WO2010096462A1 - Dérivés du diimidazole lié - Google Patents

Dérivés du diimidazole lié Download PDF

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Publication number
WO2010096462A1
WO2010096462A1 PCT/US2010/024447 US2010024447W WO2010096462A1 WO 2010096462 A1 WO2010096462 A1 WO 2010096462A1 US 2010024447 W US2010024447 W US 2010024447W WO 2010096462 A1 WO2010096462 A1 WO 2010096462A1
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Prior art keywords
optionally substituted
compound
group
pharmaceutically acceptable
acceptable salt
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PCT/US2010/024447
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English (en)
Inventor
Yat Sun Or
Xiaowen Peng
Lu Ying
Wang Ce
Datong Tang
Yao-Ling Qiu
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Enanta Pharmaceuticals, Inc
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Publication of WO2010096462A1 publication Critical patent/WO2010096462A1/fr

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    • 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
    • C07D403/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel antiviral agents. More specifically, the present invention relates to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, methods for inhibiting HCV viral replication, and methods for treating or preventing HCV infection.
  • HCV Hepatitis C virus
  • HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants.
  • Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.
  • Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection.
  • adverse side effects are commonly associated with this treatment: flu- like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology 26 (suppl 1): 71S-77S).
  • HCV is now widely accepted as the most common causative agent of post- transfusion non-A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g.
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA - A Publication of the RNA Society. 1(5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition, p931-960; Raven Press, N.Y.).
  • host and virally-encoded proteinases There are three structural proteins, C, El and E2.
  • the P7 protein is of unknown function and is comprised of a highly variable sequence. There are several non- structural proteins.
  • NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • NS5A is a membrane-anchored phosphoprotein that is observed in basally phosphorylated (56 kDa) and hyperphosphorylated (58 kDa) forms.
  • NS5A While its function has not fully been elucidated, NS5A is believed to be important in viral replication.
  • the NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 151 2-22) encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases.
  • RdRp RNA-dependent RNA polymerase
  • the NS5B protein is fairly well conserved both intra- typically (-95-98% amino acid (aa) identity across Ib isolates) and inter-typically (-85% aa identity between genotype Ia and Ib isolates).
  • 3' NTR which roughly consists of three regions: an -40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261).
  • the 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • HCV NS5A protein is described, for example, in Tan, S. -L., Katzel, M.G. Virologv 2001, 284, 1; and in Rice, C. M. Nature 2005, 435, 374. Based on the foregoing, there exists a significant need to identify compounds with the ability to inhibit HCV.
  • a general strategy for the development of antiviral agents is to inactivate virally encoded proteins, including NS5A, that are essential for the replication of the virus.
  • the relevant patent disclosures describing the synthesis of HCV NS5A inhibitors are: US 2009/0202478; US 2009/0202483; WO 2009/020828; WO
  • the present invention relates to novel antiviral compounds represented herein below, pharmaceutical compositions comprising such compounds, and methods for the treatment or prophylaxis of viral (particularly HCV) infection in a subject in need of such therapy with said compounds.
  • Compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
  • the present invention provides a compound of Formula (1-1):
  • L is an aromatic group selected from the group consisting of: i. a bicyclic aryl or bicyclic heteroaryl, wherein the rings of said bicyclic ring system are fused or covalently attached, wherein each imidazole moiety is attached to a different ring of said bicyclic ring system and wherein at least one ring of said bicyclic is a 5- or 7-membered ring; ii.
  • each A is independently a 5-7 membered aryl or heteroaryl, wherein said aryl or heteroaryl are optionally substituted;
  • W is an aliphatic group containing zero to eight carbons; preferably selected from the group consisting of O, S, SO, SO 2 , C(O), NR 11 , optionally substituted Ci-C 4 alkyl, optionally substituted C 2 -C 4 alkenyl and Ci-C 4 alkoxy;
  • R 11 at each occurrence is independently hydrogen or optionally substituted Ci-Cs alkyl
  • R 1 and R 2 at each occurrence are each independently selected from the group consisting of: halogen, cyano, optionally substituted Ci-C 4 alkyl, -0-R 11 , -NR a R b ,
  • R a and R b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cg alkyl, and optionally substituted C 2 - Cg alkenyl; or R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;
  • R 3 and R 4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C 2 -Cg alkenyl, and optionally substituted C 3 -Cg cycloalkyl; preferably hydrogen or optionally substituted Ci-C 4 alkyl; or alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -Cg cycloalkyl or optionally substituted heterocyclic;
  • R 5 at each occurrence is independently hydrogen, optionally substituted Ci-Cg alkyl, or optionally substituted C 3 -Cg cycloalkyl; preferably hydrogen or optionally substituted Ci-C 4 alkyl;
  • R 6 at each occurrence is independently selected from the group consisting of -C(O)-R 12 , -C(O)-C(O)-R 12 , -S(O) 2 -R 12 , and -C(S)-R 12 , preferably -C(O)-R 12 , more preferably an optionally substituted amino acid acyl;
  • R 12 at each occurrence is independently selected from the group consisting of: -O- R 11 , -NR a R b , -R 13 , and -NR c R d , preferably optionally substituted Ci-C 8 alkyl and -0-R 11 ;
  • R 13 at each occurrence is independently selected from the group consisting of hydrogen, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C 3 -Cg cycloalkyl, C 3 -Cg cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted Ci-C 8 alkyl; more preferably Ci-C 8 alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C 4 alkyl); and
  • R c and R d at each occurrence are each independently selected from the group consisting of hydrogen, -R 13 , -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , and -S(O) 2 N(R 13 ),;
  • m is O, 1, or 2, preferably 1;
  • n is 1, 2, 3, or 4, preferably 1 or 2;
  • X at each occurrence is independently selected from O, S, S(O), SO 2 , and C(R 7 ) 2 , preferably CH 2 or CHR 7 ; provided that when m is O, X is C(R 7 ) 2 ; and
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, -0-R 11 , -NR a R b , optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -Ci-C 4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R 7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -Cg cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C 3 -Cg cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
  • the present invention provides a compound of Formula (2-1):
  • A is absent or a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3 -Cg cycloalkyl, and C 3 -Cg cycloalkenyl, each optionally substituted;
  • Y is absent or an optionally substituted aliphatic group selected from the group consisting of O, S, N(R 11 ), Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 - C 8 cycloalkenyl, and heterocyclic, each optionally substituted; or a combination thereof;
  • Z is absent or an optionally substituted linear aliphatic group; optionally Z contains a group selected from O, N(R 11 ), C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ), N(R n )C(0)N(R ⁇ ), N(R 1 ⁇ C(O)C(O)N(R 11 ), N(R ⁇ )S(0) 2 N(R n ), C(0)N(R n )S(0) 2 and C(O)N(R 1 ⁇ S(O) 2 N(R 11 ); wherein at least two of A, Y, and Z are present;
  • R 11 at each occurrence is independently hydrogen or optionally substituted Ci-C 8 alkyl
  • R 1 and R 2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C 1 -C 4 alkyl, -0-R 11 , -NR a R b , -C(O)R 11 , -CO 2 R 11 , and -C(0)NR a R b ; preferably hydrogen, halogen and optionally substituted Ci-C 4 alkyl;
  • R a and R b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 8 alkyl, and optionally substituted C 2 - C 8 alkenyl; or R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;
  • R 3 and R 4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted Ci-C 4 alkyl; or alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic; R 5 at each occurrence is independently hydrogen, optionally substituted Ci-Cg alkyl, or optionally substituted C 3 -Cg cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl;
  • R 6 at each occurrence is independently selected from the group consisting of -C(O)-R 12 , -C(O)-C(O)-R 12 , -S(O) 2 -R 12 , and -C(S)-R 12 , preferably -C(O)-R 12 , more preferably an optionally substituted amino acid acyl;
  • R 12 at each occurrence is independently selected from the group consisting of: -O- R 11 , -NR a R b , -R 13 , and -NR c R d , preferably optionally substituted Ci-C 8 alkyl and -0-R 11 ;
  • R 13 at each occurrence is independently selected from the group consisting of hydrogen, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C 3 -Cg cycloalkyl, C 3 -Cg cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted Ci-Cg alkyl; more preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C 4 alkyl); and
  • R c and R d at each occurrence are each independently selected from the group consisting of hydrogen, -R 13 , -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , and -S(O) 2 N(R 13 ),;
  • m is O, 1, or 2, preferably 1;
  • n is 1, 2, 3, or 4, preferably 1 or 2;
