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WO2012006060A1 - Composés et méthodes de traitement ou de prévention d'infections à flavovirus - Google Patents

Composés et méthodes de traitement ou de prévention d'infections à flavovirus Download PDF

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Publication number
WO2012006060A1
WO2012006060A1 PCT/US2011/042119 US2011042119W WO2012006060A1 WO 2012006060 A1 WO2012006060 A1 WO 2012006060A1 US 2011042119 W US2011042119 W US 2011042119W WO 2012006060 A1 WO2012006060 A1 WO 2012006060A1
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Prior art keywords
alkyl
optionally substituted
independently
group
compound
Prior art date
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PCT/US2011/042119
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English (en)
Inventor
Jeremy Green
Original Assignee
Vertex Pharmaceuticals Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to JP2013518559A priority Critical patent/JP2013531011A/ja
Priority to EP11730823.9A priority patent/EP2585448A1/fr
Publication of WO2012006060A1 publication Critical patent/WO2012006060A1/fr
Priority to US13/724,014 priority patent/US20130203706A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • HCV Hepatitis C virus
  • Flaviviridae family has closest relationship to the pestiviruses that include hog cholera virus and bovine viral diarrhea virus (BVDV).
  • BVDV bovine viral diarrhea virus
  • HCV is believed to replicate through the production of a complementary negative-strand RNA template. Due to the lack of efficient culture replication system for the virus, HCV particles were isolated from pooled human plasma and shown, by electron microscopy, to have a diameter of about 50-60 nm.
  • the HCV genome is a single-stranded, positive-sense RNA of about 9,600 bp coding for a polyprotein of 3009-3030 amino-acids, which is cleaved co and post-translationally into mature viral proteins (core, El, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). It is believed that the structural glycoproteins, El and E2, are embedded into a viral lipid envelope and form stable heterodimers. It is also believed that the structural core protein interacts with the viral RNA genome to form the nucleocapsid.
  • the nonstructural proteins designated NS2 to NS5 include proteins with enzymatic functions involved in virus replication and protein processing including a polymerase, protease and helicase.
  • HCV infection The main source of contamination with HCV is blood.
  • the magnitude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers in western countries are chronically infected with HCV. For intravenous drug abusers, the prevalence varies from about 28% to 70% depending on the population studied. The proportion of new HCV infections associated with post-transfusion has been markedly reduced lately due to advances in diagnostic tools used to screen blood donors. [0004] Combination of pegylated interferon plus ribavirin is the treatment of choice for chronic HCV infection. This treatment does not provide sustained viral response (SVR) in a majority of patients infected with the most prevalent genotype (la and lb). Furthermore, significant side effects prevent compliance to the current regimen and may require dose reduction or discontinuation in some patients.
  • SVR sustained viral response
  • the present invention generally relates to compounds useful for treating or preventing Flavivirus infections, such as HCV infections.
  • the invention is directed to a compound represented by Structural Formula (I):
  • Ring A is optionally further substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CN, Ci_ 4 alkyl, and Ci_ 4
  • Ring B is a C 3 _g cycloalkyl ring or a 5-6 membered aryl ring, each of which optionally and independently is substituted with one or more substituents selected from the group consisting of halogen, -D (deuterium), -CD 3 , -CHD 2 , -CH 2 D, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -OH, -0(Ci_ 4 alkyl), -CN, -NH 2 , -NH(Ci_ 4 alkyl), and -N(C alkyl) 2 .
  • Ring C is a cyclohexyl ring optionally further substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -OH, -0(C alkyl), -CN, -NH 2 , -NH(Ci_ 4 alkyl), and -N(Ci_ 4 alkyl) 2 .
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ), -P(0)(OR 3 ) 2 , or -C(0)R 2 .
  • R 1 is -H or a Ci_ 6 alkyl, C 3-10 carbocyclic, 4-10 membered heterocyclic, C 6 -io aryl, or 5-10 membered heteroaryl group, wherein said alkyl group is optionally substituted with one or more instances of J 1A , and wherein each of said carbocyclic and heterocyclic groups is optionally and independently substituted with one or more instances of J 1B , and wherein each of said aryl and heteroaryl groups is optionally and independently substituted with one or more instances of J .
  • R 2 is a C 3 _8 carbocyclic, 3-8 membered heterocyclic, C 6 _io aryl, or 5-10 membered heteroaryl group, wherein each of said carbocyclic and heterocyclic groups is independently and optionally substituted with one or more instances of J E , and each of said aryl and heteroaryl groups is independently and optionally substituted with one or more instances of J F .
  • R 3 is -H, a Ci_6 aliphatic, C 3 _g carbocyclic, 3-8 membered heterocyclic, C 6 -io aryl, or 5-10 membered heteroaryl group, wherein said aliphatic group is optionally substituted with one or more instances of J D , each of said carbocyclic and heterocyclic groups is
  • each of said aryl and heteroaryl groups is independently and optionally substituted with one or more instances of J F .
  • R 8 is -R b , halogen, cyano, nitro, -OR b , -NR b R c , -C(0)R b , -C(0)OR b , -OC(0)R b , -NRC(0)R b , or -C(0)NR b R c ; or
  • R 9 is: i) -H; ii) a Ci_ 6 aliphatic group optionally substituted with one or more instances of J 9A ; iii) a C3_io carbocycle or 4-10 membered heterocycle, each of which is optionally and independently substituted with one or more instances of J 9B ; or iv) a C 6-1 o aryl or 5-10 membered heteroaryl group, each of which is optionally and independently substituted with one or more instances of J .
  • J 1A and J 9A independently is oxo or Q; or two J 1A and two J 9A , respectively, together with the atom(s) to which they are attached, optionally and independently form a 3- 8-membered non-aromatic ring that is optionally substituted with one or more instances of J E .
  • J 1B and J 9B are oxo, Q, or a Ci_ 6 aliphatic group optionally substituted with one or more instances of Q; or two J 1B and two J 9B , respectively, together with the atom(s) to which they are attached, optionally and independently form a 3-8- membered non-aromatic ring that is optionally substituted with one or more instances of J E .
  • Each of J and J independently is Q or a Ci_ 6 aliphatic group optionally substituted with one or more instances of Q; or two J and two J , respectively, together with the atoms to which they are attached, optionally and independently form a 3-8-membered non-aromatic ring that is optionally substituted with one or more instances of J E .
  • Each Q independently is selected from the group consisting of halogen, cyano, nitro, -OR a , -SR a , -S(0)R a , -S0 2 R a , -NRR a , -C(0)R a , -C(0)OR a , -OC(0)R a ,
  • Each R a , R b , and R c independently is: i) -H; ii) a Ci_ 6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, nitro, -CN, -OR * , -NR'R, -OCOR * , -COR", -C0 2 R', -CONR'R, -NRC(0)R, C 3 _ 8 carbocyclic group optionally substituted with one or more instances of J E , 4-8 membered heterocyclic group optionally substituted with one or more instances of J E , C 6 _io aryl group optionally substituted with one or more instances of J F , and 5-10 membered heteroaryl group optionally substituted with one or more instances of J F ; iii) a C 3 _g carbocyclic or 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one
  • R a together with R and the nitrogen atom to which it is attached, optionally forms a 4-8 membered heterocycle optionally substituted with one or more instances of J E ;
  • R b and R c together with the nitrogen atom to which they are attached, optionally forms a 4-8 membered heterocycle optionally substituted with one or more instances of J E .
  • Each R is independently -H or a Ci_ 6 aliphatic group optionally substituted with one or more instances of J D .
  • Each R' is independently -H or a Ci_ 6 aliphatic group optionally substituted with one or more instances of J D ; or two R, together with the nitrogen atom to which they are attached, optionally form a 4-8 membered heterocycle optionally substituted with one or more instances of J E .
