WO2007120595A2 - Composés organiques et leurs utilisations - Google Patents

Composés organiques et leurs utilisations Download PDF

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Publication number
WO2007120595A2
WO2007120595A2 PCT/US2007/008712 US2007008712W WO2007120595A2 WO 2007120595 A2 WO2007120595 A2 WO 2007120595A2 US 2007008712 W US2007008712 W US 2007008712W WO 2007120595 A2 WO2007120595 A2 WO 2007120595A2
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Prior art keywords
alkyl
aryl
cycloalkyl
heteroaryl
substituted
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PCT/US2007/008712
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English (en)
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WO2007120595A3 (fr
Inventor
Pascal Rigollier
Claus Ehrhardt
David Thomas Parker
Sylvain Cottens
Branko Radetich
Mohindra Seepersaud
Stefan Andreas Randl
Prakash Raman
Jiping Fu
Michael Patane
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Novartis Ag
Novartis Pharma Gmbh
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Publication of WO2007120595A2 publication Critical patent/WO2007120595A2/fr
Publication of WO2007120595A3 publication Critical patent/WO2007120595A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • Hepatitis C virus is a (-f-)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH).
  • NANBH is to be distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV) 5 cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as from other forms of liver disease such as alcoholism and primary biliar cirrhosis.
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • HDV delta hepatitis virus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • HCV protease necessary for polypeptide processing and viral replication has been identified, cloned and expressed.
  • This approximately 3000 amino acid polyprotein contains, from the amino terminus to the carboxy terminus, a nucleocapsid protein (C), envelope proteins (El and E2) and several nonstructural proteins (NSl, 2, 3, 4a, 5a and 5b).
  • NS3 is an approximately 68 kda protein, encoded by approximately 1893 nucleotides of the HCV genome, and has two distinct domains: (a) a serine protease domain consisting of approximately 200 of the N-terminal amino acids; and (b) an RNA-dependent ATPase domain at the C-terminus of the protein.
  • the NS3 protease is considered a member of the chymotrypsin family because of similarities in protein sequence, overall three-dimensional structure and mechanism of catalysis.
  • the HCV NS3 serine protease is responsible for proteolysis of the polypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions and is thus responsible for generating four viral proteins during viral replication. This has made the HCV NS3 serine protease an attractive target for antiviral chemotherapy.
  • NS4a protein an approximately 6 kda polypeptide
  • NS3/NS4a serine protease activity of NS3 It has been determined that the NS4a protein, an approximately 6 kda polypeptide, is a co-factor for the serine protease activity of NS3.
  • Autocleavage of the NS3/NS4a junction by the NS3/NS4a serine protease occurs intramolecularly (i.e., cis) while the other cleavage sites are processed intermolecularly (i.e., trans).
  • HCV has been implicated in cirrhosis of the liver and in induction of hepatocellular carcinoma.
  • the prognosis for patients suffering from HCV infection is currently poor.
  • HCV infection is more difficult to treat than other forms of hepatitis due to the lack of immunity or remission associated with HCV infection.
  • Current data indicates a less than 50% survival rate at four years post cirrhosis diagnosis.
  • Patients diagnosed with localized resectable hepatocellular carcinoma have a five-year survival rate of 10-30%, whereas those with invention.
  • the invention provides a method of treating, inhibiting or preventing the activity of HCV in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of the invention, wherein the compound interacts with any target in the HCV life cycle.
  • the target of the HCV life cycle is selected from the group consisting of NS2 protease, NS3 protease, NS3 helicase, NS5a protein andNS5b polymerase. . :
  • the invention provides a method of decreasing the HCV RNA load in a subject in need thereof comprising administering to the subject a pharmaceutically acceptable amount of a compound of the invention.
  • the compounds of the invention exhibit HCV protease activity.
  • the compounds are an HCV NS3-4A protease inhibitor.
  • the invention provides a method of treating an HCV- associated disorder in a subject, comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention, and a pharmaceutically acceptable carrier, such that the HCV-associated disorder is treated.
  • the invention provides a method of treating an HCV- associated disorder comprising administering to a subject in need thereof a pharmaceutically . effective amount of a compound of the invention, in combination with a pharmaceutically effective amount of an additional HCV-modulating compound, such as interferon or derivatized interferon, or a cytochrome P450 monooxygenase inhibitor, such that the HCV- associated disorder is treated.
  • an additional HCV-modulating compound such as interferon or derivatized interferon, or a cytochrome P450 monooxygenase inhibitor, such that the HCV- associated disorder is treated.
  • the additional HCV-modulating compound is selected from the group consisting of Sch 503034 and VX-950.
  • the invention provides a method of inhibiting hepatitis C virus replication in a cell, comprising contacting said cell with a compound of the invention.
  • the invention provides a packaged HCV-associated disorder treatment, comprising an HCV-modulating compound of the invention, packaged with instructions for using an effective amount of the HCV-modulating compound to treat an HCV-associated disorder.
  • the HCV-associated disorder is selected from the group consisting of HCV infection, liver cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma, and a suppressed innate intracellular immune response.
  • the invention provides a method of treating HCV infection, liver cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non- Hodgkin's lymphoma, and/or a suppressed innate intracellular immune response in subject in need thereof comprising administering to the subject a pharmaceutically acceptable amount of a compound of the invention.
  • the HGV to be treated is selected of any HCV genotype.
  • the HCV is selected from HCV genotype 1, 2 and/or 3.
  • This invention is directed to compounds, e.g., peptide compounds, and intermediates thereto, as well as pharmaceutical compositions containing the compounds for use in treatment of HCV infection.
  • This invention is also directed to the compounds of the invention or compositions thereof as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS3 protease inhibitors.
  • the compounds are particularly useful in interfering with the life cycle of the hepatitis C virus and in treating or preventing ah HCV infection or physiological conditions associated therewith.
  • the present invention is also directed to methods of combination therapy for inhibiting HCV replication in cells, or for treating or preventing an HCV infection in patients using the compounds of the invention oir pharmaceutical compositions, or kits thereof.
