WO2010148006A1 - Inhibiteurs du virus de l'hépatite c - Google Patents

Inhibiteurs du virus de l'hépatite c Download PDF

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Publication number
WO2010148006A1
WO2010148006A1 PCT/US2010/038699 US2010038699W WO2010148006A1 WO 2010148006 A1 WO2010148006 A1 WO 2010148006A1 US 2010038699 W US2010038699 W US 2010038699W WO 2010148006 A1 WO2010148006 A1 WO 2010148006A1
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Prior art keywords
optionally substituted
compound
compounds
alkyl
group
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PCT/US2010/038699
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English (en)
Inventor
Yat Sun Or
Xiaowen Peng
Lu Ying
Datong Tang
Ce Wang
Yao-Ling Qiu
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Enanta Pharmaceuticals, Inc.
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Publication of WO2010148006A1 publication Critical patent/WO2010148006A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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, and processes for making the compounds.
  • 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. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science 244:359-362; Miller, R.H. and R.H.
  • flaviviruses e.g. yellow fever virus and Dengue virus types 1-4
  • pestiviruses e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • HCV is an enveloped virus containing a single strand RNA molecule of positive polarity.
  • 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 single 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.
  • HCV NS5A inhibitors are: US 2009/0202478; US 2009/0202483; WO 2009/020828; WO 2009/020825; WO 2009/102318; WO 2009/102325; WO 2009/102694; WO 2008/144380; WO 2008/021927; WO 2008/021928; WO 2008/021936; WO 2006/133326; WO 2004/014852; WO 2008/070447; WO 2009/034390; WO 2006/079833; WO 2007/031791; WO 2007/070556; WO 2007/070600; WO 2008/064218; WO 2008/154601; WO 2007/082554; and
  • 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
  • a and B are each independently absent or selected from the group consisting of O, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, and optionally substituted C 2 -C 4 alkynyl;
  • Ring L is a monocyclic or polycyclic group independently selected from the group consisting of aryl, heteroaryl, heterocyclic, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, each optionally substituted;
  • Ring G and ring J are each independently an optionally substituted 5- or 5/6- fused membered heteroaryl; wherein the 5-membered heteroaryl contains one or more nitrogen, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of A, B, and ring L, and is aryl or heteroaryl;
  • W is selected from and ;
  • Q is selected from Y is CH or C(Ci-C 4 alkyl);
  • T is N, CH or C(Ci-C 4 alkyl);
  • E at each occurence is absent or independently selected from the group consisting of O, S, S(O), SO 2 , NC(O)-(Ci-C 4 alkyl), C(O), protected carbonyl, OCH 2 , OCH 2 CH 2 , SCH 2 , SCH 2 CH 2 , C(R 7 ) 2 , and C(R 7 ) 2 C(R 7 ) 2 ; preferably E is optionally substituted CH 2 ;
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(Ci-C 4 alkyl), S(Ci-C 4 alkyl), amino optionally substituted with one or two Ci-C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted Ci-C 4 alkyl; preferably hydrogen, halogen or hydroxy;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C 2 -Cs alkenyl, and optionally substituted C3-C8 cycloalkyl; preferably hydrogen or optionally substituted Ci-C 4 alkyl; alternatively, R 3 and R 4 are taken together with the carbon atom to which they are attached to form optionally substituted C3-C8 cycloalkyl or optionally substituted heterocyclic;
  • R 5 is independently hydrogen, optionally substituted Ci-Cg alkyl, or optionally substituted C3-C8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl;
  • R 6 at each occurence is independently selected from the group consisting of optionally substituted 0(Ci-C 8 alkyl), optionally substituted amino, -NR 11 NR ⁇ and
  • R 11 at each occurence is independently selected from the group consisting of hydrogen, Ci-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;
  • R a is hydrogen or optionally substituted Ci-Cg alkyl;
  • R b is -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , or -S(O) 2 N(R 13 ) 2 ;
  • R 13 at each occurence is selected from the group consisting of 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; or R a and R 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 12 at each occurrence is selected from the group consisting of hydrogen, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, C3-Cg cycloalkyl, C3-Cg cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted Ci-C 8 alkyl; also preferably Ci-Cg alkyl alkyl optionally substituted with amino, hydroxy, protected amino or 0(Ci-C 4 alkyl); and
  • the present invention provides a compound of
  • a and B are each independently absent or selected from the group consisting of O, optionally substituted Ci-C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, and optionally substituted C 2 -C 4 alkynyl;
  • Ring L is a monocyclic or polycyclic group independently selected from the group consisting of aryl, heteroaryl, heterocyclic, C 3 -Cg cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted;
  • Ring G and ring J are each independently an optionally substituted 5- or 5/6- fused membered heteroaryl; wherein the 5-membered heteroaryl contains one or more nitrogen, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of A, B and ring L, and is aryl or heteroaryl;
  • W is selected from
  • R 1 at each occurence is independently hydrogen or optionally substituted Ci-C 4 alkyl
  • R 2 at each occurence is independently hydrogen, optionally substituted Ci-Cs alkyl, or -NR a R b ;
  • R a at each occurence is independently hydrogen or optionally substituted Ci-Cs alkyl
  • R b at each occurence is independently -C(O)-R 13 , -C(O)-OR 13 , -S(O) 2 -R 13 , -C(O)N(R 13 ) 2 , or -S(O) 2 N(R 13 ) 2 ;
  • 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 13 at each occurence is independently selected from the group consisting of Ci- 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;
  • E at each occurence is independently O, S, OC(R ⁇ 2 , SC(R ⁇ 2 , OC(R 1 ) 2 C(R 1 ) 2 , or SC(R 1 ) 2 C(R 1 ) 2 ;
  • X at each occurence is independently absent, CH 2 or CH 2 CH 2 ;
  • Y at each occurence is independently absent or C(R ⁇ 2 , C(R 1 ) 2 C(R 7 ) 2 , C(R 1 ) 2 C(R 7 ) 2 C(R 7 ) 2 , C(R ⁇ 2 OC(R 1 ),, or C(R 1 ⁇ SC(R 1 ),;
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(Ci-C 4 alkyl), S(Ci-C 4 alkyl), amino optionally substituted with one or two Ci-C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 1 -C 4 alkyl; preferably hydrogen, halogen or hydroxy;
  • Q is selected from:
  • U is absent or selected from the group consisting of O, S, S(O), SO 2 , NC(O)- (Ci-C 4 alkyl), C(O), protected carbonyl, OCH 2 , OCH 2 CH 2 , SCH 2 , SCH 2 CH 2 , C(R 7 ) 2 , and C(R 7 ) 2 C(R 7 ) 2 ; preferably C(R 7 ) 2 ;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C 2 -Cs alkenyl, and optionally substituted C3-C8 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 C3-C8 cycloalkyl or optionally substituted heterocyclic;
  • R 5 is 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 is selected from the group consisting of optionally substituted 0(Ci-Cg alkyl), optionally substituted amino, -NR ⁇ NR a R b or R 12 ;
  • R 11 is 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;
  • R 12 at each occurrence is independently selected from the group consisting of hydrogen, Ci-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 C 1 -C 8 alkyl; also preferably Ci-C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(Ci-C 4 alkyl); and
  • 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 said pharmaceutical composition. Particularly, 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 with said pharmaceutical composition. Particularly, 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 filed February 9, 2010 entitled "Linked Dibenzimidiazole Antivirals"; U.S. Application Serial No. 12/702,692 filed February 9, 2010 entitled
  • 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 Formulae (l-II-l ⁇ 1-II-2), or a pharmaceutically acceptable salt thereof: wherein A, B, E, ring G, ring J, ring L, Q, R a , R b , R 6 , R 7a , R 7b , and R 11 are as previously defined in Formula (1-1); and R 21 is hydrogen or C 1 -C 4 alkyl.
