WO2002048116A2 - Inhibiteurs de la protease ns3 du virus de l'hepatite c - Google Patents

Inhibiteurs de la protease ns3 du virus de l'hepatite c Download PDF

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WO2002048116A2
WO2002048116A2 PCT/US2001/047911 US0147911W WO0248116A2 WO 2002048116 A2 WO2002048116 A2 WO 2002048116A2 US 0147911 W US0147911 W US 0147911W WO 0248116 A2 WO0248116 A2 WO 0248116A2
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amino
substituted
benzyl
group
lla
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PCT/US2001/047911
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WO2002048116A3 (fr
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Peter W Glunz
Brent D Douty
Wei Han
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Bristol-Myers Squibb Pharma Company
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Publication of WO2002048116A3 publication Critical patent/WO2002048116A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids
    • 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
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • 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
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N

Definitions

  • the present invention relates generally to a novel class of pyrimidinones that are useful as serine protease inhibitors, and more particularly as Hepatitis C virus NS3 protease inhibitors .
  • This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
  • Hepatitis C virus is the major cause of transfusion and community-acquired non-A, non-B hepatitis worldwide. Approximately 2% of the world's population are infected with the virus. In the Unites States, hepatitis C represents approximately 20% of cases of acute hepatitis. Unfortunately, self-limited hepatitis is not the most common course of acute HCV infection. In the majority of patients, symptoms of acute hepatitis resolve, but alanine aminotransferase (a liver enzyme diagnostic for liver damage) levels often remain elevated and HCV RNA persists.
  • HCV Hepatitis C virus
  • a propensity to chroninicity is the most distinguishing characteristic of hepatitis C, occurring in at least 85% of patients with acute HCV infection.
  • the factors that lead to chronicity in hepatitis C are not well defined.
  • Chronic HCV infection is associated with increased incidence of liver cirrhosis and liver cancer.
  • No vaccines are available for this virus, and current treatment is restricted to the use of alpha interferon, which is effective in only 15-20% of patients.
  • Recent clinical studies have shown that combination therapy of alpha interferon and ribavirin leads to sustained efficacy in 40% of patients (Poynard et al. Lancet 1998, 352, 1426-1432.). However, a majority of patients still either fail to respond or relapse after completion of therapy.
  • HCV is a positive-stranded RNA virus. Based on comparison of deduced amino acid sequence and the extensive similarity in the 5' untranslated region, HCV has been classified as a separate genus in the Flaviviridae family, which also includes flaviviruses such as yellow fever virus and animal pestiviruses like bovine viral diarrhea virus and swine fever virus. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame .
  • RNA genome is about 9.6 Kb in length, and encodes a single polypeptide of about 3000 amino acids.
  • the 5' untranslated region contains an internal ribosome entry site (IRES) , which directs cellular ribosomes to the correct AUG for initiation of translation.
  • IRS internal ribosome entry site
  • the precursor protein is cotranslationally and posttranslationally processed into at least 10 viral structural and nonstructural (NS) proteins by the action of a host signal peptidase and by two distinct viral proteinase activities.
  • the translated product contains the following proteins: core-El-E2-p7-NS2-NS3-NS4A-NS4B-NS5A- NS5B.
  • NS3 functions as a proteolytic enzyme that is responsible for the cleavage of sites liberating the nonstructural proteins NS4A, NS4B, NS5A, and NS5B.
  • NS3 has further been shown to be a serine protease. Although the functions of the NS proteins are not completely defined, it is known that NS4A is a protease cofactor and NS5B is an RNA polymerase involved in viral replication. Thus agents that inhibit NS3 proteolytic processing of the viral polyprotein are expected to have antiviral activity.
  • HCV NS3 protease inhibitors There are several patents that disclose HCV NS3 protease inhibitors.
  • W098/17679 describes peptide and peptidomimetic inhibitors with the following formula: U-E 8 - E 7 -E 6 -E 5 -E 4 -NH-CH(CH G 1 )-W :L , where W is one of a variety of electrophilic groups, including boronic acid or ester.
  • E4 represents either an amino acid or one of a series of peptidomimetic groups, the sythesis of which are not exemplified.
  • HCV protease inhibitors described in the present case are not covered.
  • One object of the present invention is to provide compounds, or pharmaceutically acceptable salt forms or prodrugs thereof, which are useful as inhibitors of hepatitis C virus protease, more specifically, the NS3 protease.
  • R 1 , R 2 , R 3 , R 6 , R 13 , W, A 1 and A 3 are effective inhibitors of HCV NS3 protease .