  • Each R" is a Ci_ 6 aliphatic group optionally substituted with one or more instances of
  • Each J D is independently selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(C C 6 alkyl), -0(C C 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), and phenyl.
  • Each J E is independently selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(C C 6 alkyl), -0(C C 6 haloalkyl), and C C 6 aliphatic group optionally substituted with one or more instances of J D .
  • Each J F is independently selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), and Ci-C 6 aliphatic that is optionally substituted with one or more instances of J D .
  • n 0 or 1.
  • the invention is directed to a compound represented by Structural Formula (II
  • Ring A is optionally further substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CN, Ci_ 4 alkyl, and Ci_ 4 haloalkyl.
  • Ring B is a C 3 _8 cycloalkyl ring or a 5-6 membered aryl ring, each of which optionally and independently is substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -OH, -0(Ci_ 4 alkyl), -CN, -NH 2 , -NH(Ci_ 4 alkyl), and -N(Ci_ 4 alkyl) 2 .
  • Ring C is a cyclohexyl ring optionally further substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -OH, -0(Ci_ 4 alkyl), -CN, -NH 2 , -NH(Ci_ 4 alkyl), and -N(Ci_ 4 alkyl) 2 .
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ), -P(0)(OR 3 ) 2 , or -C(0)R 2 .
  • R 1 is -H or a Ci_ 6 alkyl, C 3 _io carbocyclic, 4-10 membered heterocyclic, C 6 -io aryl, or 5-10 membered heteroaryl group, wherein said alkyl group is optionally substituted with one or more instances of J 1A , and wherein each of said carbocyclic and heterocyclic groups is optionally and independently substituted with one or more instances of J 1B , and wherein each of said aryl and heteroaryl groups is optionally and independently substituted with one or more instances of J .
  • R 2 is a C 3 _8 carbocyclic, 3-8 membered heterocyclic, C 6 -io aryl, or 5-10 membered heteroaryl group, wherein each of said carbocyclic and heterocyclic groups is independently and optionally substituted with one or more instances of J E , and each of said aryl and heteroaryl groups is independently and optionally substituted with one or more instances of J F .
  • R 3 is -H, a Ci_6 aliphatic, C 3 -8 carbocyclic, 3-8 membered heterocyclic, C 6-1 o aryl, or 5-10 membered heteroaryl group, wherein said aliphatic group is optionally substituted with one or more instances of J D , each of said carbocyclic and heterocyclic groups is
  • each of said aryl and heteroaryl groups is independently and optionally substituted with one or more instances of J F .
  • R 8 is -R b , halogen, cyano, nitro, -OR b , -NR b R c , -C(0)R b , -C(0)OR b , -OC(0)R b ,
  • R 8 is -NR b R c , R c and R 7 form a pyrrolidine ring
  • R 9 is: i) -H; ii) a Ci_ 6 aliphatic group optionally substituted with one or more instances of J ; iii) a C 3 _io carbocycle or 4-10 membered heterocycle, each of which is optionally and independently substituted with one or more instances of J 9B ; or iv) a C 6 -io aryl or 5-10 membered heteroaryl group, each of which is optionally and independently substituted with one or more instances of J .
  • J 1A and J 9A independently is oxo or Q; or two J 1A and two J 9A , respectively, together with the atom(s) to which they are attached, optionally and independently form a 3-
  • J 1B and J 9B are oxo, Q, or a Ci_ 6 aliphatic group optionally substituted with one or more instances of Q; or two J 1B and two J 9B , respectively, together with the atom(s) to which they are attached, optionally and independently form a 3-8-
  • Each of J and J independently is Q or a Ci_ 6 aliphatic group optionally substituted with one or more instances of Q; or two J and two J , respectively, together with the atoms to which they are attached, optionally and independently form a 3-8-membered non-aromatic ring that is optionally substituted with one or more instances of J E .
  • heterocycle optionally substituted with one or more instances of J E , C 6 -io aryl group optionally substituted with one or more instances of J F , and 5-10 membered heteroaryl group optionally substituted with one or more instances of J F .
  • Each R a , R b , and R c independently is: i) -H; ii) a Ci_ 6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, nitro, -CN, -OR * , -NR'R, -OCOR * , -COR", -C0 2 R * , -CONR'R, -NRC(0)R, C 3 _ 8 carbocyclic group optionally substituted with one or more instances of J E , 4-8 membered heterocyclic group optionally substituted with one or more instances of J E , C 6 _io aryl group optionally substituted with one or more instances of J F , and 5-10 membered heteroaryl group optionally substituted with one or more instances of J F ; iii) a C 3 _8 carbocyclic or 4-8 membered heterocyclic group, each of which is optionally and independently substituted with
  • R a together with R and the nitrogen atom to which it is attached, optionally forms a 4-8 membered heterocycle optionally substituted with one or more instances of J E ;
  • R b and R c together with the nitrogen atom to which they are attached, optionally forms a 4-8 membered heterocycle optionally substituted with one or more instances of J E .
  • Each R is independently -H or a Ci_ 6 aliphatic group optionally substituted with one or more instances of J D .
  • Each R' is independently -H or a Ci_ 6 aliphatic group optionally substituted with one or more instances of J D ; or two R, together with the nitrogen atom to which they are attached, optionally form a 4-8 membered heterocycle optionally substituted with one or more instances of J E .
  • Each R" is a Ci_ 6 aliphatic group optionally substituted with one or more instances of
  • Each J D is independently selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), and phenyl.
  • Each J E is independently selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), and Ci-C 6 aliphatic group optionally substituted with one or more instances of J D .
  • Each J F is independently selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), and Ci-C 6 aliphatic that is optionally substituted with one or more instances of J D .
  • n 0 or 1.
  • the invention is directed to a compound represented by any one of Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that R 4 and R 6 are each independently -H or Ci_ 6 alkyl.
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that R 4 and R 6 are each independently -H.
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that:
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ) or -P(0)(OR 3 ) 2 ;
  • R 8 is -NR b R c .
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that:
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ) or -P(0)(OR 3 ) 2 ;
  • each R 3 independently is -H, optionally substituted Ci-C 6 aliphatic, optionally substituted C3-6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl; or alternatively, each R 3 independently is -H or substituted Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl
  • R 8 is -NR b R c .
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that:
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl
  • R 5 and R 7 are each independently -H or optionally substituted Ci_ 6 alkyl.
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that:
  • R 4 and R 6 are each independently -H;
  • R 5 and R 7 are each independently -H or optionally substituted Ci_ 6 alkyl.
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that:
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl
  • R 5 and R 7 are each independently -H or optionally substituted Ci_ 6 alkyl
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ) or -P(0)(OR 3 ) 2 .
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that:
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ) or -P(0)(OR 3 ) 2 ;
  • each R 3 independently is -H, optionally substituted Ci-C 6 aliphatic, optionally substituted C3-6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl; or alternatively, each R 3 independently is -H or substituted Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(hal
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl
  • R 5 and R 7 are each independently -H or optionally substituted Ci_ 6 alkyl
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ) or -P(0)(OR 3 ) 2 ;
  • R 8 is -NR b R c .
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that:
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl
  • R 5 and R 7 are each independently -H or optionally substituted Ci_ 6 alkyl
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ) or -P(0)(OR 3 ) 2 ;
  • R 8 is -NR b R c .
  • the invention is directed to a compound represented by Structural Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of each of Structural Formulae (I) and (II) are each and independently as described above except that n is 0.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein (e.g., a compound of the invention described in the claims and FIGs. 1 and 2, such as a compound represented by any one of Structural Formulae (I)-(VII) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.
  • the invention provides methods of treating a HCV infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of the invention described in the claims and FIGs. 1 and 2, such as a compound represented by any one of Structural Formulae (I)-(VII) or a pharmaceutically acceptable salt thereof).