  • This application features novel functional substituents at the putative P2 position, P3 position, capping groups ("CG activity moiety") and the W position.
  • the characteristics of these chemical embodiments include N-alkyl glycine amino-acids, beta-amino acids and heterocyclic capping groups.
  • Pharmacokinetic properties can be improved by prolonging tl/2 as these substituents may be less likely to be recognized by degrading enzymes and other biological clearance mechnisms as compared to standard unsubstituted peptide-like amide linkages.
  • the CG activity moieties of the invention may exploit advantageous interactions within the biological target emparting superior potenty and/or replicon activity, as well as circumvent solubility and cyp interaction problems as compared to the current competitive templates.
  • the compounds of the invention are of the formula A:
  • CG is selected from the group consisting of
  • P3 is a P3 activity moiety
  • P2 is a P2 activity moiety
  • W is a W activity moiety
  • y is O or l
  • x is 0 or 1 ;
  • R 1 , R 2 , R 8 , R 9 , R 1 ' , R 12 arid R 13 are each, independently, selected from the group consisting of H, alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl- heteroaryl, cycloalkyl, alkyloxy, alkylraryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which may be further independently substituted one or more times with X 1 and X 2 ; wherein X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyi
  • X 2 is hydroxy, alkyl, aryl, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, keto, ester or nitro; wherein each of said alkyl, alkoxy, and aryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different and
  • ⁇ ⁇ are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-aikyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl and heteroarylalkyl.
  • the compounds of the invention are of the formula B:
  • P2 is represented by the formula Al:
  • R 7 , R 16 , R 15 , R 17 and R 22 are each, independently, selected from the group consisting of H, alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylarnino, arlylalkyloxy and heterocyclylamino; all of which may be further independently substituted one or more times with X 1 and X 2 ; wherein X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl
  • HCV-associated disorders There is also a need for compounds useful in the treatment or prevention or amelioration of one or more symptoms of HCV 5 as well as a need for methods oftreatment or prevention or amelioration of one or more symptoms of HCV. Furthermore, there is a need for methods for modulating the activity of HCV -serine proteases, particularly the HCV NS3/NS4a serine protease, using the compounds provided herein.
  • the invention provides compounds of the formula A, B and C, each of which share the general formula:
  • the invention provides a method of treating an HCV-associated disorder comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention, such that the HCV-associated disorder is treated.
  • the invention provides a method of treating an HIV infection comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention.
  • the invention provides a method of treating, inhibiting or preventing the activity of HCV in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of the invention.
  • the compounds of the invention inhibit the activity of the NS2 protease, the
  • R 22 and R 16 may together form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times;
  • R 7 and R 15 may together form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times; . . . or R 17 and R 16 may together form a 4, 5, 6 or 7-membered ring of the formula III:
  • n and g are each, independently, 0, 1 or 2, wherein n and g are not both 2; m is 0 or 1 ;
  • X is O, N or C; .
  • R 4 and R 4a are each, independently, selected from the group consisting of H 5 C 1 - 4 - alkyl. O-C M -alkyl, N(H)-C M -alkyl, (CH 2 )o-4-C 3 -6-cycloalkyl, aryl and heterocycle, all of which may be independently substituted one or more times with a halogen atom or Ci-4-alkyl;
  • R 5 is selected from the group consisting of oxo, -O-, H, O-Ci-4-alkyl, N(H)-C M -alkyl, (CH 2 )o- 4 -C 3 - 6 -cycloalkyl, aryl and heterocycle, and any combination thereof, all of which may be independently substituted one or more times with a halogen atom, aryl, trihalomethyl, or C ⁇ -allcyl; or R 4 and R ⁇ may together form a 4, 5, 6 or 7-membered ring that is aromatic or non- aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times; or R 15 and R 16 may together form a 4, 5, 6 or 7-membered ring that is aromatic or non- aromatic and may contain one or more heteroatoms, wherein the ring may be further 30 substituted one or more times; wherein one of the rings that R 15 and R 16 may together form is a ring of the formula IV:
  • CG is a CG activity moiety
  • P3 is a P3 activity moiety
  • W is a W activity moiety
  • x is O ⁇ r l
  • y is 0 or 1 ;
  • R 1 , R 2 , R 8 , R 9 , R 1 ', R 12 and R 13 are each,, independently, selected from the group consisting of H, alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl- heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloaikyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which may be further independently substituted one or more times with X 1 and X 2 ; wherein X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-
  • alkoxy, and aryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl and heteroarylalkyl.
  • the compounds of the invention are of the formula C:
  • CG is a CG activity moiety
  • P2 is a P2 activity moiety
  • P3 is a P3 activity moiety; x is 0 or 1; y is 0 or 1 ;
  • R 1 , R 2 , R 8 , R 9 , R 1 ', R 12 and R 13 are each, independently, selected from the group consisting of H, alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heter ⁇ aryl, alkyl- heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heterparylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which may be further independently substituted one or more times with X 1 and X 2 ; wherein X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl
  • P3 is selected from the group consisting of H, Ci- 4 -alkyl, and (CH 2 )o- 4 -C 3 - 6 -cycloalkyl, substituted or unsrubstituted aryl, and substituted or unsubstituted heterocycle.
  • P2 is represented by the formula Al, A2, A3, A4, A5, A6, A7 or A8:
  • R 7 , R 16 , R 15 , R 17 and R 22 are each, independently, selected from the group consisting of H, alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-aiylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which may be further independently substituted one or more times with X 1 and X 2 ; wherein X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocycly
  • n and g are each, independently, 0, 1 or 2, wherein ri and g are not both 2; m is 0 or 1 ;
  • X is O 5 N or C
  • R 4 and R 4a are each, independently, selected from the group consisting of H, Ci -4 - alkyl, which ;
  • R s is selected from the group consisting of oxo, -O-, H, C M -alkyl, Q-C M -alkyl, N(H)-C i- 4 -alkyl, (CH 2 )o ⁇ -C 3 - 6 -cycloalkyl, aryl and heterocycle, and any combination thereof, all of which may be independently substituted one or more times with a halogen atom, aryl, trihalomethyl, or Ci-4-alkyl; . . .