  • the present invention provides a compound of Formula (I) :
  • a 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CR 5 R 5a -, -CH 2 -CR 5 R 5a -, - CH 2 -CH 2 -CR 5 R 5a -, -A 2 -CH -, -A 2 -CH 2 CH 2 -, or -CH 2 -A 2 -CH 2 -;
  • a 2 is 0, S, or NR 7 ;
  • W is selected from the group:
  • Q is selected from the group: -(CRl ⁇ RlOc )m _ Q l -(CRl ⁇ RlOc )m _ Q 2
  • n 1, 2 , 3 , or 4;
  • Q 1 is selected from the group:
  • Q 2 is -X-NR 12 -Z, -NR 12 -Y-Z, or -X-NR 12 -Y-Z;
  • Q 3 is aryl substituted with 0-3 Z c ;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 Z c ;
  • Z is selected from the group: C1-C4 haloalkyl; C1-C4 alkyl substituted with 0-3 Z a ;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Z ;
  • Z b is selected from the group:
  • heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
  • Z c is H, F, Cl, Br, I, -N0 2 , -CN, -NCS, -CF 3 , -OCF 3 ,
  • R 1 is selected from the group: H, F;
  • Ci-C ⁇ alkyl substituted with 0-3 R la C 2 -C 6 alkenyl substituted with 0-3 R la ; C 2 -C 6 alkynyl substituted with 0-3 R la ; and C 3 -C 6 cycloalkyl substituted with 0-3 R la ;
  • R la is selected at each occurrence from the group:
  • 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R lc ;
  • R ld is selected at each occurrence from the group: H, C 1 -C 4 alkyl, phenyl and benzyl;
  • R 2 is H or C 1 -C 4 alkyl
  • R 3 is selected from the group: R 4 ,
  • p is 0 , 1 , or 2 ;
  • R 4 is selected from the group:
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-
  • R a is, at each occurrence, independently selected from: H, F, Cl, Br, I, -N0 2 , -CN, -NCS, -CF 3 , -OCF 3 ,
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-
  • R 4b is, at each occurrence, independently selected from:
  • R 4c is, at each occurrence, independently selected from:
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R 4d ;
  • R d is, at each occurrence, independently selected from:
  • R 5 and R 5a are, at each occurrence, independently selected from the group: H, C1-C4 alkyl, phenyl and benzyl;
  • R 6 is selected from the group: H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -Cg alkynyl, C 3 -C6 cycloalkyl, aryl, and 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated;
  • R ⁇ a is selected from the group: H, F, Cl, Br, I, -CF3 ,
  • 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-
  • R 7 is H or C1-C4 alkyl
  • R 8 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 3 -C4 cycloalkyl, aryl or aryl-C ⁇ -C4 alkyl;
  • R 9a is selected from the group: H;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R 9d ;
  • Ci-C ⁇ alkyl substituted with 0-3 R 9c C2-C6 alkenyl substituted with 0-3 R 9c ; C 2 -C6 alkynyl substituted with 0-3 R 9c ; C3-C10 cycloalkyl substituted with 0-4 R 9d ; aryl substituted with 0-5 R 9d ; and
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5- 10 membered heterocyclic group is substituted with 0-4 R 9d ;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5- 10 membered heterocyclic group is substituted with 0-4 R 9d ;
  • 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 R 9e ;
  • R 9e is selected at each occurrence from the group:
  • R 10 is selected from the group: -CO2R 11 , -NR 1:L R lla , and Ci-Ce alkyl substituted with 0-1 R 10a ;
  • RlOa i s selected from the group: halo, -N0 2 , -CN, -CF 3 ,
  • R 10 and RIO C can k e combined to form a C 3 -C6 cycloalkyl group substituted with 0-1 R 10a ;
  • R 11 and R lla are, at each occurrence, independently selected from the group : H;
  • R llb is OH, C 1 -C 4 alkoxy, F, Cl, Br, I, NH 2 , or -NH(C ⁇ -C alkyl ) ;
  • R 12 is H or C 1 -C 4 alkyl
  • R 13 is selected from the group: H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C ⁇ cycloalkyl (C 1 -C 4 alkyl), aryl and aryl-C ⁇ C 4 alkyl;
  • R 3 and R 13 can be combined to form a 4-7 membered cyclic group consisting of carbon atoms, optionally substituted with C 1 -C 4 alkyl; or R 3 + R 13 is
  • R 19 and R 19a are independently selected from the group: H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, aryl, aryl (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, and C 3 -Cg cycloalkyl (C 1 -C 4 alkyl);
  • NR 19 R 19a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
  • R 20 and R 2 ° a are independently selected from the group: H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, aryl, aryl(C ⁇ -C 4 alkyl)-, C 3 -C 6 cycloalkyl, and C 3 -C ⁇ cycloalkyl (C 1 -C 4 alkyl)-; alternatively, NR 20 R 20a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
  • OR 26 and OR 27 are independently selected from: a) -OH, b)-F, c)-NR 28 R 29 , d) Ci-C ⁇ alkoxy, and when taken together, OR 26 and OR 27 form: e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0; f) a cyclic boronic amide where said boronic amide contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0; or g) a cyclic boronic amide-ester where said boronic amide-ester contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0;
  • R 28 and R 29 are independently selected from: H, C 1 -C 4 alkyl, aryl (C 1 -C 4 alkyl)-, and C -C 7 cycloalkyl;
  • a 4 , A 5 , A 6 , A 7 , A 8 , and A 9 are independently selected from an amino acid residue
  • an amino acid residue at each occurence, independently comprises a natural amino acid, a modified amino acid or an unnatural amino acid wherein said natural, modified or unnatural amino acid is of either D or L configuration.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
  • a 1 is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -;
  • W is selected from the group:
  • Q is selected from the group: _ (CR 10 R 10c )m _Ql,
  • Q 2 is -X-NR 12 -Z, -NR 12 -Y-Z, or -X-NR 12 -Y-Z;
  • Q 3 is aryl substituted with 0-3 Z c ;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 Z c ;
  • Z is selected from the group:
  • C2-C4 alkynyl substituted with 0-3 Z a C 3 -C o cycloalkyl substituted with 0-5 Z b ; aryl substituted with 0-5 Z b ; and 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Z b ;