  • X at each occurrence is independently selected from O, S, S(O), SO 2 , and C(R 7 ) 2 , preferably CH 2 or CHR 7 ; provided that when m is O, X is C(R 7 ) 2 ; and
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, -0-R 11 , -NR a R b , optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -Ci-C 4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R 7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -Cg cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C 3 -Cg cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
  • the present invention provides a compound of Formula (3-1): or a pharmaceutically acceptable salt thereof, wherein:
  • A is absent, or is selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted aryl, an optionally substituted heteroaryl, and a combination thereof;
  • Y and Z at each occurrence are each independently selected from -C(O)-, -C(O)O-, -0(O)C-, -C(0)N(R llb )-, -N(R llb )C(0)-, -S(O 2 )N(R 1 lb )-, -N(R llb )S(0 2 )-, -N(R llb )C(0)0- -0C(0)N(R llb )-, and -N(R llb )C(O)N(R llc )-;
  • R llb and R llc at each occurrence is independently hydrogen or optionally substituted C r C 8 alkyl
  • R 1 and R 2 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C4 alkyl, -0-R 11 , -NR a R b , -C(O)R 11 , -CO 2 R 11 , and -C(0)NR a R b ; preferably hydrogen, halogen and optionally substituted Ci-C 4 alkyl; R 11 at each occurrence is independently hydrogen or optionally substituted Ci-Cg alkyl;
  • R a and R b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, and optionally substituted C 2 - C 8 alkenyl; or R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;
  • R 3 and R 4 at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted Ci-C 4 alkyl; or alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -Cs cycloalkyl or optionally substituted heterocyclic;
  • R 5 at each occurrence is independently hydrogen, optionally substituted Ci-Cg alkyl, or optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl;
  • R 6 is selected from the group consisting of -C(O)-R 12 , -C(O)-C(O)-R 12 , -S(O) 2 - R 12 , and -C(S)-R 12 ; preferably, -C(O)-R 12 , more preferably an optionally substituted amino acid acyl;
  • R 12 at each occurrence is independently selected from the group consisting of: -O- R 11 , -NR a R b , -R 13 , and -NR c R d ;
  • R 13 at each occurrence is independently selected from the group consisting of: hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted Ci-C 8 alkyl; more preferably Ci-C 8 alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci-C 4 alkyl); and
  • R c and R d at each occurrence are each independently selected from the group consisting of hydrogen, -R 13 , -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , and -S(O) 2 N(R 13 ),; m is O, 1, or 2; n is 1, 2, 3, or 4;
  • X is selected from O, S, S(O), SO 2 , and C(R 7 ) 2 ; provided that when m is O, X is C(R 7 ) 2 ; and
  • R 7 at each occurrence is independently selected from the group consisting of: hydrogen, halogen, cyano, -0-R 11 , -NR a R b , optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted -Ci-C 4 alkyl; preferably hydrogen, methyl or halogen; or two vicinal R 7 groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl.
  • Each preferred group stated above can be taken in combination with
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting the replication of a RNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • this invention is directed to methods of inhibiting the replication of HCV.
  • the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • this invention is directed to methods of treating or preventing infection caused by HCV.
  • Yet another aspect of the present invention provides the use of a compound or combination of compounds of the present invention, or a therapeutically acceptable salt thereof, as defined hereinafter, in the preparation of a medicament for the treatment or prevention of infection caused by RNA-containing virus, specifically HCV.
  • RNA-containing virus including, for example, HCV
  • Other compounds useful for inhibiting the replication of RNA-containing viruses and/or for the treatment or prophylaxis of HCV infection have been described in copending U.S. Application Serial No. 12/702,673 entitled “Novel Dibenzimidazole Derivatives”; U.S. Application Serial No. 12/702,692 entitled “Novel Dibenzimidazole Derivatives”; and U.S. Application Serial No. 12/702,802 entitled “Novel Dibenzimidazole Derivatives”.
  • the contents of each of the applications are expressly incorpated by reference herein.
  • Compounds having the Formula (1-1) In certain aspects, the present invention relates to compounds of Formula (1-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula (1-Ia), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1- Ib), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula
  • the present invention relates to compounds of Formula (1-Id), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-If), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-If), wherein R 12 is Ci-Cs alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl); or a pharmaceutically acceptable salt thereof.
  • the absolute stereochemistry of the pyrrolidine and 2-imidazolylmethylamine moiety is represented by Formulae (1-Ig- 1, l-Ig-2 and l-Ig-3):
  • the present invention relates to compounds of Formula (1-Ih), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-Ik), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-11), or a pharmaceutically acceptable salt thereof:
  • L and X 1 are as previously defined in Formula (1-1) andR 13a at each occurrence is independently an optionally substituted Ci-Cg alkyl; preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl).
  • the present invention relates to compounds of Formula (1-IIa), or a pharmaceutically acceptable salt thereof: wherein Q, J, A, R 1 , R 2 , and W are as previously defined in Formula (1-1); u and v at each occurrence are each independently 0, 1, 2, or 3, preferably 0 or 1.
  • the present invention relates to compounds of Formula (1-IIb), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIc), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IId), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIa), or a pharmaceutically acceptable salt thereof:
  • Q, J, W, u, v, R 1 and R 2 are as previously defined in Formula (1-1);
  • B is selected from the group consisting of phenyl and five to seven-membered heteroaryl; and Z is independently selected from the group consisting of: absent, O, S, S(O), S(O) 2 , C(O), NR 11 , and C(R n ) 2 ; and R 11 is as previously defined in Formula (1-1).
  • W and Z are attached to adjacent atoms of B.
  • the present invention relates to compounds of Formula (1-IIIb), or a pharmaceutically acceptable salt thereof:
  • Q, J, W, Z, u, v, R 1 and R 2 are as previously defined in Formula (1-1); and B 1 at each occurrence is each independently five to seven-membered heteroaryl.
  • W and Z are attached to adjacent atoms of each B 1 .
  • the present invention relates to compounds of Formula (1-IIIc), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIId), or a pharmaceutically acceptable salt thereof:
  • Q, J, B 1 , W, u, v, R 1 and R 2 are as previously defined in Formula (1-1).
  • W and one of B 1 are attached to adjacent atoms of the other B 1 .
  • B 1 is phenyl and W is -[C(R 11 )2] p -Z-[C(R 11 )2] q -; wherein Z is as previously defined in Formula (1-IIIa); p is O, 1 or 2; and q is 0, 1, 2, 3, or 4; provided that at least one of p or q is not 0.
  • the present invention relates to compounds of Formula (1-IIIe), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIf), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIg), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IIIh), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IVa), or a pharmaceutically acceptable salt thereof:
  • ring B 2 is independently a five or seven-membered heteroaryl.
  • the present invention relates to compounds of Formula (1-IVb), or a pharmaceutically acceptable salt thereof:
  • ring D 1 is independently a fused bicyclic aryl.
  • the present invention relates to compounds of Formula (1-IVc), or a pharmaceutically acceptable salt thereof:
  • ring D 2 is independently a fused bicyclic heteroaryl.
  • the present invention relates to compounds of Formula (1-IVd), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IVe), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IVf), or a pharmaceutically acceptable salt thereof: wherein Q, J, u, v, R 1 and R 2 are as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formula (1-IVg), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IVh), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IVi), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (1-IVj), or a pharmaceutically acceptable salt thereof:
  • the invention is directed to a compound of Formula
  • L is a bicyclic aryl or bicyclic heteroaryl where both rings of said said bicyclic aryl or bicyclic heteroaryl are aromatic; or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a compound of Formula (1-1), wherein L is a tricyclic aryl or tricyclic heteroaryl wherein at least two of the rings of said tricyclic aryl or tricyclic heteroaryl are aromatic; or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a compound of Formula (1-1) wherein L is a tricyclic aryl or tricyclic heteroaryl wherein each of the three rings are aromatic; or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a compound of Formula (1-1), wherein L is a tricyclic aryl or tricyclic heteroaryl, wherein neither imidazole moiety is attached to the center ring of said tricyclic ring system.
  • Representative compounds of the present invention are those selected from compounds 1-1 -a to 1-1-f (shown below) and 1-1 to 1-402 compiled in Tables 1-7:
  • the present invention relates to compounds of Formula (2-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
  • A, Y, Z, R 3 , R 4 , R 5 and R 12 are as previously defined in Formula (2-1) and X 1 at each occurrence is independently CH 2 , CHF, CH(OH), or CF 2 .