  • the present invention relates to compounds of Formulae (1-Ia-la ⁇ 1-Ia-lb), or a pharmaceutically acceptable salt thereof:
  • A, B, E, ring L, Q, R a , R b , R 6 , R 7a , R 7b , R 11 , and R 21 are as previously defined in Formula (1-1);
  • ring G 1 and ring J 1 are each independently an optionally substituted five-membered heteroaryl containing one or more nitrogen, and are each C-attached.
  • the present invention relates to compounds of Formulae (l-Ia-2a ⁇ l-Ia-2b), or a pharmaceutically acceptable salt thereof:
  • A, B, E, ring L, Q, R a , R b , R 6 , R 7a , R 7b , R 11 , and R 21 are as previously defined in Formula (1-1);
  • ring G 2 and ring J 2 are each independently an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogens and wherein the 5- membered ring is C-attached to group Q or W, and wherein the 6-membered ring of said 5/6 membered fused aryl is aryl or heteroaryl and is C-attached to one of A, B or ring L.
  • the present invention relates to compounds of
  • the present invention relates to compounds of Formulae (l-Ia-4a ⁇ l-Ia-4b), or a pharmaceutically acceptable salt thereof:
  • A, B, E, ring L, Q, R a , R b , R 6 , R 7a , R 7b , R 11 , and R 21 are as previously defined iinn FFoorrmmuullaa ((11--11));; rriinngg GG 44 aanndd ring J 4 are each independently selected from the following heteroaryl groups:
  • the present invention relates to compounds of Formulae (1-Ib-l ⁇ l-Ib-4), or a pharmaceutically acceptable salt thereof: wherein A, B, E, ring G, ring J, ring L, T, R a , R b R 3 , R 4 , R 5 , R 6 , R 7a , R 7b , R 11 , and R 21 are as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formulae (l-Ib-5 ⁇ l-Ib-6), or a pharmaceutically acceptable salt thereof:
  • A, B, E, ring G, ring J, ring L, T, R a , R b , R 6 , and R 11 are as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formulae (l-Ib-7 ⁇ l-Ib-8), or a pharmaceutically acceptable salt thereof:
  • A, B, ring G, ring J, ring L, R a , R b , R 6 , and R 11 are as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formulae (l-Ib-9 ⁇ l-Ib-10), or a pharmaceutically acceptable salt thereof:
  • the present invention relates to compounds of Formulae (1-Ib-ll ⁇ l-Ib-12), or a pharmaceutically acceptable salt thereof:
  • R 12a is independently an optionally substituted Ci-Cs alkyl optionally substituted with amino, hydoxy, protected amino or O(Ci-C 4 alkyl).
  • the present invention relates to compounds of Formulae (1-Ic-l ⁇ l-Ic-8), or a pharmaceutically acceptable salt thereof:
  • E, ring G, ring J, ring L, Q, R a , R b , R 6 , R 7a , R 7b , R 11 , and R 21 are as previously defined in Formula (1-1); and A and B are each present and as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formulae (l-Ic-9 ⁇ l-Ic-12), or a pharmaceutically acceptable salt thereof: wherein E, ring G, ring J, Q, R a , R b , R 0 , R /a , R /D , R 11 , and R Z1 are as previously defined in Formula (1-1); ring L 1 is an optionally substituted aryl or heteroaryl; and ring L 2 is an optionally substituted bicyclic aryl or bicyclic heteroaryl; wherein the rings of said bicyclic aryl or bicyclic heteroaryl can be fused or covalently attached.
  • the present invention relates to compounds of Formula (l-Ic-13 ⁇ l-Ic-16), or a pharmaceutically acceptable salt thereof:
  • E, ring G, ring J, ring L, Q, R a , R b , R 6 , R 7a , R 7b , R 11 , and R 21 are as previously defined in Formula (1-1);
  • a 1 and B 1 are each independently optionally substituted C 2 - C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • Representative compounds having the Formula (1-1) are those selected from compounds 1-1 to 1-375 compiled in the following Tables 1-14:
  • Table 1 Compounds 1-1 to 1-219.
  • Table 2 Compounds 1-220 to 1-223.
  • Table 3 Compounds 1-224 to 1-227.
  • Table 7 Compounds 1-252 to 1-261.
  • Table 8 Compounds 1-262 to 1-271.
  • Table 12 Compounds 1-344 to 1-355.
  • the present invention relates to compounds of Formula (2-1) as illustrated above, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula (2-1), or a pharmaceutically acceptable salt thereof; wherein W is selected from:
  • R 1 and R 2 are as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-1), or a pharmaceutically acceptable salt thereof; wherein G and J are each independently an optionally substituted five-membered heteroaryl containing one or more nitrogen, and are each C-attached.
  • the present invention relates to compounds of
  • Formula (2-1), or a pharmaceutically acceptable salt thereof wherein ring G and ring J are each independently an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogens and wherein the 5-membered ring is C-attached to group Q or W, and wherein the 6-membered ring of said 5/6 membered fused aryl is aryl or heteroaryl and is C-attached to one of A, B, and ring L.
  • the present invention relates to compounds of Formula (2-1), or a pharmaceutically acceptable salt thereof; wherein one of G and J is a 5-membered heteroaryl containing one or more nitrogen and is C-attached, and the other is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5- membered ring of said 5/6-membered fused heteroaryl contains one or more nitrogen and is C-attached to group Q or W, and wherein the 6-membered ring of said 5/6- membered fused heteroaryl is aryl or heteroaryl and is C-attached to one of A, B, and ring L.
  • the present invention relates to compounds of Formula (2-1), or a pharmaceutically acceptable salt thereof; wherein ring G and ring J are each independently selected from the following heteroaryl groups:
  • the present invention relates to compounds of Formulae (2-Ia- 1 ⁇ 2-Ia-6), or a pharmaceutically acceptable salt thereof:
  • A, B, E, ring G, ring J, ring L, T, U, W, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-Ia- 7), or a pharmaceutically acceptable salt thereof: wherein A, B, ring G, ring J, ring L, W, and R 6 are as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-Ia-9), or a pharmaceutically acceptable salt thereof: where siinn AA,, BB,, rriinngg GG,, rriinngg JJ,, rrii ⁇ ng L, W, and R 12 are as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-Ia-IO), or a pharmaceutically acceptable salt thereof: wherein A, B, ring G, ring J, ring L, and W are as previously defined in Formula (2-1) andR 12a is independently an optionally substituted Ci-Cg alkyl optionally substituted with amino, hydoxy, protected amino or 0(Ci-C 4 alkyl).
  • the present invention relates to compounds of Formulae (2-Ib-l ⁇ 2-Ib-4), or a pharmaceutically acceptable salt thereof: W
  • ring G, ring J, ring L, Q, and W are as previously defined in Formula (2-1); in Formula 2-Ib-2, A and B are each present; and wherein A and B are as previously defined Formula (2-1).