  • a compound described herein e.g., a compound of the invention described in the claims and FIGs. 1 and 2, such as a compound represented by any one of Structural Formulae (I)-(VII) or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of inhibiting or reducing the activity of HCV polymerase in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of the invention described in the claims and FIGs. 1 and 2, such as a compound represented by any one of Structural Formulae (I)-(VII) or a pharmaceutically acceptable salt thereof).
  • a compound described herein e.g., a compound of the invention described in the claims and FIGs. 1 and 2, such as a compound represented by any one of Structural Formulae (I)-(VII) or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a method of inhibiting or reducing the activity of HCV polymerase in a biological in vitro sample, comprising administering to the sample an effective amount of a compound of the invention described herein, such as a compound described herein (e.g., a compound of the invention described in the claims and FIGs. 1 and 2, such as a compound represented by any one of Structural Formulae (I)-(VII) or a pharmaceutically acceptable salt thereof).
  • a compound of the invention described herein such as a compound described herein (e.g., a compound of the invention described in the claims and FIGs. 1 and 2, such as a compound represented by any one of Structural Formulae (I)-(VII) or a pharmaceutically acceptable salt thereof).
  • the present invention also provides use of the compounds of the invention described herein (e.g., the compounds of the invention described in the claims and FIGs. 1 and 2, such as the compounds represented by any one of Structural Formulae (I)-(VII) or pharmaceutically acceptable salts thereof) for the manufacture of the medicament for treating a HCV infection in a subject, or for inhibiting or reducing the activity of HCV polymerase in a subject.
  • the compounds of the invention described herein e.g., the compounds of the invention described in the claims and FIGs.
  • the compounds of the invention can be employed as prodrugs which generate active metabolites (e.g., the compounds of Structural Formulae (I) or (II) wherein X is -H) useful for treating a HCV infection in a subject, or for inhibiting or reducing the activity of HCV polymerase in a subject (see, for example, Example 2).
  • active metabolites e.g., the compounds of Structural Formulae (I) or (II) wherein X is -H
  • X is -H
  • FIGs. 1 and 2 show certain compounds of the invention.
  • FIGs. 3-5 show graphs showing plasma levels of prodrugs of the invention and their conversion into corresponding active metabolites after dosing of the prodrug.
  • the compounds of the invention are as described in the claims.
  • the compounds of the invention are represented by any one of Structural Formulae (I)-(VII) or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as described in any one of the claims.
  • the compounds of the invention are represented by any chemcial formulae depicted in FIGs. 1 and 2, or pharmaceutically acceptable salts thereof.
  • the compounds of the ivnention are presented by any one of Structural Formulae (I)-(VII) or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as depicted in the chemical formulae in FIGs. 1 and 2.
  • the compounds of the invention are represented by Structural Formula (I):
  • a first set of values of the variables of Structural Formula (I) is as follows:
  • Ring A is optionally further substituted with one or more substituents.
  • substituents suitable for ring A include halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CN, Ci_4 alkyl, and Ci_ 4 haloalkyl.
  • a specific example of the substituents includes halogen.
  • Ring B is an optionally substituted C 3 _ 8 cycloalkyl ring or an optionally substituted 5- 6 membered aryl ring. In one aspect, ring B is an optionally substituted C 3 _g cycloalkyl, or C 5 _6 cycloalkyl. In another aspect, ring B is an optionally substituted cyclohexyl.
  • Typical substituents suitable for ring B include halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -OH, -0(C M alkyl), -CN, -NH 2 , -NH(Ci_ 4 alkyl), and -N(C alkyl) 2 .
  • substituents suitable for ring B include halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 . More specific examples of substituents suitable for ring B include halogen, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, and -0(CH 3 ). More specific examples of substituents suitable for ring B include halogen, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -OH, and -0(Ci_ 4 alkyl).
  • Ring C is a cyclohexyl ring that is optionally further substitued with one or more substituents.
  • substituents suitable for ring C include halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -OH, -0(Ci_ 4 alkyl), -CN, -NH 2 , -NH(Ci_ 4 alkyl), and -N(Ci_4 alkyl) 2 .
  • substituents suitable for ring C include halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 . More specific examples of substituents suitable for ring C include halogen, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, and -0(CH 3 ). More specific examples of substituents suitable for ring C include halogen, Ci_ 4 alkyl, Ci_ 4 haloalkyl, -OH, and -0(Ci_ 4 alkyl).
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ), -P(0)(OR 3 ) 2 , or -C(0)R 2 .
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ).
  • X is -C(0)R 2 .
  • Y is C 3 _8 carbocycle, optionally substituted 5-8 membered heterocycle, -(C 2 aliphatic group ⁇ R 1 , C 6 -io aryl, or 5-10 membered heteroaryl, wherein each of said carbocycle, heterocycle, aryl and heteroaryl is optionally and independently substituted with one or more instances of J Y , and wherein said C 2 aliphatic group is optionally substituted with one or more substitutents.
  • Y is optionally substituted C 3 _ 6 cycloalkyl, optionally substituted C 4 _ 6 cycloalkenyl, -(C 2 aliphatic optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl, and wherein said C 2 aliphatic group is optionally substituted.
  • Y is optionally substittued phenyl, optionally substittued thienyl, or optionally substittued pyridyl.
  • Y is optionally substituted phenyl.
  • J Y include halogen, -CN, nitro, R a , -OR a , -COR a , and -NRR a . More specific examples of J Y include halogen, -CN, nitro, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OH, -0(Ci_ 6 alkyl), -0(phenyl), -0(5-6 membered heteroaryl), -NH 2 , -NH(Ci_ 6 alkyl), -N(Ci_ 6 alkyl) 2 , and -C(0)(Ci_6 alkyl). Even more specific examples of J Y include chloro, fluoro, -CN, nitro, methyl, ethyl, -CF 3 , -OH, -OMe, -NH 2 , and -C(0)Me.
  • substituents suitable for the C 2 aliphatic group of -(C 2 aliphatic group)-R 1 include halogen, -CN, Ci_ 2 alkyl, Ci_ 2 haloalkyl, hydroxy, and methoxy.
  • R 1 is i) -H; ii) a Ci_ 6 aliphatic group optionally substituted with one or more instances of J 1A ; iii) a C 3 _io carbocycle or 4-10 membered heterocycle, each of which is optionally and independently substituted with one or more instances of J 1B ; or iv) a C 6 -io aryl or 5-10 membered heteroaryl group, each of which is optionally and independently substituted with
  • R is an optionally substituted Ci_ 6 alkyl or optionally substituted C 3 _g carbocyclic group.
  • R 1 is an optionally substituted Ci_ 6 alkyl or optionally substituted C 3 _g cycloalkyl group.
  • R 1 is optionally substituted Ci_ 6 alkyl or optionally substituted C 3 _g cycloalkyl.
  • R 1 is Ci_ 6 alkyl or C 3 _g cycloalkyl.
  • R 1 is Ci_ 6 alkyl.
  • R 1 is t-butyl or isopropyl.
  • R 2 is: i) a C 3 _io carbocyclic or 4-10 membered heterocyclic group, each of which is optionally and independently substituted with one or more instances of J E , or ii) a C 6 -io aryl or 5-10 membered heteroaryl group, each of which is optionally and independently substituted with one or more instances of J F .
  • R 2 is an optionally substituted Ci_ 6 aliphatic, optionally substituted C3-8 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl group.
  • R 2 is an optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl group.
  • R 3 is: i) -H, ii) a Ci_ 6 aliphatic group optionally substituted with one or more instances of J D , iii) a C3-10 carbocyclic or 4-10 membered heterocyclic group, each of which is optionally and independently substituted with one or more instances of J E , or iv) a C 6-1 o aryl or 5-10 membered heteroaryl group, each of which is optionally and independently substituted with one or more instances of J F .
