, 0.50 mmol), DIEA (0.4 ml, 4eq.) and HATU (0.4g, 2eq). The coupling was earned out at 0 °C over a period of 0.5-3 hours. The reaction mixture was diluted with 40 mL EtOAc and washed with 5% citric acid 2x 20 ml, water 2x20 ml, 1M NaHC034x20 ml and brine 2x10 ml, respectively. The organic phase was dried over anhydrous Na2S04 and concentrated in vacuo, affording tripeptide 4g (0.28g, 88% for two steps) that was identified by HPLC (Retention time = 14.03 min), and MS (found 672.30, M+Na+).
SYNTHESIS OF CYCLIC PEPTIDE VIA RING-CLOSING-METATHESIS (RCM).
Figure imgf000135_0001
A. A solution of linear tripeptide 4g (71 mg, 0.109 mmol) in 50- l dry DCM was deoxygenated by bubbling N2. To the resulting degassed solution was added Hoveyda's Cat. (5-10 mol% eq.) was as solid and the resulting reaction mixture was refluxed under N2 over for 5-20 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as elution phase (9:1- 5:1-»3:1-»1:1-»1:2). The macrocyclic peptide 4i was isolated as a white powder by evaporation of the elution solvents (58mg, 85.5%), identified by HPLC (Retention time = 11.80 min, 30-80%, 90%B), and MS (found 644.66, M+Na+).
IV. HYDROLYSIS OF THE ETHYL ESTER
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 , . . .
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.
[M+Na] + = 616.72.
Example 5. Compound of Formula II, wherein A = tBOC. G = OH, L = absent.
Figure imgf000136_0001
5A. PROLINE DERIVATIVE SYNTHESIS
The proline derivative of the present example was prepared by the procedure set forth in Example 4 (I) with 5-(2-bromophenyl)-1 H-tetrazole and N-Boc-cis- hydroxyprollne methyl ester 4a. [M+Na]+ = 396.39.
5B. SYNTHESIS OF LINEAR TRIEEPTIDES
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-β-vinyl "cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
[M+H]+ = 728.41
5C. RING CLOSING METATHESIS
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).
[M+Na]+ = 722.37.
5D. HYDROLYSIS OF THE ETHYL ESTER
The title compound was ultimately obtained via hydrolyisis described in Example 4 (IV) from the ethyl ester of Step 5C
[M+Hf = 672.49.
Example 6. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000136_0002
. Q = absent. Y = 3-bromophenyl. i = 3. m = s = 1. and R3 = R4 = H.
6A. PROLINE DERIVATIVE SYNTHESIS _ .. . - _
The proline derivative of the present example was prepared by the procedure set forth in Example 4 (I) with 5-(3-bromophenyl)-1 H-tetrazole and N-Boc-cis- hydroxyproline methyl ester 4a. [M+Na]+ = 396.39.
6B. SYNTHESIS OF LINEAR TRIPEPTIDES
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-β-vinyl cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
[M+H]+ = 728.41.
6C. RING CLOSING METATHESIS
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).
[M+Naf = 722.37.
6D. HYDROLYSIS OF THE ETHYL ESTER
The title compound was ultimately obtained via hydrolyisis described in Example 4 (IV) from the ethyl ester of Step 6C.
[M+Hf = 672.49.
Example 7. Compound of Formula II, wherein A = tBOC. G = OH. L = absent. zz ti
W is ^ . Q = absent. Y = 4-bromophenyl. i = 3. m = s = 1. and R3 = R4 = H.
7 A. PROLINE DERIVATIVE SYNTHESIS
The proline derivative of the present example was prepared by the procedure set forth in -Example 4 (I) with 5-(4-bromophenyl)-1 H-tetrazole and N-Boc-cis- hydroxyproline methyl ester 4a. [M+Na]+ = 396.39.
7B. SYNTHESIS OF LINEAR TRIPEPTIDES
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-β-vinyl cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
[[M+Na] +H]+ = 728.41.
7C. RING CLOSING METATHESIS , > t _ „ , „ _ ___
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).
[M+Naf = 722.37.
7D. HYDROLYSIS OF THE ETHYL ESTER
The title compound was ultimately obtained via hydrolyisis described in -Example 4 (IV) from the ethyl ester of Step 7C.
[M+Hf = 672.49.
Example 8. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000138_0001
.
8A. PROLINE DERIVATIVE SYNTHESIS
The proline derivative of the present example was prepared by the procedure set forth in Example 4 (I) with J5-(5-Bromo-2-thienyl)->1 H-tetrazole and N-Boc-cis- hydroxyproline methyl ester 4a. [M+Naf = 480.23.
8B. SYNTHESIS OF LINEAR TRIPEPTIDES
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-β-vinyl cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
[M-Boc+Hf = 634.29.
8C. RING CLOSING METATHESIS
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).
[M+Naf = 736.21.
8D. HYDROLYSIS OF THE ETHYL ESTER
The title compound was ultimately obtained via hydrolysis described in Example 4 (IV) from the ethyl ester of Step 8C.
[M+Hf = 678.22.
Example 9. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000138_0002
9A. PROLINE DERIVATIVE SYNTHESIS
The proline derivative of the present example was prepared by the procedure set forth in Example 4 (I) with 5-(2-bromo-4-pyridyl)-1 H-tetrazole and N-Boc-cis- hydroxyproline methyl ester 4a. [M+Naf = 453.23.
9B. SYNTHESIS OF LINEAR TRIPEPTIDES
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-β-vinyl cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid.
[M-Boc+Hf = 629.31.
9C. RING CLOSING METATHESIS
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).
[M+Naf = 723.36. » 9D. HYDROLYSIS OF THE ETHYL ESTER
The title compound was ultimately obtained via hydrolysis described in Example 4 (IV) from the ethyl ester of Step 9C.
[M+Hf = 673.26.
Example 10. Compound of Formula II. wherein A = tBOC, G = OH. L = absent.
N — , ^N Y
> W is . Q = absent. Y =2-biphenyl. i = 3. m = s = 1. and R3 = R4 = H.
To a deoxygenated solution of ethyl ester compound from Step 5C obtained above (40 mg), phenylboronic acid (10mg), KF (100mg), and Cs2C03 (80mg) in 5 ml DME was added Pd(PPh3)4 (5mg) in its solid form. The resulting reaction mixture was heated in an oil bath to 90 °C and vigorously stirred for 6-12 hours. The solvent was
> evaporated and the residue was purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as the elution phase (9:1-»5:1-»3:1-»1:1-»2:1). The macrocyclic bi-aryl peptide ethyl ester was then isolated as a white powder by evaporation of the elution solvents (31 mg, 78%) that was directly subjected to hydrolysis, as previously described in Example 4 (IV), and purified by HPLC.
) [M+Naf = 692.38. Example 11. Compound of Formula II, wherein A = tBOC. G = OH. L = absent.
• The title compound was prepared with the ethyl ester compound from Step 6C and phenylboronic acid via the procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV).
[M+Naf = 692.38.
Example 12. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is N . Q = absent. Y =4-biphenyl. i = 3. m = s = 1. and R3 = R4 = H.
The title compound was prepared with the ethyl ester compound from Step 7C phenylboronic acid via the procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV).
[M+Naf = 692.38.
Example 13. Compound of Formula II. wherein A = tBOC, G = OH, L = absent.
W is A* . Q = absent. Y = 3-(3-thienyl henyl . i = 3. m = s = 1. and R 3 3 = R 4 4 =
H.
The title compound was prepared with the ethyl ester compound from Step 6C and 3-thienylboronic acid via the procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of -Example 4 (IV).
[M+Naf = 698.32.
Example 14. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000140_0002
. Q = absent. Y = 3-(p-trifluoromethoxyphenyl)phenyl . i = 3. m = s = 1. and R3 = R4= H.
The title compound was prepared with the ethyl ester compound from Step 6C and p-trifluoromethoxyphenylboronic acid via the procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV).
[M+Naf = 776.35. Example 15. Compound of Formula ll. wherein A = tBOC. G = OH, L = absent.
Figure imgf000141_0001
R4= H.
The title compound was prepared with the ethyl ester compound from Step 6C and p-cyanophenylboronic acid via the procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV).
[M+Naf = 692.38.
Example 16. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is y V . Q = absent. Y = 4-(3-thienyl)phenyl . i = 3. m = s = 1. and R 3 3 = R 4 4 =
H.
The title compound was prepared with the ethyl ester compound from Step 7C and 3-thienylboronic acid via the procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV).
[M+Naf = 698.32.
Example 17. Compound of Formula H. wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000141_0002
, Q = absent, Y = 4-(p-trifluoromethoxyphenyl)phenyl . i = 3. m = s = 1, and R3 = R4= H.
The title compound was prepared with the ethyl ester compound from Step 7C and p-trifluoromethoxyphenylboronic acid via the procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV).
[M+Naf = 776.35.
Example 18. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. N — N
W is * . Q = absent. Y = 4-(p-cvanophenyl)phenyl . i = 3. m = s = 1. and R =
R4= H.
The title compound was prepared with the ethyl ester compound from Step 7C and p-cyanophenylboronic acid via the procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV). [M+Naf = 692.38.
Example 19. Compound of Formula II. wherein A = tBOC, G = OH, L = absent.
N— N
, ^% Y W is N . Q = absent. Y = 5-phenyl-2-thienyl. i = 3. m = s = 1. and R3 = R4 = H.
The title compound was prepared with the ethyl ester compound from Step 8C and phenylboronic acid via the procedure set forth in -Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV).
[M+Naf = 698.32.
Example 20. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. N — N
W is N . Q = absent. Y = 5-phenyl-3-pyridyl. i = 3. m = s = 1. and R3 = R4 = H. The title compound was prepared with the ethyl ester compound from Step 9C and phenylboronic^ acid via the -procedure set forth in Example 10, followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV).
[M+Naf= 708.30.
Example 21. Compound of Formula II. wherein A = tBOC. G = OEt, L = absent.
N — N
W is ^ . Q = absent. Y = 3-chloro-4-hvdroxyphenyl. i = 3. m = s = 1 , and R =
R4= H.
Replacement Method
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. Example 22. Compound of Formula II. wherein A = tBOC. G = OH, L = absent.
W is
Figure imgf000143_0001
. Q = absent. Y = 3-chloro-4-hvdroxyphenyl, i = 3. m = s = 1. and R =
R4= H.
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.
[M+Naf = 666.24.
Example 23. Compound of Formula II. wherein A =- tBOC. G = OH. L = absent. — N
W is ^ . Q = absent, Y = 3-bromo-4-hydroxyphenyl. i = 3. m = s = 1. and R3 =
R4= H.
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.
[M+Naf = 712.18.
Example 24. Compound of Formula II, wherein A = tBOC. G = OH. L = absent. N=_t*
W is * . Q = absent. Y = 2-methyl-4-bromophenyl. i = 3. m = s = 1. and R3 =
R4= H.
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.
[M+Naf = 708.30. li- ι ,.» ii ••• 'i-i' »•"!' ' » "U" *■ v»_t .∞ .- .. -
Example 25. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
N=N
W is , Q = absent, Y = 3-methyl-4-bromophenyl. i = 3. m = s = 1. and R =
R4= H.
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.
[M+Naf = 708.30.
Example 26. Compound of Formula l . wherein A = tBOC. G = OH. L = absent.
Figure imgf000144_0001
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.
[M+Naf = 582.33.
Example 27. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000144_0002
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.
[M+Naf = 596.36.
Example 28. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. zzzt*
W is , * N . Q = absent. Y = 4-ethoxyphenyl, i = 3: m = s = 1. and R 3 3 = R 4 4 = H.
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.
[M+Hf = 660.92. Example 29. Compound of Formula 11, wherein A = tBOC. G = OH, L = absent.
Figure imgf000145_0001
The title compound was prepared via the replacement method described in
Example 21 with mesylate 2 and tetrazole 3h from Example 3, followed by hydrolysis of
> the ethyl ester by the procedure of Example 22.
[M+Naf = 674.29.
Example 30. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
N=N
W is ^ . Q = absent. Y = 4-butoxyphenyl. i = 3. m = s = 1. and R3 = R4 = H.
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.
[M+Naf = 688.32.
Example 31. Compound of Formula II. wherein A = tBOC, G = OH. L = absent.
Figure imgf000145_0002
> 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.
[M+Naf = 646.92.
Example 32. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. Hzz n
. W is v * V . Q = absent. Y = 3.4-dimethoxyphenyl. i = 3. m = s = 1. and R 3 3 = R 4 4 =
H.
The title compound was prepared via the replacement method described in
Example 21 with mesylate 2 and tetrazole 3k from Example 3, followed by hydrolysis of the ethyl ester by the procedure of -Example 22.
> [M+Naf = 676.38. _
Example 33. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
N=l-
> . N Q--Y W is ^ . Q = absent. Y = 4-methoxy-1 -naphthyl. i = 3, m = s = 1. and R3 = R4
= H.
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.
[M+Naf = 697.00.
Example 34. Compound of Formula ll. wherein A = tBOC. G = OH. L = absent.
Figure imgf000146_0001
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.
[M+Naf = 708.51.
Example 35. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. N — N
W is . Q = absent. Y = benzyl, i = 3. m = s = 1. and R3 = R4= H.
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.
[M+Naf = 630.35.
Example 36. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000146_0002
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.
[M+Naf =706.38. Example 37. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. —
W is . Q = absent. Y = 3-chlorophenyl. i = 3. m = s = 1. and R3 = R4 = H.
The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3-chlorophenyl)-1 H-tetrazole, followed by hydrolysis
> of the ethyl ester by the procedure of Example 22.
[M+Naf =650.33.
Example 38. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000147_0001
The title compound was prepared via the replacement method described in
I 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.
[M+Naf =634.37.
Example 39. Compound of Formula II, wherein A = tBOC, G = OH. L = absent. — N
, - ^^Y W is . Q = absent. Y = 3-methoxyphenyl. i = 3. m = s = 1. and R3 = R4 = H.
> The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3-methoxyphenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
[M+Naf =646.92.
Example 40. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
) W is . Q = absent. Y = 3-phenoxyphenyl. i = 3. m = s = 1. and R3 = R4 = H.
The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3-phenoxyphenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of -Example 22.
[M+Naf =708.51. Example 41. Compound of Formula II, wherein A = tBOC. G = OH. L = absent,
Figure imgf000147_0002
- ιr--«n if ■' '(.»' *UM iι„-ιι -μ * n:,,i -.,,,11 it _ ,« - -_- -
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.
[M+Naf =722.32.
Example 42. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
N — N Atf* 3 4
W is . Q = absent. Y = 3-trifluormethylphenyl. i = 3. m = s = 1. and R* = R4 =
H.
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.
[M+Naf =684.32.
Example 43. -Compound of Formula II. wherein A =■ tBOC, G = OH. L = absent,
N — . N Q'-Y W is , Q = absent. Y = 4-bromophenyl. i = 3. m = s = 1. and R3 = R4 = H.
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.
[M+Naf =696.28.
Example 44. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000148_0001
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.
[M+Naf =634.36.
Example 45. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000148_0002
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.
[M+Naf =646.36.
> Example 46. Compound of Formula ll. wherein A = tBOC. G = OH. L = absent.
N==N
W is . Q = absent. Y = 4-ethoxyphenyl. i = 3. m = s = 1. and R3 = R4 = H.
The title compound was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(4-ethoxyphenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22. I [M+Hf =660.92.
Example 47. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000149_0001
, Q = absent, Y = 4-trifluoromethylphenyl. i = 3. m = s = 1. and R3 = R4
= H.
The title compound was prepared via the replacement method described in
> 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.
[M+Naf =684.32.
Example 48. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is . Q = absent. Y = 3.5-di(trifluoromethyl)phenyl, i = 3. m = s = 1. and R
. = R = H.
The title compound, was prepared via the replacement method described in Example 21 with mesylate 2 and 5-(3,5-di(trifluoromethyl)phenyl)-1 H-tetrazole, followed by hydrolysis of the ethyl ester by the procedure of Example 22.
[M+Naf =766.32.
> Example 49. Compound of Formula H. wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000149_0002
. Q = absent. Y = 4-(N.N-dimethylaminoy3.5-di(trifluoromethvQphenyl. i = 3. m = s = 1, and R3 = R4= H. 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.
[M+Naf =695.39.
Example 50. Compound of Formula II. wherein A = tBOC, G = OH. L = absent.
Figure imgf000150_0001
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.
[M+Naf =684.27.
Example 51-. Compound of Formula II. wherein A ~ tBOC. G = OH. L = absent.
Figure imgf000150_0002
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.
[M+Naf =684.27.
Example 52. Compound of Formula II. wherein A = tBOC, G = OH, L = absent.
Figure imgf000150_0003
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.
[M+Naf =684.27.
Example 53. Compound of Formula I . wherein A = tBOC, G = OH. L = absent.
Figure imgf000150_0004
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.
[M+Naf =617.60.
> Example 54. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. N —
11 II - Y
W is ~ . Q = absent. Y = 2-pyridyl. i = 3. m = s = 1. and R3 = R4= H.
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. ) [M+Naf =617.60.
Example 55. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is N Atf* , Q = absent. Y = 3-pyridyl. i = 3, m = s = 1. and R 3 3 = R 4 4 = H.
The title compound was prepared via the replacement method described in
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.
[M+Naf =645.24.
Example 56. Compoυnd of Formula II. wherein A = tBOC. G = OH, L = absent.
Figure imgf000151_0001
The title compound was prepared via the replacement method described in
3 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.
[M+Hf =595.50.
Example 57. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000151_0002
. Q = absent, Y = 4-methoxy-3-bromophenyl. i = 3. m = s = 1. and R =
R4 = H.
57A. Tetrazole Formation 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 Na2S04 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.
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.
[M+Naf =724.91.
Example 58. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000152_0001
,-Q = absent. Y = 4-(methylcyclopropane*)phenyl, j = 3. m = s = 1. and
R3 = R = H.
58A. Tetrazole Formation
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 Na2S04 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.
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.
[M+Naf =686.29.
Example 59. Compound of Formula IK wherein A = tBOC. G = OH. L = absent.
Figure imgf000152_0002
= 1. and R3 = R4= H.
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.
[M+Naf =720.24.
Example 60. Compound of Formula II, wherein A = tBOC. G = OH. L = absent,
W is
Figure imgf000153_0001
. Q = absent. Y = 3-chloro-4-methoxyphenyl. i = 3. m = s = 1. and R =
R4= H.
The title compound was prepared with the title compound of Example 21 and methyl iodide according to the procedure set forth in Example 59.
[M+Naf =680.23.
Example 61v Compound of Formula ll. wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000153_0002
. Q = absent. Y = 3-chloro-4-ethoxyphenyl. i = 3. m = s = 1. and R =
R4= H.
The title compound was prepared with the title compound of Example 21 and ethyl iodide according to the procedure set forth in Example 59.
[M+Naf =694.28.
Example 62. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. H —
W is v * . Q = absent. Y = 3-bromo-4-ethoxyphenyl. i = 3. m = s = 1. and R =
R4= H.
The title compound was prepared with the ethyl ester precursor to the title compound of Example 23 and ethyl iodide according to the procedure set forth in Example 59.
[M+Naf =740.17.
Example 63. Compound of Formula II. wherein A = tBOC. G = OH. L = absent,
W is
Figure imgf000153_0003
. Q = absent. Y = 3-chloro-4-(2-hvdroxyethoxy)phenyl. i = 3. m = s = 1. and R3 = R4= H. The title compound is prepared with the title compound from Example 21 and 2- iodoethanol according to the procedure set forth in Example 59.
Example 64. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. N — N
W is v ** . Q = absent. Y = 3-bromo-4-(2-hvdroxyethoxy)phenyl. i = 3. m = s - 1. and R3 = R4= H.
The title compound was prepared with the ethyl ester precursor to the title compound of Example 23 and 2-iodoethanol according to the procedure set forth in Example 59.
[M+Naf =754.27. Example 65. Compound of Formula II. wherein A = tBOC, G = OH. L = absent,
Figure imgf000154_0001
R4= H.
The title compound was prepared with the title compound from Example 21 and
3-iodopropene according to the procedure set forth in Example 59. [M+Naf =706.24.
Example 66. Compound of Formula ll, wherein A = tBOC. G = OH. L = absent. -=
W is * . Q = absent. Y = 3-bromo-4-(Q-allyl)phenyl, i = 3. m = s = 1. and RJ =
R4= H.