  • the present invention relates to compounds of Formulae (2-Ib-5 ⁇ 2-Ib-6), or a pharmaceutically acceptable salt thereof: wherein ring G, ring J, Q, and W are as previously defined in Formula (2-1); ring L 1 is an optionally substituted aryl or heteroaryl; and ring L 2 is an optionally substituted bicyclic aryl or bicyclic heteroaryl; wherein the rings of said bicyclic aryl or bicyclic heteroaryl can be fused or covalently attached.
  • the present invention relates to compounds of Formula (2-Ib-7 ⁇ 2-Ib-8), or a pharmaceutically acceptable salt thereof: wherein ring G, ring J, ring L, Q, and W are as previously defined in Formula (2-1); A 1 and B 1 are each independently optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • Representative compounds having the Formula (2-1) are those selected from compounds 2-1 to 2-376 compiled in the following Tables 15-26:
  • Table 15 Compounds 2-1 to 2-219.
  • Table 16 Compounds 2-220 to 2-237.
  • Table 17 Compounds 2-238 to 2-247.
  • Table 19 Compounds 2-252 to 2-261.
  • Table 20 Compounds 2-262 to 2-271.
  • Table 23 Compounds 2-320 to 2-343.
  • Table 24 Compounds 2-344 to 2-355.
  • any substituent or variable e.g., R 3 , R 7 , etc.
  • each of the two R 7 groups may be the same or different.
  • 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.
  • references herein to therapy and/or treatment includes, but is not limited to, prevention, retardation, prophylaxis, therapy and cure of the disease.
  • 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 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, H
  • compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • inhibitor(s) of other 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 include, but are 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.
  • Example of the RNA-containing virus includes, but not limited to, 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 coadministering 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 includes, but not limited to, 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 coadministering 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.
  • Example of the RNA-containing virus includes, but not limited to, 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.
  • Example of the RNA-containing virus includes, but not limited to, 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 a second or more 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.
  • host immune modulators include, but are 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, 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.
  • 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, in 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.
  • 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.
  • 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.
  • 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.
  • Other agents to be administered in combination with a compound of the present invention include a cytochrome P450 monooxygenase inhibitor, which is expected to inhibit metabolism of the compounds of the invention. Therefore, the cytochrome P450 monooxygenase inhibitor would be in an amount effective to inhibit metabolism of the compounds of this invention. Accordingly, the CYP inhibitor is administered in an amount such that the bioavailiablity of the protease inhibitor is increased in comparison to the bioavailability in the absence of the CYP inhibitor.
  • the invention provides methods for improving the pharmaco-kinetics of compounds of the invention.
  • the advantages of improving the pharmacokinetics of drugs are recognized in the art (see, for example, U.S. Publication App. No's. 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 2C19 (“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, ditiazem, 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 of the invention and an information insert containing directions on the use of the combination of the invention.
  • the pharmaceutical 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.
  • kits 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 NS3/4A protease inhibitor 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 each inhibitor 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.
  • viral infection refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication. Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.
  • HCV hepatitis C virus
  • immune modulator refers to any substance meant to alter the working of the humoral or cellular immune system of a subject.
  • immune modulators include inhibitors of mast cell-mediated inflammation, interferons, interleukins, prostaglandins, steroids, cortico-steroids, colony-stimulating factors, chemotactic factors, etc.
  • aryl refers to a mono- or polycyclic carbocyclic ring system including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, 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 heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. In accordance with the invention, aromatic groups can be substituted or unsubstituted.
  • bicyclic aryl or "bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and they can be fused or covalently attached.
  • tricyclic aryl or "tricyclic heteroaryl” refers to a ring system consisting of three rings wherein at least one ring is aromatic.
  • 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, 1- 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-C7-cycloalkyl 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 C5-C7 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-C6-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) 2
  • 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 linear aliphatic group can, for example, 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 aliphatic group can be represented by the formula M x -V-M x ', where M x and M x ' are each independently absent or an alkyl, alkenyl or alkynyl, each optionally substituted, and Y 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 n )C(0)N(R n ), N(R n )C(O)C(O)N(R n ), N(R 1 ⁇ S(O) 2 N(R 11 ), 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, (v) any of the above rings may be fused to an aromatic ring, and (vi) 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. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible).
  • any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, 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-Ci 2 -alkyl, -O-C 2
  • halogen refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • 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.
  • hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, 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, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl
  • 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.
  • carbonyl protecting group refers to a labile chemical moiety which is known in the art to protect a carbonyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the carbonyl protecting group as described herein may be selectively removed.
  • Carbonyl 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).
  • carbonyl protecting groups include acetals, ketals, cyclic acetals, cyclic ketals, mono- or dithioacetals, mono- or dithioketals, optionally substituted hydrazones or oximes.
  • protected carbonyl refers to a carbonyl group protected with a carbonyl protecting group, as defined above, including dimethyl acetal, 1,3-dioxolane, 1,3-dioxane, S,S'-dimethylketal, 1,3-dithiane, 1 ,3-dithiolane, 1,3- oxathiolane, N,N-dimethylhydrazone, oxime, for example.
  • 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.
  • substituted amino refers to substitution by replacement of one or two hydrogen atoms Of-NH 2 with substituents independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclic; alternatively, when disubstituted, the two substitutents can be optionally taken together with the nitrogen atom to which they are attached to form an optionallysubstituted heterocyclic group.
  • 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; hydroxy; imidazolyl; 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.
  • protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the 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.
  • 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.
  • 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, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, 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 the 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 co valently 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, hydroxy lysine, 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
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the 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, intraarticular, 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.
  • 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.
  • 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
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk 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.
  • 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. Pat. No. 5,767,068 to VanDevanter et al, U.S. Pat. No.
  • 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.
  • compositions of this invention comprise a combination of a compound of the invention 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 include, but are not limited to, immune therapies (eg.
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • 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.
  • Examplary 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 27 below.
  • the compounds of the present invention may be prepared via several different synthetic routes from a variety of 5/6-membered fused heteroaryl, 5-membered heteroaryl, and related intermediates.
  • a retro-synthesis of those title compounds include direct formation of a suitably linked core structure (5/6-membered fused heteroaryl, 5-membered heteroaryl or a combination thereof) followed by attachment of a suitable capping group (such as -COR 6 or -CONR 12 -NR a R 12 ), plus some functional group manipulations in between and/or after.
  • a suitable capping group such as -COR 6 or -CONR 12 -NR a R 12
  • Various 5/6-membered fused heteroaryl or 5-membered heteroaryl intermediates are known to those skilled in the art, for example see the encyclopedic volumns edited by A. R. Katrizky, et al, "Comprehensive Heterocyclic Chemistry” 1984; “Comprehensive Heterocyclic Chemistry II” 1996; “Com
  • the synthesis starts from the construction of an optionally substituted imidazopyridine or benzimidazole 1-2, which may be obtained by condensation of an amino acid or its derivative 1-1.1 or 1-1.2 and a 2,3-diaminopyridine or 1,2- diaminobenzene 1-1 under the conditions to those skilled in the art.