  • the present invention relates to compounds of Formula (2-If), wherein R 12 is Ci-Cg alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl); or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula (2-Ih), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-Ik), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (2-11), or a pharmaceutically acceptable salt thereof:
  • A, Y, Z and X 1 are as previously defined in Formula (2-1) andR 13a at each occurrence is independently an optionally substituted Ci-Cg alkyl; preferably Ci-Cg alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl).
  • Ci-Cg alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl).
  • Q, J, R 1 and R 2 are as previously defined in Formula (2-1); Y is present and as previously defined in Formula (2-1); and Z 1 is independently Ci-Cg alkyl, C 2 -Cg alkenyl, or Z 1 is a group containing between one and eight carbon atoms and optionally contains one group independently selected from O, N(R 11 ), C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ), N(R ⁇ )C(0)N(R n ), N(R n )C(0)C(0)N(R ⁇ ), N(R ⁇ )S(0) 2 N(R n ), C(O)N(R n )S(O) 2 and C(O)N(R 1 ⁇ S(O) 2 N(R 11 ); and R 11 is as previously defined in Formula (2-1).
  • Q, J, R 1 and R 2 are as previously defined in Formula (2-1); Y is present and as previously defined in Formula (2-1); and A 4 is an optionally substituted C 3 -Cs cycloalkyl.
  • the present invention relates to compounds of
  • Representative compounds of the present invention are those selected from compounds 2-1-a to 2-1-d (shown below) and 2-1 to 2-368 compiled in Tables 8-14:
  • A is a combination of two or more groups independently selected from an aliphatic group, an aryl, and a heteroaryl, each optionally substituted.
  • Non-limiting examples of such groups are those wherein the linker A contains, for example, two aromatic groups, an aliphatic group and an aromatic group group, two aliphatic groups and an aromatic group or two aromatic groups and an aliphatic group.
  • the present invention relates to compounds of Formula (3-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula (3-Ia), or a pharmaceutically acceptable salt thereof:
  • Q, J, Y, Z, R 1 and R 2 are as previously defined in Formula (3-1) and A 1 is an optionally substituted aryl; preferably, an optionally substituted phenyl ring.
  • the present invention relates to compounds of Formula (3-Ib), or a pharmaceutically acceptable salt thereof:
  • a 3 is an optionally substituted heterocyclic; preferably, 5-7-membered heterocyclic, optionally substituted.
  • the present invention relates to compounds of Formula (3-Id), or a pharmaceutically acceptable salt thereof:
  • a 4 is an optionally substituted C 3 -Cg cycloalkyl; preferably, 5-7-membered cycloalkyl, optionally substituted.
  • the present invention relates to compounds of Formula (3-Ie), or a pharmaceutically acceptable salt thereof:
  • a 5 is an optionally substituted C 3 -Cg cycloalkenyl; preferably, 5-7-membered cycloalkenyl, optionally substituted.
  • the present invention relates to compounds of Formula (3-If), or a pharmaceutically acceptable salt thereof:
  • Q, J, Y, Z, R 1 and R 2 are as previously defined in Formula (3-1) and A 6 is an optionally substituted C 6 -Ci 2 bicycloalkyl; preferably, Cg-Cn bicycloalkyl, optionally substituted.
  • the present invention relates to compounds of Formula (3-Ig), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Ih), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Ii), or a pharmaceutically acceptable salt thereof:
  • a 9 is a polycyclic ring system wherein said ring system comprises any combination of A 1 to A 8 , optionally substituted, and wherein said rings may be fused, covalently attached or a combination thereof.
  • the present invention relates to compounds of Formula (3-II) or (3-III), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3- Ha) or (3-IHa), or a pharmaceutically acceptable salt thereof:
  • R l lb , R 3 , R 4 , R 5 and R 6 are as previously defined in Formula (3-1).
  • the present invention relates to compounds of Formula (3- Hb) or (3-IHb), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3- Hc) or (3-IIIc), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formula (3-Hd) or (3-IHd), or a pharmaceutically acceptable salt thereof:
  • R l lb , R 12 , R 3 , R 4 and R 5 are as previously defined in Formula (3-1).
  • the present invention relates to compounds of Formula (3-He) or (3-IHe), or a pharmaceutically acceptable salt thereof: wherein A, R l lb , R 12 , R 3 , R 4 and R 5 are as previously defined in Formula (3-1) and X 1 is independently CH 2 , CHF, CH(OH), or CF 2 .
  • the present invention relates to compounds of Formula (3-IIf) or (3-IIIf), or a pharmaceutically acceptable salt thereof:
  • R l lb , X 1 and R 12 are as previously defined in Formula (3-1).
  • the present invention relates to compounds of Formulae (3-IId to 3-IIf) and (3-IIId to 3-IHf), wherein R 12 is Ci-C 8 alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci-C 4 alkyl); or a pharmaceutically acceptable salt thereof.
  • the absolute stereochemistry of the pyrrolidine and imidazolylmethylamine moiety is represented by Formula (3-IIg-l, 3-IIg-2 and 3-IIg-3) or (3-IIIg-l, 3-IIIg-2 and 3-IIIg-3):
  • Representative compounds of the present invention are those of formula (3-IV) or
  • A is selected from the group consisting of phenyl, cyclohexyl, [2,2,2]bicyclooctyl, adamantyl and cubyl;
  • R l lb is selected from the group consisting of hydrogen, methyl and ethyl; and R is selected from a group show below in Table 15:
  • any substituent or variable e.g., R 1 , R 2 , u, m, etc.
  • each of the two R 1 groups may be the same or different.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention. It should be understood that the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent.
  • references herein to therapy and/or treatment includes, but is not limited to, prevention, retardation, prophylaxis, therapy and cure of the disease. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection includes treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.
  • a further embodiment of the present invention includes pharmaceutical compositions comprising any single compound or a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or excipient.
  • Yet a further embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising any single compound or a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, in combination with one or more agents known in the art, with a pharmaceutically acceptable carrier or excipient.
  • compounds of the present invention can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection.
  • agents to be administered in combination with a compound or combination of compounds of the present invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms.
  • agents include, but not limited to, host immune modulators (for example, interferon- alpha, pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma, CpG oligonucleotides and the like); antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like); cytokines that modulate immune function (for example, interleukin 2, interleukin 6, and interleukin 12); a compound that enhances the development of type 1 helper T cell response; interfering RNA; anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV; agents that interact with host cellular components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated translation step of HCV viral replication or to block viral particle maturation and release with agents targeted toward the viroporin family of membrane proteins such as, for example
  • compositions of the present invention may further comprise other inhibitor(s) of targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • one embodiment of the present invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second or more antiviral agents, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • RNA-containing virus is hepatitis C virus (HCV).
  • a further embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • RNA-containing virus is hepatitis C virus (HCV).
  • Yet another embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.
  • a non- limiting example of the RNA-containing virus is hepatitis C virus (HCV).
  • a further embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • HIV human immunodeficiency virus
  • the agent that treats patients for disease caused by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T- 1249, or any combination thereof.
  • a non- limiting example of the RNA-containing virus is hepatitis C virus (HCV).
  • a patient may be co-infected with hepatitis C virus and one or more other viruses, including but not limited to human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV).
  • HAV human immunodeficiency virus
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • combination therapy to treat such co-infections by co-administering a compound according to the present invention with at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • the present invention provides the use of a compound or a combination of compounds of the invention, or a therapeutically acceptable salt thereof, and one or more agents selected from the group consisting of a host immune modulator and one or more additional antiviral agents, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, particularly hepatitis C virus.
  • a host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant.
  • said additional antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • combination of compound or compounds of the present invention, together with one or more agents as defined herein above can be employed in pure form or, where such forms exist, or as a pharmaceutically acceptable salt thereof.
  • such combination of therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt thereof, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be used for inhibiting the replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition.
  • RNA-containing virus particularly Hepatitis C virus (HCV)
  • HCV Hepatitis C virus
  • Such compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).
  • a still further embodiment of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt thereof, and one or more agents as defined hereinabove, with a pharmaceutically acceptable carrier.
  • an RNA-containing virus particularly a hepatitis C virus (HCV)
  • HCV hepatitis C virus
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
  • agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.
  • cytochrome P450 monooxygenase inhibitor also referred to herein as a CYP inhibitor
  • the cytochrome P450 monooxygenase inhibitor would be in an amount effective to inhibit metabolism of the compounds of this invention.
  • the CYP inhibitor is administered in an amount sufficient to increase the bioavailiablity of a compound of the invention when the bioavailability of said compound is increased in comparison to the bioavailability in the absence of the CYP inhibitor.