The title compound was prepared with the ethyl ester precursor to the title compound of Example 23 and 3-iodopropene according to the procedure set forth in Example 59.
[M+Naf =752.15.
Example 67. Compound of Formula IK wherein A = tBOC. G = OH. L = absent.
W is
Figure imgf000154_0002
. Q = absent. Y = 3-chloro-4-(Q-CH?SCH3)phenyl. i = 3. m = s = 1. and R3 = R4= H.
The title compound is prepared with the title compound from Example 21 and
CI-CH2SCH.3 according to the procedure set forth in Example 59. ■r- j.--.. i- ,■ 't. ," •.«!' 'I."" «
Example 68. Compound of Formula II, wherein A = tBOC, G = OH, L = absent.
W is
Figure imgf000155_0001
Q = absent. Y = 3-chloro-4-(Q-CH?SCHg)phenyl. i = 3. m = s = 1. and
R3 = R = H.
The title compound was prepared with the ethyl ester precursor to the title compound of Example 23 and CI-CH2SCH3 according to the procedure set forth in Example 59.
[M+Naf =752.15.
Example 69. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
I
Figure imgf000155_0002
69A. Preparation of Cvano Proline Derivative (69b)
To a solution of c/s-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-fe/f-butyl ester 2-methyl ester (69a) (3.94 g, 16.06 mmol) in CH2GI2 (40 ml) at 0 °C was DIEA (4.3 ml) and methanesulfonyl chloride (1.40 ml) dropwise. After addition, the mixture was stirred for 1.5 hours. The reaction was complete as determined by TLC analysis (50% EtOAc- hexane was used to develop the TLC). The mixture was diluted with EtOAc, washed with sat. NaHC03, brine and dried (Na2S0 ). After evaporation of the solvents, the oil . residue was used for next step without further purification. [M+Hf = 324.
The crude product from the previous step was dissolved in DMF(35 ml) and grounded KCN (2.5 g) was added. The mixture was heated at 90 °C overnight. After cooled to room temperature, the mixture was diluted with EtOAc, washed with H20 and brine, and dried over Na2S0 . The crude product was purified by silica gel chromatography (20% EtOAc/hexane).
[M+Hf = 255.
69B. Preparation of Tetrazolyl Proline Derivative (69c)
To a solution of nitrile 69b (669 mg, 2.63 mmol) in toluene (8 ml) was added NaN3 (684 mg, 10.53 mmol) and EfeN-HCI (1.45 g, 10.53 mmol). The mixture was heated at 115 °C for 18 hrs. The mixture was diluted with GH2CI2, washed with 5% citric acid aqueous solution and dried over Na2S04. Evaporation of solvent afforded the crude product 69c»EtsN additive (660 mg).
[M+Hf = 298.
69C. Preparation of the 5-Biphenylmethyl-tetrazolyl Proline (69e)
To a solution of 69c (92.8 mg, 0.31 mmol) in THF (2 ml) was added 4- phenylbenzyl bromide (90.4 mg, .0.37 mmol) and K2C03 (140 mg, 1.01 mmol). The mixture was heated at 65 °C overnight and then diluted with EtOAc, washed with brine, dried over Na2S04. After evaporation of the solvent, the crude products was dissolved in THF-MeOH-H20 (2 ml:1ml:1ml) and LiOH (130 mg) was added. The mixture was stirred at room temperature ovemight. THF and MeOH were evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried with Na2S0 . Evaporation of solvent afforded the crude product 69d and 69e.
[M+Boc+Hf= 350.
69D. Preparation of the Tripeptide (69q)
To a solution of 69d and 69e (about 0.31 mmol) in DMF (2.0 ml) was added D-β- vinyl cyclopropane amino acid ethyl ester»HCI (66 mg), DIEA (0.25 ml) and HATU (164 mg), sequentially. The mixture was stirred for 1 hr and then was diluted with EtOAc, washed with brine, 5% citric acid and dried with Na2S04. After evaporation of solvent, the residue was dissolved in 2 ml of CH2CI2, 2 ml of 4 N HCI in dioxane was added. The mixture was stirred at room temperature for 1.5 hr. solvent was evaporated. The residue was dissolved in EtOAc, neutralized with sat. NaHC03, washed with brine and dried with Na2S04. After evaporation of solvent, the residue was dissolved in DMF (2 ml), to which P3 (120 mg), DIEA and HATU were added sequentially. The resulting mixture was stirred and monitored by TLC analysis. After the reaction was complete, the mixture was diluted with EtOAc, washed with brine, 5% citric acid, sat. NaHC03, and brine again. The organic solution was dried with Na2S0 , and evaporated under vacuum to give the crude product mixture which was purified by silica gel chromatography (30% to 50% EtOAc-Hexane).
[M+Hf = 740.
69E. Ring-Closing Metathesis (69k).
Figure imgf000157_0001
69j 69k
The mixture of 69f and 69g (60 mg) was dissolved in dry CH2CI2 to make the concentration about 0.01 molar. The solution was carefully degassed with N2 stream for 15 min. 5% mol of Hoveyda's catalyst was added under N2. The mixture was refluxed overnight. Solvent was evaporated. The residue was loaded on silica gel column and eluted with 10% EtOAc to remove the catalyst. The two regioisomers were separated by elution with 30-40% EtOAc-hexane to give a less polar product 69j (37.9 mg) and more polar product 69k (14.8 mg). The regiochemistry of 69j and 69k were determined by NMR analysis.
[M+Hf = 712.
69F. Ethyl Ester Hydrolysis (69)
The ester 69h (37.9 mg) was dissolved in THF-MeOH-H20 (2 ml:ϊml:1ml) and LiOH (21 mg) was added. The mixture was stirred at room temperature overnight. THF and MeOH were evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried with Na2S04. Evaporation of solvent afforded the crude product. The crude product was purified by silica gel chromatography (5%MeOH in CH2CI2) to give the title compound 69k.
[M+Hf = 684.
Example 70. , Compound of Formula II, wherein A =. tBOC. G = OH. L = absent.
Figure imgf000158_0001
i±
The ester 69i (14.8'mg) was dissolved in THF-MeOH-H20 (2 ml:1ml:1ml) and LiOH (21 mg) was added. The mixture was stirred at room temperature ovemight. THF and MeOH were evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried with Na2S04. Evaporation of solvent afforded the crude product. The crude product was purified by silica gel chromatography (5%MeOH in CH2CI2) to give title compound 70-
[M+Hf = 684.
Example 71. Compound of Formula II, wherein A = -(C=OV-0-R1. wherein R1 -
N==N cyclopentyl, G = OH. L = absent. W is v A-rγ . Q = absent. Y = phenyl. i = 3. m = s
= 1. and R3 = R = H.
71a - Amine deprotection.
0.041 mmol of the title compound of Example 21 is dissolved in 4ml of a 4M solution of HCI in dioxane and stirred for 1 hour. The reaction residue 69a is concentrated in vacuo. . ,,„,. „ ,. .,, - , ... .,,.
71b - Chloroformate Reagent
The chloroformate reagent 71b is prepared by dissolving 0.045mmol of cyclopentanol in THF (3ml) and adding 0.09mmol of phosgene in toluene (20%). The resulting reaction mixture is stirred at room temperature for 2 hours and the solvent is removed in vacuo. To the residue is added DCM and subsequently concentrated to dryness twice in vacuo yielding chloroformate reagent 71 b.
71c - Carbamate formation
The title carbamate is prepared by dissolving residue 71a in 1ml of THF, adding 0.045mmol of TEA, and cooling the resulting reaction mixture to 0°C. To this 0°C reaction mixture is added chloroformate reagent 71b in 3ml of THF. The resulting reaction mixture is reacted for 2 hours at 0°C, extracted with EtOAc, washed by 1 M sodium bicarbonate, water and brine, dried over MgS04, and concentrated in vacuo to dryness. The crude compound ]§_ purified by silica column and the ethyl ester is subsequently hydrolyzed by procedure set forth in Example 22. Example 72. Compound of Formula II. wherein A = -(C=Q)-0-R1, wherein R1 =
cyclobutyl. G = OH. L = absent, W is
Figure imgf000159_0001
. Q = absent, Y = phenyl, i = 3. m = s
= 1. and R3 = R = H.
The title compound is prepared by the method described in Example 71 with the title compound of Example 21 and cyclobutanol, followed by ethyl ester hydrolysis by the procedure set forth in Example 22.
Example 73. Compound of Formula II. wherein A = -(C=Q)-0-R1. wherein R1 =
cyclohexyl. G = OH. L = absent W is
Figure imgf000159_0002
. Q = absent. Y = phenyl. i = 3. m = s
= 1. and R3 = R4 = H.
The title compound is prepared by the method described in Example 71 with the title compound of Example 21 and cyclohexanol, followed by ethyl ester hydrolysis by the procedure set forth in Example 22. Example 74. Compound of Formula II. wherein A = -(C=0)-0-R1. wherein R1 =
Figure imgf000160_0001
and R3 = R4 = H.
The title compound is prepared by the method described in Example 71 with the title compound of Example 21 and (R)-3-hydroxytetrahydrofuran, followed by ethyl ester hydrolysis by the procedure set forth in Example 22.
Example 75. Compound of Formula II. wherein A = -(C=0)-0-R1. wherein R1 =
Figure imgf000160_0002
and R3 = R4 = H.
[3 The title compound is prepared by the method described in Example 71 with the title compound of Example 21 and (S)-3-hydroxytetrahydrofuran, followed by ethyl ester hydrolysis by the procedure set forth in Example 22.
Example 76. Compound of Formula II, wherein A = -(C=Q)-0-R1, wherein R1 =
Figure imgf000160_0003
5 1. and R3 = R4= H.
The title compound is prepared by the method described in Example 71 with the
title compound of Example 21 and (A OH, followed by ethyl ester hydrolysis by the procedure set forth in Example 22.
Example 77. Compound of Formula II.- wherein A = -(C=0)-R1. wherein R1 =
NAQ.Y 0 cyclopentyl. G = OH. L = absent. W is . Q = absent. Y = phenyl. i = 3. m = s
= 1. and R3 = R4 = H.
The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 21 in 4ml of a 4M solution of HCI in dioxane and stirring the reaction mixture for 1 hour. The reaction residue is concentrated in vacuo. To this residue, 4ml
5 of THF and 0.045mmol of TEA is added, the mixture is cooled to 0°C, to which is added 0.045mmol of the cyclopental acid chloride. The resulting reaction mixture is stirred for 2 hours at 0°C. The reaction mixture is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgS0 and concentrated to dryness in vacuo. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 22.
Example 78. Compound of Formula IK wherein A = ~(C=0)-NH-R1. wherein R1
Figure imgf000161_0001
s = 1. and R3 = R4= H.
The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 21 in 4ml of a 4M solution of HCI in dioxane and stim'ng for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4ml THF, and cooled to 0°C. To the 0°G solution is added 0.045mmol of cy opentyl isocyanate and the resulting reaction mixture is stirred at RT for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCI, water and brine, dried over MgS0 , and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 22.
Example 79. Compound of Formula ll, wherein A = -(C=SV-NH-R1. wherein R1
N rN = cyclopentyl. G = OH. L = absent. W is v A-tf* . Q = absent, Y = phenyl, i = 3. m = s = 1. and R3 = R4= H.
The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 21 in 4ml of a 4M solution of HCI in dioxane and stim'ng for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4ml. THF, and cooled to 0°C. To the 0°C solution is added 0.045mmol of cyclopentyl isothiocyanate and the resulting reaction mixture is stirred at RT for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCI, water and brine, dried over MgS04, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 22. Example 80. Compound of Formula II. wherein A = -S(Q)?-R1. wherein R1 =
N=N cyclopentyl. G = OH. L = absent. W is . Q = absent. Y = phenyl. i = 3. m = s
= 1. and R3 = R4= H.
The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 21 in 4ml of a 4M solution of HCI in dioxane and stim'ng for 1 hour. To the resulting concentrated reaction residue, which has been dissolved in 4ml THF, is added 0.045mmol of TEA, and cooled to 0°C. To the 0°C solution is added 0.045mmol of cyclopentyl solfonyl chloride and the resulting reaction mixture is stirred at 0°C for 2 hours. The solution is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgS0 , and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 22.
Example 81. Compound of Formula II. wherein A = -(C=Q)-0-R1. R1 =
N — N cyclopentyl. G = -O-phenethyl. L = absent, W is /% Y . Q = absent. Y = phenyl. i
= 3. m = s = 1. and R3 = R4 = H.
Figure imgf000162_0001
71
81b
The title compound is prepared by adding to a solution of the title compound of -Example 71 and phenethyl alcohol 81a in 0.5 ml DCM, is added 1.2 eq. PyBrOP, 4eq. DIEA, and catalytic amount of DMAP at °0 C. The resulting reaction mixture is stirred for 1 hour at 0°C and then warmed to RT over a period of 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as elution phase (9:1-»5:1- 3:1-»1:1) to afford the title compound isolated phenethyl ester 81b. , -u„- .. „ _ ,td „ B „„ _ _
Other esters can be made using the same procedure.
Example 82. Compound of Formula 11, wherein A = -(C=0)-0-R1, R1 =
N — N cyclopentyl. G = -NH-phenethyl. L = absent. W is . Q = absent. Y = phenvK i = 3. m = s = 1. and R3 = R4 = H.
Figure imgf000163_0001
71 82b
The title compound is prepared by adding to a solution of the title compound of Example 71 and phenethylamine 82a (0.05 ml) in 0.5 ml -5MF, EDC (1.2 eq.) and DIEA (4eq.) at °0 C. The resulting reaction mixture is stirred at 1 hour. Subsequently, the reaction is warmed to RT over a period of 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexanes: EtOAc as elution phase (9:1— >5:1— 3:1— 1:1) to afford title compound phenethyl amide 82b. Other amides can be made using the same procedure.
Example 83. Compound of Formula II. wherein A = -(C=OV-O-R1. R =
cyclopentyl. G = -NHS(O) ?-phenethyl. L = absent. W is
Figure imgf000163_0002
. Q = absent. Y = phenyl. i = 3. m = s = 1. and R3 = R4 = H.
Figure imgf000163_0003
71 83b
The title compound is prepared by adding to a solution of the title compound of Example 71 and α-toluenesulfonamide 83a (10mg) in 0.5 mf DCM, is added 1.2 eq. is <-„,.. it -i- •--,-.' ,,-jnu ■■"ir,.' 1----J1. mji. ~ιr.ιi' 7S> —
PyBrOP, 4eq. DIEA, and catalytic amount of DMAP at °0 C. The resulting reaction mixture is stirred for 1 hour and then allowed to warm to RT over a period of 4-12 hours.
The reaction mixture is purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as elution phase (9:1- 5:1-»3:1-»1:1) to afford the title cornpound sulfonamide 83c.
Other sulfonamides can be made using the same procedure.
Example 84. Compound of Formula IK wherein A = -(C=Q)-0-R1. R1 =
N — N cyclopentyl, G = ~(C=0)-OH. L = absent. W is * ** . Q = absent. Y = phenyl. i =
Figure imgf000164_0001
The title compound is prepared by adding to a solution of the title compound of Example 71 in 0.5 ml THF, is added α-hydroxy-α-methyl-propionitrile (0.1 ml) and catalytic amount TFA at 0°C. The resulting reaction mixture is warmed from °0 C to RT over a period of 4-12 h followed by hydrolysis with concentrated hydrochloric acid in dioxane. The reaction is then extracted with EtOAc, and washed with water and brine to yield α- hydroxy compound 83a in its crude form. The crude compound 84a undergoes a Dess- Martin oxidation in THF (0.5 ml), providing the α-carbonyl compound 84b in crude form. The crude 84b is purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as elution phase (9:1-»5:1-»3:1-»1:1) to afford the title compound isolated keto acid 84b.
Example 85. Compound of Formula IK wherein A = -(C=0)-0-R1. R1 =
Figure imgf000164_0002
phenyl. i = 3. m = s = 1. and R3 = R4 = H. . -- , - -
The title compound is prepared with the title compound keto acid of Example 84 and phenethanol according to the procedure set forth in Example 81.
Example 86. Compound of Formula II, wherein A = ~(C=Q)-0-R1. R1 =
Figure imgf000165_0001
phenyl. i = 3. m = s = 1. and R3 = R = H.
The title compound is prepared with the title compound keto acid of Example 84 and phenethyl amine according to the procedure set forth in Example 82.
Example 87. Compound of Formula IK wherein A = -(C=OV-0-R1. R1 =
Figure imgf000165_0002
Y = phenyl. i = 3, m = s = 1. and R3 = R4 = H.
The title corhpound is prepared with the title compound keto acid of Example 84 and α-toluenesulfonamide according to the procedure set forth in Example 83.
Example 88. Compound of Formula II, wherein A = tBOC, G = OH. L =
Figure imgf000165_0003
Synthesis of (2S)-N-Boc-amino-5-oxo-non-8-enoic acid
88A. The aforementioned amino acid is prepared by adding to a solution of monoallyl ester of malonic acid in dry THF under N2 at -78°C, n-Bu2Mg dropwise over a period of 5min. The resulting suspension is then stirred at RT for 1 hour and evaporated to dryness. Solid Mg salt 88b, is dried under vacuum.
Glutamic acid derivative 88a is first mixed with 1,1'-carbonyldiimidazole in anhydrous THF and the mixture is stirred at RT for 1h to activate the free acid moiety. Subsequently, the activated glutamic acid derivative is cannulated into a solution of Mg salt 88b and the reaction mixture obtained is stirred at RT for 16h. The mixture then is diluted with ethyl acetate and the organic solution is washed with 0.5 N HCI (at 0°C) and brine, dried and evaporated. The residue obtained is resolved via silica chromatography with a 35-40% ethyl acetate in hexanes eluent system to yield diester 88c.
88B. To a stirred solution of tetrakis (triphenylphosphine) PD (0) in dry DMF is added the diester in DMF. The mixture is stirred at RT for 3.5 hours. The DMF is evaporated under reduced pressure and the residue diluted with EtOAc. The EtOAc solution is washed with 0.5N 0°C HCI, brine, dried and evaporated. The residue is chromatographed on silica gel using 15% to 20% EtOAc in hexane as eluent to afford the methyl ester intermediate.
The methyl ester intermediate is then diluted with THF and water, LiOH»H2θ is added and the resulting mixture is stirred at RT for 25 hours, wherein the completion of the hydrolysis is monitored by TLC. The reaction mixture is concentrated under vacuum to remove a majority of the THF and further diluted with methylene chloride. The resulting solution is washed with 1 N HCI, dried with anhydrous Na2S04 and concentrated under vacuum. To remove minor impurities and excess B0C2O, the crude product is purified via flash chromatography using a solvent gradient from 100% hexane --> 100% EtOAc as the eluent. (2S)-N-Boc-amino-5-oxo-non-8-enoic acid 88d is obtained. For further details of the preceding amino acid synthesis may be found in T. Tsuda et al., J. Am. Chem. Soc, 1980, 102, 6381-6384 and WO 00/59929, which are herein incoφorated by reference in their entirety.
88C. Synthesis of modified cyclic peptide precursor mesylate The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in Example 1 using (2S)-N-Boc-amino-5-oxo-non-8-enoic acid 88d in place of Boc-L-2-amino-8-nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in Example 2.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 88C and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 89. Compound of Formula IK wherein A = tBOC. G = OH. L =
N=N
-CH(CHg)CH?-, W is . Q = absent. Y = phenyl. i = 1. m = s = 1. R3 = methyl, and R4= H.
Figure imgf000167_0001
Synthesis of (2S.5RVN-Boc-2-amino-5-methyl-non-8-enoic acid (89h).
89A. To solid ethyl 2-acetamidomalonate 89b is added (R)-(+)-citronellal 89a in a solution of pyridine over 1 min. The resulting solution is cooled in a 10°C bath and acetic anhydride is added over 4 min. The resulting solution is stirred for 3 h at RT and another portion of ethyl 2-acetamidomalonate 89a is added. The resulting mixture is stirred at RT for an additional 11 hours. Ice is then added and the solution is stiπred for 1.5 hours, then the mixture is diluted with 250 ml water and extracted with two portions of wther. The organic phase is washed with 1N HCI, sat. NaHC03, dried Na2Sθ4, concentrated and purified by flash chromatography (40% EtOAc/hexane) to afford compound 89c.