  • each R 3 independently is -H, optionally substituted Ci-C 6 aliphatic, optionally substituted C3-6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl. In another specific aspect, each R 3 independently is -H or optionally substituted Ci_ 6 alkyl.
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl; and R 5 and R 7 are each independently -H or optionally substituted Ci_ 6 alkyl.
  • R 8 is -R b , halogen, cyano, nitro, -OR b , -NR b R c , -C(0)R b , -C(0)OR b , -OC(0)R b , -NRC(0)R b , or -C(0)NR b R c ; or optionally when R 8 is -NR b R c , R c and R 7 form a
  • R 8 is -H, halogen, cyano, -OR b , -NR b R c , optionally substituted Ci-C 6 aliphatic, optionally substituted C 3 _ 6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl.
  • R 8 is -NR b R c .
  • R 9 is: i) -H; ii) a Ci_ 6 aliphatic group optionally substituted with one or more instances of J 9A ; iii) a C 3 _io carbocycle or 4-10 membered heterocycle, each of which is optionally and independently substituted with one or more instances of J 9B ; or iv) a C 6 -io aryl or 5-10 membered heteroaryl group, each of which is optionally and independently substituted with one or more instances of J 9C .
  • R 9 is -H, or an optionally substituted Ci_ 6 aliphatic or optionally substituted carbocyclic group.
  • R 9 is -H or optionally substituted Ci_ 6 alkyl.
  • R 9 is -H.
  • J 1A and J 9A independently is oxo or Q; or two J 1A and two J 9A , respectively, together with the atom(s) to which they are attached, optionally and independently form a 3- 8-membered non-aromatic ring that is optionally substituted with one or more instances of J E .
  • each of J 1A and J 9A independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , C 3 _8 cycloalkyl, C 3 _ 8 cyclo(haloalkyl), or phenyl.
  • each of J 1A and J 9A independently is halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci- C 6 alkyl), -0(Ci-C 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), or phenyl.
  • each of J 1A and J 9A independently is halogen, -CN, -OH, -0(Ci_ 6 alkyl), or -0(Ci_6 haloalkyl).
  • J 1B and J 9B are oxo, Q, or a Ci_ 6 aliphatic group optionally substituted with one or more instances of Q; or two J 1B and two J 9B , respectively, together with the atom(s) to which they are attached, optionally and independently form a 3-8- membered non-aromatic ring that is optionally substituted with one or more instances of J E .
  • each of J 1B and J 9B independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , or a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , C
  • each of J 1B and J 9B independently is halogen; oxo; -CN; -OH; -NH 2 ; -NH(Ci-C 6 alkyl); -N(Ci-C 6 alkyl) 2 ;
  • Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -0(Ci_ 6 alkyl), and -0(Ci_ 6 haloalkyl).
  • each of J 1B and J 9B independently is halogen, -CN, -OH, -0(Ci_ 6 alkyl), -0(Ci_ 6 haloalkyl), Ci_ 6 alkyl, or Ci_ 6 haloalkyl.
  • Each of J and J independently is Q or a Ci_ 6 aliphatic group optionally substituted with one or more instances of Q; or two J and two J , respectively, together with the atoms to which they are attached, optionally and independently form a 3-8-membered non-aromatic ring that is optionally substituted with one or more instances of J E .
  • each of J 1C and J 9C independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , or a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , C
  • each of J and J independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , or a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a
  • each of J and J independently is halogen; oxo; -CN; -OH; -NH 2 ; -NH(Ci-C 6 alkyl); -N(C C 6 alkyl) 2 ; -OCO(C C 6 alkyl); -CO(C C 6 alkyl); -C0 2 H; -C0 2 (C C 6 alkyl); -0(Ci-C 6 alkyl); -0(Ci-C 6 haloalkyl); or Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -0(Ci_ 6 alkyl), and -0(Ci_6 haloalkyl).
  • each of J and J independently is halogen, -CN, -OH, -0(Ci_ 6 alkyl), -0(Ci_ 6 haloalkyl), Ci_ 6 alkyl, or Ci_ 6 haloalkyl.
  • each Q independently is selected from the group consisting of halogen; cyano; nitro; -OR a ; -SR a ; -S(0)R a ; -S0 2 R a ; -NRR a ; -C(0)R a ; -C(0)OR a ; -OC(0)R a ; -OC(0)OR a ; -NRC(0)R a ; -C(0)NRR a ; -NRC(0)NRR a ; -NRC(0)NRR a ;
  • each Q independently is selected from the group consisting of halogen; cyano; nitro; -OR a ; -NRR a ; -C(0)R a ; -C(0)OR a ;
  • Each R a , R b , and R c independently is: i) -H; ii) a Ci_ 6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, nitro, -CN, -OR * , -NR'R, -OCOR * , -COR", -C0 2 R', -CONR'R, -NRC(0)R , C 3 _ 8 carbocyclic group optionally substituted with one or more instances of J E , 4-8 membered heterocyclic group optionally substituted with one or more instances of J E , C 6-1 o aryl group optionally substituted with one or more instances of J F , and 5-10 membered heteroaryl group optionally substituted with one or more instances of J F ; iii) a C 3 _ 8 carbocyclic or 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one
  • each R a independently is -H, optionally substituted Ci_ 6 aliphatic, optionally substituted C 3 _ 6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl; or optionally R a , together with R and the nitrogen atom to which it is attached, forms an optionally substituted 4-8 membered heterocyclic ring; and each of R b and R c independently is -H or Ci- 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci_ 6 alkyl), -N(Ci_ 6 alkyl) 2 , -OCO(Ci_6 alkyl), -CO(Ci_ 6 alkyl), -C0 2 H, -C0 2 (Ci_ 6 alkyl), -0(C
  • each R a is independently as described in the preceeding paragraph; and each of R b and R c independently is -H or Ci- 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(d_ 6 alkyl), -N(d_ 6 alkyl) 2 , -OCO(d_ 6 alkyl), -CO(d_ 6 alkyl), -C0 2 H, -C0 2 (d_ 6 alkyl), -0(Ci_ 6 alkyl), -0(Ci_ 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl), and phenyl, or R b and R c , together with the nitrogen atom to which they are attached, optionally form a 5- 7 membered heterocyclic ring optionally substituted with one or more substituent
  • Each R is independently -H or a Ci_ 6 aliphatic group optionally substituted with one or more instances of J D .
  • Each R' is independently -H or a Ci_ 6 aliphatic group optionally substituted with one or more instances of J D ; or two R, together with the nitrogen atom to which they are attached, optionally form a 4-8 membered heterocycle optionally substituted with one or more instances of J E .
  • Each R" is a Ci_ 6 aliphatic group optionally substituted with one or more instances of
  • Each J D is independently selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(C C 6 alkyl) 2 , -OCO(C C 6 alkyl), -CO(C C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(d-C 6 alkyl), -0(d-C 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl), and phenyl.
  • Each J E is independently selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(C C 6 alkyl) 2 , -OCO(C C 6 alkyl), -CO(C C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(d-C 6 alkyl), -0(d-C 6 haloalkyl), and Ci-C 6 aliphatic group optionally substituted with one or more instances of J D .
  • Each J F is independently selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(C C 6 alkyl) 2 , -OCO(C C 6 alkyl), -CO(C C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), and Ci-C 6 aliphatic that is optionally substituted with one or more instances of J D .
  • n is 0 or 1. In one aspect, n is 0.
  • a second set of values of the variables of Structural Formula (I) is as follows:
  • Y is optionally substituted C 3 _ 6 cycloalkyl, optionally substituted C 4 _ 6 cycloalkenyl, -(C 2 aliphatic optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl, and wherein said C 2 aliphatic group is optionally substituted.
  • Y is optionally substituted phenyl, optionally substituted thienyl, or optionally substituted pyridyl.