  • Z a is selected from the group:
  • Z b is selected from the group:
  • heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
  • R 1 is selected from the group: H, F; C1-C6 alkyl substituted with 0-3 R la ;
  • R la is selected at each occurrence from the group:
  • heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
  • n 0, 1 or 2;
  • R lb is H
  • R ld is selected at each occurrence from the group: H, C 1 -C 4 alkyl, phenyl and benzyl;
  • R 2 is H, methyl or ethyl
  • p 0, 1, or 2;
  • R 4 is selected from the group:
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-
  • R a is, at each occurrence, independently selected from: H, F, Cl, Br, I, -N0 2 , -CN, -NCS, -CF 3 , -OCF 3 ,
  • R 4c is, at each occurrence, independently selected from:
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R d ;
  • R 4d is, at each occurrence, independently selected from:
  • R 6 is selected from the group: H, Ci-C ⁇ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, and 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated;
  • R 6a is selected from the group: H, F, Cl, Br, I,
  • 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5- 6 membered heterocyclic group is substituted with 0-3 R Sb ;
  • R 6b is selected from the group: H, F, Cl, Br, I,
  • R 8 is H, C1-C4 alkyl, C 2 -C4 alkenyl, C2-C4 alkynyl, C 3 -C4 cycloalkyl, phenyl or benzyl;
  • R 9a is selected from the group: H;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5- 10 membered heterocyclic group is substituted with 0-4 R 9d ;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R 9d ;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5- 10 membered heterocyclic group is substituted with 0-4 R 9d ;
  • 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 R 9e ;
  • R 10 is selected from the group: -C0 2 R 1:L , -NR 1:L R lla , and Ci-C ⁇ alkyl substituted with 0-1 R 10a ;
  • R 1 0a selected from the group: halo, -N0 2 , -CN, -CF 3 ,
  • R 10c is H or C 1 -C 4 alkyl
  • R 10 and R 10c can be combined to form a C 3 -Cg cycloalkyl group substituted with 0-1 R 10a ;
  • R 11 and R lla are, at each occurrence, independently selected from the group: H,
  • Ci-Ce alkyl substituted with 0-3 R llb C 2 -C 6 alkenyl substituted with 0-3 R llb ; C 2 -C 6 alkynyl substituted with 0-3 R llb ; C 3 -C 7 cycloalkyl substituted with 0-3 R llb ; aryl substituted with 0-3 R llb ; and aryl(C ⁇ -C alkyl)- substituted with 0-3 R llb ;
  • R llb is OH, C 1 -C 4 alkoxy, F, Cl, Br, I, NH 2 , or -NH(C ⁇ -C 4 alkyl) ;
  • R 12 is H or C 1 -C 4 alkyl ;
  • R 13 is selected from the group: H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -Cg cycloalkyl, C 3 -Cg cycloalkyl (C 1 -C 4 alkyl), aryl and aryl-C ⁇ -C 4 alkyl;
  • R 3 and R 13 can be combined to form a 4-7 membered cyclic group consisting of carbon atoms, optionally substituted with C 1 -C 4 alkyl; or R 3 + R 13 is
  • R 19 and R 19a are independently selected from the group: H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, aryl, aryl(C ⁇ -C 4 alkyl), C 3 -C 6 cycloalkyl, and C 3 -C 6 cycloalkyl (C 1 -C 4 alkyl);
  • NR 19 R 19a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: 0, S, and N;
  • R 20 and R 20a are independently selected from the group: H, C 1 -C 4 alkyl, C 3. -C 4 haloalkyl, aryl, aryl(C ⁇ -C 4 alkyl)-, C 3 -C 6 cycloalkyl, and C 3 -C 6 cycloalkyl (C 1 -C 4 alkyl)-;
  • NR 20 R 0a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: 0, S, and N;
  • OR 26 and OR 27 are independently selected from: a) -OH, b)-F, c)-NR 28 R 29 , d) Ci-C ⁇ alkoxy, and when taken together, OR 26 and OR 27 form: e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0;
  • R 28 and R 29 are independently selected from: H, C 1 -C 4 alkyl, aryl(C ⁇ -C 4 alkyl)-, and C 3 -C 7 cycloalkyl;
  • a 4 , A 5 , A 6 , A 7 , A 8 , and A 9 are independently selected from an amino acid residue
  • an amino acid residue at each occurence, independently comprises a natural amino acid, a modified amino acid or an unnatural amino acid wherein said natural, modified or unnatural amino acid is of either D or L configuration.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
  • a 1 is -CH 2 - or -CH 2 CH 2 -;
  • W is -B(0R 26 ) (OR 27 ) ;
  • R 1 is selected from the group: H;
  • R la is selected at each occurrence from the group: Cl, F, Br, CF 3 , CHF 2 , OH, C 3 -C 6 cycloalkyl, C ⁇ -C 6 alkoxy, -S- (C 1 -C 5 alkyl); C 1 -C 4 alkyl substituted with 0-2 R lc ; aryl substituted with 0-3 R lc ; and 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R lc ;
  • R lc is selected at each occurrence from the group:
  • R ld is selected at each occurrence from the group: H, C 1 -C 4 alkyl, phenyl and benzyl;
  • R 2 is H
  • p 0, 1, or 2;
  • R 4 is selected from the group:
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5- 10 membered heterocyclic group is substituted with 0-4 R b ;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-
  • R b is, at each occurrence, independently selected from:
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R d ;
  • R c is, at each occurrence, independently selected from:
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R d ;
  • R 6 is H or Ci-Cg alkyl
  • R 8 is H, methyl, ethyl, propyl, or butyl
  • R 9a is selected from the group: H;
  • heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said heterocyclic group is substituted with 0-3 R 9d ;
  • 5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5- 10 membered heterocyclic group is substituted with 0-3 R 9d ;
  • R 9c is selected from the group: CF 3 , OCF 3 , Cl, F, Br, OH, C(0)0R 1:L , NH , NH(CH 3 ), N(CH 3 ) 2 , -CN, N0 2 , phenyl and benzyl ;
  • R 9d is selected at each occurrence from the group: CF 3 , OCF 3 , Cl, F, Br, OH, C(0)OR 1:L , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , -CN, N0 2 ; C1-C4 alkyl substituted with 0-1 R 9e , C 1 -C 4 alkoxy substituted with 0-1 R 9e ,
  • 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-3 R 9e ;