  • the imidazole ring closure may be realized either in one pot by heat, optionally in the presence of an acid and/or with a dehydration reagent such as polyphosphoric acid; or in two steps: 1) amide formation between diamine 1-1 and amino acid 1-1.1 or 1-1.2 in the presence of a condensation reagent such as EDC HCl, DCC or the like; or through mixed anhydride approach by reacting acid 1-1.1 or 1-1.2 with a chloroformate such as methyl chloro formate, isobutyl chloroformate, or the like, in the presence of a base such as TEA, DIPEA, DMAP, N-methylmorpholine, or the like, followed by treating the mixed anhydride with diamine 1-1; and 2) the heterocyclic ring closure in the presence of an acid such as acetic acid, sulfuric acid or the like or a dehydration reagent such as HATU or the like, optionally with heat.
  • a condensation reagent such as EDC HCl, DCC or the like
  • the NH group in the newly formed imidazopyridine or benzimidazole ring of 1-2 may be protected with an amino protecting group, such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • SEM i.e. SEM-Cl, NaH
  • Boc Boc
  • Cbz Boc
  • Teoc Teoc
  • Troc Troc
  • the protected imidazopyridine or benzimidazole 1-2 may be subjected to lithium-halogen exchange with various ( «-, s-, or t-) butyl lithium and the resulting lithiate can be trapped with a nucleophile, i.e. a halide such as various allyl halide to give the allylated 1-6 as a key intermediate.
  • a nucleophile i.e. a halide such as various allyl halide
  • 1-6 may be obtained from the Stille reaction conditions to those skilled in the art (see reviews: 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.
  • allylstanne such as allyltributylstanne
  • allyltributylstanne an allylstanne such as allyltributylstanne
  • a key vinyl intermediates 1-3 may be prepared by Stille reaction from bromide 1-2 with tributylvinylstanne.
  • Sonogashira coupling between bromide 1-2 and propargyl alcohol or trimethylsilyl- acetylene can generate propargyl alcohol 1-4 or alkyne 1-5 after removal of TMS. Further bromination of intermediate 1-4 may form the propargyl bromide 1-9.
  • bromide 1-2 may be converted to methyl ketone 1-7 by coupling with tributyl(l-ethoxyvinyl)tin under Stille coupling conditions followed by acidic hydrolysis.
  • Further elaboration of the imidazopyridine or benzimidazole intermediates starts from the vinyl intermediate 1-3, which may be transformed to aldehyde 1-8 through ozonolysis or periodate/Os ⁇ 4 cleavage or to alcohol 1-12 by hydroboration-oxidation sequence.
  • Alcohol 1-12 may be converted to bromide 1-15 by the well-known bromination procedure, which can be further functionalized to amine 1-20 through azide substitution followed by reduction.
  • Aldehyde 1-8 can then either be reduced to alcohol 1-11, or be converted to ⁇ , ⁇ -unsatuated acid 1-10 through Horner-Wadsworth- Emmons aldehyde homologation reaction followed by saponification.
  • Alcohol 1-11 may be similarly converted to the correponding amine intermediate 1-14 and bromide intermediate 1-13 as described previously.
  • Bromide 1-13 can be homologated to alkyne intermediate 1-19 with a metal acetylide.
  • bromide 1-13 may be also tranformed to thiol 1-16 through nucleophilic substitution, which can be further oxidized to sulfonic acid 1-17.
  • Sulfonamide 1-18 may then be derived from 1-17 through the sulfonyl chloride activation process.
  • the NH group of all the imidazopyridine or benzimidazole related intermediates listed above may be protected with an amino protecting group, such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • bromo- imidazole 2a-4 can be synthesized in a three-step sequence: 1) condensation between amino acid derived aldehyde 2a-l. l or 2a-1.2 and glyoxal 2a-1.3 in the presence of methanolic ammonia to generate imidazole 2a-2; 2) bromination of 2a-2 with excess amount of bromination reagent such as 2,4,4, 6-tetrabromo-2,5-cyclohexadienone, NBS, etc.
  • the NH group of imidazole related intermediates listed above may be protected with an amino protecting group (shown in Scheme 2 as PQ theoretically the reaction will generate two regio-isomers, but only one is drawn for clarity), such as SEM (i.e. SEM-Cl, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • an amino protecting group shown in Scheme 2 as PQ theoretically the reaction will generate two regio-isomers, but only one is drawn for clarity
  • the protected imidazole 2a-5 may be deprotonated with a strong base such as LDA, BuLi, etc to generate a carbon anion, which may either undergo a nucleophilic substitution with an activated halide such as 2a-5.2 to afford aryl or heteroaryl substituted imidazole 2a-6 or couple with an aryl or heteroaryl halide 2a-5.1 in the presence appropriate transition metal salt to generate bicyclic heteroaryl 2a-7.
  • the protected bromo imidazole 2a-8 may be subjected to lithium-halogen exchange with various ( «-, s-, or t-) butyl lithium, the resulting lithiate may undergo similar reactions to afford 2a-6 and 2a-7.
  • 2a-9 may be brominated under conditions to those skilled in the art to afford bromide 2a- 10, which may be either converted to the corresponding amine 2a- 11, or coupled with protected amino acid 1-1.1 or 1-1.2 in the presence of a base such as EtsN and DIPEA to afford keto- ester 2a- 12.
  • amine 2a- 11 may be converted to the corresponding keto-amide 2a- 13 via condensation with appropriate amino acid under standard amide formation conditions.
  • 2a- 12 and 2a- 13 may be tranformed to key intermediate 2a- 14 via heating with (NH 4 )OAc under thermal or microwave conditions.
  • compounds of the present invention may be synthesized from intermediates 2b-2 and 2b-3 (as shown in Scheme 2b), which may be synthesized using similar chemistry described in Schemes 1 and 2 from the bicyclic carboxylic acid 2b- 1.
  • Bicyclic carboxylic acids or derivatives with various structural features are either commercially available or known in the literature, and have been extensively reviewed by S. Hanessian, et al ⁇ Tetrahedron 1997, 53, 12789) and A. Trabocchi, et al ⁇ Amino Acids 2008, 34, 1) which are incorporated herein by reference.
  • the compounds of the present invention may be prepared through various coupling strategy or a combination of strategies to connect two fragments, optionally with a suitable cyclic or acyclic linker or formation of a cyclic or acyclic linker.
  • 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.
  • Compound 3a-4 then may be served as a common intermediate for further derivatizations to 3a-5 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 to remove the Cbz protection group; and 2) the released amine functionality may be acylated with an N-chloroformylhydrazine derivative in the presence of a base, such as DIPEA.
  • the required N-chloroformylhydrazine reagent, such as 3a-4.1 (Scheme 4a) may be prepared from a suitably substituted hydrazine 3a- 4.1 with phosgene in the presence of a base, such as K 2 CO3.
  • 3a-5 may be further deprotected under hydro lytic conditions in the presence of an acid such as TFA or hydrogen chloride to remove the Boc protection group and the released amine functionality can be further derivatized to the title compounds Ia-I, 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.
  • carboxylic acids including amino acids in racemic or optical form are commercially available, and/or can be synthesized in racemic or optical form, see references cited in reviews by D. Seebach, et al, Synthesis 2009, 1; C. Cativiela and M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry 2007, 18, 569; 2000, 11, 645; and 1998, 9, 3517; and experimental examples compiled in patent application WO 08/021927A2 by C. Bachand, et al, from BMS, which is incorporated herein by reference.