  • the invention provides methods for improving the pharmacokinetics of compounds of the invention.
  • the advantages of improving the pharmacokinetics of drugs are recognized in the art (see, for example, US Patent App. Nos.2004/0091527; US 2004/0152625; and US 2004/0091527). Accordingly, one embodiment of this invention provides a method comprising administering an inhibitor of CYP3A4 and a compound of the invention.
  • Another embodiment of this invention provides a method comprising administering a compound of the invention and an inhibitor of isozyme 3A4 ("CYP3A4"), isozyme 2Cl 9 (“CYP2C19”), isozyme 2D6 (“CYP2D6"), isozyme 1A2 (“CYP1A2”), isozyme 2C9 (“CYP2C9”), or isozyme 2El (“CYP2E1").
  • the CYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics of the relevant compound of the invention may be used in a method of this invention.
  • CYP inhibitors include, but are not limited to, ritonavir (see, for example, WO 94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfmavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.
  • Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole. It will be understood that the administration of the combination of the invention by means of a single patient pack, or patient packs of each formulation, containing within a package insert instructing the patient to the correct use of the invention is a desirable additional feature of this invention.
  • a pack comprising at least a compound of the invention and a CYP inhibitor and an information insert containing directions on the use of the combination of the invention.
  • the pack further comprises one or more of additional agent as described herein.
  • the additional agent or agents may be provided in the same pack or in separate packs.
  • Another aspect of this involves a packaged kit for a patient to use in the treatment of HCV infection or in the prevention of HCV infection, comprising: a single or a plurality of pharmaceutical formulation of each pharmaceutical component; a container housing the pharmaceutical formulation (s) during storage and prior to administration; and instructions for carrying out drug administration in a manner effective to treat or prevent HCV infection.
  • kits for the simultaneous or sequential administration of a compound of the invention and a CYP inhibitor (and optionally an additional agent) or derivatives thereof are prepared in a conventional manner.
  • a kit will comprise, e. g. a composition of a compound of the invention and optionally the additional agent (s) in a pharmaceutically acceptable carrier (and in one or in a plurality of pharmaceutical formulations) and written instructions for the simultaneous or sequential administration.
  • a packaged kit contains one or more dosage forms for self administration; a container means, preferably sealed, for housing the dosage forms during storage and prior to use; and instructions for a patient to carry out drug administration.
  • the instructions will typically be written instructions on a package insert, a label, and/or on other components of the kit, and the dosage form or forms are as described herein.
  • Each dosage form may be individually housed, as in a sheet of a metal foil- plastic laminate with each dosage form isolated from the others in individual cells or bubbles, or the dosage forms may be housed in a single container, as in a plastic bottle.
  • the present kits will also typically include means for packaging the individual kit components, i. e., the dosage forms, the container means, and the written instructions for use.
  • Such packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.
  • aromatic group refers to a moiety that comprises at least one aromatic ring.
  • aryl refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and idenyl.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • heteroaryl refers to a mono- or polycyclic ring system comprising at least one aromatic ring having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl.
  • a polycyclic aryl can comprise fused rings, covalently attached rings or a combination thereof.
  • aromatic groups can be substituted or unsubstituted.
  • the term "bicyclic aryl” or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic.
  • tricyclic aryl or “tricyclic heteroaryl” refers to a ring system consisting of three rings wherein at least one ring is aromatic.
  • the tricyclic aryl or tricyclic heteroaryl is a linear tricyclic aryl or a linear tricyclic heteroaryl, respectively
  • Ci-C 4 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals containing between one and four, one and six, one and eight carbon atoms, or the like, respectively.
  • Examples of C 1 -C 8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
  • C 2 -C 8 alkenyl refers to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.
  • C 2 -C 8 alkynyl refers to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • C 3 -C 8 -cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted.
  • C 3 -C 8 -cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of Cs-Cycycloalkyl include, but not limited to, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and the like.
  • C 3 -C 8 cycloalkenyl refers to monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond, and the carbon atoms may be optionally oxo-substituted.
  • C 3 -C 8 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples Of Cs-C 7 cycloalkenyl include, but not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • arylalkyl refers to an aryl-substituted alkyl group. More preferred arylalkyl groups are aryl-Ci-C 6 -alkyl groups.
  • heteroarylalkyl refers to a heteroaryl-substituted alkyl group. More preferred heteroarylalkyl groups are heteroaryl-Ci-C 6 -alkyl groups. It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
  • An "aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
  • aliphatic groups are functional groups, such as, O, OH, NH, NH 2 , C(O), S(O) 2 , C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH 2 , S(O) 2 NH, S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2 , C(O)NHS(O) 2 NH or C(O)NHS(O) 2 NH 2 , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
  • functional groups such as, O, OH, NH, NH 2 , C(O), S(O
  • Carbon atoms of an aliphatic group can be optionally oxo- substituted.
  • An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example.
  • Aliphatic groups may be optionally substituted.
  • a linear aliphatic group is a non-cyclic aliphatic group.
  • the aliphatic group can be selected from one or more of the specified functional groups or a combination thereof, or a group wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a specified functional group.
  • the linear aliphatic group can be represented by the formula M-V-M', where M and M' are each independently absent or an alkyl, alkenyl or alkynyl, each optionally substituted, and V is a functional group.
  • V is selected from the group consisting of C(O), S(O) 2 , C(O)O, C(O)N(R 11 ), OC(O)O, OC(O)N(R 11 ), S(O) 2 N(R 11 ), N(R ⁇ )C(0)N(R n ), N(R 1 ⁇ C(O)C(O)N(R 11 ), N(R ⁇ )S(0) 2 N(R n ), C(O)N(R 1 ⁇ S(O) 2 or C(O)N(R 1 ⁇ S(O) 2 N(R 11 ); wherein R 11 is as previously defined.
  • an exemplary linear aliphatic group is an alkyl, alkenyl or alkynyl, each optionally substituted, which is interrupted or terminated by a functional group such as described herein.
  • alicyclic denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom, and the carbon atoms may be optionally oxo-substituted.
  • Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.
  • heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above rings may be fused to an aromatic ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo- substituted.
  • heterocycloalkyl groups include, but are not limited to, 1,3- dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted.
  • any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, and aliphatic moiety, or the like, described herein can also be a divalent group when used as a linkage to connect two groups or substituents, which can be at the same or different atom(s).
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO 2 , -N 3 , -CN, -NH 2 , protected amino, oxo, thioxo, -NH-Ci-Ci 2 -alkyl, -NH-C 2 -C 8 -alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -Ci 2 - cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci2-alkyl, -O-C 2
  • hydrox includes hydrogen and deuterium.
  • recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate and the like.
  • activated hydroxy refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t- butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy prodrug group refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the art are described generally in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t- butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • hydrocarbons such as hexane and toluene
  • halogenated hydrocarbons such as, for example, methylene chloride, ethylene chloride, chloroform, and the like
  • heterocyclic compounds such as, for example, tetrahydrofuran and N- methylpyrrolidinone
  • ethers such as diethyl ether, bis-methoxymethyl ether.
  • protic solvents refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et ah, Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, 2 nd Ed. Wiley-VCH (1999); T.W. Greene and P.G.M.
  • subject refers to an animal.
  • the animal is a mammal. More preferably, the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures.
  • the resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981).
  • the compounds described herein contain olefmic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers or cis- and trans- isomers.
  • Tautomers may be in cyclic or acyclic.
  • the configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of these compounds and mixtures thereof.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • the present invention also relates to solvates of compounds of the invention, for example hydrates.
  • This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically acceptable prodrugs of compounds of the invention.
  • compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable carrier or excipient means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra- articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsif ⁇ ers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents,
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, 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 the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
  • Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S.
  • An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • viral infections, conditions are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • an effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • the compounds of the present invention described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with pharmaceutically exipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w).
  • such preparations may contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • additional therapeutic or prophylactic agents includes but not limited to, immune therapies (eg. interferon), therapeutic vaccines, antif ⁇ brotic agents, anti- inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g.
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • anti-oxidants eg N- acetylcysteine
  • cytokine agonists e.g N- acetylcysteine
  • cytokine antagonists e.g N- acetylcysteine
  • lung surfactants e.g N- acetylcysteine
  • antimicrobial and anti-viral agents eg ribavirin and amantidine.
  • Drug resistance most typically occurs by mutation of a gene that encodes for a protein such as an enzyme used in viral replication, and most typically in the case of HCV, RNA polymerase, protease, or helicase.