  • R 4 and R 5 may together form a 4, 5, 6 or 7-membered ring that is aromatic or non- aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times; or R 15 and R 16 may together form a 4, 5, 6 or 7-membered ring that is aromatic or non- aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times; wherein one of the rings that R 15 and R 16 may together form is a ring of the formula IV:
  • n 0 or 1 ;
  • X is N or C;
  • R 4 is selected from the group consisting of H, C ⁇ -alkyl, Ci ⁇ -cycloalkyl, aryl, heterocycle and heteroaryl, all of which may be independently substituted one or more times with a halogen atom or C i- 4 -alkyl;
  • R 5 is selected from the group consisting of oxo, -O-, H, Ci - 4 -alkyl, Ci ⁇ -cycloalkyl, aryl and heteroaryl, and any combination thereof, all of which may be independently substituted one or more times with a halogen atom, aryl, .
  • R 4 and R 5 may together form a dimethyl cyclopropyl ring, a cyclopentane ring, or a phenyl ring, wherein the phenyl ring and dimethyl cyclopropyl ring may be substituted with a halogen atom, aryl, trihalomethyl, or C ⁇ -alkyl, or such that a fused ring system is formed; and
  • R 6 and R 7 are each, independently, selected from the group consisting of H, C ⁇ -alkyl and (GH 2 )o-4-C 3 ⁇ -cycloalkyl;
  • R 4 , R 5 and R 6 are each, independently, selected from the group consisting of H, alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamin ⁇ , cycloalkylamino, carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which may be further independently substituted one or more times with X 1 and X 2 ; wherein X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl
  • W is selected from the group consisting of H, alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl- heteroaryl, cycloalkyl, alkyloxy, aikyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which may.
  • X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroarylalkyl; wherein X 1 can be independently substituted with one or more of X 2 moieties which can be the same or different and are independently selected; wherein X 2 is hydroxy, alkyl, aryl, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido,
  • X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroarylalkyl; wherein X 1 can be independently substituted with one or more of X 2 moieties which can be the same or different and are independently selected; wherein X 2 is hydroxy, alkyl, aryl, alkoxy, aryloxy,
  • R 22 and R 7 are each, independently, selected from the group consisting of H, C 1-4 - alkyl, O-d ⁇ -alkyl, N(H)-Ci- 4 -alkyl, (CH 2 ) 0 - 4 -C 3-6 -cycloalkyl, aryl and heterocycle, all of which may be independently substituted one or more times with a halogen atom, Ci-4-alkyl, O- C 1-4 -alkyl, N(H)-C 1 - 4 -alkyl, Ci- 4 -alkyl substituted by one or more halogen atoms, or C3-6- cycloalkyl; n and g are each, independently, 0, 1 or 2, wherein n and g are not both 2; . . ' rri is O or 1;
  • X is O, N or C
  • R 4 and R 4a are each, independently, selected from the group consisting of H, C 1-4 - alkyl, O- C 1-4 -alkyl, N(H)-Ci - 4 -alkyl, (CH 2 )o- 4 -C 3 ⁇ -cycloalkyl, aryl and heterocycle, all of . which may be independently substituted one or more times with a halogen atom or Ci- 4 -alkyl;
  • R 5 is selected from the group consisting of oxo, -O-, H, Ci-4-alkyl, O-Ci-4-alkyl, N(H)-C 1 - 4 -alkyl, (CH 2 )o- 4 -C 3 - 6 -cycloalkyl, aryl and heterocycle, and any combination thereof, all of which may be independently substituted one or more times with a halogen atom, aryl, trihalomethyl, or Ci-4-alkyl;
  • R 6 are each, independently, selected from the group consisting of H, Ci-4-alkyl, O-Cu 4 -alkyl, N(H)- C 1-4 -alkyl, and (CH 2 )o- t -C 3 ⁇ -cycloalkyl; or R 4 and R 5 may together form a 4, 5, 6 or 7-membered ring that is aromatic or non-r aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times; ' ⁇
  • R 7 , R 15 , R 22 , R 25 and R 26 are each, independently, selected from the group consisting of H, alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycl ⁇ alkylamin ⁇ , carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which may be further independently substituted one or more times with X 1 and X 2 ; wherein X 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
  • R 7 , R 17 , R 22 , R 27 and R 28 have the meanings for R 26 of A4 above; wherein R 7 , R 16 , R 22 , R 29 and R 30 have the meanings for R 26 of A4 above;
  • R 7 , R 15 , R 30 and R 31 have the meanings for R 26 of A4 above;
  • R 7 and R 15 have the meanings for R 26 of A4 above.
  • R 1 , R 2 , R 8 , R 9 , R 11 , R 12 and R 13 are each, independently, selected from the group consisting of H, C ⁇ -alkyl, and (CH2)o-4-C3-6- cycloalkyl.
  • R 33 is selected from the group consisting of H, phenyl, methyl, CF3, tBu, NO 2 , Cl, CN, NH 2 , OH, NHCH 3 , OCH 3 , NHPh, OPh, NHCOCH 3 , NHCOPh, 0CH2Ph, COCH 3 , CO 2 Et, CO 2 CH 3 , CONHPh and CONHCH 3 , or R 33 can be fused with the phenyl ring to form a naphthyl ring. .
  • each R 24 is independently selected from the group consisting of H, substituted or substituted or unsubstituted-(CH 2 ) 0-4 -C3-6-cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle.
  • the compounds of the invention are found to show IC50 values for HCV inhibition in the range from 10 to more than 100 ⁇ M, or 0.5 to 30 ⁇ M, including, for example, the range from 0.5 tolO ⁇ M or less. . .
  • a compound of the present invention is further characterized as a modulator of HCV, including a mammalian HCV, and especially including a human HCV.