  • R 9e is selected at each occurrence from the group:
  • R 11 and R lla are, at each occurrence, independently selected from the group: H, C 1 -C 4 alkyl substituted with 0-1 R llb , phenyl substituted with 0-2 R llb ; and benzyl substituted with 0-2 R ll ;
  • R ll is OH, C 1 -C 4 alkoxy, F, Cl, Br, I, NH , or -NH(C ⁇ -C alkyl) ;
  • R 13 is selected from the group: H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -Cg cycloalkyl (C 1 -C 4 alkyl), aryl and aryl-C -C alkyl;
  • OR 26 and OR 27 are independently selected from: a) -OH, d) C 1 -C 8 alkoxy, and when taken together, OR 26 and OR 27 form: e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 16 carbon atoms;
  • a 4 and A 5 are independently selected from an amino acid residue wherein said amino acid residue, at each occurence, is independently selected from the group: Ala, Arg, Asn, Asp, Aze, Cys, Gin, Glu, Gly, His, Hyp, lie, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, Val, Abu, Alg, Ape, Cha, Cpa, Cpg, Dfb, Dpa, Gla, Irg, HomoLys, Phe (4-fluoro) , Tpa, Asp(OMe), Glu (OMe), Hyp (OMe), Asp(OtBu), Glu(O t Bu), Hyp(O t Bu), Thr( ⁇ t Bu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), Pro(OBzl), Thr(OBzl), cyclohexylglycine, cyclohexylalanine, cycl
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein :
  • a 1 is -CH 2 -;
  • W is -B(OR 26 ) (OR 27 ) ;
  • R 1 is selected from the group: H; C 1 -C 4 alkyl substituted with 0-2 R la ;
  • R la is selected at each occurrence from the group: Cl, F, Br, CF 3 , and CHF 2 ;
  • R 2 is H
  • R 3 is selected from the group: R 4 , -(CH 2 ) P -NH-R 4 ,
  • p is 0 or 1;
  • R 4 is selected from the group:
  • 5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, lf-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl , oxazolopyridinyl , imidazolopyridinyl , pyrazolopyridinyl , 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl
  • R 4b is, at each occurrence, independently selected from:
  • R c is, at each occurrence, independently selected from:
  • R d is, at each occurrence, independently selected from:
  • R 6 is H, methyl, ethyl, propyl, or butyl
  • R 8 is H or methyl
  • R 9a is selected from the group: H;
  • 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-3 R 9d ;
  • R 9c is selected from the group: CF 3 , 0CF 3 , Cl, F, Br, OH, C(0)OR 1:L , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , -CN, N0 2 , and phenyl ,-
  • R 9d is selected at each occurrence from the group: CF 3 , OCF 3 , Cl, F, Br, OH, C(0)OR 1:L , NH , NH(CH 3 ), N(CH 3 ) 2 , -CN, N0 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and phenyl ;
  • R 11 and R ll are, at each occurrence, independently selected from the group: H, methyl, ethyl, propyl, butyl, phenyl and benzyl;
  • R 13 is selected from the group: H, C 1 -C 4 alkyl, phenyl and phenyl-C 1 -C 4 alkyl ;
  • OR 26 and OR 27 are independently selected from: a) -OH, d) C1-C8 alkoxy, and when taken together, OR 26 and OR 27 form: e) a cyclic boronic ester where said cyclic boronic ester is formed from the group: pinanediol, pinacol, 1, 2-ethanediol, 1, 3-propanediol, 1,2- propanediol, 2, 3-butanediol, 1,2- diisopropylethanedio, 5, 6-decanediol, 1,2- dieye1ohexy1ethanedio1 , diethano1amine , and 1,2- diphenyl-1 , 2-ethanediol ; and
  • a 4 is selected from the group: Ala, Arg, Asn, Asp, Aze, Cys, Gin, Glu, Gly, His, Hyp, lie, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, Val, Abu, Alg, Ape, Cha, Cpa, Cpg, Dfb, Dpa, Gla, Irg, HomoLys, Phe (4- fluoro) , Tpa, Asp(OMe), Gl (OMe), Hyp(OMe), Asp(O t Bu), Glu(O fc Bu), Hyp(O t Bu), Thr(O t Bu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), Pro(OBzl), Thr(OBzl), cyclohexylglycine, cyclohexylalanine, cyclopropylglycine, t-butylglycine, phenyl
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein : A 1 is -CH -;
  • W is pinanediol boronic ester
  • R 1 is selected from the group: H; C 1 -C 4 alkyl substituted with 0-2 R la ;
  • R la is selected at each occurrence from the group: Cl, F, Br, CF 3 , and CHF 2 ;
  • R 2 is H
  • R 3 is selected from the group: R 4 , -(CH 2 ) P -NH-R 4 ,
  • p is 0 or 1;
  • R 4 is selected from the group:
  • R d is, at each occurrence, independently selected from:
  • R 6 is H, methyl, ethyl, propyl, or butyl
  • R 8 is H or methyl;
  • R 9a is selected from the group: H;
  • 5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-3 R 9d ;
  • R 9c is selected from the group: CF 3 , OCF 3 , Cl, F, Br, OH, C(0)OR 11 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , -CN, N0 2 , and phenyl ;
  • R 9d is selected at each occurrence from the group:
  • R 11 and R lla are, at each occurrence, independently selected from the group: H, methyl, ethyl, propyl, butyl, phenyl and benzyl;
  • R 13 is selected from the group: H, C 1 -C 4 alkyl, phenyl and phenyl-C ⁇ -C 4 alkyl;
  • a 4 is selected from the group: Val, lie, Leu, cyclohexylglycine, cyclopropylglycme, t-butylglycine, phenylglycine, and 3 , -diphenylalanine.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein :
  • a 1 is -CH 2 -;
  • W is pinanediol boronic ester
  • R 1 is H, ethyl, allyl, or 2, 2-difluoro-ethyl
  • R 2 is H
  • R 3 is selected from the group: R 4 , -(CH 2 ) P -NH-R 4 ,
  • p is 0 or 1 ;
  • R 4 is selected from the group: methyl, isopropyl, t-butyl, phenyl, benzyl, phenethyl, Ph-propyl, phenyl,
  • R 6 is H
  • R 8 is H
  • R 9a is selected from the group: H; C 1 -C 4 alkyl substituted with 0-1 R 9c ; phenyl substituted with 0-3 R 9d ; and 5-6 membered heterocyclic group consisting of carbon atoms and 1-3 heteroatoms selected from the group: 0, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-2 R 9d ;
  • R 9c is selected from the group: CF 3 , 0CF 3 , Cl, F, Br, OH, C(0)0R 1:L , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , -CN, N0 2 , and phenyl ;
  • R 9d is selected from the group: CF 3 , OCF 3 , Cl, F, Br, OH,
  • R 11 is selected from the group: H, methyl, ethyl, propyl, butyl and benzyl;
  • R 13 is selected from the group: H, methyl and Ph-propyl .