89B. To a degassed solution of 89c in dry ethanol is added (S,S)-Et- PUPHOS Rh(COD)OTf. The mixture is subjected to 30 psi of hydrogen and stirred on a Parr shaker fo'r 2 hours. The resulting mixture is evaporated to dryness to obtain the crude compound 50d, which is used in the subsequent step without purification.
89C. Compound 89d is dissolved in a mixture of tBuOH/acetone/H20 (1:1:1) and placed in an ice bath (0°C). NMMO and Os04 is consecutively added and the reaction mixture is stirred at RT for 4 hours. A majority of the acetone is removed by evaporation under vacuum and then the mixture is extracted with ethyl acetate. The organic layer is further washed with water and brine, dried over anhydrous MgS04 and evaporated to dryness. The diol 50e is obtained in high purity after flash column chromatography using 1% ethanol in ethyl acetate as the ejuent.
89D. To a solution of diol 89e in THF/HzO (1:1) at 0°C, Nal04 is added and the reaction mixture is stiπred at RT for 3.5 hours. A majority of the THF solvent is subsequently removed by evaporation under vacuum and the remaining mixture is extracted with EtOAc. The combined organic layers is further washed with 5% aqueous citric acid solution, 5% aq. NaHC03 and brine, then the organic phase is dried over MgS04 and evaporated to dryness under vacuum. Aldehyde intermediate 89f is used in the following step in its crude form.
89E. To a solution of Ph3PCH3Br in anhydrous toluene, KHMDS is added forming a suspension which is stirred at RT for 30 min. under N2. After stirring, the suspension is cooled to 0°C, a solution of aldehyde intermediate 89f in THF is added, the mixture is warmed to RT, and stirred for 1 hour. A majority of the THF is evaporated under vacuum, EtOAc is added to the mixture and the organic phase is washed with water, 5% aq. NaHC03 and brine. The organic phase is then dried over MgS04 and evaporated to dryness under vacuum. Pure compound 89g is isolated after purification via flash chromatography on silica gel, using hexane:EtOAc (3:2) as the eluent.
89F. To a solution of crude 89g in THF, Boc∑O, and DMAP is added and the reaction mixture is heated to reflux for 2.5 hours. Subsequently, a majority of the THF is evaporated, the crude mixture is diluted with methylene chloride and washed with 1 N HCI to remove DMAP. The organic layer is further extracted with saturated aq. NaHC03, dried with anyhrous Na2S04 and concentrated under vacuum. The crude product is then diluted with THF arid water, LiOH»H2θis added and the resulting mixture is stirred at RT for 25 hours, wherein the completion of the hydrolysis is monitored by TLC. The reaction mixture is concentrated under vacuum to remove a majority of the THF and further diluted with methylene chloride. The resulting solution is washed with 1 N HCI, dried with anhydrous Na2S04 and concentrated under vacuum. To remove minor impurities and excess Boc∑O, the crude product is purified via flash chromatography using a solvent gradient from 100% hexane - 100% EtOAc as the eluent. (2S, 5R)-N-Boc-2-amino-5-methyl-non-8-enoic acid 89h is obtained. For further details of the preceding amino acid synthesis see WO 00/59929, which is herein incoφorated by reference In its entirety.
89G. Synthesis of modified cyclic peptide precursor mesylate
The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in Example 1 using ((2S, 5R)-N-Boc-2-amino-5-methyl-non-8- enoic acid 89h in place of Boc-L-2-amino-8-nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in Example 2.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 89G and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 90. Compound of Formula II. wherein A = tBOC. G = OH. L = -0-. W is
Figure imgf000169_0001
. Q = absent. Y = phenyl. i = 0. m = s = 1. R = methyl, and R = hydrogen.
Figure imgf000169_0002
90a 90b 90c 90d
Synthesis of N- Boc-O-allvMLHhreonine (90d) ,,,,. π - „ ,,, _ __
90A. Boc-(L)-threonine 90a is partially dissolved in methylene chloride/methanol at 0°C. A solution of diazomethane in diethyl ether is added until yellow, indicating the presence of diazomethane. Upon evaporation of the solvents, crude methyl ester 90b is obtained.
90B. Intermediate 90b is dissolved in anhydrous diethyl ether, Ag20 is added and freshly activated 4A molecular sieves. Finally, allyl iodide is added to the reaction mixture and is stirred at reflux. Two additional portions of allyl iodide are added to the reaction mixture after a period of 20 hours and 30 hours and stirring is continued for a total of 36 hours. The mixture is then filtered through celite and purified by flash chromatography on silica gel, using EtOAc/hexane (1:4) as the eluent, to afford compound 90c.
90C. Compound 90c is dissolved in a mixture of THF/MeOH/H20 (2:1:1) and LiOH*H2θ is added. The solution's stirred at RT for 2h, and the is acidified with 1 N HCI to pH -3 before the solvents are removed under vacuum. The resulting crude compound 90d is obtained. For further details of the preceding amino acid synthesis see WO 00/59929, which is herein incoφorated by reference in its entirety.
90D. Synthesis of modified cyclic peptide precursor mesylate .
The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in -Example 1 using N- Boc-0-allyl-(L)-threonine 90d in place of Boc-L-2- amino-8-nonenoic acid 1a followed by conversion to the coπresponding mesylate via the method described in Example 2.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 90D and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 91. Compound of Formula II. wherein A = tBOC. G - OH. L = -S-. W is
- v%* γ . Q = absent. Y = phenyl. i = 0. m = s = 1. R = methyl, and R4 = hydrogen.
Figure imgf000171_0001
Synthesis of (2S.3S V-Boc-2 amino-3(mercaptoallyl)butanoic acid (91 e).
91A. Compound 91a is dissolved in pyridine and the solution is cooled to 0°C in an ice bath, tosyl chloride is added in small portions and the reaction mixture is partitioned between diethyl ether and H20. The ether layer is further washed with 0.2 N HCI and brine, dried over anhydrous MgS04, filtered and concentrated to dryness under vacuum. Purification of the crude material by flash chromatography on silica gel, using hexane/EtOAc (gradient from 8:2 to 7:3 ratio) as the eluent, led to isolation of tosyl derivative 91b.
91 B. To a solution of tosyl derivative 91b in anhydrous DMF, potassium thioacetate is added and the reaction mixture is stirred at RT for 24 hours. A majority of the DMF is then evaporated under vacuum and the remaining mixture is partitioned between EtOAc and H2O. The aqueous layer is re-extracted with EtOAc, the combined organic layers are washed with brine, dried over anhydrous MgS04 and evaporated to dryness. Purification of the crude material by flash chromatography on silica gel using hexane/EtOAc (4:1 ratio) as the eluent, affords thioester 91c.
91 C. To a solution of thioester 91c is H∑O/EtOH (3:5 ratio) and aqueous solution of 0.2M NaOH is added and the mixture is stirred at RT for 1.5 hours. Allyl iodide is then added and stirring is continued at RT for an additional 30 min. The reaction mixture is concentrated to half of its original volume and then extracted with EtOAc. The aqueous layer is acidified to pH ~3 with cold, aqueous 0.5N HCI and re-extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgS04 and evaporated to dryness under vacuum. The crude reaction mixture contains at least four products; all of the products are isolated after flash chromatography on silica gel, using hexane/EtOAc (gradient from 9:1 to 3:1). The desired product 91 d is the least polar compound.
91 D. A solution of compound 91 d in MeOH/H20 (3:1) is mixed with aqueous NaOH (0.3 N) for 24 hours at RT and for 1 hour at 40°C. The reaction mixture is acidified with cold aqueous 0.5 N HCI, the MeOH is removed under vacuum and the remaining aqueous mixture is extracted with EtOAc. The organic phase is dried over MgS04 and evaporated to dryness in order to obtain compound 91 e. For further details of the preceding amino acid synthesis see WO 00/59929, which is herein incorporated by reference in its entirety.
91 E. Synthesis of modified cyclic peptide precursor mesylate
The modified cyclic peptide^precursor mesylate is prepared using the synthetic route detailed in Example 1 using (2S, 3S)-Λ/-Boc-2 amino-3(mercaptoallyl)butanoic acid 52e in place of Boc-L-2-amino-8-nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in Example 2.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 91 E and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 92. Compound of Formula II. wherein A = tBOC. G = OH. L = -S(O
W is
Figure imgf000172_0001
. Q = absent. Y = phenyl. i = 2. m = s = 1. R3 = methyl, and R4 = hydrogen.
Figure imgf000172_0002
92A. The modified amino acid is prepared by dissolving sodium metaperiodate (1.1 eq.) in water and cooled to 0°C in an ice bath followed by adding dropwise a -,, , , ,„, „,,
solution of compound 91 d in dioxane. The resulting reaction mixture is stirred for one hour at 0°C and 4 hours at 40°C. The reaction mixture is concentrated, water is added, and the mixture is extracted with methylene chloride twice. The combined organic layers are washed with water, brine, dried with anhydrous MgS04 and concentrated in vacuo. The methyl ester is then reduced via the method set forth in Example 91 D to am've upon the modified amino acid 92a. For further details of the preceding amino acid synthesis may be found in T. Tsuda et al., J. Am. Chem. Soc, 1980, 102, 6381- 6384 and WO 00/59929, which are herein incoφorated by reference in their entirety. 92B. Synthesis of modified cyclic peptide precursor mesylate
The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in Example 1 using the modified amino acid 92a in place of Boc-L-2- amino-8-nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in Example 2. "*
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 92B and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 93. Compound of Formula II. wherein A = tBOC. G = OH. L = -S(O)?-.
W is
Figure imgf000173_0001
. Q = absent. Y = phenyl. i = 2. m = s = 1. R3 = methyl, and R4 = H.
Figure imgf000173_0002
93A. The modified amino acid is prepared by dissolving sodium metaperiodate (1.1 eq.) in water and cooled to 0°C in an ice bath followed by adding dropwise a solution of compound 92d in dioxane. The resulting reaction mixture is stirred for one hour at 0°C and 4 hours at 40°C. The reaction mixture is concentrated, water is added, and the mixture is extracted with methylene chloride twice. The combined organic layers are washed with water, brine, dried with anhydrous MgS0 and concentrated in vacuo. The methyl ester is then reduced via the method set forth in Example 91 D to arrive upon the modified amino acid 92a. For further details of the preceding amino acid synthesis may be found in T. Tsuda et al., J. Am. Chem. Soc, 1980, 102, 6381-6384 and WO 00/59929, which are herein incoφorated by reference in their entirety. 93B. Synthesis of modified cyclic peptide precursor mesylate
The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in Example 1 using the modified amino acid 93a in place of Boc-L-2- amino-8-nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in Example 2.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 93B and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 94. Compound of formula II. wherein A = tBOC, G = OH. L =
Figure imgf000174_0001
Qϊ_k_
Figure imgf000174_0002
94» 94b
94A. Synthesis of (SVN-Boc-2-amino-3-methyl-3( 1 -mercapto-4-butenyl)butanoic acid (94b)
L-Penicillamine 94a is dissolved in DMF/DMSO (5:1), subsequently, 4- bromopentene and CsOH»H2θ are added to the mixture and stirring is continued for an additional 12 hours. The DMF is subsequently removed in vacuo, the remaining mixture is diluted with 0.5 N HCI (at 0°C) to adjust the pH to -4-5 and then extracted with 2 portions of EtOAc. The organic phase is washed with brine (2x), dried over MgS0 and evaporated to dryness to afford the crude carboxylic acid 94a. For further details of the preceding amino acid synthesis see WO 00/59929, which is herein incorporated by reference in its entirety. 94B. Synthesis of modified cyclic peptide precursor mesylate
The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in Example 1 using the modified amino acid 94a in place of Boc-L-2- amino-8-nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in Example 2.
The title compound is prepared , with the modified cyclic peptide precursor mesylate formed in 94B and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 95. Compound of Formula II. wherein A = tBOC, G = OH. L =
-CF?CH?-. W is
Figure imgf000175_0001
. Q absent, Y = phenyl. i = 1. m = s = 1. and R3 = R4 = j±
Figure imgf000175_0002
Synthesis of (2SVN-Boc-amino-5-difluoro-non-8-enoic acid (95b).
95A. To a solution of the ketone compound 88d (0.30g, 1 mmol) in 5 ml DCM, DAST (Diethylaminosulfurtrifluoride, 0.2g, 1.2 eq) is added. The reaction is kept at RT over a period of 2-3 days. The solvent is evaporated and the residue is purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as eluent (9:1-»5:1- 3:1-»1:1), providing the isolated methyl ester 95a. For further details concerning the preceding synthesis, see Tius, Marcus A et al., Tetrahedron, 1993, 49, 16; 3291-3304, which is herein incorporated by reference in its entirety.
95B. Methyl ester 95a is dissolved in THF/MeOH/H20 (2:1:1) and LiOH«H20 is added. The solution is stirred at RT for 2hours, and is then acidifies with 1N HCI to pH - --■' ---. ,.' ., ■ ii .'' > -- - 3 before the solvents are removed in vacuo to afford the crude (2S)-N-Boc-amino-5- difluoro-non-8-enoic acid 95b.
95C. Synthesis of modified cyclic peptide precursor mesylate
The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in Example 1 using crude (2S)-N-Boc-amino-5-difluoro-nonτ8-enoic acid 95b in place of Boc-L-2-amino-8-nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in Example 2.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 95C and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 96. Compound of Formula II, wherein A = tBOC. G = OH, L = - N=N
, ^N * _--Y
-CFHCH?-. W is . Q = absent. Y = phenyl, i = 1. m = s = 1. and R3 = R =
Figure imgf000176_0001
Synthesis of (2S)-N-Boc-amino-5-fluoro-non-8-enoic acid (96c).
96A. To a solution of the ketone compound 88d in 5 ml methanol, NaBH4 (2.2 eq) is added. The reaction mixture is stirred at RT over a period of 2-6 hours, and then quenched by 1M ammonium chloride and extracted with EtOAc (30 ml). The solvent is ) evaporated and the crude hydroxy compound 96a is obtained. - L-, il ..•'' '-•- » «■•» "+■''" !!J ' ""!1" '' ;;1 . - --
96B. The hydroxy compound 96a is dissolved in 5 ml DCM to which DAST (0.2g, 1.2 eq) is added and stirred at -45 °C for 1 hour. The reaction mixture is then warmed to RT and stirred over a period of 2-3 days. The solvent is evaporated and the residue is purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as eluent (9:1-»5:1-»3:1-»1:1), providing the isolated monofluoro compound methyl ester 95b. For further details concerning this synthesis see Buist, Peter H et al., Tetrahedron Lett., 1987, 28, 3891-3894, which is herein incoφorated by reference in its entirety.
96B. Methyl ester 96b is dissolved in THF/MeOH/H20 (2:1:1) and LiOH»H20 is added. The solution is stirred at RT for 2hours, and is then acidifies with 1 N HCI to pH ~ 3 before the solvents are removed in vacuo to afford the crude (2S)-N-Boc-amino-5- difluoro-non-8-enoic acid 96c.
96C. Synthesis of modified cyclic peptide precursor mesylate
The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in Example 1 using crude (2S)-N-Boc-amino-5-monofluoro-non-8-enoic acid 96b in place of Boc-L-2-amino-8-nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in -Example 2.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 96C and 5-phenyl-1 H-tetrazole by the replacement method elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
Example 97. Compound of Formula III, wherein A = tBOC. G = OH. L = absent.
Figure imgf000177_0001
97A. The saturated cyclic peptide precursor mesylate is prepared by catalytic reduction of the mesylate cyclic peptide precursor 2 with Pd/C in MeOH in the presence of H2.
The title compound is prepared with the saturated cyclic peptide precursor mesylate formed in 97A and 5-phenyl-1 H-tetrazole by the replacement method ii,-, li ,■" u a- iui ""!- •••' ιut .'."* ""ϊf' *' ■•>' elucidated in Example 21 followed by hydrolysis of the ethyl ester via the method set forth in Example 22.
The compounds of the present invention exhibit potent inhibitory properties against the HCV NS3 protease. The following examples elucidate assays in which the compounds of the present invention were tested for anti-HCV effects.
Example 98. Triazole Synthesis
Exemplary triazole derivatives for use in preparing compounds of the invention may be prepared as set forth in the examples below.
Figure imgf000178_0001
Triazoles of the present invention may be prepared" by reacting 4mmol of alkyne compound 98a, which is commercially available or made from procedures elucidated infra, and 8mmol of trimethylsilyl azide in 2ml of xylenes in a pressure tube for 24-72 hours at 140°C. The resulting reaction mixture was directly separated by silica column, yielding triazole 98b In 30-90% yield.
Example 99. Alykvne Synthesis 99A. Sonogashira Reaction
Pd (I]), 5% cq
Cul
TEA,
MeC „
X - I I + Y— alide reflux, 12 h "* halide * I, Br 9S*
Alkynes used in the present invention can be made by the Sonogashira reaction by reaction of a degassed solution of 4mmol of primary alkyne compound 99a, 4mmol of an aryl halide (Y-halide), and 1ml of triethylamine and 10ml of acetonitrile with 140mg(0.2mmol) of PdC^PPha^ and 19mg(0. Immol) of Cul. The resulting reaction mixture is degassed and stirred for 5 minutes at RT. The reaction is then heated to 90°C and stirred for 12 hours. Subsequently, the reaction mixture is concentrated in i --,,.. n u aniJ 'i!' ui -a "- *' ■",.> vacuo and purified by silica column to afford the substituted alkyne 98a in a 60-90% yield.
99B. Synthesis of Alkynyl Amides
H
Figure imgf000179_0001
Additional alkynes used in the present invention can be made by reacting 10mmol of alkynyl acid 99b, 11 mmol of BOP, and 22mmol of DIEA in 15ml of DMF with 11mmol of amine 99b and stim'ng at room temperature for 3 hours. The reaction mixture is then extracted by ethyl acetate (2x50ml); washed with 1M NaHCO3(2x30ml), water(2x30ml), 5% citric acid(2x50ml) and brine(2x30ml); dried over anhydrous sodium sulfate; and concentrated in vacuo to afford alkyne 99d in a 90% yield.
Example 100. Compound of Formula IK wherein A = tBOC. G = OH, L = absent.
Figure imgf000179_0002
The title compound was prepared by the following method: 2mmol (0.54g) of Boc methyl ester azidoproline 100a and 2.5mmol of 4-tert-Butylphenylacetylene 100b were
) dissolved in 2ml of xylenes and stirred at 110°C for 12 hours. The resulting reaction mixture was directly separated by silica column to resolve isomers 100c and 100d, with a yield of 90%. I ii,.-. li ■■' ».-' ■-.- '- u '"if" / 'i-11 ••"■" •>' ■■
The title compound was then formed via the RCM procedure described in Example 1 using 100b in the place of hydroxyl proline, followed by hydrolysis of the ethyl ester via the procedure described in Example 106.
[M+Na]+ = 671.72.
Example 101. Compound of Formula II, wherein A = tBOC. G = OH L = absent.
Figure imgf000180_0001
The title compound was prepared via RCM procedure described in Example 1 using 100c in the place of hydroxyl proline, followed by hydrolysis of the ethyl ester via the procedure described in Example 106.
[M+H]+ = 649.44.
Example 102. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. x
N'
W is -i-- , X and Y are taken together = phenyl. i = 3. m = s = 1. and R3 = R4 = H.
Figure imgf000180_0002
The triazole-substituted proline corresponding to the title compound was prepared by dissolving 1.5mmol(0.5g) of hydroxyproline mesylate 102a and 4.5 mmol of benzotriazole 102b in 5ml of DMF, adding 9mmol(2.9g) of cesium carbonate and stirring the resulting reaction mixture at 70°C for 12 hours. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate and brine. The organic layer was dried over MgS04 and concentrated in vacuo. Expected isomers 102c and 102d were resolved via silica column chromatography. ,, ii / u> .".:. ui "" ".■' ,.,' ..... >i
The title compound was then formed via the RCM procedure described in Example 1 using 102d in the place of hydroxyl proline, followed by hydrolysis of the ethyl ester via the procedure described in Example 106.
[M+Naf = 588.46.
Example 103. Compound of Formula II, wherein A = tBOC, G = OH, L = absent.
Figure imgf000181_0001
The title compound was formed via the RCM procedure described in Example 1 using 102c in the place of hydroxyl proline, followed by hydrolysis of the ethyl ester via the procedure described in Example 106.