  • R la and R 2a at each occurrence are each independently selected from the group consisting of halogen, cyano, optionally substituted Ci-C 4 alkyl, -0-(Ci-C 4 alkyl), -N(C x -C 4 alkyl) 2 , -CO 2 (Ci-C 4 alkyl), and -C(O)N(Ci-C 4 alkyl) 2 ; preferably hydrogen, halogen and optionally substituted Ci-C 4 alkyl.
  • Both bromides 3b- 1 and 3b-2 can be prepared using the procedures described in Scheme 1, Scheme 2, Scheme 2b.
  • Bromide 3b-2 can be converted to the corresponding metalated aryl 3b-3 under Suzuki or Stille conditions, which may be further coupled with imidazopyridine bromide 3b- 1 under similar conditions to generate a structural core 3b-4.
  • Compound 3b-4 then may be served as a common intermediate for further derivatizations to 3b-5 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 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 coupling reagent such as HATU in combination with an organic base such as DIPEA
  • the released amine may be reacted with an isocyanate, carbamoyl chloride or chloroformate to provide an urea or carbamate.
  • 3b-5 may be further deprotected under hydrolytic conditions in the presence of an acid such as TFA or hydrogen chloride to remove the Boc protection group and the released amine functionality can be further derivatized to the title compounds Ib-I, with an carboxylic acid using the conditions described above.
  • an acid such as TFA or hydrogen chloride
  • linkers that may be used to construct the title compounds of the present invention are compiled in the table below, in which PG and PG' at each occurrence are each independently amino or alcohol protecting group, such as Boc, Cbz, Troc, Teoc, PMB, TMS etc. These linkers are either commercially available or may be synthesized in several steps through strategies which are known to those skilled in the art.
  • the compounds of the present invention may also be derived from bromoimidazopyridine or bromobenzimidazole 3a- 1 and imidazole 3a-2a using the procedures described previously.
  • the intermediates 3a- Ia and 3a-2a have the desired acyl groups already installed as seen in amino acid derivatives 1-1.
  • Ib and l-1.2b which can be prepared from protected amino acids 1-1.Ia and 1-1.2a through the sequences shown in Scheme 1 and 2a.
  • Ib-I may also be derived from bromoimidazopyridine or bromobenzimidazole 4b- Ia and imidazole 4b-3a using the procedures described previously.
  • the intermediates 4b- Ia and 4b-3a have the desired acyl groups already installed as seen in amino acid derivatives 1-1.
  • Ib and l-1.2b which can be prepared from protected amino acids 1-1.Ia and 4b-2a through the sequences shown in Schemes 1, 2a and 2b.
  • the compounds of the present invention containing f ⁇ ve-membered heteroaryl other than imidazole may be prepared using similar procedures described above in Schemes 1, 2a, 2b, 3a, 3b, 4a and 4b.
  • some intermediates containing a desired, suitably substituted f ⁇ ve-membered heteroaryl have been published in US 2008/0311075A1 by C. Bachand, et al from BMS, which is incorporated by reference. These intermediates are compiled in the following table.
  • the synthesis of the compounds of the present invention involves 5/6- membered fused heteroaryl intermediates other than imidazopyridines or benzimidazoles, various 5/6-membered fused heteroaryl are known in the literature.
  • the synthesis of other 5/6-membered fused heteroaryl intermediates depends on the chemical features of each structure. For example, a typical synthesis of indole intermediate is illustrated in Scheme 5.
  • the commercially available bromoiodoaniline 5-1 may be coupled to the commercially available acetylene 5-1.1 under the Sonogashira conditions to give phenylacetylene 5-2.
  • the latter may be cyclized to indole 5-3 under heat or microwave condition in the presence of a copper catalyst.
  • the synthesis of the compounds of the present invention involves 5- to 6- membered cyclic hydrazine derivatives, such as 1-2 shown in Scheme 6, in which n is 1 or 2.
  • the commercially available 5-bromo-2-chlorobenzimidazole 6-1 can be protected as SEM-derivative 6-2 (two regio-isomers are possible, but only one is drawn for clarity).
  • the latter can be converted into the desired cyclic hydrazine derivative 6-3 by a nucleophilic substitution with a commercially available cyclic hydrazine, such as pyrazolidine or hexahydropyridazine or its corresponding salt of an appropriate acid, such as HCl, optionally in the presence of base and heating.
  • Installation of the desired acyl group to 6-3 may provide 6-4, in which the SEM-protection group can be removed using the conditions discussed earlier to give 6-5.
  • the bromide 6-5 can then serve as an universal intermediate for cross-coupling with a boron or tin partner 6.5-1 using the conditions discussed previously to give the title compound 1-2.
  • the invention encompasses a process of making a compound of the invention comprising: i) Preparing a compound of Formula (l-III):
  • a 0 and B 0 are each independently absent, or optionally substituted C 2 -C 4 alkenyl or
  • X a is N or CH; Z a is an amino protecting group or -C(O)-R 6 ; when X is N, Z is an amino protecting group or -C(O)-R 5 ; and when X is CH, Z is an amino protecting group or -C(O)-NR 11 NR ⁇ ; ii) When Z or Z a is an amino protecting group, fully or selectively deprotecting a compound of Formula (l-III) to give the corresponding amine of Formula (1-IV):
  • Z b is hydrogen, an amino protecting group or -C(O)-R 6 ; iii) Capping the released amino group of a compound of Formula (1-IV) with LG-C(O)-R 6a , wherein LG is a leaving group such as OH, Cl, OMs, imidazolyl, or the like; R 6a is NR n NR a R b when X is CH; or R 6a is independently R 6 when X is N; to give the compound of Formula (1-V):
  • Z c is an amino protecting group or -C(O)-R 6 ; and iv) Repeated reaction sequence of deprotecting and capping (step ii-iii) when Z c is an amino protecting group to give the compound of the present invention of Formula (1-VI),
  • the invention encompasses a process of making a compound of the invention: v) Preparing a compound of Formula (2-III):
  • ring G, ring J, ring L, U, R 1 , R 7a , and R 7b are as defined in Formula (2-1);
  • a 0 and B 0 are each independently absent, optionally substituted C 2 -C 4 alkenyl or
  • R 20 is hydrogen or C 1 -C 4 alkyl
  • Z a is an amino protecting group or -C(O)-R 6 ;
  • Z b is an amino protecting group or -C(O)-OR 13 ; vi) When Z or Z a is an amino protecting group, fully or selectively deprotecting a compound of Formula (2-III) to give the corresponding amine of Formula (2-IV):
  • Z c is hydrogen, an amino protecting group or -C(O)-R 6 ; vii) Capping the released amino group of a compound of Formula (2-IV) with LG- C(O)-OR 13 , wherein R 13 is as defined in Formula (2-1); LG is a leaving group; to give the compound of Formula (2-V) : - wherein Z d is an amino protecting group -C(O)-R 5 ; and viii) Repeated reaction sequence of deprotecting and capping (step vi-vii) to give the compound of Formula (2-VI),
  • Examples 1-1 to 1-219 may be prepared using procedures similar to those described in examples 1-Pre368, 1-368 to 1-375 (described below), and/or as described in the Synthetic Methods. Table 1: Examples 1-1 to 1-219.