  • a compound of the present invention can also be administered in combination or alternation with antiviral agent.
  • antiviral agents include ribavarin, interferon, interleukin or a stabilized prodrug of any of them. More broadly described, the compound can be administered in combination or alternation with any of the anti-HCV drugs listed in Table 16 below:
  • PPh 3 for triphenyl-phosphine
  • Troc for 2,2,2-trichloroethyl carbonyl
  • Ts for tosyl or -SO 2 - C 6 H 4 CH 3
  • Ts 2 O for tolylsulfonic anhydride or tosyl-anhydride
  • TsOH for p-tolylsulfonic acid
  • TMS for trimethylsilyl
  • TMSCl trimethylsilyl chloride.
  • the compounds of the present invention may be prepared via several different synthetic routes, depending upon the chemotypes of title compounds. The most straightforward way may involve generation of imidazole-containing building blocks followed by integration with a suitable linkage. Alternatively the title compounds of the present invention may be prepared by imidazole ring closure from a suitable imidazole precursor with well-installed linkage.
  • Schemes Ia, 2a and 3a One of the most straightforward method is shown in Schemes Ia, 2a and 3a, in which s and t at each occurrence are each independently 0, 1, 2 or 3; M, M 1 , and M 2 at each occurrence are each independently a boron, tin, silicon, zinc, zirconium, or copper species; PG is a hydroxy or amino protection group.
  • the synthesis starts from the construction of an optionally substituted imidazole la-2 or la-3, which may be obtained by condensation of glyoxal with another aldehyde Ia-I or Ia-1.1 derived from an amino acid, followed by bromination of the imidazole ring under the conditions which are known to those skilled in the art.
  • the bromination of the imidazole ring may be realized either in one pot by NBS, bromine, 2,4,4,6-tetrobromo-2,5- cyclohexadienone, or the like; or in two steps: 1) dibromide formation in the presence of excess bromination reagent such as NBS, bromine, 2,4,4,6-tetrobromo-2,5- cyclohexadienone, or the like, optionally with heat; and 2) reduction of the dibromide to monobromide in the presence of a reducing reagent such as NaHSO 3 , Na 2 S 2 O 3 , Na 2 SO 3 , or the like.
  • a reducing reagent such as NaHSO 3 , Na 2 S 2 O 3 , Na 2 SO 3 , or the like.
  • the bromides la-2 and la-3 may be coupled with partner la-2.1, a bismetallated reagent under Suzuki or Stille conditions which are known to those skilled in the art (see reviews: A. Suzuki, Pure Applied Chem. 1991, 63, 419; A. Suzuki, Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 249; A. Anastasia, et al, Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 311; F. Bellina, et al, Synthesis 2004, 2419; M. G. Organ, et al, Synthesis 2008, 2776; A. T. Lindhardt, et al, Chem. - A European J. 2008, 14, 8756; E. A. B.
  • Kantchev, et al Angew. Chem. Int. Ed. 2007, 46, 2768; V. Farina, et al, Advances in Metal-Organic Chem. 1996, 5, 1), to provide the linked diimidazole core la-4.
  • bromoimidazole la-2 may be converted to intermediate 1-5 by selectively reacting with metallic reagent la-2.2 under the Suzuki or Stille conditions described previously.
  • intermediate la-5 may be prepared by treating Ia- 2 with dimetallic agent la-2.3 to afford organometallic la-6, followed by coupling with dibromide la-2 A, both may be under the previously decribed Suzuki or Stille reaction conditions.
  • the bromide la-5 may be further converted to organometallic la-7 with dimetallic agent la-2.3 using the conditions described above to prepare la-6. Under the Suzuki or Stille conditions, bromide la-3 may be coupled with organometallic la-7 to afford the linked diimidazole core la-4.
  • Core la-4 may then serve as a common intermediate for further derivaizations to la-8 in two steps: 1) mono-deprotection of the linear or cyclic amine moiety may be accomplished, for example, treatment to hydrogenolytic conditions under Pd catalyst in the presence of a base such as potassium carbonate to remove the Cbz protection group; and 2) the released amine functionality may be acylated with an carboxylic acid under standard acylation conditions, for example a coupling reagent such as HATU in combination with an organic base such as DIPEA can be used in this regard; alternatively, the released amine may be reacted with an isocyanate, carbamoyl chloride or chloroformate to provide an urea or carbamate.
  • a base such as potassium carbonate
  • the released amine functionality may be acylated with an carboxylic acid under standard acylation conditions, for example a coupling reagent such as HATU in combination with an organic base such as DIPEA can be used in this regard; alternatively, the released
  • the compounds of the present invention may also be derived from bromoketone 2a-2, which can be prepared from the corresponding diketone 2a- 1 in the presence of a bromination reagent such as NBS, bromine, or the like, optionally in the presence of an acid and/or with heating. As shown in Scheme 2a, 2a-2 can be converted to keto-ester 2a-
  • 2a-2 can give rise to diamine 2a-4 by displacement with a nucleophile such as azide, phthalimide or sodium formylamide, followed by deprotection.
  • keto-amide 2a-5 can be converted to keto-amide 2a-5 via condensation with excess amount of an appropriate cyclic or acyclic amino acid under standard amide formation condition. Both keto-ester 2a-3 and keto-amide 2a-5 can give rise to diimidazole 2a-6 via heating with ammonium acetate under thermal or microwave condition. Diimidazole 2a-6 may also be prepared by reacting 2 equivalent of la-3.1 with dimetallic agent la-2.1 under the Suzuki or Stille conditions described previously. The linked diimidazole 2a-6 can be further converted to the title compound Ia-b using the conditions described in Scheme Ia.
  • key intermediate 3a-4 may be prepared from the coupling of bromide 3a-3 with organometallic 3a-2 under Suzuki or Stille conditions described previously.
  • Organometallic 3a-2 may be prepared by reacting bromide 3a- 1 with dimetallic agent 3a- 1.1.
  • Intermediates 3a-4 may be then converted to the title compound Ia-c using the procedures described in Scheme Ia.
  • Protected amino aldehyde Ib- 1.1 may be converted to the corresponding imidazole lb-2.1 by condensation with glyoxal in the presence of ammonia optionally with thermal or microwave condition.
  • Bromination of imidazole lb-2.1 with bromine source such as NBS, bromine, 2,4,4,6-tetrabromo-cyclohexa-2,5-dienone, or the like, in protic solvents such as AcOH, EtOH, zPrOH, or the like, may provide dibrommide lb-3.1, which may then be reduced with NaHSO 3 , Na 2 S 2 O 3 , Na 2 SO 3 , or the like to afford monobromide lb-4.1.
  • the free amino group in Ib4.1 may then be protected with using suitable methods which are known in the art to afford Boc protected bromoimidazole Ib- 5.1.
  • Alkene functionality in compound lb-6.1 may then be transformed to aldehyde lb-7.1 by ozonolysis or by oxidative cleavage with reagents such as sodium periodate, sodium chlorite, or the like, in the presence of a catalyst such as but not limited to ruthenium(III) chloride, or osmium tetraoxide, typically in solvents such as THF, water, or the like.
  • Alcohol lb-8.1 may then be derived from reduction of aldehyde lb-7.1 with a reductive reagent such as but not limited to NaBH 4 , lithium aluminum hydride, or diisobutylaluminum hydride.
  • Hydroxy group in lb-8.1 may be converted to LG, which is a leaving group such as but not limited to mesylate, triflate, bromide or iodide, using suitable methods which are known in the art to afford compound lb-9.1.
  • aldehyde Ib- 1.1 could be converted to cyanide lb-10.1 by condensation with reagent such as hydroxylamine, 0-acetylhydroxylamine or the like in presence of a base such as but not limited to NaOH, DIPEA, or DBU, optionally under thermal or microwave condition.
  • Cyanide Ib- 10.1 may be transformed to compound Ib-11.1 by reaction with benzylthiol in solvents such as THF, Et 2 O, or the like, optionally in the presence of acid such as HCl, TFA, or the like at temperature between - 20 0 C to 100 0 C, preferably at rt.
  • Compound Ib-11.1 could be further converted to amine lb-12.1 by coupling with cyanamide in the presence of a base such as pyridine, Et 3 N, DIPEA, or the like in an aprotic solvent such as chloroform, CH 2 Cl 2 , or the like.
  • a desired linkage A may be executed following various synthetic routes, for example, as illustrated in Scheme 2b, in which R s is independently R s ; A al , A a2 , A a3 and A a4 are independently selected from aromatic, heteroaromatic or alkenyl, provided that M attached to an unsaturated bond.