  • the compound of the invention is an HCV inhibitor.
  • the compound of the invention is not VX-950 or Sch 503034 (see, e.g. , Curr. Med. Chem., 2005, 12, 2317-2342; and Antimicrob Agents Chemother. 2006» Mar;50(3): 1013-20, both of which are incorporated herein by reference in their entirety).
  • HCV-associated state or "HCV-associated disorder” include disorders and states (e.g., a disease state) that are associated with the activity of HCV, e.g.) infection of HCV in a subject.
  • HCV-associated states include HCV -infection, liver cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non-Hodgkin's.
  • HCV-associated states are often associated with the NS3 serine protease of HCV. which is responsible for several steps in the processing of the HCV polyprotein into smaller functional proteins.
  • NS3 protease forms a heterodimeric complex with the NS4A protein, an essential cofactor that enhances enzymatic activity, and is believed to help anchor HCV to the endoplasmic reticulum.
  • NS3 first autocatalyzes hydrolysis of the NS3-NS4 A juncture, and then cleaves the HCV polyprotein intermolecularly at the NS4A-NS4B, NS4B-NS5 A and NS5A-NS5B intersections.
  • This process is associated with replication of HCV in a subject. Inhibiting or modulating the activity of one or more of the NS3, NS4A, NS4B, NS5A and NS5B proteins will inhibit or modulate replication of HCV in a subject, thereby preventing or treating the HCV-associated state.
  • the HCV-ass ⁇ ciated state is associated with the activity of the NS3 protease.
  • the HCV- associated state is associated with the activity of NS3-NS4A heterodimeric complex.
  • the compounds of the invention are NS3/NS4A protease inhibitors.
  • the compounds of the invention are NS2/NS3 protease inhibitors. Without being bound by theory, it is believed that the disruption of the above protein- protein interactions by the compounds of the invention will interfere with viral polyprotein processing by the NS3 protease and thus viral replication.
  • HCV-associated disorders also include HC V-dependent diseases.
  • HVC-dependent diseases include, e.g., any disease or disorder that depend on or related to activity or misregulation of at least one strain of HCV.
  • the present invention includes treatment of HCV-associated disorders as described above, but the invention is not intended to be limited to the manner by which the compound performs its intended function of treatment of a disease.
  • the present invention includes treatment of diseases described herein in any manner that allows treatment to occur, e.g., HCV infection.
  • the compounds of the invention can be useful for treating diseases related to HIV, as well as HIV infection and AIDS (Acquired Immune Deficiency Syndrome).
  • the invention provides a pharmaceutical composition of any of the compounds of the present invention.
  • the invention provides a pharmaceutical composition of any of the compounds of the present invention and a pharmaceutically acceptable carrier or excipient of any of these compounds, hi certain embodiments, the invention includes the compounds as novel chemical entities.
  • the invention includes a packaged HCV-associated disorder treatment.
  • the packaged treatment includes a compound of the invention packaged with instructions for using an effective amount of the compound of the invention for an intended use.
  • the compounds of the present invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating HCV-associated disorders.
  • the pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the present active agent along with other pharmaceutically acceptable excipients, carriers, fillers, diluents and the like.
  • pharmaceutically effective amount indicates an amount necessary to administer to a host, or to a cell, issue, or organ of a host, to achieve a therapeutic result, especially an anti-HCV effect, e.g., inhibition of proliferation of the HCV virus, or of any other HCV-associated disease.
  • the diseases to be treated by compounds of the invention include, for example, HCV infection, liver cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non-Hodgkih's lymphoma, and a suppressed innate intracellular immune response.
  • the present invention provides a method for inhibiting the activity of HCV.
  • the method includes contacting a cell with any of the compounds of the present invention.
  • the method further provides that the compound is present in an amount effective to selectively inhibit the activity of one or more of the NS3, NS4A, NS4B, NS5 A and NS5B proteins.
  • the method provides that the compound is present in an amount effective to diminish the HCV RNA load in a subject. .
  • the present invention provides a use of any of the compounds of the invention for manufacture of a medicament to treat HCV infection in a subject.
  • the invention provides a method of manufacture of a medicament, including formulating any of the compounds of the present invention for treatment of a subject. . .
  • CG activity moiety includes moieties that allow the compound of the invention to perform its intended function by, e.g., enhancing the bioavailability, e.g., enhancing the solubility, of the compound of the invention such that the compound will properly interact with the HCV target.
  • bioavailability refers to the amount of the administered drug therapy (in this case the compound of the invention) that reaches and acts upon its target: The term is used for drugs whose efficacy is measured relative to the concentration in the blood even though the ultimate site of action of the drug might be outside the blood, e.g., intracellular (see van Berge-Henegouwen et al., Gastroenterology, 1977, 73, 300).
  • CG activity moieties include substituted and unsubstituted heterocycles.
  • P3 activity moiety includes moieties that allow the compound of the invention to perform its intended function by, e.g., improving the cellular potentcy of the compound of the invention, and/or reducing the hydrolytic instability of the compound of the invention, as well as increasing the bioavailability of the compound (see, e.g., Curr Med
  • the P3 activity moiety may also conformationally restrain the template backbone of the compound of the invention, which optimizes the interaction with the HCV target, hi an embodiment, the P3 activity moiety is selected from the group consisting of H, alkyl, and
  • W activity moiety includes moieties that allow the compound of the invention, to perform its intended function by, e.g., reversibly binding to the NS3/NS4A serine protease of the HCV target (see, e.g., Expert Opin. Invesig. Drugs (2005) 14(9): 1129- 1144, which is incorporated herein by reference in its entirety).
  • W activity moieties include those substituents with a carbonyl functionality.
  • the W activity moiety contains an amide functional group.
  • P2 activity moiety includes moieties that allow the compound of the invention to perform its intended function by, e.g., situating the W activity moiety in the correct geometry such that the W-activity moiety can optimally interact with the HCV target.