  • the present invention provides a compound, or a stereoisomer or a pharmaceutically acceptable salt form or prodrug thereof, selected from:
  • compositions comprising one or more of the foregoing compounds and methods of using such compositions in the treatment of hepatitis C virus, such as inhibition of hepatitis C virus protease, in mammals or as reagents used as inhibitors of hepatitis C virus protease in the processing of blood to plasma for diagnostic and other commercial purposes.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating a viral infection which comprises administering to a host in need of such treatment a therapeutically effective amount of compounds of Formula (I) or pharmaceutically acceptable salt forms or prodrug thereof.
  • the present invention provides A method of treating HCV which comprises administering to a host in need of such treatment a therapeutically effective amount of compounds of Formula (I) or pharmaceutically acceptable salt forms or prodrug thereof .
  • Abu is L-aminobutyric acid
  • Ala is L-alanine
  • Alg is L-2-amino-4-pentenoic acid
  • Arg is L-arginine,-
  • Asn is L-asparagine
  • Asp is L-aspartic acid
  • Aze is azedine-2-carboxlic acid
  • Cha is L-2-amino-3-cyclohexylpropionic acid
  • Cpa is L-2-amino-3-cyclopropylpropionic acid
  • Cpg is L-2-amino-2-cyclopropylacetic acid
  • Cys is L-cysteine
  • Dfb is L-4, 4' -difluoro-1-amino-butyric acid
  • Dpa is L-2-amino-3 , 3-diphenylpropionic acid
  • Gla is gamma-carboxyglutamic acid
  • Gin is L-glutamine
  • Glu is L-glutamic acid
  • Gly is glycine
  • His is L-histidine; HomoLys is L-homolysine;
  • Hyp is L-4-hydroxyproline; lie is L-isoleucine;
  • Lys is L-lysine
  • Met is L-methionine
  • Orn is L-ornithine
  • Phe is L-phenylalanine
  • Phe (4-fluoro) is para-fluorophenylalanine
  • Pro is L-proline
  • Ser is L-serine
  • Trp is L-tryptophan
  • Tyr is L-tyrosine
  • Val is L-valine.
  • the "D” prefix for the foregoing abbreviations indicates the amino acid is in the D-configuration.
  • “D,L” indicates the amino is present in mixture of the D- and the L-configuration.
  • the prefix "boro” indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic ester. For example, if R 1 is isopropyl and Y 1 and Y 2 are OH, the C-terminal residue is abbreviated “boroVal-OH” where "-OH” indicates the boronic acid is in the form of the free acid.
  • the pinanediol boronic ester and the pinacol boronic ester are abbreviated "-C 10 H 16 " and "-C 6 H 12 ", respectively.
  • Examples of other useful diols for esterification with the boronic acids are 1, 2-ethanediol, 1, 3-propanediol, 1, 2-propanediol, 2, 3-butanediol, 1,2- diisopropylethanediol, 5, 6-decanediol, and 1,2- dicyclohexylethanediol .
  • Analogs containing sidechain substituents are described by indicating the substituent in parenthesis following the name of the parent residue. For example the analog of boroPhenylalanine containing a meta cyano group is -boroPhe ( CN) - .
  • the following abbreviations may also be used herein and are defined as follows.
  • DIBAL diisobutylalummum hydride.
  • RaNi means Raney nickel.
  • LAH means lithium aluminum hydride .
  • 1,1' -CDI means 1,1'- carbonyldiimidazole.
  • Bn means benzyl.
  • BOC means t-butyl carbamate.
  • CBZ means benzyl carbamate.
  • BSA benzene sulfonic acid
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • EDCI 1- dimethylaminopropyl-3-ethylcarbodiimide hydrochloride
  • HOAt l-hydroxy-7-azabenzotriazole
  • DIEA N,N- diisopropylethylamine
  • Boc- t-butoxycarbonyl-
  • Ac- acetyl
  • pNA p-nitro-aniline
  • DMAP 4-N,N- dimethylaminopyridine
  • Tris Tris (hydroxymethyl ) aminomethane
  • PyAOP 7- azabenzotriazol-1-yloxytris (pyrrolidino)phosphonium hexafluorophosphate
  • MS mass spectrometry
  • FAB/MS fast atom bombardment mass spectrome
  • stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • two hydrogens on the atom are replaced.
  • any variable e.g., R a or R 11
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 4a the definition of R a
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds .
  • stable compound it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
  • amino acid residue refers to natural, modified or unnatural amino acids of either D- or L-configuration and means an organic compound containing both a basic amino group and an acidic carboxyl group. Natural amino acids residues are Ala, Arg, Asn, Asp, Aze, Cys, Gin, Glu, Gly, His, Hyp, lie, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, discloses numerous suitable unnatural amino acids and is incorporated herein by reference for that purpose.
  • acylic N-alkyl and acyclic ⁇ , ⁇ - disubstituted amino acids Included in the scope of the present invention are N-alkyl, aryl, and alkylaryl analogs of both in chain and N-terminal amino acid residues.
  • alkyl, aryl, and alkylaryl maybe substituted for the alpha hydrogen. Illustrated below are examples of N- alkyl and alpha alkyl amino acid residues, respectively.
  • Modified amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, an N-CBZ-protected amino acid, 2 , 4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, 3,3- diphenylalanine, naphthylalanine, phenylglycine, ⁇ -phenylproline, tert-leucine, cyclohexylalanine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3, 4-dehydroproline, t-butylglycine,
  • amino acid residue also refers to various amino acids where sidechain functional groups are modified with appropriate protecting groups known to those skilled in the art.
  • the Peptides Vol 3, 3-88 (1981) discloses numerous suitable protecting groups and is incorporated herein by reference for that purpose.
  • amino acids where sidechain functional groups are modified with appropriate protecting groups include, but are not limited to, Asp(OMe), Glu (OMe), Hyp(OMe), Asp(O fc Bu), GlufOt ⁇ u),
  • amino acid residue in the present invention includes, but is not limited to, Ala,
  • a preferred scope of substituent A 4 is Val, lie, Leu, cyclohexylglycine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3 , 3-diphenylalanine .
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "C 1 -C 6 alkyl” denotes alkyl having 1 to 6 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2- methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl .
  • alkenyl or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration having the specified number of carbon atoms and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain.
  • alkenyl include, but are not limited to, ethenyl, 1- propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
  • Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • Cycloalkyl is intended to include saturated ring groups, having the specified number of carbon atoms. For example, “C 3 -C 6 cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Alkoxy or "alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
  • alkylthio or “thioalkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulpher bridge.
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2 , 2 , 2-trifluoroethyl, heptafluoropropyl , and heptachloropropyl .
  • haloalkyl also include “fluoroalkyl” which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
  • “carbocycle” , “carbocyclic ring”, “carbocyclic group”, or “carbocyclic ring system” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4. O]bicyclodecane (decalin) , [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) .
  • heterocycle As used herein, the term “heterocycle”, “heterocyclic group”, “heterocyclic ring” “heterocyclic ring system” or “Het” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
  • heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5, 2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1, 2 , 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl , benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, benzo [1,3] dioxol-yl, 2,3-dihydro-benzo [1,4] dioxin-yl , carbazoly
  • Preferred 5-10 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, lff-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl
  • Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles .
  • Het- (lower alkyl)- means a heterocyclic ring as defined above linked through a chain or branched Ci-C ⁇ alkyl group.
  • aryl or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl and naphthyl .
  • NH 2 -blocking group refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substitutes on these groups maybe either alkyl, aryl, alkylaryl which may contain the heteroatoms, O, S, and N as a substituent or in-chain component.
  • a number of NH 2 -blocking groups are recognized by those skilled in the art of organic synthesis. By definition, an NH 2 -blocking group may be removable or may remain permanently bound to the NH 2 .
  • Suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as, benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t- butoxycarbonyl or adamantyloxycarbonyl .
  • aromatic urethane protecting groups such as, benzyloxycarbonyl
  • aliphatic urethane protecting groups such as t- butoxycarbonyl or adamantyloxycarbonyl .
  • Amine protecting groups may include, but are not limited to the following: 2,7-di-t- butyl- [9- (10 , 10-dioxo-lO ,10,10, 10-tetrahydrothio- xanthyl) ]methylo xycarbonyl; 2- trimethylsilylethyloxycarbonyl ; 2-phenylethyloxycarbonyl ; 1, 1-dimethyl-2, 2-dibromoethyloxycarbonyl; 1-methyl-l- (4- biphenylyl) ethyloxycarbonyl; benzyloxycarbonyl ; p- nitrobenzyloxycarbonyl ; 2- (p- toluenesulfonyl) ethyloxycarbonyl; m-chloro-p- acyloxybenzyloxycarbonyl; 5- benzyisoxazolylmethyloxycarbonyl; p- (dihydroxyboryl) benzyloxycarbonyl
  • cyclic boronic ester is intended to mean a stable cyclic boronic moiety of general formula -B(OR) (OR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or O. Cyclic boronic esters are well known in the art.
  • cyclic boronic ester examples include, but are not limited to, pinanediol boronic ester, pinacol boronic ester, 1, 2-ethanediol boronic ester, 1, 3-propanediol boronic ester, 1,2- propanediol boronic ester, 2 , 3-butanediol boronic ester, 1, 2-diisopropylethanediol boronic ester, 5, 6-decanediol boronic ester, 1, 2-dicyclohexylethanediol boronic ester, diethanolamine boronic ester, and 1, 2-diphenyl-1, 2- ethanediol boronic ester.
  • cyclic boronic amide is intended to mean a stable cyclic boronic amide moiety of general formula -B(NR) (NR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0.
  • Examples of cyclic boronic amide include, but are not limited to, 1, 3-diaminopropane boronic amide and ethylenediamine boronic amide .
  • cyclic boronic amide-ester is intended to mean a stable cyclic boronic amide-ester moiety of general formula -B(OR) (NR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or O.
  • cyclic boronic amide include, but are not limited to, 3-amino-l-propanol boronic amide-ester and ethanolamine boronic amide-ester.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic ' residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p.1418, the disclosure of which is hereby incorporated by reference.
  • Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I), and the like.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
  • novel compounds of this invention may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art.
  • the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • one or two electrophiles may be introduced to give substituted bicyclic pyrimidinone 1.7.
  • electrophiles such as aldehydes and epoxides may be employed and the resultant carbanols may optionally be eliminated to afford the alkene.
  • substituents R 3 and R 13 of compound 1.8 may optionally be modified, followed by deprotection to reveal carboxylic acid 1.9.
  • Peptide coulping of acid 1.10 with serine-trap 1.11 affords amide 1.12.
  • the R- derived carbamate functionality is cleaved.
  • R 1 , R 3 , and R 13 functionality may be modified and R 2 may be introduced to afford inhibitor 1.13.
  • Inhibitor 2.9 is prepared analogously to inhibitor 1.13 from piperazinone 2.8.
  • Compound 2-8 is prepared via reductive amination of piperazinone 2-7, which is prepared according to the chemistry developed by Aebischer et al. (Helv. Chim. Acta 1989, 72, 1043-51).
  • Inhibitor 2.12 is prepared from bicyclic pyrimidinone 2.11 via chemistry analogous to the preparation of inhibitor 1.13.
  • Intermediate 2.11 in turn is prepared via a condensation amidine 1.5 and methylene malonate 2.10 followed by N- bromosuccinimide-promoted unsaturation.
  • Compound 2.11 is prepared following chemistry described by Veale et al. (J. Org. Chem. 1993, 58, 4490-4493.).
  • Inhibitor 2.14 is prepared from morpholinone 2.13 via chemistry analogous to the preparation of inhibitor 1.13.
  • Intermediate 2.13 is prepared via a condensation of CbzSerOtBu and methyl bromoacetate .
  • diol protecting groups for example but not to be limiting the scope of workable and known diol protecting groups, pinacol, 1,2- ethanediol, 1, 2-propanediol, 1, 3-propanediol, 2,3- butanediol, 1, 2-diisopropylethanediol, 5, 6-decanediol, 1,2- dicyclohexylethanediol, are known to those skilled in the art .