  • Bromide lb-4.1 may be coupled independently with reagent 2b- 1.1.1, 2b-2.1.1, 2b-3.1.1 or 2b-4.1.1 via Suzuki or Stille conditions as previously described to afford products with a variety of functional groups at terminal such as protected alkyne 2b- 1.1, alkene 2b-2.1, alcohol 2b-3.1 or amine 2b-4.1.
  • Alkynyl group in protected allkyne 2b- 1.1 may be exposed to basic conditions and the released alkyne may be coupled to intermediate 2b- 1.2.1 via Sonogashira type conditions (see review: The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry R. Chinchilla, C. Najera, Chem. Rev. 2007; 107, 874) to afford compound 2b- 1.2.
  • Alkene 2b-2.1 may be reacted with alkene 2b-2.2.1 via cross-metathesis reactions (see review: R. H. Grubbs (Ed.), Handbook of Metathesis, Wiley-VCH, Weinheim, 2003) to afford alkene 2b-2.2.
  • Alcohol 2b-3.1 may be coupled with reagent 2b-3.2.1 in the presence a base such as but not limited to NaOH, NaH, t-BuOK or DIPEA, in aprotic solvents such as CH 2 Cl 2 , tolunene, xylenes, or the like to afford ether 2b-3.2.
  • Amine 2b-4.1 may be connected with amine 2b-4.2.1 to give urea 2b-4.2 by treatment with reagents such as phosgene, triphosgene or the like, in the presence of a base such as but not limited to DBU or DIPEA, in aprotic solvents such as CH 2 Cl 2 , THF, or the like.
  • the compounds of the present invention may be prepared through various coupling strategy or a combination of strategies to connect two suitably substituted imidazoles with a suitable linker, such as illustrated in Scheme 2b.
  • the said strategy includes, but not limited to, Stille coupling, Suzuki coupling, Sonogashira coupling, Heck coupling, Buchwald amidation, Buchwald amination, amide coupling, ester bond formation, William etherification, Buchwald etherification, alkylation, pericyclic reaction with different variations, or the like which are known to those skilled in the art.
  • Diketone 3b- 1.1 may be brominated by reagents such as but not limited to bromine or hydrobromous acid in solvents such as CH 2 Cl 2 , AcOH or the like to afford dibromide 3b-2.1, which may be coupled with acid 3b-2.2 in the presence of a base such as but not limited to NaH, DIPEA, Et 3 N or NaOH in aprotic solvent such as THF, CH 3 CN, DMF, CH 2 Cl 2 or the like typically, to afford diester 3b-3.1.
  • reagents such as but not limited to bromine or hydrobromous acid in solvents such as CH 2 Cl 2 , AcOH or the like to afford dibromide 3b-2.1, which may be coupled with acid 3b-2.2 in the presence of a base such as but not limited to NaH, DIPEA, Et 3 N or NaOH in aprotic solvent such as THF, CH 3 CN, DMF, CH 2 Cl 2 or the like typically, to afford diester 3b-3.1.
  • Diimidazole 3b-4.1 may be formed by reaction of diester 3b-3.1 with an ammonia reagent such as but not limited to amonium acetate, or ammonium chloride in aprotic solvent such as toluene, xylenes, benzene or the like at a temperature typically between rt to 180 0 C.
  • an ammonia reagent such as but not limited to amonium acetate, or ammonium chloride in aprotic solvent such as toluene, xylenes, benzene or the like at a temperature typically between rt to 180 0 C.
  • core 4b- 1.1 may then serve as a common intermediate for further derivaizations to 4b-2.1 in two steps: 1) mono-deprotection of the linear or cyclic amine moiety may be accomplished, for example, treatment to hydrogenolytic conditions under Pd catalyst in the presence of a base such as potassium carbonate to remove the Cbz protection group; and 2) the released amine functionality may be acylated with an carboxylic acid under standard acylation conditions, for example a coupling reagent such as HATU in combination with an organic base such as DIPEA can be used in this regard; alternatively, the released amine may be reacted with an isocyanate, carbamoyl chloride or chloroformate to provide an urea or carbamate.
  • a base such as potassium carbonate
  • the released amine functionality may be acylated with an carboxylic acid under standard acylation conditions, for example a coupling reagent such as HATU in combination with an organic base such as DIPEA can be used in this regard; alternative
  • the NH group in the newly formed imidazole lc-4 may be optionally protected using an amino protecting group, such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • an amino protecting group such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • the imidazole ester lc-4 may be converted to the imidazole carboxylic acid lc-5 utilizing a suitable deprotection pathway, depending on the nature of the PG group, found, but are not restricted to, those in T W Greene and P G M Wuts "Protective Groups in Organic Synthesis", 3rd Ed (1999), J Wiley and Sons.
  • the double amide formation between diamine lc-6 and imidazole carboxylic acid lc-5 may be realized in an aprotic solvent such as acetonitrile, DMF, DMSO or the like, optionally with heat, in the presence of a condensation reagent such as EDCI, DCC, HATU or the like, in combination with an organic base such as TEA, DIPEA or the like; or through mixed anhydride approach by reacting acid lc-5 with a chloroformate such as methyl chloroformate, isobutyl chloroformate, or the like, in the presence of a base such as TEA, DIPEA,
  • the compounds of the present invention may also be derived from aldehyde 2c- 1, as illustrated in Scheme 2c.
  • the imidazole ring closure may be accomplished by condensation of 2c- 1 and glyoxal in the presence of ammonia in an alcoholic solvent such as MeOH, EtOH or the like.
  • the NH on the resulting imidazole 2c- 2 may be protected as described above.
  • the protected imidazole 2c-3 may be subjected to various (n-, s-, or t-) butyl lithium and the resulting lithiate can be trapped with carbon dioxide to give the imidazole carboxylic acid 2c-4.
  • Compounds with formula 2c-4 can be converted to the title compounds (3 -lie) using similar conditions as described above in Scheme Ic.
  • the protected imidazole 2c-3 may be subjected to various (n-, s-, or t-) butyl lithium and the resulting lithiate can be trapped with a bis- isocyanate 3c-l to give the diamide 3c-2.
  • Compounds with formula 3c-2 can be converted to the title compounds 3c-4 using similar conditions as described above in Scheme Ic.
  • the compounds of the present invention may be derived from the protected imidazole carboxylic acid 2c-4, as outlined in Scheme 4c.
  • the amino imidazole 4c- 1 may be prepared from the carboxylic acid 2c-4 via Curtius rearrangement (see Michael B. Smith and Jerry March "March's advanced organic chemistry", 5th Ed (2001), Wiley-Interscience).
  • imidazole compounds 4c- 1 can be reductively aminated to give secondary amine 4c-2 using an alkyl aldehyde in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride or hydrogenolytic conditions under Pd catalyst.
  • Step 1-la A solution of bromine (1.23 ml, 23.97 mmol) in glacier acetic acid (6 ml) was added dropwise into a suspension of 2,7-diacetylfluorene (3.0 g, 11.99 mmol) in glacier acetic acid (50 ml) at 50 0 C. Upon completion of the addition, heating was stopped and the mixture was stirred at rt for 24 hr. More bromine (0.31 ml, 6.05 mmol) in glacier acetic acid (1 ml) was added. The mixture was stirred at rt for another 20 hr before being filtered to afford the crude desired dibromide as a yellow solid (5.413 g). Step 1-lb.
  • Step 1-lc A suspension of the compound from step 1-lb (0.970 g, 1.433 mmol) and NH 4 OAc (2.210 g, 28.67 mmol) in xylenes (10 mL) was heated to 140 0 C under microwave for 60 minutes. The mixture was allowed to cool down, partitioned between CH 2 Cl 2 and saturated aqueous NaHCO 3 . The aqueous layer was extracted with CH 2 Cl 2 .