[M+Naf = 588.50.
Example 104. Compound of Formula II, wherein A = tBOC. G = OH, L = absent.
Figure imgf000181_0002
The triazole-substituted proline corresponding to the title compound was prepared by dissolving 1.5mmol(0.5g) of hydroxyproline mesylate 102a and 4.5 mmol of benzotriazole 102b in 5ml of DMF, adding 9mmol(2.9g) of cesium carbonate and stirring the resulting reaction mixture at 70°C for 12 hours. The reaction mixture was extracted with EtOAc, washed with 1 M sodium bicarbonate and brine. The organic layer was
I - dried over MgS04 and concentrated in vacuo.
The title compound was then formed via the RCM procedure described in Example 1 using the triazole-substituted proline of the present example in the place of hydroxyl proline, followed by hydrolysis of the ethyl ester via the procedure described in Example 106.
[M+Naf = 690.42. B -L « ■' ii.-M";i' ii„l! ""!!• ' IU- ----. ■
Example 105. Compound of Formula II. wherein A = tBOC. G = OEt, L = absent.
Figure imgf000182_0001
2 105
The title compound was prepared by dissolving 0.041 mmol of the title compound of Example 2 and-Q.123mmol of 4,5 -diphenyltriazole in 3ml of DMF, adding 0.246mmol of cesium carbonate (80mg), and reacting at 70°C for 12 hours. The reaction mixture was then extracted with EtOAc and washed with 1M sodium bicarbonate (2x30ml) and water (2x30ml). The resulting organic solution was concentrated in vacuo to dryness.
) Example 106. Compound of Formula ll, wherein A = tBOC. G = OH. L = absent.
Figure imgf000182_0002
The title compound was prepared by dissolving 0.041 mmol of the title compound of Example 105 in 3ml of dioxane, adding 2ml of 1M LiOH, and reacting at RT for 8 hours. Subsequently, the pH of reaction mixture was adjusted to 3 with citric acid, extracted with EtOAc, followed by washing with brine and water. The organic solution was concentrated in vacuo for purification by HPLC.
[M+Naf = 690.42. ■» u •■' .'- " " .' -»ι i >
Example 107. Compound of Formula II. wherein A = tBOC. G = OH, L = absent. x
N
W is . X = Y = phenyl. i = 3. m = s = 1. and R3 = R4 = H.
Figure imgf000183_0001
107a 107b
The triazole-substituted proline precursor of the title compound was prepared by dissolving 0.93mmol (0.25g) of azidoproline 100a and Immol of diphenyl acetylene in 2ml of xylenes, heated to 110°C, and stirred for 12 hours. The reaction mixture was directly separated by silica column to afford 0.27g of 107a (90%). [M+H]+: 449.05. 0.26g of 107b was obtained by the hydrolysis procedure elucidated in Example 105 (99%).
The title compound was then formed via the RCM procedure described in Example 1 using 107b in the place of hydroxyl proline. [M+Naf = 691.99.
Example 108. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000183_0002
108a Triazole Formation
The 4-(n-propyl)-5-phenyltriazole was prepared via the procedure of Example 98 using n-propyl phenylacetylene and sodium azide. -P ..,,-- It / 'Ui ,'-. '-„« "- " ... ,,- " ' - . -
The title compound was prepared with the title compound of Example 2 and 4-(n- propylj-5-phenyltriazole 108a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106. [M+Naf = 657.99. >
Example 109. Compound of Formula IK wherein A = tBOC. G = OH. L = absent.
Figure imgf000184_0001
H-
109a Alkyne Formation . The 2-(m-methoxyphenyl)-4-methoxyphenylacetylene was prepared via the procedure of Example 99A from 4-methoxyphenylacetylene and 3-bromoanisole.
109b Triazole Formation
The 4-(m-methoxyphenyl)-5-(p-methoxyphenyl)triazole was prepared via the
> procedure of Example 3 using alkyne 109a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-(m-methoxyphenyl)-5-(p-methoxyphenyl)triazole 109a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of ) -Example 106.
[M+Naf = 752.08.
Example 110. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000184_0002
> H.
110a Alkyne Formation - / :-iι .. " " - < i .
The 2-(m-bromophenyl)-4-methoxyphenylacetylene was prepared via the procedure of Example 99A from 4-methoxyphenylacetylene and 3-iodo-5- bromobenzene.
110b Triazole Formation
The 4-(m-bromophenyl)-5-(p-methoxyphenyl)triazole was prepared via the procedure of Example 3 using alkyne 110a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the
> 4-(m-bromophenyl)-5-(p-methoxyphenyl)triazole 110a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106.
[M+Naf = 800.05.
> Example 111. Compound of Formula II. wherein A = tBOC, G = OH. L = absent,
Figure imgf000185_0001
111a Alkyne Formation
The 2-(1-napthyl)-4-methoxyphenylacetylene was prepared via the procedure of Example 99A from 1-iodonapthelene and 4-methoxyphenylacetylene. )
It'1 --, - 'l -i' iϋt ,H " k" . „ -- „ [ " . -J' " -.'
111b Triazole Formation
The 4-(m-bromophenyl)-5-(p-methoxyphenyl)triazole was prepared via the procedure of Example 3 using 2-(1-napthyl)-4-methoxyphenylacetylene 113a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-(1-napthyl)-5-(p-methoxyphenyl)triazole 113a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106. [M+Naf = 772.11.
Example 112. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000186_0001
112a Alkyne Formation The 2-(2-thienyl)-4-methoxyphenylacetylene was prepared via the procedure of Example 99A from 2-iodo-thiophene and 4-methoxyphenylacetylene.
112b Triazole Formation
The 4-(2-thienyl)-5-(p-methoxyphenyl)triazole was prepared via the procedure ) of Example 3 using 2-(2-thienyl)-4-methoxyphenylacetylene 112a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-(2-thienyl)-5-(p-methoxyphenyl)triazole 112a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of > Example 106.
[M+Hf = 705.31. -['"" It-,,-. 11 / i|.,l' ..-.ll n " ,„.ι .' -
Example 113. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000187_0001
113a Alkyne Formation
The 2-(3-thienylH-metnoχypher.ylacetylene was prepared via the procedure
> of Example 99a from 2-iodo-thiophene and 4-methoxyphenylacetylene.
113b Triazole Formation
The 4-(3-thienyl)-5-(p-methoxyphenyl)triazole was prepared via the procedure of Example 3 using 2-(3-thienyl)-4-methoxyphenylacetylene 113a and sodium azide. )
The title compound was prepared with the title compound of Example 2 and the 4-(3-thienyl)-5-(p-methoxyphenyl)triazole 113a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106.
> [M+Naf = 727.21.
Example 114. Compound of Formula IK wherein A = tBOC. G = OH. L = absent.
Figure imgf000187_0002
114a Alkyne Formation ) The 2-(4-pyrazolyl)-4-methoxyphenylacetylene was prepared via the procedure of Example 99A from 4-iodopyrazole and 4-methoxyphenylacetylene.
114b Triazole Formation
The 4-(4-pyrazolyl)-5-(p-methoxyphenyl)triazole was prepared via the procedure of Example 3 using 2-(4-pyrazolyl)-4-methoxyphenylacetylene 114a and sodium azide. iι,„, .•• .„ .. ι i -----. - .u i -i - - ■ --
The title compound was prepared with the title compound of Example 2 and the 4-{4-pyrazolyl)-5-(p-methoxyphenyl)triazole 114a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106. > [M+Hf = 700.82.
Example 115. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000188_0001
115a Alkyne Formation ) The 2-(3-pyridyl)-4-methoxyphenylacetylene was prepared via the procedure of -Example 99A from 3-iodopyridine and 4-methoxyphenylacetylene.
115b Triazole Formation
The 4-(3-pyridyl)-5-(p-methoxyphenyl)triazole was prepared via the procedure 5 of Example 3 using 2-(3-pyridyl)-4-methoxyphenylacetylene 115a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-(3-pyridyl)-5-(p-methoxyphenyl)triazole 115a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of 0 Example 106.
[M+Hf = 700.36.
Example 116. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000188_0002
116a Alkyne Formation
The 2-(2-pyridyl)-4-methoxyphenylacetylene was prepared via the procedure of Example 99A from 2-iodopyridine and 4-methoxyphenylacetylene. - L,-, 11 / U .-:"!ι i-.-.i "'ii- / ι| „- -r'MI' ••_9 - - .- . -- -
116b Triazole Formation
The 4-(2-pyridyl)-5-(p-methoxyphenyl)triazole was prepared via the procedure of Example 3 using 2-(2-pyridyl)-4-methoxyphenylacetylene 116a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-(2-pyridyl)-5-(p-methoxyphenyl)triazole 116a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106. » [M+Hf = 700.82.
Example 117. Compound of Formula H, wherein A = tBOC, G = OH. L = absent.
Figure imgf000189_0001
Pd (ll), 5% eq Cul
Figure imgf000189_0002
117a 117b 117c
117A. Alkyne Formation
The alkyne of the current example, 2-(2-thiazolyl)-4-memoxyphenylacetylene was prepared by adding to a degassed solution of 4mmol of 4-ethynylanisole, 4mmol of 2-bromothiazole, and 1ml of triethylamine in 10ml of acetonitrile,140mg(0.2mmol) of PdCI2(PPh3)2 and 19mg(0.1mmol) of Cul. The mixture was degassed and stirred for 5 minutes at RT and heated to 90°C for 12 hours. The reaction mixture was concentrated in vacuo and purified by silica column to afford 0.61 g of brown liquid in a 70% yield.
[M+H]+: 216.17, 1HNMR (CDCI3, 500MHz) δ7.765(d, J=3Hz, 1H), 7.472~7.455(m, 2H), 7.277 (d, J=3.5Hz, 1H), 6.837-6.820 (m, 2H), 3.768 (s, 3H). L„. i / .--_- - " ' -
Figure imgf000190_0001
117B. Triazole Formation
The 4-(2-thiazolyl)-5-(p-methoxyphenyl) triazole 117d was prepared by adding to a pressure tube 0.3g of 117c, 0.74m! of trimethylsilyl azide, and 4ml of xylenes and heating the mixture to 140°C for 48 hours. The reaction mixture was directly separated by silica column to afford a brown liquid (117d) after purification (0.18g, 50%).
[M+H]+: 259.27, 1HNMR (DMSO-d6), 500MHz) S 8.016(d, J=8.5Hz, 2H), 7.929(d, J=3Hz, 1H), 7.817(d, J=3Hz, 1H), 7-066(d, J=8.5Hz, 2H), 3.824(s, 3H).
Figure imgf000190_0002
117c. Ethyl Ester 117e was prepared by dissolving 0.041 mmol of mesylate of macrocyclic precursor 117d and 0.123mmol of 117d in 3ml of DMF, adding 0.246mmol cesium carbonate, and reacting, at 70°C for 12 hours. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate (2x30ml) and water (2x30ml), and concentrated in vacuo to obtain ethyl ester 117e.
[M+H]+: 734.34
Preparation of title compound I . / '!--' --I' U " " ..-.» ""II" ..i' "-.' - -_-- - -
Figure imgf000191_0001
Hydrolysis of ethyl ester 117c was achieved by dissolving 117e in 3ml of dioxane, adding 2ml of 1M LiOH, and stirring the resulting reaction mixture at RT for 8 hours. The pH of the reaction mixture was adjusted to 3 with citric acid; then the reaction mixture was extracted with EtOAc, and washed with brine and water. The organic solution was concentrated in vacuo for purification by HPLC which afforded a yellow powder after lyophilization (10mg, yield 34%).
[M+H]+: 706.33, 1HNMR (DMSO-d6, 500MHz) δ 12.283 (s, broad, 1H), 8.750 (s, broad, 1H), 8.014 (d, J=9Hz, 2H), 7.938 (d, J=3.5Hz, 1H), 7.852 (d, J=3.5Hz, 1H), 6.997 (d, J=8Hz, 2H), 6.927 (d, J=7, 1H), 5.555 (s, broad, 1H), 5.499 (m, 1H), 5.298 (t, J=18Hz and 9Hz, 1H), 4.643 (t, J=16 Hz and 8Hz, 1H), 4.558 (d, J=11.5Hz, 1H), 4.125-4.093 (m, 2H), 3.802 (s, 3H), 2.890-2.847 (m, 1H), 2.542-2.497(m, 2H), 2.123-2.106 (m, 1H), 1.806(s, broad, 1H), 1.701~1.663(m, 1H), 1.519(s, broad, 1H),
1.460-1.435(m, 1H), 1.314-1.074(m, 16H). ά
Example 118. Compound of Formula IK wherein A = tBOC. G = OH. L = absent.
Figure imgf000191_0002
118a Alkyne Formation
The 2-(benzyl)-4-methoxyphenylacetylene was prepared via the procedure of Example 117A from 4-iodobenzene and 3-phenyl-propyne. -' ..' .„' ...„ι .. .' ....' ..... ■ .i -
118b Triazole Formation
The 4-(benzyl)-5-(p-methoxyphenyl)tιiazole was prepared via the procedure of Example 3 using 2-(benzyl)-4-methoxyphenylacetylene 118a and sodium azide. >
The title compound was prepared with the title compound of Example 2 and the 4-(2-benzyl)-5-(p-methoxyphenyl)triazole 118a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106. ) [M+Hf = 700.82.
Example 119. Compound of Formula II. wherein A = tBOC. G = OH, L = absent.
Figure imgf000192_0001
5 119a Triazole Formation
The 4-(n-butyl)-5-phenyl triazole was prepared via the procedure of Example 3 using n-butyl-1-phenylacetylene and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 3 4-(n-butyl)-5-phenyl triazole 119a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106. [M+Hf = 649.44.
Example 120. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000192_0002
120a Triazole Formation „ ,.■ .r . '" >»» Λ
The 4,5-(n-propyl)triazole was prepared via the procedure of Example 3 using -octyne and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4,5-(n-propyl)triazole 120a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106
[M+Hf = 601.46.
Example 121. Compound of Formula II, wherein A = tBOC, G = OH, L = absent,
Figure imgf000193_0001
:ih 12[jl.A. |H^^ phenyl triazole 121b was prepared by dissolving Immol of 121a (Triazole 121a was prepared by the method set forth in Example 2 using commercial phenyl acetylene and sodium azide) in 16ml 1:15 MeOH/CHCfe, adding 0.28ml of TEA, and in a dropwise manner adding 0.128ml of bromine. The resulting reaction mixture was stirred for 2 hours. To the reaction mixture was added cold 10% Na2S205 until the the mixture turned colorless. The mixture was extracted with EtOAc, washed with brine and water, dried over Na2Sθ4, and concentrated in vacuo to afford 0.216g of 121b after purification by silica column (97%). [M+H]+: 224.19.
121B. Mesylate replacement. 0.2g of 121c was prepared via the procedure elucidated in Example 3 from purified 121b and the title compound from Example 2. [M+Na]+: 721.00.
121C. Suzuki Coupling. Ethyl ester 121d was prepared by dissolving 0.07mmol (50mg) of 121c in 3ml of DME and adding to this solution 0.21 mmol (35mg) of 4- dimethylaminophenyl boric acid, 137mg of cesium carbonate, and 100mg of KF. To the subsequently degassed reaction mixture was added 5mg of Pd(PPh3)4. The resulting reaction mixture was heated to 90°C and stirred for 12 hours. The reaction mixture then was extracted with EtOAc, washed with brine and water, dried over Na2S04, concentrated in vacuo, and purified by silica column to afford 40mg (78% yield) of 121d.
121D. Ethyl Ester Hydrolysis. 12mg of 121 e was made via the procedure set forth in 106 from 121d after purification by HPLC (30%). [M+H]+: 712.33.
Example 122. Compound of Formula II, wherein A = tBOC, G = OH, L = absent.
Figure imgf000194_0001
H.
122a Triazole Formation p C-lihe Λ was prepared via the procedure of Example 3 using 3-diethylamino-1-phenylpropyne and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-(N,N-diethylaminomethyl)-5-phenyltriazole 122a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106.
[M+Hf = 678.44.
Example 123. Compound of Formula II. wherein A = tBOC, G = OH. L = absent.
Figure imgf000195_0001
-±
123 A. Alkyne Formation
Figure imgf000195_0002
Alkyne 123a was prepared by dissolving 10mmol of phenylpropynoic acid, 11 mmol of BOP, and 22mmol of DIEA in 15ml of DMF and to which was added 11 mmol of diethylamine. The resulting reaction mixture was then stirred at RT for 3 hours. The reaction mixture was extracted with EtOAc (2x50ml), washed with 1M NaHC03 (2x30ml), water (2x30ml), 5% citric acid (2x50ml), and brine (2x30ml). The organic extract was dried over anhydrous Na2S04 and concentrated in vacuo to afford 1.8g (90%) of 123a [M+HJ+: 202.09.
123B. Triazole Formation
The 4-(N,N-diethylaminocarbonyl)-5-phenyltriazole 123b was prepared via the procedure of Example 3 using 123a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-(N,N-diethylaminocarbonyl)-5-phenyltriazole 123b according to the procedure set forth ii Ex wriy©5i!aii. ϊ- ϋer hydrolysis of the ethyl ester via the procedure of Example 106.
[M+H]+: 692.47.
Example 124. Compound of Formula II, wherein A = tBOC, G = OH. L = absent.
Figure imgf000196_0001
124a Alkyne Formation
The 2-(m-chlorophenyl)-4-methoxyphenylacetylene was prepared via the procedure of Example 99 from 3-chloro-bromobenzene and 4-methoxyphenylacetylene.
124b Triazole Formation
The 4-(m-chlorophenyl)-5-(p-methoxyphenyl)triazole was prepared via the procedure of Example 3 using 2-(m-chlorophenyl)-4-methoxyphenylacetylene 124a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-( m-chlorophenyl)-5-(p-methoxyphenyl)triazole 124a according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106.
[M+Hf = 747.37.
Example 125. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
N-. ,N N
W is X . X = 2-phenylethenyl. Y = phenyl. i = 3. m = s = 1. and R3 = R4 = H.
The title compound was prepared with by the Suzuki reaction described in Example 121 from 121c and phenylethenylboronic acid and subsequent hydrolysis by the procedure described in Example 106.
[M+Hf = 695.30. l-----. il / U 3 U "f ' U. ---. "■ if *' v» -- . -- -- -- .
Example 126. Compound of Formula II. wherein A = tBOC. G = OH, L = absent.
W is 5,6-methylbenzotriazole. i = 3. m = s = 1 , and R3 = R4 = H.
The title compound was prepared with the title compound of Example 2 and the 5,6-methylbenzotriazole according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106.
[M+Hf = 595.42.
Example 127. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000197_0001
127a. Alkyne Formation
Figure imgf000197_0002
Alkyne 127a was prepared by dissolving 10mmol of phenylpropynoic acid, 11 mmol of BOP, and 22mmol of DIEA in 15ml of DMF and to which was added 11 mmol of ethylamine. The resulting reaction mizture was then stirred at RT for 3 hours. The reaction mixture was extracted with EtOAc (2x50ml), washed with 1M NaHC03 (2x30ml), water (2x30ml), 5% citric acid (2x50ml), and brine (2x30ml). The organic extract was dried over anhydrous Na2Sθ4 and concentrated in vacuo to afford 1.8g (90%) of 127a. [M+H]+: 177.09.
127b Triazole Formation
The 4-(N-ethylaminocarbonyl)-5-phenyltriazole was prepared via the procedure of Example 3 using 127a and sodium azide.
The title compound was prepared with the title compound of Example 2 and the 4-(N-ethylaminocarbonyl)-5-phenyltriazole 127b according to the procedure set forth in Example 105 and subsequent hydrolysis of the ethyl ester via the procedure of Example 106. ' --,«-. n ,.'. ' ...,. . , „j ---,
Example 128. Compound of Formula ll, wherein A = -(C=OVO-R1, wherein R1 =
Figure imgf000198_0001
and R3 = R4= H.
128a - Amine deprotection.
0.041 mmol of the title compound of Example 105 is dissolved in 4ml of a 4M solution of HCI in dioxane and stirred for 1 hour. The reaction residue 128a is concentrated in vacuo.