  • Y is optionally substituted phenyl. Suitable substituents for the values of Y are as described above in the first set of variables of Structural Formula (I).
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a third set of values of the variables of Structural Formula (I) is as follows:
  • Y is optionally substituted C3-6 cycloalkyl or optionally substituted C4-6 cycloalkenyl. In one specific aspect, Y is optionally substituted C 4 _ 6 cycloalkenyl. In another specific aspect, Y is optionally substituted cyclohexenyl. Suitable substituents for the values of Y are as described above in the first set of variables of Structural Formula (I).
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a fourth set of values of the variables of Structural Formula (I) is as follows:
  • each J Y is independently selected from the group consisting of halogen, -CN, nitro, R a , -OR a , -COR a , and -NRR a .
  • each J Y is independently selected from the group consisting of halogen, -CN, nitro, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OH, -0(Ci_ 6 alkyl), -O(phenyl), -0(5-6 membered heteroaryl), -NH 2 , -NH(Ci_ 6 alkyl), -N(Ci_ 6 alkyl) 2 , and -C(0)(Ci_ 6 alkyl).
  • each J Y is independently selected from the group consisting of halogen, -CN, nitro, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OH, -0(Ci_ 6 alkyl), -NH 2 , -NH(Ci_ 6 alkyl), -N(Ci_ 6 alkyl) 2 , and -C(0)(Ci_ 6 alkyl).
  • each J Y is independently selected from the group consisting of halogen, -CN, nitro, methyl, ethyl, -CF 3 , -OH, -OMe, -NH 2 , and -C(0)Me.
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a fifth set of values of the variables of Structural Formula (I) is as follows:
  • Y is -(C 2 aliphatic and wherein said C 2 aliphatic group is optionally substituted.
  • Y is or -C ⁇ CR 1 .
  • Y is -C ⁇ CR 1 .
  • substituents suitable for the C 2 aliphatic group of -(C 2 aliphatic group)-R 1 include halogen, -CN, Ci_ 2 alkyl, Ci_ 2 haloalkyl, hydroxy, and methoxy.
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a sixth set of values of the variables of Structural Formula (I) is as follows:
  • Y is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • R 1 is an optionally substituted Ci_ 6 alkyl or optionally substituted C3-8 carbocyclic group. Suitable substituents for the values of R 1 are each and independently as described above in the first set of variables of Structural Formula (I).
  • R 1 is an optionally substituted Ci_ 6 alkyl or C 3 _ 8 cycloalkyl, each of which is optionally and independently substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C 3 _ 7 cyclo
  • R 1 is an optionally substituted Ci_ 6 alkyl.
  • R 1 is Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, and -0(Ci-C 6 alkyl).
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a seventh set of values of the variables of Structural Formula (I) is as follows:
  • Y is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • R 1 is as described above in the sixth set of values of the variables of Structural Formula (I).
  • R 2 is an optionally substituted Ci_ 6 aliphatic, optionally substituted C 3 _8 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl group. Suitable substituents for the values of R 2 are each and independently as described above in the first set of variables of Structural Formula (I).
  • R 2 is Cs-Cg cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen; oxo; -CN; -OH; -NH 2 ; -NH(Ci-C 6 alkyl); -N(C C 6 alkyl) 2 ; -OCO(C C 6 alkyl); -CO(C C 6 alkyl); -C0 2 H; -C0 2 (C C 6 alkyl); -0(Ci-C 6 alkyl); -0(Ci-C 6 haloalkyl); and a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(C C 6 alkyl) 2 , -OCO(C C 6 alkyl), -CO(
  • R 2 is optionally substituted cyclohexyl.
  • R 2 is cyclohexyl optionally substituted with one or more instances of J 2B independently selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci_6 alkyl), -N(Ci_ 6 alkyl) 2 , -0(Ci_ 6 alkyl), and Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci_6 alkyl), -N(Ci_ 6 alkyl) 2 , -0(Ci_ 6 alkyl), and -0(Ci_ 6 haloalkyl).
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ) or -P(0)(OR 3 ) 2 .
  • R 1 and R 2 are each and independently as described above in the seventh set of values of the variables of Structural Formula (I).
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a ninth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, R 1 and R 2 are each and independently as described above in any one of the first through eighth set of values of the variables of Structural Formula (I).
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • X, Y, Q, R 1 and R 2 are each and independently as described above in any one of the first through ninth set of values of the variables of Structural Formula (I).
  • R a is -H, optionally substituted Ci_ 6 aliphatic, optionally substituted C 3 _ 6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl; or optionally R a , together with R and the nitrogen atom to which it is attached, forms an optionally substituted 4-8 membered heterocyclic ring.
  • Suitable substituents for the values of R a are each and independently as described above in the first set of variables of Structural Formula (I).
  • R b and R c independently is -H or Ci- 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci_6 alkyl), -N(Ci_ 6 alkyl) 2 , -OCO(Ci_ 6 alkyl), -CO(Ci_ 6 alkyl), -C0 2 H, -C0 2 (Ci_ 6 alkyl), -0(Ci_6 alkyl), -0(Ci_ 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), and phenyl, or R b and R c , together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of halogen, ox
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • X, Y, Q, R 1 , R 2 , R a , R b and R c are each and independently as described above in any one of the first through ninth set of values of the variables of Structural Formula (I).
  • Each R 3 independently is -H, optionally substituted Ci-C 6 aliphatic, optionally substituted C 3 _ 6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl. Suitable
  • R 4 , R 5 , R 6 , and R 7 independently is -H; or Ci_ 6 alkyl optionally substituted with one or more substitutents selected from the group consisting of -OH, -NH 2 ,
  • R 8 independently is -H, halogen, cyano, -OR b , -NR b R c , optionally substituted Ci-C 6 aliphatic, optionally substituted C 3 _ 6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl.
  • Suitable substituents for the values of R 8 are each and independently as described above in the first set of variables of Structural Formula (I).
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a twelfth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, Q, R 1 , R 2 , R a , R b and R c are each and independently as described above in any one of the first through ninth set of values of the variables of Structural Formula (I).
  • Each R 3 independently is -H or Ci_ 6 alkyl optionally substituted with one or more instances of J D .
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl.
  • R 5 and R 7 are each independently -H or Ci_ 6 alkyl optionally substituted with one or more instances of J D .
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a thirteenth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R a , R b and R c are each and independently as described above in any one of the first through twelfth set of values of the variables of Structural Formula (I).
  • R 8 is -NR b R c .
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a fourteenth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b and R c are each and independently as described above in any one of the first through thirteenth set of values of the variables of
  • J 1A and J 9A independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a ,
  • J 1B and J 9B independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a ,
  • -COR a -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , or a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a ,
  • J 1C and J 9C independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , or a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -NRC(0)OR a
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a fifteenth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, Q, R 1 , R 2 , R 3 , R 8 , R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C , and J 9C are each and independently as described above in any one of the first through fourteenth set of values of the variables of Structural Formula (I).
  • R 4 and R 6 are independently -H or Ci_ 6 alkyl.
  • R b and R c independently is -H or Ci- 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci_6 alkyl), -N(Ci_ 6 alkyl) 2 , -OCO(Ci_ 6 alkyl), -CO(Ci_ 6 alkyl), -C0 2 H, -C0 2 (Ci_ 6 alkyl), -0(Ci_6 alkyl), -0(Ci_ 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), and phenyl, or R b and R c , together with the nitrogen atom to which they are attached, optionally form a 5-7 membered heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of halogen,
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a sixteenth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, Q, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C , and J 9C are each and independently as described above in any one of the first through fifteenth set of values of the variables of Structural Formula (I).
  • R 3 is -H or Ci_6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl), and phenyl.
  • substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ,
  • R 3 is -H or Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl), and phenyl.
  • substituents selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl), and phenyl.