  • the P2 activity moiety can also play a role in inducing an effective stabilization of the catalytic His- Asp hydrogen bond of the NS3 protease of the HCV target, by shielding that region of the protease from the solvent (see, e.g., EMBO J. 2000 Mar 15;19(6):1195-206., incorporated herein by reference.)
  • the P2 activity moiety is a ⁇ -amino acid derivative, or an N-alkyl glycine derivative.
  • CG activity moiety, P3 activity moiety, W activity moiety, and P2 activity moiety for the HCV target are known in the art. Examples of such methods, e.g., assays and NMR methodologies for, can be found, for example, in Curr Opin Drug Discov Devel.2004 Jul;7(4):446-59; Anal Biochem. 1996 Aug 15;240(l):60-7; Antimicrob Agents Chemother. 2006 Mar;50(3):1013-20; EMBO j. 2000 Mar 15;19(6): 1195-206; Curr Med Chem.
  • treat includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
  • the treatment comprises the induction of an HCV- inhibited state, followed by the activation of the HCV-modulating compound, which would in turn diminish or alleviate at least one symptom associated or caused by the HCV-associated state, disorder or disease being treated.
  • treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • subject is intended to include organisms, e.g., prokaryotes and eukaryotes, which are capable of suffering from or afflicted with an HCV-associated disorder.
  • subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of
  • the subject is a cell;
  • HCV-modulating compound refers to compounds that modulate, e.g. , inhibit, or otherwise alter, the activity of HCV.
  • an "NS3/NS4 A protease inhibitor,” or an “NS2/NS3 protease inhibitor” refers to a compound that modulates, e.g. ,. inhibits, or otherwise alters, the interaction of these proteases with one another.
  • HCV-modulating compounds include compounds of the formula A, B and C, as well as Table A (including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof).
  • the method includes administering to a subject an effective amount of an HCV-modulating compound of the invention, e.g., HCV-modulating compounds of the formula A, B and C, as well as Table A (including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof).
  • an HCV-modulating compound of the invention e.g., HCV-modulating compounds of the formula A, B and C, as well as Table A (including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof).
  • alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • alkyl also includes alkenyl groups and alkynyl groups.
  • C x -C y -alkyl indicates a particular alkyl group (straight- or branched-chain) of a particular range of carbons.
  • Ci-C 4 -alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl and isobutyl.
  • C 3 - 6 -cycloaikyl includes, but is not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. As discussed below, these alkyl groups, as well as cycloalkyl groups, may be further substituted.
  • alkyl further includes alkyl groups which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C 1 -Ci 0 for straight chain, C 3 -Ci 0 for branched chain), and more preferably 6 or fewer carbons.
  • preferred cycloalkyls have from 4-7 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • alkyl e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl include both "unsubstituted alkyl” and “substituted alkyl", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, which allow the molecule to perform its intended function.
  • substituted is intended to describe moieties having substituents replacing a hydrogen on one or more atoms, e.g. C, O or N, of a molecule.
  • substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • substituents of the invention include moieties selected from straight or branched alkyl (preferably C1-C5), cycloalkyl (preferably C3-C8), alkoxy (preferably Ci -C 6 ), thioalkyl (preferably Ci -C 6 ), alkenyl (preferably C 2 -Ce), alkynyl (preferably C 2 -C O ), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroaryl group, (CR'R")o- 3 NR'R" (e
  • substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, oxime, sulfhydryl, alkylthio, arylthio, .
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (i.e., benzyl)).
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched- chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, de
  • alkenyl further includes alkenyl groups that include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -Ce for straight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both "unsubstituted alkenyls" and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, aryicarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, al
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched- chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups that include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone. (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both "unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, caxboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino
  • alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,. sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • amine or “amino” should be understood as being broadly applied to both a molecule, or a moiety or functional group, as generally understood in the art, and may be primary, secondary, or tertiary.
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon, hydrogen or heteroatom.
  • alkylamino comprises groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
  • dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and diarylamino include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminbalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • amide refers to compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thipcarbonyl . group.
  • the terni includes "alkaminocarbonyl” or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl or alkynyl groups bound to an amino group bound to a carbonyl group. It includes arylaminocarbonyl and arylcarbonylamino groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarbonyl alkenylaminocarbonyl
  • alkynylaminocarbonyl alkynylaminocarbonyl
  • arylaminocarbonyl alkylcarbonylamino
  • alkenylcarbonylamino alkynylcarbonylamino
  • arylcarbonylamino alkylcarbonylamino
  • alkenylcarbonylamino alkynylcarbonylamino
  • arylcarbonylamino alkylcarbonylamino
  • aryl includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, anthryl, phenanthryl, napthridine, indole, benzofuran, purine, benzofuran, deazap ⁇ rine, or indolizine.
  • multicyclic aryl groups e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, anthryl, phenanthryl, napthridine, indole, benzofuran, purine
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxy carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthi ⁇ carbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino,
  • alkylaryl or an aromatic or heteroaromatic moiety.
  • Aryl groups cah also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
  • heteroaryl represents a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyraz ⁇ nyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • heteroaryl is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl.
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10-membered aromatic or nonaromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups.
  • Heterocyclyl therefore includes the above mentioned heteroaryls, as well as dihydro and tetrathydro analogs thereof.
  • heterocyclyl include, but are not limited to the following: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridppyridinyl, pyridazinyl, pyri
  • acyl includes compounds and moieties which contain the acyl radical (CH 3 CO-) or a carbonyl group.
  • substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminbcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbbnylamino), acylamin
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • alkoxy includes substituted and unsubstiruted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, isoprppyloxy, propoxy, butoxy, and pentoxy groups and may include cyclic groups such as cyclopentoxy.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
  • halogen substituted alkoxy groups include, but are not limited to, flu ⁇ r ⁇ methbxy, difluoromethoxy, trifluoromethoxy, chlororriethoxy, dichlorometh ⁇ xy, trichloromethoxy, etc.
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof.