128b - Chloroformate Reagent
The chloroformate reagent 128b is prepared by dissolving 0.045mmol of cyclopentanol in THF (3ml) and adding 0.09mmol of phosgene in toluene (20%). The resulting reaction mixture is stirred at room temperature for 2 hours and the solvent is removed in vacuo. To the residue is added DCM and subsequently concentrated to dryness twice in vacuo yielding chloroformate reagent 128b.
128c - Carbamate formation
The title carbamate is prepared by dissolving residue 128a in 1ml of THF, adding 0.045mmol of TEA, and cooling the resulting reaction mixture to 0°C. To this 0°C reaction mixture is added chloroformate reagent 128b in 3ml of THF. The resulting reaction mixture is reacted for 2 hours at 0°C, extracted with EtOAc, washed by 1M sodium bicarbonate, water and brine, dried over MgSθ4, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 106.
Examble 11 9 1) S C^lnlB ui'dl'of^irmula K wherein A = -(C=OVO-R1, wherein R1 =
Figure imgf000199_0001
and R3 = R4 = H.
The title compound is prepared by the method described in Example 33 with the title compound of Example 105 and cyclobutanol, followed by ethyl ester hydrolysis by the procedure set forth in Example 106.
Example 130. Compound of Formula IK wherein A = -(C=0)-Q-R1, wherein R =
Figure imgf000199_0002
and R3 = R4= H.
The title compound is prepared by the method in Example 33 with the title compound of Example 105 and cyclohexanol, followed by ethyl ester hydrolysis by the procedure set forth in Example 106.
Example 131. Compound of Formula I. wherein A = -(C=0)-0-R1. wherein R1 =
Figure imgf000199_0003
= R = H.
The title compound is prepared by the method described in Example 33 with the title compound of Example 105 and (R)-3-hydroxytetrahydrofuran, followed by ethyl ester hydrolysis by the procedure set forth in Example 106.
Exarr-p- '32- ' U S TOnpb nd 'o'f Fo mula II, wherein A = ~(C=OVO-R1. wherein R1 =
Figure imgf000200_0001
= R4= H.
The title compound is prepared by the method in Example 33 with the title compound of Example 105 and (S)-3-hydroxytetrahydrofuran, followed by ethyl ester hydrolysis by the procedure set forth in Example 106.
Example 133. Compound of Formula IK wherein A = -(C=Q)-0-R1. wherein R1 =
Figure imgf000200_0002
and R3 = R4 = H.
The title compound is prepared by the method in Example 33 with the title
compound of Example 105 and OH, followed by ethyl ester hydrolysis by the procedure set forth in Example 106.
Example 134. Compound of Formula II, wherein A = -(C=Q -R1, wherein R1 =
Figure imgf000200_0003
and R3 = R4= H.
The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 105 in 4ml of a 4M solution of HCI in dioxane and stirring the reaction mixture for 1 hour. The reaction residue is concentrated in vacuo. To this residue, 4ml of THF and 0.045mmol of TEA is added, the mixture is cooled to 0°C, to which is added 0.045mmol of the cyclopental acid chloride. The resulting reaction mixture is stirred for 2 hours at 0°C. The reaction mixture is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSQj and concentrated to dryness in vaci/p-F,;:
Figure imgf000201_0001
by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 106.
Example.135. Compound of Formula II. wherein A = -(C=Q)-NH-R1. wherein R1
Figure imgf000201_0002
and R3 = R4 = H.
The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 105 in 4ml of a 4M solution of HCI in dioxane and stim'ng for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4ml THF, and cooled to 0°C. To the 0°C solution is added 0.045mmol of cyclopentyl isocyanate and the resulting reaction mixture is stirred at RT for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCI, water and brine, dried over MgS04, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 106.
Example 136. Compound of Formula II. wherein A = -(C=SV-NH-R1. wherein R1
Figure imgf000201_0003
and R3 = R4 = H.
The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 105 in 4ml of a 4M solution of HCI in dioxane and stiπing for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4ml THF, and cooled to 0°C. To the 0°C solution is added 0.045mmol of cyclopentyl isothiocyanate and the resulting reaction mixture is stirred at RT for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCI, water and brine, dried over MgSθ4, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 106. Exarr.p'li-I "3?:"' U E* @o.r.pόιMdllif¥olrmula IK wherein A = -SrøyR1, wherein R1 =
Figure imgf000202_0001
and R3 = R4= H.
The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 105 in 4ml of a 4M solution of HCI in dioxane and stirring for 1 hour. To the resulting concentrated reaction residue, which has been dissolved in 4ml THF, is added 0.045mmol of TEA, and cooled to 0°C. To the 0°C solution is added 0.045mmol of cyclopentyl solfonyl chloride and the resulting reaction mixture is stirred at 0°C for 2 hours. The solution is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgS04, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 106.
Example 138. Compound of Formula II. wherein A = -JC=Q)-0-R1. R1 =
Figure imgf000202_0002
m = s = 1. and R3 = R4 = H.
Figure imgf000202_0003
The title compound is prepared by adding to a solution of the title compound of Example 128 and phenethyl alcohol 138a in 0.5 ml DCM, is added 1.2 eq. PyBrOP, 4eq. DIEA, and catalytic amount of DMAP at 0°C. The resulting reaction mixture is stirred for 1 hour at 0°C and then warmed to RT over a period of 4-12 hours. The reactl§ιS: rHixtulέ'% i rifrei^by!l4iϊϊcSi!igel flash chromatography using different ratios of hexanesiEtOAc as elution phase (9:1-»5:1- 3:1->1:1) to afford the title compound isolated phenethyl ester 138b. Other esters can be made using the same procedures.
Example 139. Compound of Formula II, wherein A = -(C=OV-0-R1, R1 =
Figure imgf000203_0001
m = s = 1. and R3 = R4 = H.
Figure imgf000203_0002
128 139b
The title compound is prepared by adding to a solution of the title compound of
Example 128 and phenethylamine 139a (0.05 ml) in 0.5 ml DMF, EDC (1.2 eq.) and
DIEA (4eq.) at 0°C. The resulting reaction mixture is stirred at 1 hour. Subsequently, the reaction is warmed to RT over a period of 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexanes:EtOAc as elution phase (9:1-»5:1- 3:1- 1:1) to afford title compound phenethyl amide 139b.
Other amides can be made using the same procedures.
Example 140. Compound of Formula II. wherein A = -(C=0)-0-R1. R1 =
Figure imgf000203_0003
i = 3. m = s = 1. and R3 = R4 = H.
Figure imgf000204_0001
The title compound is prepared by adding to a solution of the title compound of Example 128 and α-toluenesulfonamide 140a (10mg) in 0.5 ml DCM, is added 1.2 eq. PyBrOP, 4eq. DIEA, and catalytic amount of DMAP at 0°C. The resulting reaction mixture is stirred for 1 hour and then allowed to warm to RT over a period of 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexanesiEtOAc as elution phase (9:1-»5:1— >3:1— 1:1) to afford the title compound sulfonamide 140b.
Other sulfonamides can be made using the same procedure.
Example 141. Compound of Formula II. wherein A = -(C=Q)-0-R1, R1 =
Figure imgf000204_0002
= s = L and and R3 = R4= H.
Figure imgf000204_0003
The title compound is prepared by adding to a solution of the title compound of Example 128 in 0.5 ml THF, is added α-hydroxy-α-methyl-propionitrile (0.1 ml) and catalytic amount TFA at 0°C. The resulting reaction mixture is warmed from 0°C to RT over a period of 4-12 h followed by hydrolysis with concentrated hydrochloric acid in dioxane. Th l- €a ioήliέϊ i H^xfr ϊt d rø- tOAc, and washed with water and brine to yield α- hydroxy compound 141a in its crude form. The crude compound 46b undergoes a Dess-Martin oxidation in THF (0.5 ml), providing the α-carbonyl compound 46b in crude form. The crude 141b is purified by silica gel flash chromatography using different ratios of hexanesiEtOAc as elution phase (9:1— >5:1— >3:1— >1:1) to afford the title compound isolated keto acid 141c.
Example 142. Compound of Formula II. wherein A = -(C=Q)-0-R1. R1 =
Figure imgf000205_0001
i = 3, m = s = 1. and and R3 = R4 = H.
The title compound is prepared with the title compound keto acid of Example
141 and phenethanol according to the procedure set forth in Example 138.
Example 143. Compound of Formula II, wherein A = -(C=Q)-0-Ri, R1 =
phenyl. i = 3, m = s = 1, and and R3 = R4 = H.
The title compound is prepared with the title compound keto acid of Example 141 and phenethyl amine according to the procedure set forth in Example 139.
Example 144. Compound of Formula IK wherein A = -(C=Q)-0-R1. R1 =
Figure imgf000205_0003
phenyl. i = 3. m = s = 1. and and R3 = R4= H.
The title compound is prepared with the title compound keto acid of Example 141 and α-toluenesulfonamide according to the procedure set forth in Example 140. Exa;rrι>Jei14&J β O oiτfp uι i>Pi Formula I. wherein A = tBOC. G = OH. L =
Figure imgf000206_0001
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in Example 88C and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106.
Example 146. Compound of Formula II. wherein A = tBOC. G = OH. L =
Figure imgf000206_0002
R4= H.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in Example 89G and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106.
Example 147. Compound of Formula II. wherein A = tBOC. G = OH. L = -Q-. W is
Figure imgf000206_0003
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in Example 90D and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106.
Figure imgf000207_0001
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in Example 91 E and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106.
Example 149. Compound of Formula IK wherein A = tBOC. G = OH. L = -S(OV-.
Figure imgf000207_0002
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in Example 92B and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106.
Example 150. Compound of Formula IK wherein A = tBOC. G = OH. L = -S(O)?-.
Figure imgf000207_0003
The title compound is prepared with the modified, cyclic peptide precursor mesylate formed in Example 93B and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106.
Example 151. Compound of Formula II. wherein A = tBOC. G = OH. L =
Figure imgf000207_0004
Figure imgf000208_0001
151a 151b
151A. Synthesis of (SVN-Boc-2-amino-3-methyl-3(1-mercapto-4- butenvDbutanoic acid (151 b)
L-Penicillamine 151a is dissolved in DMF/DMSO (5:1), subsequently, 4- bromopentene and CsOH»H20 are added to the mixture and stim'ng is continued for an additional 12 hours. The DMF is subsequently removed in vacuo, the remaining mixture is diluted with 0.5 N HCI (at 0°C) to adjust the pH to -4-5 and then extracted with 2 portions of EtOAc. The organic phase is washed with brine (2x), dried over MgSθ4 and evaporated to dryness to afford the crude carboxylic acid 151a.
151B. Synthesis of modified cyclic peptide precursor mesylate
The modified cyclic peptide precursor mesylate is prepared using the synthetic route detailed in Example 1 using the modified amino acid 151a in place of Boc-L-2-amino-8- nonenoic acid 1a followed by conversion to the corresponding mesylate via the method described in Example 2.
The title compound is prepared with the modified cyclic peptide precursor mesylate foπmed in 151B and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method, set forth in Example 106.
Example 152. Compound of Formula II. wherein A = tBOC. G = OH. L = CF?CH?.
Figure imgf000208_0002
§ h) itI£BΦJft' ^^ with the modified cyclic peptide precursor mesylate formed in Example 95C and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106.
Example 153. Compound of Formula II, wherein A = tBOC, G = OH, L =
Figure imgf000209_0001
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in Example 96C and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106.
Example 154. Compound of Formula 111, wherein A = tBOC. G = OH, L = absent,
Figure imgf000209_0002
154A. The saturated cyclic peptide precursor mesylate is prepared by catalytic reduction of the mesylate cyclic peptide precursor 2 with Pd/C in MeOH in the presence of H2.
The title compound is prepared with the saturated cyclic peptide precursor mesylate formed in 154A and 4,5 -diphenyltriazole by the replacement method elucidated in Example 105 followed by hydrolysis of the ethyl ester via the method set forth in Example 106. Exapqjle"f5,S.-i J s liClόirtigi ϋl-IIof' e-rmula II. wherein A = tBOC. G = OH, L = absent.
Figure imgf000210_0001
155A. Substituted benzotriazole formation
Figure imgf000210_0002
155a 155b
The bromo-substituted benzotriazole 155b of the present -Example is prepared by combining 2.15g (10mmol) of 5-bromo-3, 4-dimethylbenzene-1 ,2-diamine, 1.15ml (20mmol) of glacial acetic acid, and 10ml of water and heating the resulting mixture to obtain a clear solution. The clear solution is then cooled to 5°C, a cold solution of 0.83g (12mmol) of sodium nitrite in 5ml of water is added, and the reaction mixture is heated to 70~80°C for 2 hours. The reaction mixture is then extracted with EtOAc, washed by brine and water, dried over Na2S04, and concentrated in vacuo. The crude product is purified by silica column.
155B. Replacement
Figure imgf000210_0003
The ethyl ester 155c is prepared by the replacement method described in Example 105 with the title compound of Example 2 and bromo-substituted benzotriazole 155b. jjFhe t»ti§J®^ prepared with ethyl ester 155c by the hydrolysis procedure set forth in Example 106.
Example 156. Compound of Formula II. wherein A = tBOC, G = OH, L = absent.
Figure imgf000211_0001
, j = 3. m = s = 1. and R3 = R4 = H.
156A. Suzuki Reaction
Figure imgf000211_0002
Compound 156a of the present Example is prepared via a Suzuki coupling reaction with 155c and 3-thienyl boronic acid as described in Example 26C.
156B. Hydrolysis
The title compound is prepared with ethyl ester 156a by the hydrolysis procedure set forth in Example 106.
Example 157. Compound of Formula II. wherein A = tBOC. G = OH. L = absent.
Figure imgf000211_0003
157a. Bicyclic Compound Formation p CTfle ',' bi p tr-;Mic 'ι ^δ Hd>liloifil the present invention is prepared with 2,3-di aminopyridine by the procedure set forth in Example 157A.
The title compound is prepared with the bicyclic compound prepared in 157a and the title compound of Example 2 by the replacement method described in Example 105, followed by hydrolysis of the ethyl ester via the procedure set forth in Example 106.
Example 158. Compound of Formula II. wherein A = tBOC. G = OEt. L = absent.
X = Y = bromo. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
To a mixture of macrocyclic compound 1 (185 mg, 0.38 mmol), 4,5-dibromo-2H- pyridazin-3-one (95 mg, 0.38 mmol) and triphenylphosphine (197 mg, 0.75 mmol) in THF (5 mL) is added DIAD (148 μL, 0.75 mmol) dropwise at 0°C. After stirring at 0°C for 15 min., the solution is warmed to room temperature and is further stirred for 16 hours. The mixture is then concentrated in vacuo and the residue is purified by column chromatography eluting with 40% ethyl acetate-hexane to give 235 mg (86%) of the title compound.
1H-NMR (500 MHz, CDCI3) δ (ppm): 7.8 (s, 1H), 7.1 (brs, 1H), 5.5 (m, 2H), 5.2 (m, 2H), 5.0 (m, 1H), 4.4 (brt, 1H), 4.0-4.2 (m, 4H), 2.9 (m, 1H), 2.6 (m, 1H), 1.8-2.3 (m, 5H), 1.4 (s, 9H), 1.2 (t, 3H). [M+Hf = 730.6.
Example 159. Compound of Formula II. wherein A = tBOC. G = OEt, L = absent.
X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
A mixture of the title compound of Example 162 (40 mg, 0.055 mmol), 3- thiophene boronic acid (35mg, 0.28 mmol), cesium carbonate (71 mg, 0.22 mmol), potassium fluoride monohydrate (41 mg, 0.44 mmol) is placed in a round bottom flask and is flushed twice with nitrogen. To this mixture is added DME and the resulting solution is flushed again with nitrogen before palladium tetrakis(triphenylphopshine) (7 mg, 10 mol%) is added. After flushing two more times with nitrogen, the mixture is heated to reflux for 20 hours. The mixture is then cooled and then diluted with water and extracted three times with EtOAc. The combined EtOAc layers are washed once with
Figure imgf000213_0001
in vacuo. The residue is purified by column chromatography eluting with 20-40% EtOAc-hexane to give the title compound as a clear film (24 mg, 60%).
1H-NMR (500 MHz, CDCI3) δ (ppm): 7.9 (s, 1H), 7.6 (s, 1H), 7.3 (s, 1H), 7.3 (m, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 5.7 (m, 1H), 5.5 (m, 1H), 5.4 (brd, 1H), 5.2 (t, 1H), 5.0 (m, 1H), 4.6 (brt, 1H), 4.0-4.2 (m, 4H), 2.9 (m, 1H), 2.6 (m, 1H), 2.0-2.3 (m, 5H), 1.4 (s, 9H), 1.2 (t, 3H). [M+Naf = 758.63.
Example 160. Compound of Formula IK wherein A = tBOC. G = OH, L = absent, X
= Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
To a solution of the title compound in Example 2 (24 mg, 0.033 mmol) in THF/MeOH/H20 (2/1/0.5 mL) is added lithium hydroxide (14 mg, 0.33 mmol). After stirring for 16 hours at room temperature, the mixture is acidified to pH 4 with citric acid and extracted three times with EtOAc. The combined organic extracts are washed once with brine, dried (MgS04), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 5-10% methanol-chloroform to give the title compound (13 mg, 56%).
[M+Hf = 708.3.
Example 161. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= Y = phenyl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared by a double Suzuki coupling with phenylboronic acid and the title compound of Example .158 according to the procedure set forth in Example 159, followed by hydrolysis of the ethyl ester via the method described in Example 160.
[M+Hf = 696.40 Examj lp}| »16j . y igBQφpoup Φf. o-iinula IK wherein A = tBOC. G =T)H. L = absent. X = Y = 4-(N.N-dimethylamino)phenyl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared by a double Suzuki coupling with 4-(N,N- dimethylamino)phenyl boronic acid and the title compound of Example 158 according to the procedure set forth in Example 159, followed by hydrolysis of the ethyl ester via the method described in Example 160. . [M+Hf = 782.30
Example 163. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= Y = -4-(trifluoromethoxy)phenyl. Z = hydrogen, i = 3. m = s = 1, and R3 = R4 = hydrogen.
The title compound is prepared by a double Suzuki coupling with 4- (trifluoromethoxy)phenyl boronic acid and the title compound of Example 158 according to the procedure set forth in Example 159, followed by hydrolysis of the ethyl ester via the method described in Example 160.
[M+Hf = 864.09
Example 164. Compound of Formula II. wherein A = tBOC, G = OH. L = absent. X
= Y = 4-(methanesulfonyl)phenyl, Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared by a double Suzuki coupling with 4- (methanesulfonyl)phenyl boronic acid and the title compound of Example 158 according to the procedure set forth in Example 159, followed by hydrolysis of the ethyl ester via the method described in Example 160.
Example 165. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= Y = 4-(cvano)phenyl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen. -, „•' 3 ' '.'• -- ' '-" .. . <
The title compound is prepared by a double Suzuki coupling using 4-cyanophenyl boronic acid and the title compound of Example 158 according to the procedure set forth in Example 159, followed by hydrolysis of the ethyl ester via the method described in Example 160.
[M+Hf = 746.14
Example 166. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= Y = pyrid-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared by a double Suzuki coupling using 3-pyridyl boronic acid and the title compound of Example 158 according to the procedure set forth in Example 159, followed by hydrolysis of the ethyl ester via the method described in Example 160.
[M+Hf = 698.3.
Example 167. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= Y = 4-(morpholin-4-yl-methanonyl)phenyl. Z = hydrogen, i = 3, m = s = 1 , and R3 = R4 = hydrogen.
The title compound is prepared by a double Suzuki coupling using 4- carboxyphenyl boronic acid and the title compound of Example 158 according to the procedure set forth in Example 159, followed by amide formation with morpholine, under standard amide bond formation conditions, e.g. PyBrOP, DIEA, and DMAP in DMF. The ethyl ester of the resulting compound is then hydrolyzed via the hydrolysis procedure of Example 160.
Example 168. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= bromo, Y = methoxy, Z = hydrogen, i = 3. m = s = 1 , and R3 = R4 = hydrogen. gftgg titie I BP&Hb ' l-l -pr }ai!rel from the title compound in Example 158 via hydrolysis of the ethyl ester according to the procedure described in Example 160, however addition of methoxy to the 5 position is observed in addition to hydrolysis of the ethyl ester.
[M+Hf = 652.2, 654.2.