  • R 3 is -H or Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -0(Ci-C 6 alkyl), C 3 _ 7 cycloalkyl, and phenyl.
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a seventeenth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, Q, R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C , and J 9C are each and independently as described above in any one of the first through sixteenth set of values of the variables of Structural Formula (I).
  • Each of R 4 and R 6 is independently -H.
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • X, Y, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , J 1A , J 9A , J 1B , J 9B , J 1C , and J 9C are each and independently as described above in any one of the first through seventeenth set of values of the variables of Structural Formula (I).
  • R b and R c independently is -H or Ci- 6 alkyl, or optionally, together with the nitrogen atom to which they are attached, form an optionally substituted, 5-7 membered, heterocyclic ring.
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a nineteenth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C , and J 9C are each and independently as described above in any one of the first through seventeenth set of values of the variables of Structural Formula (I).
  • Ring B is optionally substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • Ring C is optionally further substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of variables of Structural Formula (I).
  • a twentieth set of values of the variables of Structural Formula (I) is as follows:
  • X, Y, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C , and J 9C are each and independently as described above in any one of the first through seventeenth set of values of the variables of Structural Formula (I).
  • Ring B is C 3 _g cyclcoalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • variables of Structural Formula (II) are each and independently as described above in any one of the first through twentieth sets of values of the variables of Structural Formula (I).
  • Suitable vairables for Rings A, B and C are each and independently as described above in the first set of values of the variables of Structural Formula (I). [0050] In a twenty first set of values of the variables of Structural Formula (II):
  • R 1 is an optionally substituted Ci_ 6 alkyl or optionally substituted C3-8 carbocyclic group.
  • R 2 is an optionally substituted Ci_ 6 aliphatic, optionally substituted C 3 _8 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl group.
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 and R 2 are each independently as described above in the twenty first set of values of the variables of Structural Formula (II).
  • X is [-C(0)-C(R 4 R 5 )-N(R)-] n -C(0)C(R 6 R 7 R 8 ) or -P(0)(OR 3 ) 2 .
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 2 and X are each independently as described above in the twenty second set of values of the variables of Structural Formula (II).
  • Q independently is selected from the group consisting of halogen; cyano; nitro; -OR a ; -SR a ; -S(0)R a ; -S0 2 R a ; -NRR a ; -C(0)R a ; -C(0)OR a ; -OC(0)R a ;
  • Q independently is selected from the group consisting of halogen; cyano; nitro; -OR a ; -SR a ; -S(0)R a ; -S0 2 R a ; -NRR a ; -C(0)R a ;
  • Suitable substitutents for the C 3 _g carbocyclic, heterocyclyl, phenyl; and heteroaryl groups are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , X, and Q are each independently as described above in the twenty third set of values of the variables of Structural Formula (II).
  • R a is -H, optionally substituted Ci_ 6 aliphatic, optionally substituted C3-6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl; or optionally R a , together with R and the nitrogen atom to which it is attached, forms an optionally substituted 4-8 membered heterocyclic ring.
  • Suitable substitutents for the aliphatic, carbocyclic, heterocyclyl, phenyl; and heteroaryl groups are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R b and R c independently is -H or Ci- 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci_6 alkyl), -N(Ci_ 6 alkyl) 2 , -OCO(Ci_ 6 alkyl), -CO(Ci_ 6 alkyl), -C0 2 H, -C0 2 (Ci_ 6 alkyl), -0(Ci_6 alkyl), -0(Ci_ 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl), and phenyl, or R b and R c , together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -
  • the remaining variables of Structural Formula (I) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 2 , X, Q, R a , R b and R c are each independently as described above in the twenty fourth set of values of the variables of Structural Formula (II).
  • R 3 is -H, optionally substituted Ci-C 6 aliphatic, optionally substituted C3-6
  • R 4 , R 5 , R 6 , and R 7 independently is -H; or Ci_ 6 alkyl optionally substituted with one or more substitutents selected from the group consisting of -OH, -NH 2 ,
  • R 8 independently is -H, halogen, cyano, -OR b , -NR b R c , optionally substituted Ci-C 6 aliphatic, optionally substituted C3-6 carbocyclic, optionally substituted 4-8 membered heterocyclic, optionally substituted phenyl, or optionally substituted 5-6 remembered heteroaryl.
  • Suitable substituents for the carbocyclic, heterocyclic, phenyl, and heteroaryl groups are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 2 , X, Q, R a , R b and R c are each independently as described above in the twenty fifth set of values of the variables of Structural Formula (II).
  • R 3 is -H or optionally substituted Ci_ 6 alkyl.
  • R 4 and R 6 are each independently -H or Ci_ 6 alkyl.
  • R 5 and R 7 are each independently -H or optionally substituted Ci_ 6 alkyl.
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 R 7 , X, Q, R a , R b and R c are each independently as described above in the twenty sixth set of values of the variables of Structural Formula (II).
  • R 8 is -NR b R c .
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 R 7 , R 8 , X, Q, R a , R b and R c are each independently as described above in the twenty seventh set of values of the variables of Structural Formula (II).
  • J 1A and J 9A independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -OCOOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , C 3 _8 cycloalkyl, C 3 _ 8 cyclo(haloalkyl), optionally substisuted 5-6 membered heterocyclyl, or optionally substituted phenyl.
  • each of J 1A and J 9A independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -OCOOR a , -COR a , -C0 2 R a , -
  • each of J 1A independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , C 3 _ 8 cycloalkyl, C 3 _ 8 cyclo(haloalkyl), or phenyl; and each of J 9A independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -OCOOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -C(0)NRR a ,
  • J 1B and J 9B independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , or a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , C 3 _ 8
  • J 1C and J 9C independently is halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , or a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR a , -NRR a , -OCOR a , -COR a , -C0 2 R a , -NRC(0)R a , -C(0)NRR a , -NRC(0)NRR a , -NRC(0)OR a , -OCONRR a , C 3 _ 8
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , R 3 , R 8 , X, Q, R a , J 1A , J 9A , J 1B , J 9B , J 1C and J 9C are each independently as described above in the twenty eighth set of values of the variables of Structural Formula (II).
  • R 4 and R 6 are independently -H or Ci_ 6 alkyl.
  • R b and R c independently is -H or Ci- 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci_6 alkyl), -N(Ci_ 6 alkyl) 2 , -OCO(Ci_ 6 alkyl), -CO(Ci_ 6 alkyl), -C0 2 H, -C0 2 (Ci_ 6 alkyl), -0(Ci_6 alkyl), -0(Ci_ 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), and phenyl, or R b and R c , together with the nitrogen atom to which they are attached, optionally form a 5-7 membered heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of halogen,
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , R 4 , R 5 , R 6 R 7 , R 8 , X, Q, R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C and J 9C are each independently as described above in the twenty ninth set of values of the variables of Structural Formula (II).
  • R 3 is -H or Ci_6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(C C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(C C 6 alkyl), -0(Ci-C 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl), and phenyl.
  • substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO
  • R 3 is -H or Ci_6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), and phenyl.
  • R 3 is -H or Ci_6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -0(Ci-C 6 alkyl), C 3 _ 7 cycloalkyl, and phenyl.
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , X, Q, R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C and J 9C are each independently as described above in the thirtieth set of values of the variables of Structural Formula (II).
  • Each of R 4 and R 6 is independently -H.
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , X, Q, R a , J 1A , J 9A , J 1B , J 9B , J 1C and J 9C are each independently as described above in the thirty first set of values of the variables of Structural Formula (II).
  • Each of R b and R c independently is -H or Ci- 6 alkyl, or optionally, together with the nitrogen atom to which they are attached, form an optionally substituted, 5-7 membered, heterocyclic ring.
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , X, Q, R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C and J 9C are each independently as described above in the thirty second set of values of the variables of Structural Formula (II).