  • Step 1-ld A solution of the compound from step 1-lc (81.0 mg, 0.127 mmol) in CH 2 Cl 2 (5 mL) was treated with HCl in 1,4-dioxane (4 M, 10 mL) at rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • Step 1-lf To a solution of (S)-proline aldehyde (5.00 g, 25.09 mmol) in 7 N ammonia in methanol (100 mL) at 0 0 C was added glyoxal (40% in water, 10 mL) slowly. After the addition, the mixture was allowed to warm to rt gradually and stirred at rt for 24 hr. The volatiles were evaporated off. The residue was partitioned between CH 2 Cl 2 and H 2 O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 1-lg A solution of the compound from step 1-lf (3.56 g, 15.00 mmol) in ethanol (350 mL) was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (90%, 17.07 g, 37.50 mmol) at rt. The mixture was stirred at rt for 24 hr before being concentrated. The residue was partitioned between EtOAc (with 1% Et 3 N) and aqueous NaHCO 3 . The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 1-lh A solution of the compound from step 1-lg (3.164 g, 8.008 mmol) in ethanol (50 mL) was treated with aqueous Na 2 SO 3 (10%, 100 mL) at rt. The resulting suspension was refluxed overnight. The mixture was allowed to cool down and concentrated. The residue was partitioned between CH 2 Cl 2 and H 2 O. The aqueous layer was extracted with EtOAc.
  • Step 1-li A mixture of 2,6-anthracene-bis-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (prepared according to J. Am. Chem. Soc. 2005, 127, 2406-2407, 100.0 mg, 0.232 mmol), the compound from step Ih (161.1 mg, 0.5114 mmol), NaHCO 3 (126.9 mg, 1.511 mmol) and Pd(PPh 3 ) 4 (26.9 mg, 0.02325 mmol) in DME (3 mL) and H 2 O (1 mL) was degassed and then refluxed under N 2 for 18 hours before being allowed to cool down and partitioned between CH 2 Cl 2 and H 2 O.
  • Step 1-lj A solution of the compound from step 1 - Ii (80.1 mg, 0.124 mmol) in 1,4- dioxane (2 mL) was treated with HCl in 1,4-dioxane (4 M, 8 mL) at rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step.
  • Step 1-lk A mixture of the crude compound from step 1-lj (0.124 mmol at most) and
  • Step 1-11 A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol) and JV-Boc-L- praline (3.87 g, 18.0 mmol) in CH 3 CN (60 mL) was added TEA (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at rt until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 1-lm A solution of the compound from step 1-11 (6.73 g, 16.3 mmol) in toluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol) and the resultant mixture was heated up at 100 0 C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHCOs). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%).
  • Step 1-lp A solution of the compound from step l-lo (1.47 g, 3.52 mmol) in toluene (22 mL) was added ammonium acetate (5.42 g, 70.3 mmol) and the resultant mixture was heated up to 100 0 C for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHCO 3 ). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 1-lq A mixture of the compound from step 1-ln (0.204 g, 0.512 mmol), the compound from step 1-lp (0.150 g, 0.342 mmol) and NaHCO 3 (0.115 g, 1.37 mmol) in DME (6 mL) and H 2 O (2 mL) was added Pd(PPh 3 ) 4 (39.4 mg, 34.1 ⁇ mol). The resultant mixture were degassed and heated to 80 0 C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 O). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 1-lr A solution of the compound from step 1-lq (80.0 mg, 0.127 mmol) in 1,4- dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) rt for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • Basic copper(II) carbonate (Cu 2 COs(OH) 2 , 0.663g, 3 mmol) was then added and the resulting mixture was heated at 165 0 C for another 16 hours.
  • the reaction mixture was partitioned between hexanes and water. The organic phase was washed with brine, dried (Na 2 SO 4 ) and evaporated.
  • Step 1-lu A mixture of the compound from step 1-lt (500 mg, 2 mmol), bromine (0.15 mL, 3 mmol) and Cu 2 CO 3 (OH) 2 (480 mg, 3 mmol) in AcOH (0.5 mL) was heated at 60 0 C for 1 hour. The reaction mixture was partitioned between EtOAc and water.
  • Step 1-lv A mixture of the compound from step 1-lu (700 mg, 2.13 mmol), tributyl(l- ethoxy)vinyltin (7.65 mmol, 2.6mL), and Pd(PPh 3 ) 2 Cl 2 (225 mg, 0.32 mmol) in dioxane (6 mL) was degassed and heated at 150 0 C under microwave for 10 minutes. It was partitioned between EtOAc and water. The organic phase was washed with aqueous NH 4 Cl, dried (Na 2 SO 4 ) and evaporated. The residue was redissolved in THF (10 mL) and treated with aqueous HCl (37%, 1 mL) at rt for 1.5 hours.
  • examples 1-3 to 1-402 may be prepared using procedures similar to those described in examples 1-1-2, 1-1 -a to 1-1-f and/or as described in the Synthetic Method.
  • Step 2- Ia Into a solution of acetyl chloride (10 g, 0.127 mol) and AlCl 3 (20 g, 0.15 mol) in carbon disulfide (40 mL) was added cyclohexene (10 g, 0.12 mol) at -50 0 C. The resulting mixture was stirred at -50 0 C for 40 min and the liquid was quickly decanted. The residue was added benzene (100 mL) and the resulting slurry was heated at 45 0 C for 3 hours before it was slowly added into a mixture of ice and 2 M aqueous HCl. The organic phase was washed with aqueous NaOH (1 M), dried (Na 2 SO 4 ) and evaporated.
  • Step 2-lb Into a solution of the compounds from step 2-la (145 mg, 0.59 mmol) in AcOH (2 mL) was added bromine (0.05 mL). The mixture was stirred at rt for 2 hours before all volatiles were removed by rotavap.
  • Example 2-1-b Example 2-1-b.
  • Step 2- Id Into a solution of the compounds from step 2- Ic (65 mg, 0.11 mmol) in CH 2 Cl 2 (1 mL) was added HCl in dioxane (4 M, 5 mL). The resulting mixture was stirred at rt for 40 minutes before all volatiles were removed by rotavap. The residue was redissolved in DMF (2 mL) and was added DIPEA (0.32 mL, 2.3 mmol), HATU (92 mg, 0.24 mmol) and (i?)-(methoxycarbonyl)amino phenyl acetic acid (prepared according to WO 2008/021927, 56 mg, 0.27 mmol).
  • Step 2-lf A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol) and JV-Boc-L- proline (3.87 g, 18.0 mmol) in CH 3 CN (60 mL) was added TEA (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at rt until the disappearance of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 2-li A suspension of the compound from step 2-lh (0.288 g, theo. 0.8636 mmol) and K 2 CO 3 (0.298 g, 2.159 mmol) in methanol (10 ml) was stirred at rt for 1 hour. The volatiles were evaporated off. The residue was taken up in CH 2 Cl 2 /Et0Ac (1/2) and filtered through a short pad of silica gel. The filtrate was concentrated. The residue was combined with another bath (80 mg) and purified by flash column chromatography (silica, dichloromethane-ethyl acetate) to give the desired compound as a white solid (0.123g, 31% over 2 steps).
  • Step 2-lj A mixture of compound from step 2-lg (90.0 mg, 0.2296 mmol) and compound from step 2-li (60.0 mg, 0.2296 mmol), CuI (3 mol%, 0.00689 mmol) and Pd(PPh 3 ) 4 (10 mol%, 26.5 mg, 0.02296 mmol) in acetonitrile (2 mL) and Et 2 N (0.3 mL) was degassed and then refluxed under N 2 for 16 hours before being allowed to cool down and concentrated.
  • Step 2-299a A solution of the compound from step 2-1-d (56.9 mg, 0.0994 mmol) in 1,4- dioxane (1.5 mL) was treated with HCl in 1,4-dioxane (4 M, 6 mL) at rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step.
  • Step 2-362a To a solution of (5)-2-(5-Bromo-lH-imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (prepared according to WO 2008/021927, 0.598 g, 1.892 mmol) and di-tert-butyl dicarbonate (0.619 g, 2.838 mmol) in dichloromethane (10 mL) and Et 3 N (0.79 mL, 5.674 mmol)) was added DMAP (46.2 mg, 0.378 mmol) at rt. The solution was stirred at rt for 2 hours before being concentrated.
  • Step 2-362c To a solution of the compound from step 2-362b (92.0 mg, 0.253 mmol) in THF/H 2 O (3/1, 4 ml) was added OsO 4 (4 wt% in H 2 O, 0.03 mL, 2 mol%), followed by NaIO 4 (113.7 mg, 0.532 mmol) at rt. After 3 hours at rt, more NaIO4 (162.4 mg, 0.759 mmol) was added. After another 2 hours at rt, the reaction was quenched with saturated Na 2 S 2 O 3 solution and extracted with EtOAc.