  • moieties that contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • the term “carboxy moiety” or “carbonyl moiety” refers to groups such as “alkylcarbonyl” groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl” groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl” groups wherein an alkynyl group is covalently bound to a carbonyl group, "arylcarbonyl” groups wherein an aryl group is covalently attached to the carbonyl group.
  • the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety.
  • the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon of the carbonyl group, e.g. , an amide), aminocarbonyloxy moieties, wherein an oxygen and a nitrogen atom are both bond to the carbon of the carbonyl group (e.g., also referred to as a "carbamate").
  • aminocarbonylamino groups e.g., ureas
  • the heteroatom can be further substituted with one or more alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.
  • thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • thiocarbonyl moiety includes moieties that are analogous to carbonyl moieties.
  • thiocarbonyl moieties include aminothiocarbonyl, wherein an amino group is bound to the carbon atom of the thiocarbonyl group, furthermore other thiocarbonyl moieties include, oxythiocarbonyls (oxygen bound to the carbon atom), aminothiocarbonylamino groups, etc.
  • ether includes compounds or moieties that contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom that is covalently bonded to another alkyl group.
  • esters includes compounds and moieties that contain a carbon or a heteroatom bound to an oxygen atom that is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom that is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • hydroxy or "hydroxyl” includes groups with an -OH or -O " . .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms. .
  • polycyclyl or “polycycHc radical” include moieties with two or more rings ⁇ e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbdnyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • any combination thereof implies that any number of the listed functional groups and molecules may be combined to create a larger molecular architecture.
  • the structures of some of the compounds of this invention include asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates) are included within the scope of this invention. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical ⁇ controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Compounds described herein may be obtained through art recognized synthesis strategies.
  • substituents of some of the compounds of this invention include isomeric cyclic structures. It is to be understood accordingly that constitutional isomers of particular substituents are included within the scope of this invention, unless indicated otherwise.
  • tetrazole includes tetrazole, 2Z/-tetrazole, 3H- tetrazole, 4H-tetrazole and 5H-tetrazole.
  • the compounds of the present invention have valuable pharmacological properties and are useful in the treatment of diseases.
  • compounds of the invention are useful in the treatment of ⁇ CV-associated disorders, e.g., as drugs to treat HC V infection.
  • use includes any one or more of the following embodiments of the invention, respectively: the use in the treatment of HCV-associated disorders; the use for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, e.g., in the manufacture of a medicament; methods of use of compounds of the invention in the treatment of these diseases; pharmaceutical preparations having compounds of the invention for the treatment of these diseases; and compounds of the invention for use in the treatment of these diseases; as appropriate and expedient, if not stated otherwise.
  • diseases to be treated and are thus preferred for use of a compound of the present invention are selected from HCV-associated disorders, including those corresponding to HCV-infection, as well as those diseases that depend on the activity of one or more of the NS3, NS4A, NS4B, NS5 A and NS5B proteins, or a NS3-NS4A, NS4A-NS4B, NS4B-NS5A or NS5A-NS5B complex.
  • the term "use” further includes embodiments of compositions herein which bind to an HCV protein sufficiently to serve as tracers or labels, so that when coupled to a fluor or tag, or made radioactive, can be used as a research reagent or as a diagnostic or an imaging agent.
  • a compound of the present invention is used for treating HCV-associated diseases, and use of the compound of the present invention as an inhibitor of any one or more HCVs. It is envisioned that a use can be a treatment of inhibiting one or more strains of HCV. .
  • the inhibition of HCV activity may be measured as using a number of assays available in the art. An example of such an assay can be found in. Anal Biochem. 1996 240(1): 60-7; which is incorporated by reference in its entirety. Assays for measurement of HCV activity are also described in the experimental section below.
  • an effective amount of the compound is that amount necessary or sufficient to treat or prevent an HCV-associated disorder, e.g. prevent the various morphological and somatic symptoms of an HCV-associated disorder, and/or a disease or condition described herein.
  • an effective amount of the HCV -modulating compound is the amount sufficient to treat HCV infection in a subject.
  • an effective amount of the HCV-modulating compound is the amount sufficient to treat HCV infection, liver cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non-Hodgkin's lymphoma, and a suppressed innate intracellular immune response in a subject.
  • the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. For example, the choice of the compound of the invention can affect what constitutes an "effective amount.”
  • One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount of the compounds of the invention without undue experimentation.
  • the regimen of administration can affect what constitutes an effective amount.
  • the compound of the invention can be administered to the subject either prior to or after the onset of an HCV-associated state. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the cpmpound(s) of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • Compounds of the invention may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. Methods of use of compounds of the present invention in the treatment of these diseases, or pharmaceutical preparations having compounds of the present invention for the treatment of these diseases.
  • composition includes preparations suitable for administration to mammals, e.g., humans.
  • pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • phrases "pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: 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, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene 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'
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration; The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect.. Generally, out of one hundred per cent, this amount, will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-iri-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monoste
  • compositions may also comprise buffering agents.
  • 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 sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant . (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable . medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs, hi addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, .
  • solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, . perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, . perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, p ⁇ lyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, p ⁇ lyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature andj therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature andj therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • 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, bentonites, 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, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound 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 and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by . dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions* suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. • .
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the . absorption of the drug from subcutaneous or intramuscular injection.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending oh 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 that are compatible with body tissue.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous admini stration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. .
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and . prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • intravenous and subcutaneous doses of the compounds of this invention for a patient when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day.
  • An effective amount is that amount treats an HCV-associated disorder.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • a compound of the present invention While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.
  • protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as e.g., Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp. (URL: http://www.science-of-synthesis.com (Electronic Version, 48 Volumes)); J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G.
  • a characteristic of protecting groups is that they can be removed readily (i.e., without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g. , by enzymatic cleavage).
  • Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se.
  • salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethylhexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates, such
  • Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. , by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.
  • Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereoisomers can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by, e.g., medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials. .
  • Intermediates and final products can be worked up and/or purified according to standard methods, e.g., using chromatographic methods, distribution methods, (re-) crystallization, and the like. . .