Example 169. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X and Y taken together = phenyl. Z = 4-methoxyphenyl. i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared according to the Mitsunobu conditions set forth in Scheme 20 with commercially available 4-(4-methoxy-phenyl)-2H-phthalazin-1-one, and subsequent hydrolysis of the ethyl ester via the procedure of Example 160.
[M+Hf = 700.1.
Example 170. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X and Y taken together = phenyl. Z = 4-chlorophenyl. i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared according to the Mitsunobu conditions set forth in Scheme 20 with commercially available 4-(4-chloro-phenyl)-2H-phthalazin-1-one, and subsequent hydrolysis of the ethyl ester via the procedure of Example 160.
[M+Hf = 704.2.
Example 171. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= 4-fluorophenyl. Y = hydrogen. Z = phenyl. i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared according to the Mitsunobu conditions set forth in Scheme 20 with commercially available 4-(4-fluoro-phenyl)-6-phenyl-2H-pyridazin-3- one, and subsequent hydrolysis of the ethyl ester via the procedure of Example 160.
[M+Hf = 704.2. -.
Example 172. Compound of Formula II, wherein A = tBOC. G = OH, L = absent. X
= hydrogen, Y = 1-piperidyl, Z = phenyl, i = 3, m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared according to the Mitsunobu conditions set forth in Scheme 20 with commercially available 6-phenyl-5-piperidin-1-yl-2H-pyridazin-3-one, and subsequent hydrolysis of the ethyl ester via the procedure of Example 160.
[M+Hf = 702.3.
Example 173. Compound of Formula II. wherein A = tBOC. G = OEt. L = absent.
X = hydrogen, Y = bromo, Z = phenyl, i = 3, m = s = 1, and R3 = R4 = hydrogen.
The title compound is prepared according to the Mitsunobu conditions set forth in Scheme 20 with commercially available 5-Bromo-6-phenyl-2H-pyridazin-3-one. [M+Hf = 726.3, 728.3.
Example 174. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= hydrogen. Y = thiophen-3-yl, Z = phenyl, i = 3, m = s = 1 , and R3 = R4 = hydrogen.
The title compound is prepared with the title compound of Example 173 and thiophen-3-yl boronic acid according to the Suzuki coupling conditions described in Example 159, followed by the hydrolysis of the ethyl ester via the method described in Example 160.
[M+Hf = 730.3
Example 175. Compound of Formula II. wherein A = tBOC. G = OEt. L = absent.
X = bromo. Y = 1-pyrrolidyl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
► A mixture of the title compound in -Example 158 (45 mg, 0.062 mmol), pyrrolidine
(21 mL, 0.25 mmol), and potassium carbonate (34 mg, 0.25 mmol) in 2 mL of acet©Yiitπ ,lsl.h-β hours. After cooling to room temperature, the mixture is filtered through a sinter glass funnel and the filtrate is concentrated in vacuo. The residue is re-dissolved in ethyl acetate and then washed once with saturated sodium carbonate, once with brine, dried (MgSO4), filtered, and concentrated under vacuum to give a yellow residue which is chromatographed over silica gel eluting with 3% methanol-chloroform to give 37 mg (83%) of the title compound. [M+Hf = 719.2, 721.2.
Example 176. Compound of Formula II, wherein A = tBOC. G = OH. L = absent. X
= thiophen-3-yl. Y = 1-pyrrolidyl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared with the title compound in Example 175 and thiephen-3-yl boronic acid using the Suzuki conditions described in Example 159, followed by hydrolysis of the ethyl ester according to the method set forth in Example 160.
[M+Hf = 694.3.
Example 177. Compound of Formula II, wherein A = tBOC, G = OEt. L = absent,
X = bromo. Y = azido. Z = hydrogen, i = 3. m = s = 1 , and R3 = R4 = hydrogen.
A mixture of the title compound in Example 158 (45 mg, 0.062 mmol), sodium azide (16mg, 0.25 mmol), and potassium carbonate (34 mg, 0.25 mmol) in 2 mL of acetonitrile is heated to reflux for 3 hours. After cooling to room temperature, the mixture is filtered through a sinter glass funnel and the filtrate is concentrated in vacuo. The residue is re-dissolved in ethyl acetate and then washed once with saturated sodium carbonate, once with brine, dried (MgSO-j), filtered, and concentrated under vacuum to give a yellow residue which is chromatographed over silica gel eluting with 3% methanol-chloroform to give 37 mg (83%) of the title compound.
Example 178. Compound of Formula II. wherein A = tBOC. G = OEt. L = absent.
X = thiophen-3-yl. Y = azido. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen. " l„ - C li ' . i' --
The title compound is prepared with the title compound in Example 177 and thiophen-3-yl boronic acid using the Suzuki conditions described in Example 159.
Example 179. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= thiophen-3-yl, Y = azido, Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared by hydrolysis of the ethyl ester of the title compound of Example 178 via the hydrolysis procedure of Example 160.
Example 180. Compound of Formula II. wherein A = tBOC, G = OH. L = absent, X
= thiophen-3-yl, Y = tetrazol-2-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
To a solution of the title compound of Example 178 (2.63 mmol) in toluene (8 ml) is added KCN (10.53 mmol) and Et3N»HCI (10.53 mmol). The mixture is heated at 115 °C for 18 hrs, diluted with DCM, washed with 5% citric acid (aq), dried over anhydrous Na2S04, and concentrated in vacuo to afford the ethyl ester of the title compound in crude form. Hydrolysis of the ethyl ester via the method described in Example 160 yields the title compound.
Example 181. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X
= Y = mercapto-2-pryrimidine. Z = hydrogen, i = 3, m = s = 1 , and R3 = R4 = hydrogen.
Figure imgf000219_0001
A mixture of the title compound in Example 158 (45 mg, 0.062 mmol), pyrimidine-2-thiol (0.25 mmol), and potassium carbonate (34 mg, 0.25 mmol) in 2 mL of acetori-rile, .^ hours. After cooling to room temperature, the mixture is filtered through a sinter glass funnel and the filtrate is concentrated in vacuo. The residue is re-dissolved in ethyl acetate arid then washed once with saturated sodium carbonate, once with brine, dried (MgSO4), filtered, and concentrated under vacuum to give a yellow residue which is chromatographed over silica gel eluting with 3% methanol-chloroform to afford 181b in a 19% yield. The ethyl ester of compound 181b is then hydrolyzed via the method described in Example 160 to give the title compound.
[M+Hf = 764.3.
Example 182. Compound of Formula II, wherein A = tBOC. G = OH, L = absent. X
= bromo, Y = mercapto-2-pryrimidine, Z = hydrogen, i = 3, m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared by hydrolysis of the ethyl ester of compound 181a, formed in Example 181, via the method set forth in Example 160.
[M+Hf = 732.2, 734.2.
Example 183. Compound of Formula IK wherein A = tBOC. G = OH, L = absent. X
= thiophen-3-yl. Y = mercapto-2-pryrimidine. Z = hydrogen, i = 3, m = s = 1 , and R3 = R4 = hydrogen.
The title compound is prepared with compound 181a from Example 181 and ; thiophen-3-yl boronic acid according to the Suzuki coupling conditions set forth in Example 159, followed by hydrolysis of the ethyl ester via the method described in Example 160.
Example 184. Compound of Formula II. wherein A = tBOC. G = OEt. L = absent.
) X = Y = thiazol-2-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
To a degassed solution of the title compound of Example 158 (1 mmol) and thiazol-2-yl stannane (2 mmol) is added Pd(PPh3)-» (10 mol%). The mixture is degassed
Figure imgf000221_0001
is iheated to 100 °C for 3 hour. The cooled mixture is concentrated under vacuum and the residue is purified by column chromatography eluting with 30% EtOAc/Hexane followed by the hydrolysis of the ethyl ester via the method of Example 160 to give the title compound. [M+Hf = 710.3.
Example 185. Compound of Formula II, wherein A = tBOC. G = OH. L = absent. X
= Y = imidazol-1-yl. Z = hydrogen, i = 3. m = s = 1 , and R3 = R4 = hydrogen.
The title compound is prepared by adding to a dry mixture of the title compound from Example 158 (0.068 mmol), imidazole (2 eq.), Cs2C03 (3 eq.), Xantphos (30 mol %), and Pd(OAc)2 under nitrogen dioxane. The reaction mixture is then degassed and stiπred at 75°C for 18 hours. Upon completion of the reaction, monitored via TLC, the reaction mixture is diluted with DCM, filtered, and concentrated in vacuo. The reaction mixture is then purified via silica column chromatography with 5% MeOH/CHCI3 to afford the ethyl ester of the title compound. The ethyl ester is then hydrolyzed by the conditions set forth in Example 160 to afford the title compound.
Example 186. Compound of Formula II, wherein A = tBOC. G = OH, L = absent. X
= 2-(cyclopropylamino)-thiazol-4-yl, Y = 4-methoxyphenyl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
Formation of 4-(2-Cyclopropylamino-thiazol-4-yl)-5-(4-methoxy-phenyl)-2H- pyridazin-3-one (186h)
Figure imgf000222_0001
186A. A mixture of commercially available 4,5-dichloropyridazin3(2H)-one (18 mmol), benzyl bromide (19 mmol), potassium carbonate (45 mmol), tetrabutylammonium bromide (1 mmol) and acetonitrile (45 mL) is stirred and heated under reflux for 1h. After cooling, the solvent is evaporated under reduced pressure. The residue is purified by filtration on a small silica gel column eluting with 10% EtOAc Hexane to give compound 186a as a white powder (81%). [M+Hf = 256.3.
186B. To a magnetically stirred solution of 186a (4.5 mmol) in dry dioxane (20 mL) is added 1.0 mL of 21 wt% solution of sodium methoxide at room temperature. After 1 hour, the mixture is poured into water/ethyl acetate and the organic layer is dried over MgS04 and concentrated to an oil. The oil residue is purified by column chromatography eluting with 10% EtOAc/Hex to give 85% of 186b. [M+Hf = 251.7.
Alternate substitution of pyridazinone 186b can be achieved via this step using MeOH rather than dioxane as a solvent, wherein the methoxy occupies the 5 position on the pyridazinone ring and the chloro resides at the 4 position. i fC-;
Figure imgf000223_0001
! mmol) is dissolved in DME. To this mixture is added Pd(PPh3)4 (10 mol%) and the mixture is stirred at room temperature for 10 min before 4 methoxybenzeneboronic acid (2 mmol) and aqueous 1 mL of Na2Cθ3 (10 wt%) are added. Subsequently, the reaction mixture is heated to reflux for 18 hours. The cooled reaction mixture is diluted with water and extracted 3 times with ethyl acetate. The combined organic layers are dried (MgS04), filtered and concentrated under vacuum. The residue is purified by column chromatography on silica gel eluting with 15% EtOAc/Hexane to give compound 186c. [M+Hf = 323.3.
186D. To a solution of 186c (3 mmol) in DME is added 2N KOH and the resulting mixture is heated to reflux for 1 hour. The cooled mixture is diluted with water and acidified with solid citric acid to pH - 5 and extracted 3 times with CH2CI2. The organic layers are washed once with brine, dried (MgS04), filtered and concentrated under vacuum to give compound 186d. [M+Hf = 309.3.
186E. To a cooled solution of compound 186d (2 mmol), triethylamine (0.4 mL) in dichloromethane (10 mL) (ice-acetone bath) is added trifluoromethanesulfonic anhydride (0.4 mL) dropwise. The resulting solution is stirred for 30 min at -5°C. The reaction mixture is then poured into dilute HCI (0.5 M) and extracted with CH2CI2. The combined organic layers are washed with a 1% NaHC03, brine and dried (MgS04), filtered and concentrated under vacuum to give a brown oil. Compound 186e is used immediately without further purification. [M+Hf = 441.4.
186F. Commercially available 2,4-dibrømothiazole (2 mmol) is dissolved in cyclopropylamine (3 mL) and the reaction mixture is heated to 50°C for 8 hour. The cooled mixture is then poured into water and extracted 2 times with ether. After drying the combined organic fractions (MgS04), evaporation of solvents, and purification by flash column chromatography (silica gel, 15% EtOAc Hexane) furnished 2- cyclopropylamine-4-bromothiazole which is further converted to the corresponding stannane 186f. A solution of 2-cyclopropylamine-4-bromothiazole in degassed DME is treated with hexamethylditin and Pd(PPfi3)4 and heated at 80°C for 18 hour. The cooled mi tiμip -js _,, f πcg tipj-edj icfej vacuum and the residue is purified by column chromatography eluting with 20% EtOAc/Hexane/2%Et3N to give Stannane 186f. [M+Hf = 304.1.
186G. To a degassed solution of compound 186e (1 mmol) and stannane 186f (2 mmol) is added Pd(PPh3)4 (10 mol%). The mixture is degassed two additional times with nitrogen and subsequently heated to 100 °C for 3 hour. The cooled mixture is concentrated under vacuum and the residue is purified by column chromatography eluting with 30% EtOAc/Hexane to give compound 186g. [M+Hf = 431.6.
186H. A solution of compound 186g and 10% Pd/C (wet) in MeOH is subjected to a hydrogen balloon for 2 hours. The mixture is filtered through a pad of celite and the filtrate is concentrated under vacuum to give compound 186h. [M+Hf = 341.4.
The title compound is prepared from pyridazinone 186h and the cyclic peptide precursor 1 of Example 1 via the Mitsunobu conditions set forth in Example 158, followed by the hydrolysis of the ethyl ester via the hydrolysis conditions described in Example 159.
Example 187. Compound of Formula II. wherein A = tBOC. G = OH. L = absent. X and Y taken together = 6-methoxy-isoguinolin-(3,4)-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
Figure imgf000224_0001
187 A. Pyridazinone 186b (2 mmol) is dissolved in DME. To this mixture is added Pd(PPh3)4 and the mixture is stirred at room temperature for 10 min before 2- forηfy^-l merø and aqueous Na2C03 (10 wt%) are added.
Subsequently, the reaction mixture is heated to reflux for 18 hours. The cooled reaction mixture is diluted with water and extracted 3 times with ethyl acetate. The combined organic layers are dried (MgS04), filtered and concentrated under vacuum. The residue is purified by column chromatography on silica gel eluting with 20% EtOAc/Hexane to give compound 187a. [M+Hf = 351.4.
187B. A mixture of pyridazinone 187a (1 mmol), MeOH (20 mL) and NH4OH (10 mL, 28-30 wt%) is heated at 60°C for 30 min. After cooling, the precipitate, compound 187b, is filtered and rinsed with MeOH (15 mL). [M+Hf = 317.4.
187C. A mixture of pyridazinoisoquinolinone 187b (0.5 mmol), AICI3 and toluene is stirred and heated at 70°C for 1 hour. After cooling, water is added and the mixture is filtered and rinsed with water. The residue is purified by column chromatography on silica gel eluting with 50% EtOAc/Hex to give compound 187c. [M+Hf = 227.3.
The title compound is prepared from pyridazinoisoquinolinone 187c and the cyclic peptide precursor 1 of Example 1 via the Mitsunobu conditions set forth in Example 162, followed by the hydrolysis of the ethyl ester via the hydrolysis conditions described in Example 159.
Example 188. Compound of Formula II. wherein A = -(C=OV-Q-R1. wherein R1 = cyclopentyl. G = OH, L = absent, X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
188a- Amine deprotection.
0.041 mmol of the title compound of Example 159 is dissolved in 4ml of a 4M solution of HCI in dioxane and stirred for 1 hour. The reaction residue 188a is concentrated in vacuo.
188b - Chloroformate Reagent The <j5h|prf fpπj^^ by dissolving 0.045mmόl of cyclopentanol in THF (3ml) and adding 0.09mmol of phosgene in toluene (20%). The resulting reaction mixture is stirred at room temperature for 2 hours and the solvent is removed in vacuo. To the residue is added DCM and subsequently concentrated to dryness twice in vacuo yielding chloroformate reagent 188b.
188c - Carbamate formation
The title carbamate is prepared by dissolving residue 188a in 1ml of THF, adding 0.045mmol of TEA, and cooling the resulting reaction mixture to 0°C. To this 0°C reaction mixture is added chloroformate reagent 188b in 3ml of THF. The resulting reaction mixture is reacted for 2 hours at 0°C, extracted with EtOAc, washed by 1 M sodium bicarbonate, water and brine, dried over MgS04, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 160.
Example 189. Compound of Formula II, wherein A = -(C=0 -0-R1, wherein R1 = cyclobutyl, G = OH, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 , and R3 = R4 = hydrogen.
The title compound is prepared by the method described in Example 188 with the title compound of Example 159 and cyclobutanol.
Example 190. Compound of Formula II, wherein A = -(C=Q)-0-R1, wherein R1 = cyclohexyl. G = OH. L = absent. X = Y = thiθphen-3-yl, Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared by the method described in Example 188 with the title compound of Example 159 and cyclohexanol. Example 191. Compound of Formula II. wherein A = -JC=0)-0-R1. wherein R1 =
Figure imgf000226_0001
. G = OH. L = absent. X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1, and R3 = R4= hydrogen.
Figure imgf000227_0001
the method described in Example 188 with the title compound of Example 159 and (R)-3-hydroxytetrahydrofuran.
Example 192. Compound of Formula II. wherein A = -(C=Q)-0-R1. wherein R1 =
Figure imgf000227_0002
= R4 = hydrogen.
The title compound is prepared by the method described in Example 188 with the title compound of Example 159 and (S)-3-hydroxytetrahydrofuran.
Example 193. Compound of Formula II. wherein A = -JC=0)-0-R1. wherein R1 =
Figure imgf000227_0003
and R3 = R4 = hydrogen.
The title compound is prepared by the method described in Example 188 with the
title compound of Example 159 and OH.
Example 194. Compound of Formula II. wherein A = -(C=Q)-R1. wherein R1 = cyclopentyl, G = OH. L = absent. X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared with the title compound from Example 159 in 4ml of a 4M solution of HCI in dioxane and stirring the reaction mixture for 1 hour. The reaction residue is concentrated in vacuo. To this residue, 4ml of THF and 0.045mmol of TEA is added, the mixture is cooled to 0°C, to which is added 0.045mmol of the cyclopentyl acid chloride. The resulting reaction mixture is stirred for 2 hours at 0°C. The reaction mixture is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSθ4 and concentrated to dryness in vacuo. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 160. L- ii i|,.ii ::3 ii,„ii "f'/ .-- .-a. '..' ■•> •-J* --. .-.
Example 195. Compound of Formula II, wherein A = -(C=0)-NH-R1, wherein R1
= cyclopentyl. G = OH. L = absent, X = Y = thiophen-3-yl. Z = hydrogen, i = 3, m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared with the title compound from Example 159 in 4ml of a 4M solution of HCI in dioxane and stim'ng for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4ml THF, and cooled to 0°C. To the 0°C solution is added 0.045mmol of cyclopentyl isocyanate and the resulting reaction mixture is stirred at RT for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCI, water and brine, dried over MgS04, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 160.
Example 196. Compound of Formula II, wherein A = -(C=S)-NH-R1, wherein R1
= cyclopentyl. G = OH. L = absent, X = Y = thiophen-3-yl, Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared with the title compound from Example 159 in 4ml of a 4M solution of HCI in dioxane and stiπing for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4ml THF, and cooled to 0°C. To the 0°C solution is added 0.045mmol of cyclopentyl isothiocyanate and the resulting reaction mixture is stirred at RT for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCI, water and brine, dried over MgSθ4, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 160.
Example 197. Compound of Formula II. wherein A = -S(Q)?-R1. wherein R1 = cyclopentyl. G = OH. L = absent. X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared with the title compound from Example 159 in 4ml of a 4M solution of HCI in dioxane and stim'ng for 1 hour. To the resulting concentrated reaction residue, which has been dissolved in 4ml THF, is added 0.045mmol of TEA, and cJpτo| d|ft
Figure imgf000229_0001
is added 0.045mmol of cyclopentyl sulfonyl chloride and the resulting reaction mixture is stirred at 0°C for 2 hours. The solution is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSθ , and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 160.
Example 198. Compound of Formula IK wherein A = -(C=Q)-0-R1, R1 = cyclopentyl, G = -O-phenethyl. L = absent, X = Y = thiophen-3-yl, Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
Figure imgf000229_0002
194 DCM
198b
The title compound is prepared by adding to a solution of the title compound of Example 194 and phenethyl alcohol 198a in 0.5 ml DCM, is added 1.2 eq. PyBrOP, 4eq. DIEA, and catalytic amount of DMAP at 0°C. The resulting reaction mixture is stirred for 1 hour at 0°C and then warmed to RT over a period of 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexanesiEtOAc as elution phase (9ι1→5:1->3ι1- 1ι1) to afford the title compound isolated phenethyl ester 198b.