  • Step 2-362d A solution of the compound from step 2-362c (0.253 mmol at most) in i- PrOH (4 mL) was treated with excess NaBH 4 at 0 0 C until TLC indicated the completion of the reaction. Saturated NH 4 Cl solution was carefully added to quench the reaction, i- PrOH was evaported off. The residue was extracted with EtOAc and dichloromethane. The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • Step 2-362f A solution of the compound from step 2-362e (15.0 mg, 0.0191 mmol) in 1,4-dioxane (0.5 mL) was treated with HCl in 1,4-dioxane (4 M, 2 mL) at rt for 1 h. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step.
  • Step 2-363a A mixture of the compound from step 2-362a (0.650 g, 1.56 mmol), ethynyl-trimethylsilane (2.16 mL, 15.6 mmol), CuI (8.9 mg, 46.8 ⁇ mol) and Pd(PPh 3 ) 4 (90.3 mg, 78.1 ⁇ mol) in CH 3 CN (5 mL) and triethylamine (10 mL) was degassed and heated to 80 0 C under N 2 overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 2-363b The compound from step 2-363a (0.560 g, 1.29 mmol) in MeOH (30 mL) was treated with potassium carbonate (0.535 g, 3.88 mmol) for 30 minutes before being evaporated to dryness. The residue was partitioned (EtOAc - water), and the organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 2-363C A mixture of the compound from step 2-363b (0.103 g, 0.395 mmol), 1,4- diiodo-benzene (62.0 mg, 0.188 mmol), CuI (2.1 mg, 11.2 ⁇ mol) and Pd(PPh 3 ) 4 (21.6 mg, 18.7 ⁇ mol) in CH3CN (1 niL) and triethylamine (4 mL) was degassed and heated to 60 0 C under N 2 for 4 hours.
  • Step 2-364a A solution of the compound from Example 2-363 (73.3 mg, 0.123 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 397.26 [M+H] + .
  • examples 2-1 to 2-360 may be prepared using procedures similar to that described in Examples 2-1 -a to 2-1-d, 2-299, 2-361 to 2-368, and/or as described in the Synthetic Method.
  • Step 3-la DIPEA (9.2 mL, 53.0 mmol) was added to a mixture of JV-Boc-L-proline (11.4 g, 53.0 mmol) and 3-bromo-2-oxo-propionic acid methyl ester (9.2 g, 50.8 mmol) in acetonitrile (110 mL) at 20 0 C. The mixture was stirred at room temperature for 12 hours and then was concentrated in vacuo. The residue was dissolved in EtOAc and washed with half saturated aqueous sodium chloride. The organic phase was evaporated to dryness to give a dark brown foam used directly for the next step. Step 3-lb.
  • Step 3-2a The title compound from example 3-1 (10 mg, 0.015 mmol) was dissolved in 1,4-dioxane (0.5 mL). HCl in 1,4-dioxane (4 M, 1 mL) was added at room temperature and stirred for 2 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 441.24 [M+H] + .
  • Step 3-3a (S)-tert-butyl 2-(4-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate
  • Step 3-3b A stirred THF (5 ml) solution of the compound from step 3-3a (125 mg, 0.28 mmol) was cooled to -78 0 C. tert-Butylithium (1.7 M solution in pentane, 0.3 ml, 0.51 mmol) was added dropwise. After 10 minutes, a THF (2 ml) solution of 1 ,4-phenylene diisocyanate (20 mg, 0.125 mmol) was added dropwise. After 30 minutes, the cooling bath was removed. After 1 hour, water was added and the mixture was extracted with EtOAc twice. The combined organic phases were washed with brine and dried over MgSO 4 and concentrated to dryness.
  • A is selected from phenyl, cyclohexyl, [2,2,2]bicyclooctyl, adamantyl or cubyl;
  • R l lb is selected from hydrogen, methyl or ethyl; and
  • R is selected from a group shown below in Table 15:
  • HCV replicon cell lines (kindly provided by R. Bartenschlager) isolated from colonies as described by Lohman et al. (Lohman et al. (1999) Science 285: 110-113, expressly incorporated by reference in its entirety) and used for all experiments.
  • HCV replicon has the nucleic acid sequence set forth in EMBL Accession No.: AJ242651, the coding sequence of which is from nucleotides 1801 to 8406.
  • HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the neomycin phosphotransferase gene (neo), (iii) the IRES from encephalomyocarditis virus (EMCV), and (iv) HCV NS2 to NS5B genes and the HCV 3'UTR.
  • HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the firefly luciferase reporter gene, (iii) the ubiquitin gene, (iv) the neomycin phosphotransferase gene (neo), (v) the IRES from encephalomyocarditis virus (EMCV), and (vi) HCV NS3 to NS5B genes that harbor cell culture adaptive mutations (E1202G, T1280I, K1846T) and the HCV 3'UTR.
  • HCV replicon RNA which consists of (i) the HCV 5'UTR fused to the first 12 amino acids of the capsid protein, (ii) the firefly luciferase reporter gene, (iii) the ubiquitin gene, (iv) the neomycin phosphotransferase gene (neo), (v) the IRES
  • EC50 values of single agent compounds and combinations were determined by HCV RNA detection using quantitative RT-PCR, according to the manufacturer's instructions, with a TaqMan® One-Step RT-PCR Master Mix Reagents Kit (Cat# AB 4309169, Applied Biosystems) on an ABI Model 7500 thermocycler.
  • the TaqMan primers used for detecting and quantifying HCV RNA were obtained from Integrated DNA Technologies.
  • HCV RNA was normalized to GAPDH RNA levels in drug-treated cells, which is detected and quantified using the Human GAPDH Endogenous Control Mix (Applied Biosystems, AB 4310884E).
  • Total cellular RNA is purified from 96-well plates using the RNAqueous 96 kit (Ambion, Cat# AMI 812). Chemical agent cytotoxicity is evaluated using an MTS assay according to the manufacturer's directions (Promega).
  • HCV replicon system assessed the potential use of the compound of the present invention or in combination therapies with Interferon alpha, cyclosporine analogs and inhibitors targeting other HCV proteins.
  • the acute effects of a single or combinations of drugs are studied in the "Huh-luc/neo-ET" replicon with each chemical agent titrated in an X or Y direction in a 6 point two-fold dilution curve centered around the EC50 of each drug.
  • replicon cells are seeded at 7,000 cells per well in 90 ul DMEM (without phenol red, Invitrogen Cat.# 31053-036) per well with 10% FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of IOOX penicillin/streptomycin and incubated overnight at 37°C, 5% CO 2 , 100% relative humidity.
  • test compounds previously solubilized and titrated in dimethyl sulfoxide (“DMSO”) from each X plate and Y plate are diluted 1 : 100 in DMEM (without phenol red, Invitrogen Cat.# 31053-036) with 10% FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of IOOX penicillin/streptomycin and added directly to the 96-well plate containing cells and growth medium at a 1 :10 dilution for a final dilution of compound and DMSO of 1 : 1000 (0.2% DMSO final concentration).
  • DMSO dimethyl sulfoxide
  • Drug treated cells are incubated at 37°C, 5% CO 2 , 100% relative humidity for 72 hours before performing a luciferase assay using 100 ul per well BriteLite Plus (Perkin Elmer) according to the manufacturer's instructions.
  • Data analysis utilizes the method published by Prichard and Shipman (Antiviral Research, 1990. 14:181-205). Using this method, the combination data are analyzed for antagonistic, additive, or synergistic combination effects across the entire combination surface created by the diluted compounds in combination.
  • the compounds of the present invention can be effective against the HCV Ib genotype. It should also be understood that the compounds of the present invention can inhibit multiple genotypes of HCV. In one embodiment compound of the present invention are active against the Ia, Ib, 2a, 2b, 3a, 4a, and 5a genotypes.
  • Table 17 shows the EC50 values of representative compounds of the present invention against the HCV Ib genotype from the above described qRT-PCR or luciferase assay. EC50 ranges against HCV Ib are as follows: A >10 nM; B 1-10 nM; C ⁇ InM.

Abstract

La présente invention porte sur des composés de dérivés du diimidazole lié ou sur des sels, esters ou pro-médicaments pharmaceutiquement acceptables desdits composés qui inhibent un virus contenant un ARN, particulièrement le virus de l'hépatite C (HCV). Par conséquent, les composés selon la présente invention interfèrent avec le cycle de vie du virus de l'hépatite C et sont également utiles en tant qu'agents antiviraux. La présente invention porte en outre sur des compositions pharmaceutiques comprenant les composés susmentionnés destinées à être administrées à un sujet souffrant d'une infection du virus de l'hépatite C. L'invention porte également sur des méthodes de traitement d'une infection du virus de l'hépatite C chez un sujet par l'administration d'une composition pharmaceutique comprenant les composés selon la présente invention.
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