  • Table 2 Examples 1-220 to 1-223.
  • Table 3 Examples 1-224 to 1-227.
  • Table 4 Examples 1-228 to 1-237.
  • Table 5 Examples 1-238 to 1-241
  • Table 7 Examples 1-252 to 1-261.
  • Table 8 Examples 1-262 to 1-271.
  • Table 12 Examples 1-344 to 1-355.
  • Table 13 Examples 1-356 to 1-367.
  • Step l-Pre-368a To a solution of 5-bromo-2-chloro-lH-l,3-benzimidazole (0.600 g, 2.592 mmol) in DMF (12 mL) cooled at 0 0 C was added NaH (60% in mineral oil,
  • Step l-Pre-368b A mixture of the compounds from step l-Pre-368a (0.115 g, 0.319 mmol), pyrazolidine hydrochloride (0.185 g, 1.276 mmol) and DIPEA (0.89 mL, 5.086 mmol) in DMF (2.1 mL) was heated at 128 0 C with a microwave for 55 minutes. The mixture was allowed to cool down and freed of volatiles by a stream of N 2 . The residue was taken up in EtOAc and dichloromethane, washed with H 2 O, brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • Step l-Pre-368d A solution of 6-bromo-N-methoxy-N-methyl-2-naphthamide (prepared according to J. Med. Chem., 2006, 49, 4721-4736; 3.57 g, 12.1 mmol) in THF (60 mL) was treated with methyl magnesium bromide (3 M in Et 2 O, 8.09 mL, 24.3 mmol) slowly at 0 0 C for 1 hour. The solution was allowed to warm up to rt for 2 hours before being quenched with aqueous NH 4 Cl. The volatiles were removed and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to give the crude desired compound as a white solid (2.89 g, 96%).
  • Step l-Pre-368e The compound from step l-Pre-368d (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).
  • Step l-Pre-368g To a solution of the compound from step l-Pre-368f (at most 11.6 mmol) in toluene (60 mL) was added ammonium acetate (13.4 g, 0.174 mol) and the resultant mixture was heated at 100 0 C for 14 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. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow brown powder (3.14 g, 4 steps, 61%).
  • Step l-Pre-368h A solution of the compound from step l-Pre-368g (0.120 g, 0.271 mmol) in 1 ,4-dioxane (3 mL) was treated with HCl in 1 ,4-dioxane (4 M, 6 mL) at rt for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step. Step l-Pre-368i.
  • Step l-369a To a mixture of 2-bromo-l-(4-iodophenyl)ethanone (5 g, 15.4 mmol) and N-Boc-L-proline (3.48g, 16.1 mmol) in acetonitrile (40 mL) was added diisopropylethylamine (2.4 mL, 17 mmol). The resulting mixture was stirred at rt for 3 hours before being partitioned between EtOAc and aqueous NaHCO 3 . The organic phase was separated, dried (Na 2 SO 4 ) and concentrated to afford a brown oil.
  • Step l-369b The mixture of compound from step l-369a (6.Og, 12.5 mmol) and ammonium acetate (15.1 g, 196 mmol) in toluene (80 mL) was stirred at 110 0 C for 3 hours before being partitioned between CH 2 Cb and aqueous NaHCO 3 . The organic phase was separated, dried (Na 2 SO 4 ) and concentrated to afford a deep red oil.
  • Step l-369e A mixture of the compound from step l-369d (2.010 g, 5.488 mmol), trimethylsilylacetylene (2.33 ml, 16.46 mmol), CuI (0.110 g, 0.576 mmol) and Pd(PPh 3 ) 2 Cl 2 (0.308 g, 0.439 mmol) in Et 3 N (50 mL) was degassed and then heated at 80 0 C under N 2 overnight before being evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1 % Et 3 N in ethyl acetate) to give the desired compound as a yellow foam (1.140 g, 54%).
  • Step l-369f A suspension of the compound from step l-369e (1.140 g, 2.972 mmol) and K 2 CO 3 (1.027 g, 7.430 mmol) in methanol (30 ml) was stirred at rt for 2 hour. The volatiles were evaporated off. The residue was patitioned (EtOAc - H 2 O). The organic layer was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • Step l-369g A solution of the compound from step l-369f (1 g, 3.21 mmol) in dichloromethane (20 mL) was treated with HCl in 1,4-dioxane (4 M, 12 mL) at room temperature for 1 hour. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step. Step l-369h.
  • Step 1-369L A mixture of the compound from step l-369b (0.477 g, 1.086 mmol), the compound from step l-369h (0.400 g, 1.086 mmol), Pd(PPh 3 ) 4 (5 mol%, 62.7 mg, 54.3 ⁇ mol) and CuI (3 mol%, 6.2 mg, 32.6 ⁇ mol) in Et 3 N (3 mL) and THF (9 mL) was degassed and stirred at 50 0 C under N 2 overnight. The volatiles were evaporated.
  • Step 1-369J A solution of the compound from step 1-3691 (0.100 g, 0.147 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at rt for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step.
  • Step l-369k To a solution of methyl 2-isopropylhydrazinecarboxylate (prepared according to J. Am. Chem. Soc. 2004, 126, 6759; 21.4 mg, 0.162 mmol) in toluene (1.5 mL) at rt was added potassium carbonate (40.7 mg, 0.294 mmol), followed by the slow addition of phosgene (20% in toluene, 0.12 mL, 0.221 mmol). The resulting mixture was stirred at room temperature for 30 minutes before being filtered through a cotton plug. The volatiles were removed by rotavapor.
  • the title compound was prepared from methyl 2-isopropylhydrazinecarboxylate (prepared according to J. Am. Chem Soc. 2004, 126, 6759) and methyl (S)-3-methyl-l- oxo-l-((S)-2-(5-(4'-(2-((S)-pyrrolidin-2-yl)-lH-imidazol-5-yl)biphenyl-4-yl)-lH- imidazol-2-yl)pyrrolidin-l-yl)butan-2-ylcarbamate (trihydrochloric acid salt, prepared according to WO 2008/021927) using procedures similar to that described in example 1-373.
  • ESIMS m/z 739.96 [M+H] + .
  • the title compound was prepared from methyl 2-ethylhydrazinecarboxylate (prepared according to J. Am. Chem Soc. 2004, 126, 6759) and methyl (S)-3-methyl-l-oxo-l- ((S)-2-(5-(4'-(2-((S)-pyrrolidin-2-yl)-lH-imidazol-5-yl)biphenyl-4-yl)-lH-imidazol-2- yl)pyrrolidin-l-yl)butan-2-ylcarbamate (trihydrochloric acid salt, prepared according to WO 2008/021927) using procedures similar to that described in example 1-374.
  • ESIMS m/z 726.38 [M+H] + .
  • Examples 2-1 to 2-367 may be prepared using procedures similar to those described in examples 2-368 to 2-376 (described below), and/or as described in the Synthetic Methods. Table 14: Examples 2-1 to 2-219.
  • Step 2-368a A suspension of (3R,6S ⁇ aS)-6- ⁇ [(9H-fluoren-9- ylmethoxy)carbonyl]amino ⁇ -5 -oxohexahydro-SH- [ 1 ,3 jthiazolo [3 ,2-a]pyridine-3 - carboxylic acid (0.300 g, 0.684 mmol) and 2,4'-dibromoacetophenone (0.200 g, 0.718 mmol) in CH 3 CN (7 ml) was treated with DIPEA (0.24 mL, 1.368 mmol) at rt. The reaction mixture was stirred at rt for 2 hours.