Other esters can be made using the same procedures.
Example 199. Compound of Formula II. wherein A = -(C=OV-Q-R1. R1 = cyclopentyl. G = -NH-phenethyl. L = absent. X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
Figure imgf000230_0001
The title compound is prepared by adding to a solution of the title compound of Example 194 and phenethylamine 199a (0.05 ml) in 0.5 ml DMF, EDC (1.2 eq.) and DIEA (4eq.) at 0°C. The resulting reaction mixture is stirred at 1 hour. Subsequently, the reaction is warmed to RT over a period of 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexanesiEtOAc as elution phase (9:1->5:1-»3:1- 1:1) to afford title compound phenethyl amide 199b.
Other amides can be made via the same procedure.
Example 200. Compound of Formula II. wherein A = -(C=OVO-R1. R1 = cyclopentyl. G = -NHS(Q) ?-phenethyl. L = absent X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
Figure imgf000230_0002
The title compound is prepared by adding to a solution of the title compound of Example 194 and α-toluenesulfonamide 200a (10mg) in 0.5 ml DCM, is added 1.2 eq. PyBrOP, 4eq. DIEA, and catalytic amount of DMAP at 0°C. The resulting reaction mixture is stirred for 1 hour and then allowed to warm to RT over a period of 4-12 hours. The
Figure imgf000231_0001
gel flash chromatography using different ratios of hexanesiEtOAc as elution phase (9:1- 5:1— >3:1— >1:1) to afford the title compound sulfonamide 200b.
Other sulfonamides can be made via the same procedure.
Example 201. Compound of Formula II. wherein A = -(C=Q)-0-R1. R1 = cyclopentyl. G = -(C=QV-OH. L = absent. X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and and R3 = R4 = hydrogen.
Figure imgf000231_0002
The title compound is prepared by adding to a solution of the title compound of Example 194 in 0.5 ml DMF, EDC (1.2 eq.) and DIEA (4eq.) at 0°C. The resulting reaction mixture is stirred at 1 hour. Subsequently, the reaction is warmed to RT over a period of 4-12 hours. The reaction mixture is purified by silica gel flash chromatography to
Figure imgf000232_0001
is then treated with DIBAL-H at -78°C in
THF for 2 hours. The reaction mixture is then diluted with 8 ml EtOAc, washed with water and brine, dried over Na2Sθ4, and concentrated in vacuo to yield aldehyde 201a. To a solution of aldehyde 39a in 0.5 ml THF, is added α-hydroxy-α-methyl-propionitrile (0.1 ml) and catalytic amount TFA at 0°C. The resulting reaction mixture is warmed from 0° C to RT over a period of 4-12 hours followed by hydrolysis with concentrated hydrochloric acid in dioxane. The reaction is then extracted with EtOAc, and washed with water and brine to yield α-hydroxy compound 201b in its crude form. The cmde compound 201b undergoes a Dess-Martin oxidation in THF (0.5 ml), providing the α- carbonyl compound 201c in cmde form. The crude 201c is purified by silica gel flash chromatography using different ratios of hexanesiEtOAc as elution phase (9:1- 5:1→3ι1- 1:1) to afford the title compound isolated keto acid 201c.
Example 202. Compound of Formula II. wherein A = -(C=OV-Q-R1. R1 = cyclopentyl. G = -(C=Q>-Q-phenethyl, L = absent, X = Y = thiophen-3-yl. Z = hydrogen, i = 3, m = s = 1. and and R3 = R4 = hydrogen.
The title compound is prepared with the title compound keto acid of Example 201 and phenethanol according to the procedure set forth Example 198.
Example 203. Compound of Formula IK wherein A = -(C=0)-0-R1. R1 = cyclopentyl. G = -(C=OV-NH-phenethyl. L = absent. X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and and R3 = R4 = hydrogen.
The title compound is prepared with the title compound keto acid of Example 201 and phenethyl amine according to the procedure set forth in Example 199.
Example.204. Compound of Formula IK wherein A = -(C=Q)-0-R1. R1 =
Figure imgf000232_0002
hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared with the title compound keto acid of Example 201 and α-toluenesulfonamide according to the procedure set forth in Example 200. Example 205. Compound of Formula 11. wherein A = tBOC. G = OH. L =
-(C=0,CH?-. X = Y = thiophen-3-yl. Z = hydrogen. 1 = 1. m = s = 1. and R3 = R4 = hydrogen.
> The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 88C and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160.
) Example 206. Compound of Formula II. wherein A = tBOC. G = OH. L =
-CH(CHg)CH2-. X = Y = thiophen-3-yl, Z = hydrogen. i = 1. m = s = 1. R3 = methyl, and R4 = hydrogen.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 89G and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu
> conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160.
Example 207. Compound of Formula II. wherein A = tBOC. G = OH. L = -Q-. X =
Y = thiophen-3-yl. Z = hydrogen, i = 0. m = s = 1, R3 = methyl, and R4 = hydrogen.
) The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 90D and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160.
> Example 208. Compound of Formula II. wherein A = tBOC. G = OH. L = -S-. X =
Y = thiophen-3-yl. Z = hydrogen. i = 0. m = s = 1. R3 = methyl, and R4 = hydrogen.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 91 E and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the . method set forth in Example 160. Example 209. Compound of Formula II. wherein A = tBOC. G = OH. L = -S(O
X = Y = thiophen-3-yl. Z = hydrogen. i = 2, m = s = 1, R3 = methyl, and R4 = hydrogen.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 92B and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160.
Example 210. Compound of Formula II. wherein A = tBOC. G = OH. L = -S(O)? X
= Y = thiophen-3-yl, Z = hydrogen. i = 2. m = s = 1. R3 = methyl, and R4 = hydrogen.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 93B and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160.
Example 211. Compound of Formula II, wherein A = tBOC. G = OH. L =
-SCHgCH?-. X = Y = thiophen-3-yl. Z = hydrogen, i = 0. m = s = 1. and R3 = R4 = CH3.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 94B and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160.
Example 212. Compound of Formula II. wherein A = tBOC. G = OH. L = CF?CH?.
X = Y = thiophen-3-yl. Z = hydrogen, i = 1. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 95C and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160. ExaipRJe f 13-U S I JiC'omP u-iai. ^''".Formula II. wherein A = tBOC. G = OH. L = -CHFCH?-. X = Y = thiophen-3-yl. Z = hydrogen. 1 = 1. m = s = 1. and R3 = R4 = hydrogen.
The title compound is prepared with the modified cyclic peptide precursor mesylate formed in 96C and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160.
Example 214. Compound of Formula III, wherein A = tBOC, G = OH, L = absent.
X = Y = thiophen-3-yl. Z = hydrogen, i = 3. m = s = 1. and R3 = R4 = hydrogen.
214A. The saturated cyclic peptide precursor mesylate is prepared by catalytic reduction of the mesylate cyclic peptide precursor of Example 2 with Pd/C in MeOH in the presence of H2.
The title compound is prepared with the saturated cyclic peptide precursor mesylate formed in 214A and 4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditions elucidated in Example 158 followed by hydrolysis of the ethyl ester via the method set forth in Example 160.
The compounds of the present invention exhibit potent inhibitory properties against the HCV NS3 protease. The following examples elucidate exemplary assays in which the compounds of the present invention are tested for anti-HCV effects.
Example 215. NS3/NS4a Protease Enzyme Assay
HCV protease activity and inhibition is assayed using an internally quenched fluorogenic substrate. A DABCYL and an EDANS group are attached to opposite ends of a short peptide. Quenching of the EDANS fluorescence by the DABCYL group is relieved upon proteolytic cleavage. Fluorescence was measured with a Molecular Devices Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm. p^e g-tøtøφlrf In ■•C^rilr-i -White half-area 96-well plates (VWR 29444-312 [Coming 3693]) with full-length NS3 HCV protease 1b tethered with NS4Λ cofactor (final enzyme concentration 1 to 15 nM). The assay buffer is complemented with 10 μM NS4A cofactor Pep 4A (Anaspec 25336 or in-house, MW 1424.8). RET S1 (Ac-Asp- Glu-Asp(EDANS Glu-GIu-Abu-[COO]Ala-Ser-Lys-(DABCYL)-NH2iAnaSpec 22991, MW 1548.6) is used as the fluorogenic peptide substrate. The assay buffer contained 50 mM Hepes at pH 7.5, 30 mM NaCI and 10 mM BME. The enzyme reaction is followed over a 30 minutes time course at room temperature in the absence and presence of inhibitors.
The peptide inhibitors HCV Inh 1 (Anaspec 25345, MW 796.8) Ac-Asp-Glu-Met- Glu-Glu-Cys-OH, [-20°C] and HCV Inh 2 (Anaspec 25346, MW 913.1 ) Ac-Asp-Glu- Dif-Cha-Cys-OH, were used as reference compounds.
IC50 values were calculated using XLFit in ActivityBase (IDBS) using equation 205: y=A+((B-A)/(1+((C/x)ΛD))).
Example 216. Cell-Based Replicon Assay
Quantification of HCV replicon RNA in cell lines (HCV Cell Based Assay)
Cell lines, including Huh-11-7 or Huh 9-13, harboring HCV replicons (Lohmann,
3 et al Science 285:110-113, 1999) are seeded at 5x10 cells/well in 96 well plates and fed media containing DMEM (high glucose), 10% fetal calf serum, penicillin- streptomycin and non-essential amino acids. Cells are incubated in a 5% CO2 incubator at 37 °C. At the end of the incubation period, total RNA is extracted and purified from cells using Qiagen Rneasy 96 Kit (Catalog No. 74182). To amplify the HCV RNA so that sufficient material can be detected by an HCV specific probe (below), primers specific for HCV (below) mediate both the reverse transcription of the HCV RNA and the amplification of the cDNA by polymerase chain reaction (PCR) using the TaqMan One- Step RT-PCR Master Mix Kit (Applied Biosystems catalog no.4309169). The nucleotide sequences of the RT-PCR primers, which are located in the NS5B region of the HCV genome, are the following:
Figure imgf000237_0001
5'GCTGCGGCCTGTCGAGCT:
HCV Reverse primer "RBNSδBrev":
5'CAAGGTCGTCTCCGCATAC
Detection of the RT-PCR product was accomplished using the Applied Biosystems (ABI) Prism 7700 Sequence Detection System (SDS) that detects the fluorescence that is emitted when the probe, which is labeled with a fluorescence reporter dye and a quencher dye, is processed during the PCR reaction. The increase in the amount of fluorescence is measured during each cycle of PCR and reflects the increasing amount of RT-PCR product. Specifically, quantification is based on the threshold cycle, where the amplification plot crosses a defined fluorescence threshold. Comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples (ABI User Bulletin #2 December 11, 1997). The data is analyzed using the ABI SDS program version 1.7. The relative template concentration can be converted to RNA copy numbers by employing a standard curve of HCV RNA standards with known copy number (ABI User Bulletin #2 December 11, 1997).
The RT-PCR product was detected using the following labeled probe: 5' FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA FAM= Fluorescence reporter dye. TAMRA:=Quencher dye.
The RT reaction is performed at 48 °C for 30 minutes followed by PCR. Thermal cycler parameters used for the PCR reaction on the ABI Prism 7700 Sequence Detection System were: one cycle at 95 °C, 10 minutes followed by 35 cycles each of which included one incubation at 95 °C for 15 seconds and a second incubation for 60 °C for 1 minute.
To normalize the data to an intemal control molecule within the cellular RNA, RT- PCR is performed on the cellular messenger RNA glyceraldehydes-3-phosphate dehγir©g-fnas§f (| ^^ copy number is very stable irTthe cell lines used. GAPDH RT-PCR is performed on the same exact RNA sample from which the HCV copy number is determined. The GAPDH primers and probes, as well as the standards with which to determine copy number, are contained in the ABI Pre- Developed TaqMan Assay Kit (catalog no.4310884E). The ratio of HCV/GAPDH RNA is used to calculate the activity of compounds evaluated for inhibition of HCV RNA replication.
Activity of compounds as inhibitors of HCV replication (Cell based Assay) in replicon containing Huh-7 cell lines
The effect of a specific anti-viral compound on HCV replicon RNA levels in Huh- 11-7 or 9-13 cells was determined by comparing the amount of HCV RNA normalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposed to compound versus cells exposed to the 0% inhibition and the100% inhibition controls. Specifically, cells were
3 seeded at 5x 10 cells/well in a 96 well plate and were incubated either with: 1) media containing 1% DMSO (0% inhibition control), 2) 100 intemational units, lU/ml Interferon- alpha 2b in media/1 %DMSO or 3) media/1 %DMSO containing a fixed concentration of compound. 96 well plates as described above were then incubated at 37 °C for 3 days (primary screening assay) or 4 days (IC50 determination). Percent inhibition was defined as:
% lnhibition= [100-((S-C2)/C1 -C2))]x100 where
S= the ratio of HCV RNA copy number/GAPDH RNA copy number in the sample;
C1= the ratio of HCV RNA copy number/GAPDH RNA copy number in the 0% inhibition control (media/1 %DMSO); and
C2= the ratio of HCV RNA copy number/GAPDH RNA copy number in the 100% inhibition control (100 lU/ml Interferon-alpha 2b).
The dose-response curve of the inhibitor was generated by adding compound in serial, three-fold dilutions over three logs to wells starting with the highest concentration of a
Figure imgf000239_0001
with the lowest concentration of 0.01 uM. Further dilution series (1uM to 0.001 uM for example) was performed if the IC50 value was not in the linear range of the curve. IC50 was determined based on the IDBS Activity Base program using Microsoft Excel "XL Fit" in which A=100% inhibition value (100IU/ml Interferon-alpha 2b), B= 0% inhibition control value (media/1 %DMSO) and C= midpoint of the curve as defined as C=(B-A/2)+A. A, B and C values are expressed as the ratio of HCV RNA/GAPDH RNA as determined for each sample in each well of a 96 well plate as described above. For each plate the average of 4 wells were used to define the 100% and 0% inhibition values.
Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.

Claims

-"' -.„.. ..' , >.,„ , -- , .... -
What is claimed is:
1. A compound having the Formula I:
W
Figure imgf000240_0001
wherein:
A is selected from the group consisting of H, - (C=0)-R2, -(C=0)-O-R1 , -C(=0)- NH-R2, -C(=S)-NH-R2, -S(0)2-R2, -(C=NR1)-R1, and -(C=NR1)-NH-R1 ;
G is selected from the group consisting of -OH, -0-(C C12 alkyl), -NHS(0)2-R1, - (C=0)-R1, -(C=0)-0-R1, and -JC=0)-NH-R1;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, - S(0)2-, -S(0)2CH2CH2-, -S{θy, -S(0)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, - CH(CH3)CH2-, -CFHCH2-, -CF2CH2-, and -CRX=CRX- where Rx = H or halogen; j is O, 1, 2, 3, or 4; . m is O, 1, or 2; s is 0, 1 or 2;
R1 is selected form the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; I ΩsTseϊW S^ of H, C C6 alkyl, C3-C12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; .
R3 and R4 are each independently selected from the group consisting of hydrogen, OH, CH3, CN, SH, halogen, N02, NH2, amide, methoxy, trifluoromethoxy, and trifluoromethyl;
E is selected from -CH=CH- or-CH2-CH2-; and
W is a substituted or unsubstituted heterocyclic ring system.
2. A compound according to claim 1 wherein W is substituted with one or more substituents, each of said substituents being independently selected from any of (a), (b), (c), (d) and (e):
(a) alkenyl; alkoxy; alkoxyalkyl; alkyl; alkylamino; alkylaryl; alkylsulfonyl; alkynyl; amide; amido optionally mono-substituted with C Cβ alkyl; aryl; arylalkanoylalkyl; arylalkyl; arylaminoalkyl; aryloxyalkyl; arylsulfonyl; cycloalkoxy; cycloalkyl; dialkylamino; dialkylaminoalkyl; diarylaminoalkyl; haloalkyl; heteroaryl; heteroarylalkyl; heterocyclo; heterocycloalkyl; heterocycloalkylalkyl; thioalkyl; monoalkylaminoalkyl; sulfonyl; (lower alkyl)sulfonyl; haloalkyl; carboxyl; amide; (lower alkyl)amide; heterocyclo optionally substituted with C Cβ alkyl; perhaloalkyl; sulfonyl; thioalkyl; urea, C(=0)-R11; OC(=0)R11; C(=0)0-R11; C(=0)N(R11)2; C(=S)N(R11)2; S02R11; NHS(02)R11; N(R12)2; N(R12)C(=O)R11; wherein each of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy, perhaloalkyl;
(b) C7-C14 aralkyl; C2-C7cycloalkyl; Cβ-Cι0 aryl; heterocyclo; (lower alkyl)- heterocyclo; wherein each aralkyl, cycloalkyl, aryl, heterocyclo or (lower alkyl)-heterocyclo may be optionally substituted with R6, where R6 is halogen, C C β alkyl, C3-C β cycloalkyl, d-C 6 alkoxy, C3-C 6 cycloalkoxy, N02, N(R7)2, NH-C(0)-R7 or NH-C(O)- NHR7; where R7 is H, C C6 alkyl or C3-C6 cycloalkyl; or R6 is NH-C(0)-OR8 where R8 is C C 6 alkyl or C3-C 6 cycloalkyl;
Figure imgf000242_0001
R5 is independently H, C C6 alkyl or C3-C6 cycloalkyl, C6 or C10 aryl, C7-C 1 aralkyl, heterocyclo or (lower alkyl)- heterocyclo;
(d) NH-C(O)-OR8 where R8 is C C 6 alkyl or C3-C 6 cycloalkyl;
(e) formyl; halogen;, hydroxy; N02; OH; SH; halo; CN; wherein each R11 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, arylaminoalkyl, diarylaminoalkyl, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl; and each R12 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 diarylaminoalkyl, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl.
3. The compound of claim 1 wherein W is selected from the group consisting of:
(a) 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 the group consisting of OH, CN, halogen, formyl, R10 and R11; and
(b) 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 R10; wherein: !feic ,Rlι?. .ι O^ alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heretoaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, heteroaryl or urea, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl; C(=0)-R11, 0C(=O)R11, C(=0)0-R11, C(=0)N(R11)2, C(=S)N(R11)2, S02R11, NHS(02)R11, N(R12)2, and N(R12)C(=0)R11; each R11 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, arylaminoalkyl, diarylaminoalkyl, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl; each R12 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 diarylaminoalkyl, wherein any of the foregoing can be optionally be substituted with up to three groups selected from halogen, OH, alkoxy and perhaloalkyl.
4. The compound of claim 3 wherein 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 the group consisting of OH, CN, halogen, formyl, R10 and Rn.
5. The compound of claim 3 wherein W is an aliphatic 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 substitQefϊts- 'sele'cte lif om ffiiS&roϋplconsisting of OH, CN, halogen, formyl, R10 and R11.
6. The compound of claim 5 herein said optionally substituted aliphatic heteromonocyclic ring system has five ring atoms and 1 or 2 ring hetero atoms selected from O, N and S.
7. The compound of claim 6 wherein said optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of pyrrolidines, pyrazolidines, pyrrolines, tetrahydrothiophenes, dihydrothiophenes, tetrahydrofurans, dihydrofurans, imidazolines, tetrahydroimldazoles, dihydropyrazoles, tetrahydropyrazoles, and oxazolines.
8. The compound of claim 5 wherein said optionally substituted aliphatic heteromonocyclic ring system has six ring atoms and 1 or 2 ring hetero atoms selected from O, N and S.
9. The compound of claim 8 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, perhydro pyrimidine, morpholine, thioxane, and thiomorpholine.
10. The compound of claim 5 wherein said optionally substituted aliphatic heteromonocyclic ring system has seven ring atoms and 1 or 2 ring hetero atoms selected from O, N and S.
11. The compound of claim 8 wherein said optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of hexamethyleneimine, and hexamethylenesulfide.
12. | hi cό ^-Sldlof laϊMlΦwKerein 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 R10.
13. The compound of claim 12 wherein said optionally substituted aliphatic heterobicyclic ring system has eight to twelve ring atoms and 1 to 4 ring hetero atoms selected from O, N and S.