  • Peptide boronic esters can be prepared from commercially available materials by methods known to one skilled in the art of organic synthesis.
  • Peptide boronic acids and esters are generally well known in the art; however, for a general reference to synthesis of peptide boronic esters, see: Kettner, C; Forsyth, T. Houben-Weyl Methods of Organic Chemistry 1999, in press; for a reference to synthesis of fluorinated peptide residues see Matassa et al . , PCT Application WO 9964442. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application USSN 60/142,561, filed July 7, 1999; herein incorporated in its entirety by reference; as well as copending commonly assigned U.S. Provisional Patent Application USSN
  • Catalytic hydrogenation of 4.13b gives ⁇ -hydroxy ketoester 4.13c.
  • 4.13b is hydrolyzed to free acid 4.13d and coupled to amine H 2 -Q to give Cfoz-protected amino ⁇ - hydroxy amide 4.13e.
  • Catalytic hydrogenation of 4.13e gives ⁇ -hydroxy ketoamide 4.13f .
  • amides or other electrophilic carbonyl derivatives see: Peet et al., Tetrahedron Lett . 1988, 3433-3436; Edwards, P. D. & Bernstein, P. R. , Medicinal Res .
  • Amines of formula H 2 N-Q can be prepared from commercially available materials by methods known to one skilled in the art of organic synthesis. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application USSN 60/168,998, filed December 3, 1999; herein incorporated in its entirety by reference.
  • the serine traps described above are generally coupled to the free acid of the dihydropyrrolopyrazinone using known peptide coupling procedures, preferably by the phosphonium salt PyAOP (Carpino et al . , J. Chem. Soc , Chem. Commun . 1994, 201-203) .
  • the alcohol functionality of the hydroxy serine trap is oxidized by procedures known to those skilled in the art, such as Dess-Martin periodinane method (Dess, D. B & Martin, J. C, J " . Org. Chem. 1983, 48, 4155-4156) in the final step to give a compound of structure 1.11 and 1.12 wherein W contains an activated carbonyl .
  • racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride (Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy 1995, 2602-2605) .
  • a chiral compound may also be directly synthesized using a chiral catalyst or a chiral ligand (Andrew S. Thompson, et al, Tet. lett . 1995, 36, 8937-8940) .
  • Examples are defined as follows: “ °C” for degrees Celsius, “MS” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR” for high resolution, “LC-MS” for liquid chromatography mass spectrometry, “eq” for equivalent or equivalents, “g” for gram or grams, “h” for hour or hours, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “mmol” for millimolar, “M” for molar, “min” for minute or minutes, “HPLC” for high pressure liquid chromatography, “rt” for room temperature, “NMR” for nuclear magnetic resonance spectroscopy, “tic” for thin layer chromatography, “atm” for atmosphere, and “ ⁇ ", “ ⁇ ”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar to one skilled in the art.
  • Boc is tert-butyloxycarbonyl
  • Cbz is benzyloxycarbonyl
  • DCE is 1, 2-dichloroethane
  • DIEA is diethylpropyl amine
  • DMAP is dimethylaminopyridine
  • DMF is dimethylformamide
  • DPPA diphenylphosphoryl azide
  • EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOAt is l-hydroxy-7-azabenzotriazole
  • LiHMDS is bis (trimethylsilyl) amide
  • TBAI is tetrabutylammonium iodide
  • TEA is triethylamine
  • TFA is trifluoroacetic acid
  • tert-Butyl ester lh (11.13g, 28.9 mmol) was dissloved in 1:1 CH 2 C1 2 /TFA. 1 mL H 2 0 was added and the mixture was stirred overnight at rt. The mixture was concentrated and the resultant residue was co-evaporated with CC1 4 (3X) . The residual oil was triturated with 1:1 Et 2 0/hexanes (100 mL) and the solid (9.0 g, 95%) was collected and dried, to provide li . ⁇ -H NMR (300 MHz, CDC1 3 ) ⁇ 8.69 (br s, IH) , MS
  • Example 3 To Example 3 (5.0 mg, 0.011 mmol) in 0.5 mL DCE, were added
  • Example 3 To a solution of amine HCI salt Example 3 (5.0 mg, 0.011 mmol) in 1 mL CH 2 C1 2 , were added DMAP (catalytic), BzCl (1 drop) , TEA (2 drops) . The mixture was stirred at rt for 16.5 h, then concentrated. Purification by flash chromatography (5% MeOH/EtOAc) afforded 4.5 mg (78%) of Example 6. MS (HR-ESI) calculated for C 28 H 36 B ⁇ 4 0 5 (M + H + ) , found 519.2773.
  • the protected pyroglutamate 8b (370 mg, 0.850 mmol) was partially dissolved in 1:1 EtOAc/hexanes (20 mL) and 100 DL
  • Methyl ester 8g (46 mg, 0.112 mmol) was dissolved in 1 mL MeOH at 0°C. To this solution, was added IM LiOH (112 ⁇ L, 0.112 mmol) . The mixture was allowed to slowly warm to rt with stirring for 22 h. The volatiles were evaporated. The mixture was diluted with Et 2 0 and extracted with H 2 0 (3X) .
  • Example 8 (12.2 mg, 0.0183 mmol) and cat. 10% Pd-C were taken up in 2 mL MeOH and 1 drop cone . HCI . The mixture was evacuated and flushed with H 2 (3X) and stirred under an atmosphere of H for 1 h. The mixture was filtered and concentrated to afford the amine as the HCI salt. To a solution of the amine in DCE (1 mL) , was added m ⁇ trifluoromethylbenzaldehyde (23 ⁇ L, 0.18 mmol), TEA (2.5 ⁇ L, 0.018 mmol), AcOH (5.1 ⁇ L, 0.089 mmol), and Na(OAc) 3 BH
  • Example 9 (4.7 mg, 0.0071 mmol) afforded 2.0 mg (41%) of Example 11.