  • a mixture of the compound from step 2-368a (0.380 g, 0.598 mmol) and ammonium acetate (0.507 g, 6.577 mmol) in xylenes (10 mL) was heated at 140 0 C with a microwave for 80 minutes.
  • the mixture was cooled down and combined with another batch started from 37.0 mg of the compound from step 2-368a.
  • the combined mixture was evaporated.
  • the residue was partitioned between CH 2 Cl 2 and saturated aqueous NaHCO 3 .
  • the aqueous layer was extracted with CH 2 Cl 2 .
  • the combined organics were dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 2-368C A solution of the compound from step 2-368b (0.138 g, 0.224 mmol) in CH 3 CN (3 ml) was treated with piperidine (0.066 mL, 0.672 mmol) at rt. The resulting suspension was stirred at rt for 40 minutes. The volatiles were evaporated off.
  • Step 2-368d A suspension of the compound from step 2-368c (84.0 mg, 0.214 mmol) in THF (7 ml) and DIPEA (0.11 mL, 0.641 mmol) was treated with methyl chloro formate (0.017 mL, 0.224 mmol) at rt. The reaction mixture was stirred at rt for 20 minutes. The volatiles were evaporated off. The residue was taken up in MeOH (4 mL) and treated with K 2 CO3 (88.6 mg, 0.641 mmol) at rt. The suspension was stirred at rt for 5 minutes before being concentrated. The residue was taken up in CH 2 CI 2 and filtered through a short pad of Celite.
  • Step 2-368e A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol), N-Boc-L- proline (3.87 g, 18.0 mmol) and in CH 3 CN (60 mL) was treated with TEA (5.40 mL, 37.8 mmol) at rt until the disappearence of the starting material. The volatiles were evaporated off and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 2-368f A solution of the compound from step 2-368e (6.73 g, 16.3 mmol) in toluene (100 mL) was treated with ammonium acetate (25.1 g, 0.327 mol) at 100 0 C for 14 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - aqueous NaHCO 3 ). The organics were washed with brine, dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%).
  • Step 2-368g A mixture of the compound from step 2-368f (1.00 g, 2.55 mmol), bis(pinacolato)diboron (1.35 g, 5.33 mmol), Pd(PPh 3 ) 4 (0.147 g, 0.128 mmol) and potassium acetate (0.640 g, 6.53 mmol) in 1,4-dioxane (20 mL) was degassed and heated at 80 0 C under N 2 for 14 hours. 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 2-368h A mixture of the compound from step 2-368d (96.0 mg, 0.213 mmol), the compound from step 2-368g (93.5 mg, 0.213 mmol), Pd(PPh 3 ) 4 (24.6 mg, 21.3 ⁇ mol) and NaHCO 3 (62.5 mg, 0.744 mmol) in DME (3 mL) and H 2 O (1 mL) was degassed and heated at 98 0 C under N 2 overnight. The mixture was cooled down and partitioned (EtOAcZCH 2 Cl 2 - H 2 O). The aqueous layer was extracted with CH 2 Cl 2 . The combined organics were dried (Na 2 SO 4 ), filtered and evaporated.
  • Step 2-368L A solution of the compound from step 2-368h (60.0 mg, 0.0877 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at rt for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step. Step 2-368J.
  • Step 2-369a The desired compound benzyl (3S,6S,8aS)-3-(5-(4-bromophenyl)-lH- imidazol-2-yl)-5-oxooctahydroindolizin-6-ylcarbamate was prepared from (3S,6S,8aS)- 6-(benzyloxycarbonyl-amino)-5-oxooctahydroindolizine-3-carboxylic acid (prepared according to Tetrahedron. 2000, 56, 4289) and 2,4'-dibromoacetophenone using procedures similar to that described in steps from 2-368a to 2-368f and WO 2008/021927.
  • ESIMS m/z 509.92 [M+H] + .
  • Step 2-369b The desired compound methyl (S)-l-((S)-2-(5-(4-bromophenyl)-lH- imidazol-2-yl)pyrrolidin- 1 -yl)-3 -methyl- l-oxobutan-2-ylcarbamate was prepared from the compound of step 2-368f using procedures similar to that described in steps 2-368i and 2-368J.
  • ESIMS m/z 449.12 [M+H] + .
  • Step 2-369C The desired compound methyl (S)-3 -methyl- l-oxo-l-((S)-2-(5 -(4- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)-lH-imidazol-2-yl)pyrrolidin- 1 - yl)butan-2-ylcarbamate was prepared from compound of step 2-369b using procedure similar to that described in step 2-368g.
  • ESIMS m/z 497.19 [M+H] + . Step 2-369d.
  • Step 2-372a A solution of methyl 5-chloro-5-oxopentanoate (4.2 mL, 30 mmol) and 2,6-lutidine (3.85 ml, 33 mmol) in THF (60 ml) was charged Pd on carbon (5%, 1.0 g). It was stirred at rt under H 2 (30 psi) for 2 days and then filtered through Celite. The filtrate was concentrated and the residue was dissolved in methylene chloride and washed with water. The organics were dried (Na2SO/i) and concentrated to give an aldehyde intermediate (4 g) as a pale yellow oil.
  • Step 2-372b A solution of the desired minor compound from step 2-372a (0.26 g, 1.21 mmol) in THF/MeOH (2: 1, 4 ml) was treated with aqueous LiOH (1 M, 2.5 ml) for 16 hours at rt before being concentrated.
  • the aqueous residue was acidified with 1 N HCl to pH 1 and saturated with ammonium chloride and extracted with EtOAc three times. The combined organics were concentrated to dryness.
  • the white residue and 2,4'- Dibromoacetophenone (358 mg, 1.29 mmol) were dissolved in acetonitrile (10 ml).
  • Step 2-372d A solution of the compound from step 372c (105 mg, 0.28 mmol) and the the compound from step 368g (130 mg, 0.30 mmol) in DME/H 2 O (3: 1, 8 ml) was charged NaHCO 3 (80 mg, 0.95 mmol) and Pd(PPh 3 ) 4 (51 mg, 0.044 mmol). It was degassed before being stirred at 90 0 C for 18 hours. It was partioned (EtOAc - saturated NaHCO 3 ). The organics were dried (Na 2 SO 4 ) and evaporated, followed by column purification (EtOAc/hexanes 1 : 1 to 5:1) to afford the desired product 61 mg (36% yield) as a yellow foam.
  • Step 2-372e A solution of the compound from step 2-372d (59 mg, 0.097 mmol) in CH 2 Cl 2 (1 ml) was treated with HCl in dioxane (4 M, 3 ml) at rt for 1.5 hours and then concentrated to dryness. The resulting yellow solid and (5)-2-(methoxycarbonylamino)- 3-methylbutanoic acid (prepared according to WO 2008/021927, 19 mg, 0.11 mmol) were dissolved in DMF (1.5 ml). Diisopropylethyl amine (0.2 ml, 1.15 mmol) was added followed by HATU (37.5 mg, 0.099 mmol).