  • Ring B is optionally substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • Ring C is optionally further substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , X, Q, R a , R b , R c , J 1A , J 9A , J 1B , J 9B , J 1C and J 9C are each independently as described above in the thirty second set of values of the variables of Structural Formula (II).
  • Ring B is optionally substituted C 3 _g cyclcoalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • Ring C is optionally further substituted with one or more substituents selected from the group consisting of halogen, -D, -CD 3 , -CHD 2 , -CH 2 D, -CH 3 , -CF 3 , -OH, -0(CH 3 ), -CN, -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • the remaining variables of Structural Formula (II) are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • Ring A is not further substituted, and the remaining variables of Structural Formula (II) are each independently as described above in any one of the first through thrity fourth sets of values of the variables of Structural Formula (II).
  • the compounds of the invention are represented by any one of Structural Formulae III)-(VII) or pharmaceutically accpetable salts thereof:
  • each ring B independently is optionally substituted cyclohexyl
  • each ring C is optionally substituted cyclohexyl.
  • the variables of these structural formulae are each and independently as described above in any one of the first through thrifty fifth sets of values of the variables of Structural Formula (II).
  • Suitable vairables for Rings B and C are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R b and R c independently is -H or Ci- 6 alkyl.
  • Each R 3 independently is -H or Ci_ 6 alkyl.
  • Each R 6 independently is -H.
  • R b and R c independently is -H or Ci- 6 alkyl.
  • Each R 1 independently is an optionally substituted Ci_ 6 alkyl or optionally substituted
  • Each R 3 independently is -H or Ci_ 6 alkyl.
  • Each R 6 independently is -H.
  • R b and R c independently is -H or Ci- 6 alkyl.
  • Each R 1 is optionally substituted Ci_ 6 alkyl or optionally substituted C3-8 cycloalkyl, each of which is optionally and independently substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(C C 6 alkyl), -CO(C C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(C C 6 alkyl), -0(Ci-C 6 haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl), and
  • R 1 is Ci_ 6 alkyl or C3-8 cycloalkyl, each of which optionally and independently substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -0(Ci_6 alkyl), and -0(Ci_ 6 haloalkyl).
  • R 1 is Ci_ 6 alkyl or C 3 _ 8 cycloalkyl.
  • R 1 is Ci_ 6 alkyl.
  • R 1 is t-butyl or isopropyl.
  • Each R 3 independently is -H or Ci_ 6 alkyl.
  • Each R 6 independently is -H.
  • R b and R c independently is -H or Ci- 6 alkyl.
  • R 1 , R 3 , R 6 , R 7 , R b , and R c are each independently as described above in any one of the first through thirty ninth set of values of the variables of Structural Formulae (III)-(VII).
  • Each R 9 independently is -H, or an optionally substituted Ci_ 6 aliphatic or optionally substituted carbocyclic group. Suitable substituents for the Ci_ 6 aliphatic and carbocyclic groups are each and independently as described above in the first set of values of the variables of Structural Formula (I).
  • R 1 , R 3 , R 6 , R 7 , R b , and R c are each independently as described above in any one of the first through thirty ninth set of values of the variables of Structural Formulae (III)-(VII).
  • Each R 9 independently is -H or Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(C C 6 alkyl), -OCOO(C C 6 alkyl), -CO(C C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), phenyl, and 5-6 membered heterocycle optionally substituted with one or more substitutents selected from oxo and Ci-C 6 alkyl.
  • substituents selected from the group consisting of halogen,
  • each R 9 independently is -H or Ci_6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C 6 alkyl), -CO(Ci-C 6 alkyl), -C0 2 H, -C0 2 (Ci-C 6 alkyl), -0(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), C 3 _ 7 cycloalkyl, C 3 _ 7 cyclo(haloalkyl), and phenyl.
  • substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 al
  • R 1 , R 3 , R 6 , R 7 , R b , and R c are each independently as described above in any one of the first through thirty ninth set of values of the variables of Structural Formulae (III)-(VII).
  • Each R 9 is -H.
  • the compounds of the invention are represented by Structural Formula (I) or (II), wherein:
  • R 2 is C5-C8 cycloalkenyl optionally substituted with one or more substituents selected from the group consisting of halogen; oxo; -CN; -OH; -NH 2 ; -NH(Ci-C 6 alkyl); -N(Ci-C 6 alkyl) 2 ; -OCO(Ci-C 6 alkyl); -CO(Ci-C 6 alkyl); -C0 2 H; -C0 2 (Ci-C 6 alkyl); -0(Ci-C 6 alkyl); -0(Ci-C 6 haloalkyl); and a Ci-C 6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -OCO(Ci-C
  • R 2 is optionally substituted cyclohexenyl. More specifically, R 2 is cyclohexenyl optionally substituted with one or more instances of J 2B independently selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci_ 6 alkyl), -N(Ci_ 6 alkyl) 2 , -0(Ci_ 6 alkyl), and Ci_ 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH 2 , -NH(Ci_ 6 alkyl), -N(C 1-6 alkyl) 2 , -0(Ci_ 6 alkyl), and -0(Ci_ 6 haloalkyl).
  • the compounds of the invention are represented by any one of the structural formulae depicted in FIG. 1, or pharmaceutically acceptable salts thereof . In other embodiments, the compounds of the invention are represented by any one of the structural formulae depicted in FIG. 2 or pharmaceutically acceptable salts thereof.
  • the compounds according to the invention described herein can be prepared by any suitable method known in the art.
  • the compounds can be prepared in accordance with procedures described in US 6,881,741, US 2005/0009804, US
  • the compounds of the invention can be prepared as depicted in General Schemes 1 and 2.
  • the compounds of Structural Formulae (I), (II), (III), (IV), (V), (VI), and (VII) can be prepared as shown in General Schemes 1-2.
  • Any suitable condition known in the art can be employed for each step described in the schemes. Specific exemplary conditions are described in the schemes, and exemplary detailed procedures are described below in the Exemplification section.
  • the methods further comprise the step of preparing compound (lj).
  • the methods further comprise the step of preparing compound (lj) as described in General Scheme 1.
  • the present invention provides methods of preparing a compound represented by Structural Formula (II).
  • General Scheme 2 shows a general synthetic scheme for the compounds of Structural Formula (II). The synthetic details are each and independently as described above for General Scheme 1.
  • compounds (If), (2g), (2h), (2i), and (2j) are each and independently as described in General Scheme 1 for compounds (If), (lg), (lh), (li), and (lj), respectively.
  • the methods further comprise the step of preparing compound (2j) as described in the preceding paragraph for compound (lj). Specifically, compound (2j) can be prepared starting from compound (If).
  • Reaction of compound (If) with R 1 -C ⁇ CH can produce compound (2g); subsequent treatment of compound (2g) with an acid (e.g., HC1) in an aqueous condition can produce compound (2h); reduction of the ketone group at ring C of compound (2h) can produce compound (2i);
  • an acid e.g., HC1
  • compound (2i) under a suitable hydrolysis condition, for example in the presence of LiOH in H 2 0, can produce compound (2j) where R 9 is -H.
  • compound (2j) can be further reacted with a suitable reagent(s) known in the art to form compounds having other than -H for R 9 .
  • compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the compounds described above.
  • substituents such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the compounds described above.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group.
  • substituent When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. When the term “optionally substituted” precedes a list, said term refers to all of the subsequent substitutable groups in that list. If a substituent radical or structure is not identified or defined as “optionally substituted", the substituent radical or structure is unsubstituted. For example, if X is optionally substituted Ci_C 3 alkyl or phenyl; X may be either optionally substituted C 1 -C 3 alkyl or optionally substituted phenyl.
  • up to refers to zero or any integer number that is equal or less than the number following the phrase.
  • up to 3 means any one of 0, 1, 2, and 3.