14. The compQund of claim 13 wherein said optionally substituted aliphatic heterobicyclic ring system eight to twelve ring atoms and 1 or 2 ring hetero atoms selected from O and N.
15. The compound of claim 3 wherein W is 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 0.
16. The compound of claim 3 wherein 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 Rio.
17. The compound of claim 15 wherein said optionally substituted aromatic heteromonocyclic ring system has five ring atoms and 1 or 2 ring hetero atoms selected from O, N and S.
18. The compound of claim 17 wherein said optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyrroles,
Figure imgf000246_0001
pyrazoles, imidazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, and isothiazoles.
19. The compound of claim 16 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.
20. The compound of claim 19 wherein said optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyridines, pyrimidines, pyrazines, pyrans, and triazines.
21. The compound of claim 16 wherein said optionally substituted aromatic heteromonocyclic ring system has five ring atoms and 3 or 4 ring hetero atoms selected from O, N and S.
22. The compound of claim 21 wherein said optionally substituted aromatic heteromonocyclic ring system is triazolyl or tetrazolyl.
23. The compound of claim 3 wherein W is an aromatic 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, CN, halogen, formyl and Rio-
24. The compound of claim 23 wherein said optionally substituted aromatic heterobicyclic ring system is selected from the group consisting of adenines, azabenzimidazoles, azaindoles, benzimidazoles, benzo isothiazoles, benzofurans, benzoisoxazoles, benzooxazoles, benzothiadiazoles, benzothiazoles, benzothienes, benzothiophenes, benzoxazoles, carbazoles, cinnolines, guanines, imidazopyridines, indazoles, indoles, isoindoles, isoquinolines, phthalazines, purines, pyrrolo pyridines, quinazolines, quinolines, quinoxalines, thianaphthenes, and xanthines.
25. t lEft cd^^^ 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, Rio and Rn-
26. The compound of claim 25 wherein said optionally substituted aromatic heterotricyclic ring system is selected from the group consisting of carbazoles, bibenzofurans, psoralens, dibenzothiophenes, phenazines, thianthrenes, phenanthrolines, phenanthridines.
27. A compound of Formula II
Figure imgf000247_0001
Wherein:
A is selected from the group consisting of H, -(C=0)-R2, -(C^J-O-R1, - C(=0)-NH-R1, -C(=S)-NH-R2 , -S(0)?-R2, -(C=NR R1, and -(C=NR NH-R1;
G is selected from the group consisting of -OH, -0-(C Ci2 alkyl), - NHS(0)2-R', -(C=0)-R2, -(00)-0-R. , and -(C=O)-NH-R2;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, -S(0)2-, -S(0)2CH2CH2-, -S(O)-, -S(0)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2-, -CF2CH2-, and -CRX=CRX- where Rx = H or halogen; W is selected from the group consisting
Figure imgf000248_0001
Figure imgf000248_0002
Q is selected from the group consisting of absent, -CHr, -0-, -NH-, - N(R1)-, -S-, -S(0)2-, and -(C=0)-;
Q' is selected from the group consisting of absent, -CH2-, and -NH-;
Y is selected from the group consisting of H, Q-Cβ 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;
R1 is selected from the group consisting of H, Q-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, C Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen and methyl.
28. A compound according to claim 27, wherein: A is -(C=0)-0-R1; G is hydroxyl;
Figure imgf000249_0001
i = 3; m = s = 1 ; and
R3 and R4 are hydrogen.
29. A compound according to claim 27, wherein:
A is -(C=0)-0-tert-butyl;
G is hydroxyl;
L is absent; j = 3; m = s = 1 ; and
R3 and R4 are hydrogen.
30. A compound according to claim 27, wherein:
A is -(C=0)-0-R1,
G is hydroxyl;
L is absent; j = 3; m = s = 1 ; and
R3 and R4 are hydrogen.
31. A compound according to claim 27, wherein:
A is -(C=O)-0-terf-butyl; G is hydroxyl; L is absent;
Figure imgf000249_0002
i = 3; m = s = 1; and
R3 and R4 are hydrogen. ii,,-.. ii „' il,uμ ..„lt l'..,!i -■■ , , .u .i
32. A compound according to claim 27 which is selected from the group consisting of:
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
33.
Figure imgf000255_0001
27 which is selected from the group consisting of:
Figure imgf000255_0002
34. A compound according to claim 27 which 'is selected from the group consisting of:
Figure imgf000256_0001
35. A compound according to claim 27 which is selected from the group consisting of:
Figure imgf000256_0002
Figure imgf000257_0001
36. A compound of Formula III:
Figure imgf000258_0001
Formula III
wherein
A is selected from the group consisting of H, -(C=0)-R2, -(C=O)-0-R1, - C(=O)-NH-R2, -C(=S)-NH-R2 , -S(0)2-R2, -(C=NR1)-R1, and -(C=NR1)-NH-R1;
G is selected from the group consisting of -OH, -0-(Cι-Cι2 alkyl), - NHS(O)rR1, -(C=O)-R2, -(C=O)-O-R', and -(C=O)-NH-R2;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, -S(O)2-, -S(0)2CH2CH2-, -S(θy, -S(0)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=0)-CH2-, -CH(CH3)CH2-, -CFHCH2- , -CF2CH2-, and -CRX=CRX- where Rx = H or halogen;
W is selected from the group consisting of
Figure imgf000258_0002
Figure imgf000258_0003
Q is selected from the group consisting of absent, -CH2-, -O-, -NH-, - N(R1h -S-, -S(0)2-, and -(C=O)-;
Q' is selected from the group consisting of absent, -CH2-, and -NH-;
Y is selected from the group consisting of H, Q-Cβ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; j = 0, 1, 2, 3, or 4; WSOH otiB;; s = 0,1 or 2;
R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, -Ce alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen and methyl.
37. A compound according to claim 36, wherein:
A is -(C=O)-O-R1;
G is hydroxyl;
L is absent; j = 3; m = s = 1 ; and
R3 and R4 are hydrogen.
38. A compound according to claim 36, wherein:
Figure imgf000259_0001
G is hydroxyl;
L is absent; j = 3; m = s = 1 ; and
R3 and R4are hydrogen.
39. A compound according to claim 36, wherein: p C T" i§ ! τ )-C# RiS B" - '7' 91 G is hydroxyl; L is absent;
Figure imgf000260_0001
j = 3; m = s = 1 ; and
R3 and R4 are hydrogen.
40. A compound according to claim 36, wherein: A is -(C=O)-0-terf-butyl; G is hydroxyl; L is absent;
Figure imgf000260_0002
j = 3; m = s = 1 ; and
R3 and R4 are hydrogen.
. ■■' .J' .',--. IU- '"-"•- • . 3 ""lf . 1' " .» -- . . -
41. A compound of Formula II:
Figure imgf000261_0001
Formula II wherein
A is selected from the group consisting of H, -(C=0)-R2, -(C=O)-0-R', -C(=0)-NH-R2, -C(=S)-NH-R2 , -S(O)2-R2, -(C=NR R1, and -(C=NR1)-NH-R1;
G is selected from the group consisting of -OH, -O-(Cι-Cι2 alkyl), -NHS(O)2-R', -(C=O)-R2, -(C=0)-O-R'( and -(C=O)-NH-R2;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, -S(O)2-, -S(O)2CH2CH2-, S(θy, -S(O)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=O)-CH2-, -CH(CH3)CH2-, -CFHCH2-, -CF2CH2-, and -CRX=CRX- where Rx = H or halogen;
W is selected from the group consisting of
Figure imgf000261_0002
aanndd
Figure imgf000261_0003
where X and Y are independently selected from the group consisting of H, halogen, Ci- Cβ alkyl, C3-C12 cycloalkyl, -CH2-alkylamino, -CH2-dialkyIamino, -CH2-arylamino, -CH2- diarylamino, -(C=0)-alkylamino, -(C=O)-dialkylamino, -(C=0)-arylamino, -(C=0)- diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occ p^Jng "tK-URΦfiPβ- p ! i©ns ©Wie triazole ring, to which X and Y are attached, for a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j = 0, 1, 2, 3, or 4; m = 0, 1, or 2; s = 0, 1 or 2;
R1 is selected from the group consisting of H, Ci-Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, Cι-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen and methyl.
42. A compound according to claim 41 , wherein:
A is -(C=0)-O-R1;
G is hydroxyl;
L is absent; j = 3; m=s=1; and
R3 and R4 are hydrogen.
43. A compound according to claim 41 , wherein:
Figure imgf000262_0001
G is hydroxyl; L is absent; j = 3;
Figure imgf000263_0001
R3 and R4 are hydrogen.
44. A compound according to claim 41 , wherein: A is -(C=O)-O-R1, G is hydroxyl; L is absent;
W is
Figure imgf000263_0002
j = 3; m = s = 1 ; and
R3 and R4 are hydrogen.
45. A compound according to claim 41 , wherein: A is -(C=O)-O-fert-butyl; G is hydroxyl; L is absent;
Figure imgf000263_0003
J = 3; •
M = s = 1; and
R3 and R4 are hydrogen.
46. A compound according to claim 41 which is selected from the group consisting of:
Figure imgf000263_0004
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
47. A compound according to claim 41 which is selected from the group consisting of:
Figure imgf000267_0002
Figure imgf000268_0001
48. A compound according to claim 41 which is selected from the group consisting of:
Figure imgf000268_0002
Figure imgf000269_0001
-'"- ϋ ,' ιu' .:-i-ιu-B"tt\-' ι.-j -----'"«"-.• ^
49. A compound according to claim 41 which is selected from the group consisting of:
Figure imgf000270_0001
Figure imgf000271_0004
50. A compound of Formula III:
Figure imgf000271_0001
Formula III
wherein
A is selected from the group consisting of H, -(0=O)-R2, -(C=0)-O-R1, -C(=O)-NH-R2, -C(=S)-NH-R2 , -S(O)2-R2, -(C=NR1)-R1, and -(C=NR1)-NH-R1;
G is selected from the group consisting of -OH, -0-(C Ci2 alkyl), -NHS(0)2-R', -(C=0)-R2, -(C=O)-0-R,, and -(C=O)-NH-R2;
L is selected from the group consisting of absent, -S-, -SCH2-, -SCH2CH2-, - S(0) , -S(0)2CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=O)-CH2-, -CH(CH3)CH2-, -CFHCH2- , -CF2CH2-, and -CRX=CRX- where Rx = H or halogen;
from the group consisting of
Figure imgf000271_0002
and
Figure imgf000271_0003
where X and Y are independently selected from the group consisting of H, halogen, CrC6 alkyl, C3-C12 cycloalkyl; j H ^ øøijhin II-PW ^lkylamino, -CH2-arylamino, -CH2-diarylamino, - (C=0)-alkylamino, -(C=0)-dialky!amino, -(C=O)-arylamino, -(C=O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; in the alternative, X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, for a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; j = 0, 1, 2, 3, or 4; m = 0, 1, or 2; s = 0, 1 or 2;
R1 is selected from the group consisting of H, C C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R2 is selected from the group consisting of H, CrC6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and
R3 and R4 are each independently selected from the group consisting of hydrogen and methyl.
51'. A compound according to claim 50, wherein: A is -(C^J-O-R1; G is hydroxyl; L is absent; j = 3; m = s = 1; and R3 and R4 are hydrogen.
52.
Figure imgf000273_0001
50, wherein:
A is -(C=0)-O-fer--butyl;
G is hydroxyl;
L is absent; j = 3; m = s = 1 ; and
R3 and R4 are hydrogen.
53. A compound according to claim 50, wherein:
A is -(C^O-R1, G is hydroxyl; L is absent;
Figure imgf000273_0002
j = 3; m = s = I; and
R3 and R4 are hydrogen.
54. A compound according to claim 50, wherein: A is -(C=0)-0-fert-butyl; G is hydroxyl; • L is absent;
W
Figure imgf000273_0003
j = 3; m = s = 1 ; and
5. A compound of Formula IV:
Figure imgf000274_0001
( IV )
wherein
A is hydrogen, -(C=0)-R1 , -(C=0)-0-R1, -C(=O)-NH-R2 , -C(=S)-NH-R2, - S(O)2-R2, -(C=NR1)-R1 , or -(C=NR1 )-NH-R1 ;
G is -OH, -0-(C C12 alkyl), -NHS(O)2-R', -(C=0)-R2, -(C=O 0-R', or -(C=O)-NH-R2;
L . is -S-, -SCH2-, -SCH2CH2-, -S(O)2-, -S(0)2CH2CH2-, -S(O)-, -S(O)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=O)-CH2-, -CH(CH3)CH2-, -CFHCH2- - CF2CH2-, or -CRχ=CRx- where Rx = H or halogen;
X, Y, and Z are independently selected from the group consisting of hydrogen, N3, halogen, Q-Cβ alkyl, C3-C12 cycloalkyl, alkylamino, dialkylamino, -Cβ 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, -0-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl,
Figure imgf000275_0001
substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or, in the alternative, X and Y or Y and Z taken together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl cyclic moiety; j = 0, 1, 2, 3, or 4; m = 0, 1, or 2; s = 0, 1 or 2;
R1 is hydrogen, C|-C6 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;
R2 is hydrogen, C Cβ alkyl, C3-C12 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
R3 and R4 are each independently hydrogen or methyl.
56. A compound according to claim 55, wherein:
A is -(C=O)-O-R1;
G is hydroxyl;
L is absent; j = 3; m = s = 1; and
R3 and R4 are hydrogen.
57. A compound according to claim 55, wherein:
A is -(C=O)-0-ferf-butyl; G is hydroxyl; L is absent; j = 3;
Figure imgf000276_0001
R3 and R4 are hydrogen.
58. A compound according to claim 55 which is selected from the group consisting of:
Figure imgf000276_0002
Figure imgf000277_0001
Figure imgf000278_0001
59. A compound according to claim 55 which is selected from the group consisting of:
Figure imgf000278_0002
Figure imgf000279_0001
Figure imgf000279_0002
61. A compound according to claim 55 which is selected from the group consisting of:
Figure imgf000280_0001
62. A compound of Formula IV:
Figure imgf000281_0001
( IV )
wherein
A is hydrogen, -(C=0)-R1 , -(C^J-O-R1, -C(=0)-NH-R2 , -C(=S)-NH-R2 , or -S(O)2-R2, -(C=NR1)-R1, or -(C=NR1)-NH-R1;
G is -OH, -O-(d-Cι2 alkyl), -NHS(O)2-R', -(C=0)-R2, -(C=O)-O-R,, or -(C=0)-NH-R2;
L is absent, -S-, -SCH2-, -SCH2CH2-, -S(0)2-, -SfOkCHzCH , -S(O)-, -S(0)CH2CH2-, -O-, -OCH2-, -OCH2CH2-, -(C=O)-CH2-, -CH(CH3)CH2-, -CFHCH2-, - CF2CH2-, or -CRX=CRX- where Rx = H or halogen -;
X, Y, and Z are independently selected from the group consisting of hydrogen, N3, halogen, C C6 alkyl, C3-C12 cycloalkyl, alkylamino, dialkylamino, Ci-Cβ 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,
Figure imgf000282_0001
heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or, in the alternative, X and Y or Y and Z taken together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, and substituted heteroaryl cyclic moiety; j = 0, 1, 2, 3, or 4; m = 0, 1, or 2; s = 0, 1 or 2;
R1 is hydrogen, C Cβ alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;
R2 is hydrogen, C Cβ alkyl, C3-C12 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
R3 and R4 are each independently hydrogen or methyl.
63. A compound according to claim 62, wherein:
A is -(C=O)-O-R1;
G is hydroxyl;
L is absent; j = 3; m = s = 1; and
R3 and R4 are hydrogen.
64. A compound according to claim 62, wherein:
Figure imgf000282_0002
G is hydroxyl; L is absent; m = s = 1; and
R3 and R4 are hydrogen.
65. A pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound according to claim 1, 27, 36, 41, 50, 55, or 62, or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
66. A method of treating a hepatitis C viral infection in a subject, comprising administering to the subject an anti-hepatitis C virally effective amount of a pharmaceutical composition according to claim 65.
67. A method of inhibiting the replication of hepatitis C virus, the method comprising supplying a hepatitis C viral NS3 protease inhibitory amount of the phamnaceutical composition of claim 65.
68. The method of claim 66 further comprising administering concurrently an additional anti-hepatitis C virus agent.
69. The method of claim 68, wherein said additional anti-hepatitis C vims agent is selected from the group consisting of a-interferon, β-interferon, ribavarin, and adamantine.
70. The method of claim 68, wherein said additional anti-hepatitis C virus agent is aη inhibitor of other targets in the hepatitis C virus life cycle which is selected from the group consisting of helicase, polymerase, metal loprotease, and IRES.
71. fAeόiii-pϋUH fe ctέ lilrrϊ-tBέ "group consisting of:
Figure imgf000284_0001
Figure imgf000284_0002
Figure imgf000284_0003
Figure imgf000284_0004
Figure imgf000285_0001
Figure imgf000285_0002
Figure imgf000285_0003
Figure imgf000285_0004
Figure imgf000286_0001
Figure imgf000286_0002
Figure imgf000286_0003
Figure imgf000286_0004
Figure imgf000287_0001
Figure imgf000287_0002
Figure imgf000287_0003
Figure imgf000287_0004
Figure imgf000288_0001
Figure imgf000288_0002
Figure imgf000288_0003
.»" il,,-- li ,.' 'I ,---• .„--- l -t '"II HJ-.
Figure imgf000289_0001
Figure imgf000289_0002
and pharmaceutically, acceptable, salts, and, isomers, thereof, 72. A compound selected from the group consisting of:
Figure imgf000289_0004
- -„,. l ■ '!.,!.. i -- --.■ t-. -.,. ■
Figure imgf000290_0001
Figure imgf000290_0002
Figure imgf000290_0003
Figure imgf000290_0004
-1 ,., -' .,_,- u.- -u ,. -«-. I
Figure imgf000291_0001
Figure imgf000291_0002
Figure imgf000291_0003
Figure imgf000291_0004
- -,-,. .' >.,-, ' n-"~' -ι ;,
Figure imgf000292_0001
Figure imgf000292_0002
Figure imgf000292_0003
Figure imgf000292_0004
--,- ■•■ " . , . ___ - -- _
Figure imgf000293_0001
Figure imgf000293_0002
Figure imgf000293_0003
,i "- tl,„. !l ,.' 'I _V ■.- ,11 iLJt '
Figure imgf000294_0001
Figure imgf000294_0002
and pharmaceutically acceptable salts and isomers thereof. 73. A compound selected from the group consisting of:
- --„.. .■ ..... WI ,. _-.i -.,... _ _
Figure imgf000295_0001
Figure imgf000295_0002
Figure imgf000295_0003
- '" U. μ it ,.' ι„l> US iι. ,li '
Figure imgf000296_0001
Figure imgf000296_0002
and pharmaceutically acceptable salts and isomers thereof.
74. A method for making a compound of Formula I in claim 1 , comprising the steps of: (i) reacting a proline derivative of formula VI:
Figure imgf000296_0003
VI
wherein,
P is a nitrogen-protecting group; L is a leaving group; 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 in claim 1.
75. A method for making a compound of Formula I in claim 1 , comprising the steps of: (i) reacting a compound of formula VII:
Figure imgf000297_0001
Formula VII
wherein,
L is a leaving group;
A is a nitrogen protecting group; and the remaining variables are as defined in claim 1 ; with a nucleophilic heterocyclic compound; and (ii) converting the resulting compound to a compound of Formula I in claim 1.
76. The compound of formula I in claim 1 , wherein W is
Figure imgf000298_0001
wherein V, X, Y, and Z are each independently selected from: j) -Ci-Cβ 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; k) -C2-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;
I) -C-2-C6 alkynyl 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; m) aryl; n) substituted aryl; o) heteroaryl; p) substituted heteroaryl; q) heterocycloalkyl; or r) substituted heterocycloalkyl; or in the alternative, V and X, X and Y, or 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;
77. The compound of formula I in claim 1 , wherein W
Figure imgf000298_0002
wherein X, Y, and Z are each independently selected from: a)
Figure imgf000299_0001
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) -C2-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; p) -C2-C6 alkynyl 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; d) aryl; e) substituted aryl; f) heteroaryl; g) substituted heteroaryl; h) heterocycloalkyl; or i) substituted heterocycloalkyl; or in the alternative, 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.
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