  • Example 14 According to the procedure for the preparation of Example 13, 13a (10 mg, 0.0166 mmol) and phenyl chloroformate (2.3 ⁇ L, 0.018 mmol) afforded 3.2 mg (23%) of Example 14 as the
  • Example 17 According to the procedure for the preparation of Example 16, 13a (8.0 mg, 0.0105 mmol) and benzoyl isocyanate (1.5 mg, 0.0105 mmol) afforded 5.8 mg (64%) of Example 17 as the TFA salt. MS (HR-ESI) calculated for C 38 H 45 BF 3 N 6 0 6 (M + H + ) , found 749.3461.
  • Example 18 (65, 8i?) -N- ⁇ ( lR) -l- [ (3aS, 45, 65, laR) -Hexahydro-3a, 5, 5- trimethyl-4, 6-methano-l, 3 , 2-benzodioxaborol-2-yl]propyl ⁇ -8- ⁇ [ (4-methoxyanilino) carbonyl] amino ⁇ -8-methyl-4-oxo-3- ⁇ [3- ( trifluoromethyl) benzyl] amino ⁇ -4, 6,7,8- tetrahydropyrrolo [1, 2-a]pyrimidine-6-carboxamide
  • Example 18 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 4-methoxyphenyl isocyanate (2.5 mg, 0.017 mmol) afforded 5.3 mg (37%) of Example 18 as the TFA salt. LC-MS (ESI) 751.26 (M + H + ) .
  • Example 19
  • Example 21 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 1-naphthyl isocyanate (2.8 mg, 0.017 mmol) afforded 6.0 mg (41%) of Example 21 as the TFA salt.
  • Example 24 (65, 82?) -N- ⁇ (l2?)-l-[ (3a5, 45, SS, laR) -Hexahydro-3 a, 5, 5- trimethyl-4, 6-methano-l, 3 , 2-benzodioxaborol-2-yl]propyl ⁇ -- 8-methyl-4-oxo-8- ⁇ [ (4-phenoxyanilino) carbonyl] amino ⁇ 3- ⁇ [3- ( trifluoromethyl) benzyl] amino ⁇ -4, 6,7,8- tetrahydropyrrolo [1, 2-a]pyrimidine-6-carboxamide
  • Example 25 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 4-phenoxyphenyl isocyanate (3.5 mg, 0.017 mmol) afforded 6.8 mg (44%) of Example 24 as the TFA salt. LC-MS (ESI) 813.31 (M + H + ) .
  • Example 25 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 4-phenoxyphenyl isocyanate (3.5 mg, 0.017 mmol) afforded 6.8 mg (44%) of Example 24 as the TFA salt. LC-MS (ESI) 813.31 (M + H + ) .
  • Example 25 Example 25
  • Example 16 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 4-acetylphenyl isocyanate (2.7 mg, 0.017 mmol) afforded 6.5 mg (45%) of Example 25 as the TFA salt.
  • Example 27 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and trans-2- phenylcyclopropyl isocyanate (2.6 mg, 0.017 mmol) afforded 4.4 mg (30%) of Example 27 as the TFA salt. LC-MS (ESI) 761.22 (M + H+) .
  • Example 28
  • Example 16 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 2, 4-difluorophenyl isocyanate (2.6 mg, 0.017 mmol) afforded 5.4 mg (37%) of Example 28 as the TFA salt.
  • Example 29 (65, 82?) -N- ⁇ (12?)-l-[ (3a5, 45, SS, laR) -Hexahydro-3a, 5, 5- trimethyl-4, 6-methano-l, 3 , 2-benzodioxaborol-2-yl]propyl ⁇ -8- ⁇ [ (2 , 5-difluoroanilmo) carbonyl] amino ⁇ -8-methyl-4-oxo-3- ⁇ [3- (trifluoromethyl)benzyl] amino ⁇ -4, 6,7,8- tetrahydropyrrolo [1,2-a] yrimidine-6-carboxamide
  • Example 31 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 2-methoxyphenyl isocyanate (2.5 mg, 0.017 mmol) afforded 4.4 mg (31%) of Example 30 as the TFA salt. LC-MS (ESI) 751.25 (M + H + ) . Example 31
  • Example 37 (65, 82?) -N- ⁇ (12?) -1- [ (3a5, 45, 65, 7a2?) -Hexahydro-3a, 5, 5- trimethyl-4, 6-methano-l, 3 , 2-benzodioxaborol-2-yl]propyl ⁇ -8- ⁇ [ (2, 6-diisopropylanilino) carbonyl] amino ⁇ -8-methyl-4-oxo-3- ⁇ [3- (trifluoromethyl) benzyl] amino ⁇ -4, 6,7,8- tetrahydropyrrolo [1, 2-a]pyrimidine-6-carboxamide
  • Example 37 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 2, 6-diisopropylphenyl isocyanate (3.4 mg, 0.017 mmol) afforded 4.9 mg (32%) of Example 37 as the TFA salt.
  • Example 38 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and methyl 2- isocyanatobenzoate (2.9 mg, 0.017 mmol) afforded 4.9 mg (33%) of Example 38 as the TFA salt.
  • Example 39 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and ethyl 2- isocyanatobenzoate (3.2 mg, 0.017 mmol) afforded 4.2 mg (28%) of Example 39 as the TFA salt.
  • Example 40 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 2-isopropylphenyl isocyanate (2.7 mg, 0.017 mmol) afforded 4.9 mg (34%) of Example 40 as the TFA salt.
  • Example 41 According to the procedure for the preparation of Example 16, 13a (10.0 mg, 0.0166 mmol) and 3 , 4, 5-trimethoxyphenyl isocyanate (3.5 mg, 0.017 mmol) afforded 3.7 mg (24%) of Example 41 as the TFA salt.

Abstract

L'invention concerne une nouvelle classe de pyrimidinones de formule (I) qui sont utiles comme inhibiteurs de la protéase à sérine, et plus spécialement comme inhibiteurs de la protéase NS3 du virus de l'hépatite C. L'invention concerne également des compositions pharmaceutiques renfermant ces composés et des procédés d'utilisation de ces dernières.
PCT/US2001/047911 2000-12-13 2001-12-12 Inhibiteurs de la protease ns3 du virus de l'hepatite c WO2002048116A2 (fr)

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