  • the process steps to synthesize the compounds of the invention can be carried out under reaction conditions that are known per se, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence.
  • ion exchangers such as cation exchangers, e.g., in the H + form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about -100 0 C to about 190 0 C, including, for example, from approximately - 8O 0 C to approximately.15O 0 C, for example at from -80 to -60 0 C, at room temperature, at from -20 to 4O 0 C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.
  • ion exchangers such as cation exchangers, e.g., in the H + form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about -100 0 C to about 190 0 C, including, for example, from approximately - 8O 0 C
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described in Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. .
  • solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofurane or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, .
  • esters such as lower alkyl-lower alkanoates, for example ethyl acetate
  • ethers such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofurane or dioxane
  • liquid aromatic hydrocarbons such as benzene or toluene
  • alcohols such as
  • acetonitrile such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2- one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes.
  • solvent mixtures may also be used in working up, for example by chromatography or partitioning.
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • the present invention also relates to pro-drugs of a compound of the present invention, that are converted in vivo to the compounds of the present invention as described herein. Any reference to a compound of the present invention is therefore to be understood as referring also to the corresponding pro-drugs of the compound of the present invention, as appropriate and expedient. Combinations .
  • a compound of the present invention may also be used in combination with other agents, e.g., an additional HCV-modulating compound that is or is riot of the the formula A, B and C, for treatment of and HCV-associated disorder in a subject.
  • additional HCV-modulating compound that is or is riot of the the formula A, B and C
  • combination is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the present invention and a combination partner may be administered independently at the same time or . separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof. .
  • WO 2005/042020 describes the combination of various HCV inhibitors with a cytochrome P450 ("CYP") inhibitor.
  • CYP cytochrome P450
  • Any CYP inhibitor that improves the pharmacokinetics of the relevant NS3/4A protease may be used in combination with the compounds of this invention.
  • CYP inhibitors include, but are not limited to, ritonavir (WO 94/14436, incorporated herein by reference in its entirety), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, .
  • CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.
  • a compound to be evaluated may be incubated with 0.1 , 0.5, and 1.0 mg protein/ml, or other appropriate concentration of human hepatic microsomes (e. g., commercially available, pooled characterized hepatic microsomes) for 0, 5, 10, 20, and 30 minutes, or other appropriate times, in the presence of an NADPH- generating system. Control incubations may be performed in the absence of hepatic microsomes for 0 and 30 minutes (triplicate). The samples may be analyzed for the presence of the compound.
  • a compound one concentration, ⁇ IC n , may be incubated with pooled human hepatic microsomes in the absence or presence of a CYP inhibitor (such as ritonavir) under the conditions determined above.
  • a CYP inhibitor such as ritonavir
  • control incubations should contain the same concentration of organic solvent as the incubations with the CYP inhibitor.
  • concentrations of the compound in the samples may be quantitated, and the rate of disappearance of parent compound may be determined, with rates being expressed as a percentage of control activity.
  • one embodiment of this invention provides a method for administering an inhibitor of CYP3 A4 and a compound of the invention.
  • Another embodiment of this invention provides a method for administering an inhibitor of isozyme 3 A4 ("CYP3 A4"), isozyme 2C19 (“CYP2C19”), isozyme 2D6 (“CYP2D6"), isozyme 1 A2 (“CYP1A2”), isozyme 2C9 (“CYP2C9”), or isozyme 2El (“CYP2E1").
  • CYP3A4 activity is broadly observed in humans. Accordingly, embodiments of this invention involving inhibition of isozyme 3A4 would be expected to be applicable to a broad range of patients.
  • this invention provides methods wherein the CYP inhibitor is administered together with the compound of the invention in the same dosage form or in separate dosage forms.
  • Methods of this invention may also involve administration of another component comprising an additional agent selected from an immunomodulatory agent; an antiviral agent; an inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; a CYP inhibitor; or combinations thereof.
  • this invention provides a method comprising administering a compound of the invention and another anti- viral agent, preferably an anti- HCV agent.
  • anti-viral agents include, but are not limited to, immunomodulatory agents, such as ⁇ , ⁇ , and ⁇ interferons, pegylated derivatized interferon-a compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudi ⁇ e; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including helicase, polymerase, and metalloprotease inhibitors- inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g ⁇ ., compounds ofUnited States Patent 5,807, 876,6, 498,178, 6,344, 465,6, 054,472,
  • interferons for use in combination with the compounds of the invention, include, but are not limited to, interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2 A, lymphoblastoid interferon, and interferon tau; and.
  • said compound having anti-hepatitis C virus activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
  • agents e.g., non-immunomodulatory or immunomodulatory compounds
  • a compound of this invention include, but are not limited to, those specified in WO 02/18369, which is incorporated herein by reference.
  • Still other agents for use in combination with the compounds of the invention include, but are not limited to, PEG-INTRON® (peginteferon alfa-2b, available from Schering
  • ALFERON® a mixture of natural alpha interferons made by Interferon Sciences, and available from Purdue Frederick Co., CT
  • a- interferon natural alpha interferon 2a; natural alpha interferon 2b; pegylated alpha interferon
  • Each component of a combination according to this invention may be administered separately, together, or in any combination thereof.
  • dosages of interferon are typically measured in IU ⁇ e.g., about 4 million IU to about 12 million IU) ⁇
  • each component may be administered in one or more dosage forms.
  • Each dosage form may be administered to the patient in any order.
  • the compound of the invention and any additional agent may be formulated in separate dosage forms.
  • the compound of the invention and any additional agent may be formulated together in any combination.
  • the compound of the invention inhibitor may be formulated in one dosage form and the additional agent may be formulated together in another dosage form. Any separate dosage forms may be administered at the same time or different times.
  • composition of this invention comprises an additional agent as described herein.
  • Each component may be present in individual compositions, combination compositions, or in a single composition.