  • the tiltle compound (10 mg as a white solid) was prepared from the desired major product in step 2-372a using procedures similar to that described in steps from 2-372b to 2-372e.
  • ESIMS m/z 668.27 [M+H] + .
  • Step 2-374a A solution of ethyl L-pyroglutamate (2.2 g, 14 mmol) and BoC 2 O (4 g, 18 mmol) in methelene chloride (30 ml) was charged DMAP (1.7 g, 14 mmol) in portions. The mixture was stirred at rt for 1 hour. It was partioned (EtOAc - saturated NaHCOs). The organics were dried (Na 2 SO/() and evaporated, followed by column purification (EtOAc/hexanes 2:1) gave a light yellow solid. This yellow solid was dissolved in methylene chloride (30 ml) and cooled to -78 0 C. DIBAL (1 M, 30 ml) was added dropwise. After 1 hour, isopropanol (2 ml) was added and the cooling batch was removed. The reaction mixture was concentrated and the residue was dissolved in
  • Step 2-374b A solution of the compound from step 2-374a (5.0 g, 17.4 mmol) and allyltrimethylsilane (4.97 g, 43.5 mmol) in methylene chloride (50 ml) at -78 0 C was treated with BF 3 OEt 2 (4.4 ml, 35 mmol) for 2 hours before water (5 ml) was added. It was partioned (EtOAc - saturated NaHCOs). The organics were dried (Na 2 SOz I ) and evaporated, followed by column purification (EtOAc/hexanes 0-40%) afforded the desired C-allylated intermediate (3.4 g, 69% yield) as a clear oil.
  • Step 2-374e The desired compound (11 mg, as a yellow foam, 57% yield) was obtained from the minor compound of step 2-374d (12 mg, 0.032 mmol) and the compound from step Ig (15 mg, 0.034 mmol) using procedures similar to that described in step 2-372d.
  • ESIMS m/z 607.37 [M+H] + .
  • Step 2-374f The title compound (6 mg, as a white solid, 50% yield two steps) was obtained from the compound of step 2-374e (11 mg, 0.018 mmol) using procedures similar to that described in step 2-372e.
  • ESIMS m/z 664.59 [M+H] + .
  • Example 2-375 The title compound (6 mg, as a white solid, 50% yield two steps) was obtained from the compound of step 2-374e (11 mg, 0.018 mmol) using procedures similar to that described in step 2-372e.
  • ESIMS m/z 664.59 [M+H] + .
  • Example 2-375 The title compound (6 mg, as a white solid, 50% yield two steps) was obtained from the compound of step 2-374e (11 mg, 0.018 mmol) using procedures similar to that described in step 2-372e.
  • ESIMS m/z 664.59 [M+H] + .
  • Example 2-375 The title compound (6 mg, as a white solid, 50% yield two steps) was obtained
  • Step 2-376a CuBr Me 2 S (4.93 g, 24 mmol) was suspended in THF (55 ml) and cooled to -40 0 C.
  • (Z)-prop-l-enylmagnesium bromide (0.5 M in THF, 48 ml, 24 mmol) was added dropswise. After 45 minutes the resulting solution was further cooled to -78 0 C and BFa OEt 2 (3 ml, 24 mmol) was added dropwise. After 30 minutes a THF (10 ml) solution of the starting material (1.76 g, 6.12 mmol) was added and the cooling batch was removed after 30 minutes.
  • Step 2-376b The compound from step 2-376a (440 mg, 1.55 mmol) was treated with HCl in dioxane (4 M, 3 ml) at room temperature for 1.5 hours and then concentrated to dryness. The resulting yellow solid and (5)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (622 mg, 1.57 mmol) were dissolved in DMF (8 ml). Diisopropylethyl amine (0.9 ml, 5.16 mmol) was added followed by HATU (587 mg, 1.54 mmol). The reaction mixture was stirred at room temperature for an hour. It was partioned (EtOAc - saturated NaHCOs).
  • Step 2-376c The compound from step 2-376b (425 mg, 1.12 mmol) was dissolved in methylene chloride (120 ml). Hovada-Grubbs 2nd generation catalyst (55 mg, 0.088 mmol) was added and the reaction mixture was stirred at 40 0 C for 20 hours. The solvent was removed and the greenish oily residue was dissolved in EtOAc (10 ml).
  • Step 2-376d The compound from step 2-376c (315 mg, 0.93 mmol) was dissolved in THF/MeOH (2:1, 6 ml). Aqueous LiOH (1 M, 3 ml) was added. The reaction mixture was stirred for 16 hours at room temperature, and then concentrated to remove volatiles. The aqueous residue was acidified with 1 N hydrochloric acid to pH 1. The aqueous was saturated with ammonium chloride and extracted with EtOAc three times. The organic phases were combined and concentrated to dryness. The brown residue and 2,4'-Dibromoacetophenone (310 mg, 1.12 mmol) were dissolved in acetonitrile (10 ml). Diisopropyl ethyl amine (0.5 ml, 2.87 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours and then concentrated. Standard
  • Step 2-376f The compound from step 2-376e (44 mg, 0.098 mmol) and the compound from step 2-368g (44 mg, 0.1 mmol) were dissolved in DME/H 2 O (3: 1, 4 ml). Sodium bicarbonate (28 mg, 0.34 mmol) was added. The resulting mixture was degassed by bubbling dry nitrogen through. Tetrakis(triphenylphosphine)palladium(0) (17.5 rng, 0.015 mmol) was added and the reaction mixture was stirred at 90 0 C for 18 hours. It was partioned (EtOAc - saturated NaHCOs).
  • Step 2-376g The compound from step 2-376f (37 mg, 0.054 mmol) was dissolved in methylene chloride (1 ml). HCl in dioxane (4 M, 3 ml) was added. The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated to dryness.
  • HCV Replicon Cell Lines 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.
  • the 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.
  • the coding sequence of the published HCV replicon was synthesized and subsequently assembled in a modified plasmid pBR322 (Promega, Madison, WI) using standard molecular biology techniques.
  • 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 neomycin phosphotransferase gene (neo), (iii) the IRES from encephalomyocarditis virus (EMCV), and (iv) HCV NS2 to NS5B genes and the HCV 3'UTR.
  • Another replicon cell line (“Huh-luc/neo-ET) described by Vrolijk et. al. (Vrolijk
  • 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# AM1812). Chemical agent cytotoxicity is evaluated using an MTS assay according to the manufacturer's directions (Promega).
  • 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 twofold 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 may inhibit HCV by mechanisms in addition to or other than NS5A inhibition. In one embodiment, the compounds of the present invention inhibit HCV replicon and in another embodiment the compounds of the present invention inhibit NS5A.
  • 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 14 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 ou sels, esters ou promédicaments pharmaceutiquement acceptables de ceux-ci, qui inhibent un virus contenant de l'ARN, en particulier le virus de l'hépatite C (VHC). Par conséquent, les composés de 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 mentionnés ci-dessus pour une administration à un sujet souffrant d'une infection par le VHC. L'invention porte également sur des procédés de traitement d'une infection par le VHC chez un sujet par l'administration d'une composition pharmaceutique comprenant les composés de la présente invention.
PCT/US2010/038699 2009-06-16 2010-06-15 Inhibiteurs du virus de l'hépatite c WO2010148006A1 (fr)

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