  • All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
  • R-4N-Boc-piperazine 2-carboxylic acid methyl ester (679.4mg, 2.78mmol) and 4- chlorobenzaldehyde (390.94mg, 2.78mmol) are mixed in dichloromethane(l ⁇ ml) for 30 minutes.
  • Sodium triacetoxyborohydride (800mg, 3.77mmol) is added.
  • the mixture is stirred at room temperature for 16 hf .
  • Water is added.
  • the aqueous layer is extracted with dichloromethane twice (3OmL x2).
  • the dichloromethane solution is treated with trifluoracetic acid (30ml). After 4 hrs the solvent is evaporated and re-disolved in water.
  • the water solution is basified by adding K 2 CO 3 (solid).
  • This compound is prepared similarly using (R)- 1 -(4-Chloropheny l)-piperazine-2- carboxylic acid methyl ester as prepared below (after treatment with trifluoroacetic acid and basification with sodium carbonate) in place of (R)-I -(4-Chloro-benzyl)-piperazine-2- carboxylic acid methyl ester.
  • R-4N-Boc-piperazine 2-carboxylic acid methyl ester (4.0gms, 16.4mmol) and 4- chlorophenylboronic acid (5.0gms, 32.8mmol) are mixed in dichloromethane (5OmI) . followed by addition of cupric acetate (3.0gms, 16.4mmol), 4 A molecular sieves (1 gm) and pyridine (3.28ml, 32.8mmol). The mixture is stirred at room temperature for 50 hr. The reaction mixture is concentrated directly in vacuo, diluted with ethyl acetate, and filtered through Celite. The organic filtrate is concentrated and the remaining residue is purified over silica gel column chromatography eluting with hexane and ethyl acetate to give 860 mg as a white solid.
  • Step D dropwis . e.
  • the reaction mixture is gradually warmed to room temperature and stirred foi * . overnight. All the volatiles are removed under vacuum and the residue is dissolved in ethyiacetate (500 mL).
  • the organic layer is washed with water (100 mL), aqueous IN HCl (100 mL), aqueous saturated sodium bicarbonate solution (100 mL), and brine (100 mL).
  • the organic layer is dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • API-MS beiizenesulfonylaminocarbonyl ⁇ -vinyl-cyclopropyll-amide hydrochloride (0.08 g), 1- (chloromethyl)-naphthalene (0.033 g), and K 2 CO 3 (0.066 g) in 1 mL of DMF is stirred at RT overnight. The reaction mixture is taken up in IN HCl, extracted with EtOAc, and concentrated.
  • inhibitory activities of the compounds of the invention against HCV NS3-4A serine protease is determined in a homogenous assay using the full-length NS3-4A protein (genotype Ia, stram HC V-I) and a commercially available internally-quenched fluorogenic peptide substrate as described by Taliani, M., et al. 1996 Anal. Biochem. 240:60-67.
  • the antiviral activity and cytotoxicity of the compounds of the invention is . . determined using a subgenomic genotype Ib HCV replicon cell line (Huh-Luc/neo-ET) containing a luciferase reporter gene, the expression of which is under the control of HCV RNA replication and translation. Briefly, 5,000 replicon cells are seeded in each well of 96- well tissue culture plates and are allowed to attach in complete culture media without G418 overnight. On the next day, the culture media are replaced with media containing a serially diluted compound of the invention in the presence of 10% FBS and 0.5% DMSO.
  • IC 50 is the concentration of the compound of the invention at which the luciferase activity in the replicon cells is reduced by 50%.
  • the cytotoxicity of the compound of the invention are evaluated using an MTS-based cell viability assay.

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Abstract

Cette invention porte sur des composés organiques qui sont utilisés dans le traitement, la prévention et/ou l'amélioration de maladies humaines.
PCT/US2007/008712 2006-04-11 2007-04-09 Composés organiques et leurs utilisations WO2007120595A2 (fr)

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US7825152B2 (en) 2006-04-11 2010-11-02 Novartis Ag Organic compounds and their uses
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US9643999B2 (en) 2012-11-02 2017-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
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US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives

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WO2012109398A1 (fr) 2011-02-10 2012-08-16 Idenix Pharmaceuticals, Inc. Inhibiteurs macrocycliques de sérine protéase, compositions pharmaceutiques les contenant et leur utilisation pour le traitement des infections par le vhc
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US7825152B2 (en) 2006-04-11 2010-11-02 Novartis Ag Organic compounds and their uses
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US8008263B2 (en) 2007-10-10 2011-08-30 Novartis Ag Organic compounds and their uses
JP2011500528A (ja) * 2007-10-10 2011-01-06 ノバルティス アーゲー スピロピロリジン類およびｈｃｖおよびｈｉｖ感染に対するその使用
US8222425B2 (en) 2007-10-10 2012-07-17 Novartis Ag Organic compounds and their uses
EA020951B1 (ru) * 2007-10-10 2015-03-31 Новартис Аг Спиропирролидины и их применение для борьбы с инфицированием посредством hcv (вирус гепатита с) и вич (вирус иммунодефицита человека)
US9422333B2 (en) 2008-08-15 2016-08-23 Celgene Avilomics Research, Inc. HCV protease inhibitors and uses thereof
US8188137B2 (en) 2008-08-15 2012-05-29 Avila Therapeutics, Inc. HCV protease inhibitors and uses thereof
US8980935B2 (en) 2008-08-15 2015-03-17 Celgene Avilomics Research, Inc. HCV protease inhibitors and uses thereof
US8524760B2 (en) 2008-08-15 2013-09-03 Celgene Avilomics Research, Inc. HCV protease inhibitors and uses thereof
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US8512690B2 (en) 2009-04-10 2013-08-20 Novartis Ag Derivatised proline containing peptide compounds as protease inhibitors
US8840878B2 (en) 2009-04-10 2014-09-23 Novartis Ag Peptidomimetic sulfamide compounds and antiviral uses thereof
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US9206232B2 (en) 2009-04-10 2015-12-08 Novartis Ag Organic compounds and their uses
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US11866422B2 (en) 2016-06-21 2024-01-09 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives

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