  • a specified number range of atoms includes any integer therein. For example, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. Only those choices and
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched), or branched, hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation but is non-aromatic. Unless otherwise specified, aliphatic groups contain 1-10 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups.
  • Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert- butyl and acetylene.
  • alkyl as used herein means a saturated straight or branched chain hydrocarbon.
  • alkenyl as used herein means a straight or branched chain hydrocarbon comprising one or more double bonds.
  • alkynyl as used herein means a straight or branched chain hydrocarbon comprising one or more triple bonds.
  • Each of the "alkyl”, “alkenyl” or “alkynyl” as used herein can be optionally substituted as set forth below.
  • the "alkyl” is Ci-C 6 alkyl or C 1 -C 4 alkyl.
  • the "alkenyl” is C 2 -C 6 alkenyl or C 2 -C 4 alkenyl.
  • the "alkynyl” is C 2 -C 6 alkynyl or C 2 -C 4 alkynyl.
  • cycloaliphatic refers to a non-aromatic carbon only containing ring system which can be saturated or contains one or more units of unsaturation, having three to fourteen ring carbon atoms.
  • the number of carbon atoms is 3 to 10.
  • the number of carbon atoms is 4 to 7.
  • the number of carbon atoms is 5 or 6.
  • the term includes monocyclic, bicyclic or poly cyclic, fused, spiro or bridged carbocyclic ring systems.
  • the term also includes poly cyclic ring systems in which the carbocyclic ring can be "fused" to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the carbocyclic ring.
  • "Fused" bicyclic ring systems comprise two rings which share two adjoining ring atoms.
  • Bridged bicyclic group comprise two rings which share three or four adjacent ring atoms.
  • Spiro bicyclic ring systems share one ring atom.
  • Examples of cycloaliphatic groups include, but are not limited to, cycloalkyl and
  • cycloalkenyl groups include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.
  • heterocycle refers to a non-aromatic ring system which can be saturated or contain one or more units of unsaturation, having three to fourteen ring atoms in which one or more ring carbons is replaced by a heteroatom such as, N, S, or O.
  • non-aromatic heterocyclic rings comprise up to three heteroatoms selected from N, S and O within the ring.
  • non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N, S and O within the ring system.
  • non-aromatic heterocyclic rings comprise up to three heteroatoms selected from N and O within the ring system. In yet other embodiments, non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N and O within the ring system.
  • the term includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. The term also includes polycyclic ring systems in which the heterocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring. Examples of heterocycles include, but are not limited to, piperidinyl, piperizinyl,
  • pyrrolidinyl pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, morpholino, including, for example, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4- thiomorpholino, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-te
  • aryl (or “aryl ring” or “aryl group”) used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, “aryloxyalkyl”, or “heteroaryl” refers to carbocyclic aromatic ring systems.
  • aryl may be used interchangeably with the terms “aryl ring” or “aryl group”.
  • Carbocyclic aromatic ring” groups have only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to one another.
  • Carbocyclic aromatic ring or “carbocyclic aromatic”, as it is used herein, is a group in which an aromatic ring is “fused” to one or more non- aromatic rings (carbocyclic or heterocyclic), such as in an indanyl, phthalimidyl,
  • heteroaryl refers to heteroaromatic ring groups having five to fourteen members, in which one or more ring carbons is replaced by a heteroatom such as, N, S, or O.
  • heteroaryl rings comprise up to three heteroatoms selected from N, S and O within the ring.
  • heteroaryl rings comprise up to two heteroatoms selected from N, S and O within the ring system.
  • heteroaryl rings comprise up to three heteroatoms selected from N and O within the ring system. In yet other embodiments, heteroaryl rings comprise up to two heteroatoms selected from N and O within the ring system.
  • Heteroaryl rings include monocyclic heteroaromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other aromatic rings. Also included within the scope of the term "heteroaryl", as it is used herein, is a group in which an aromatic ring is "fused” to one or more non-aromatic rings (carbocyclic or heterocyclic), where the radical or point of attachment is on the aromatic ring.
  • Bicyclic 6,5 heteroaromatic ring as used herein, for example, is a six membered heteroaromatic ring fused to a second five membered ring, wherein the radical or point of attachment is on the six membered ring.
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, for example, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5 -imidazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyrazo
  • cyclo As used herein, "cyclo”, “cyclic”, “cyclic group” or “cyclic moiety”, include mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.
  • a "bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common).
  • Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.
  • a "bridged bicyclic ring system” refers to a bicyclic
  • bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.
  • a bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycl
  • heteroaralkyloxy aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
  • heterocycloalkyl carbonylamino
  • (heterocycloalkylalkyl)carbonylamino heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • bridge refers to a bond or an atom or an unbranched chain of atoms connecting two different parts of a molecule.
  • the two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are denotated as
  • spiro refers to ring systems having one atom (usually a quaternary carbon) as the only common atom between two rings.
  • ring atom is an atom such as C, N, O or S that is in the ring of an aromatic group, cycloalkyl group or non-aromatic heterocyclic ring.
  • a "substitutable ring atom" in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom.
  • the hydrogen can be optionally replaced with a suitable substituent group.
  • substituted ring atom does not include ring nitrogen or carbon atoms which are shared when two rings are fused.
  • substituted ring atom does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • an optionally substituted aralkyl can be substituted on both the alkyl and the aryl portion. Unless otherwise indicated as used herein optionally substituted aralkyl is optionally substituted on the aryl portion.
  • an aliphatic group and a heterocyclic ring may be any suitable aliphatic group and a heterocyclic ring.
  • Suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring are selected from those described above.
  • Optional substituents on the aliphatic group of R are selected from NH 2 , NH(Ci_ 4 aliphatic), N(Ci_ 4 aliphatic) 2 , halogen, Ci_ 4 aliphatic, OH, 0(Ci_ 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (Ci_ 4 aliphatic), 0(halo Ci_ 4 aliphatic), or halo(Ci_ 4 aliphatic), wherein each of the foregoing Ci_ 4 aliphatic groups of R is unsubstituted.
  • optional substituents on the nitrogen of a heterocyclic ring include those described above.
  • suitable substituents include -OH, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), -0(Ci-C 4 alkyl), and C 1 -C4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci- C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(C C 4 alkyl), -CO(C C 4 alkyl), -C0 2 H, -C0 2 (C C 4 alkyl), -0(
  • substituents include -R + , -N(R + ) 2 , -C(0)R + , -C0 2 R + , -C(0)C(0)R + , -C(0)CH 2 C(0)R + , -S0 2 R + ,
  • Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(Ci_ 4 aliphatic), N(Ci_ 4 aliphatic) 2 , halogen, Ci_ 4 aliphatic, OH, 0(Ci_ 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (Ci_ 4 aliphatic), 0(halo Ci_ 4 aliphatic), or halo(Ci_ 4 aliphatic), wherein each of the foregoing Ci_ 4 aliphatic groups of R + is unsubstituted.
  • an aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from those described above.
  • halogen -CN, -OH, -NH 2 , -NH(C C 4 alkyl), -N(C C 4 alkyl) 2 , -OCO(C C 4 alkyl), -CO(C r C 4 alkyl), -C0 2 H, -C0 2 (C C 4 alkyl), -0(C C 4 alkyl), and C C 4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (C C 4 alkyl), -0(C C 4 alkyl), C 3 _ 7 cycloalkyl, and C
  • each independent occurrence of R° is selected from hydrogen, optionally substituted Ci_ 6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH 2 (Ph), or, two independent occurrences of R°, on the same substituent or different substituents, taken together with the atom(s) to which each R° group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Optional substituents on the aliphatic group of R° are selected from NH 2 , NH(Ci_ 4 aliphatic), N(Ci_ 4 aliphatic) 2 , halogen, Ci_ 4 aliphatic, OH, 0(Ci_ 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (Ci_
  • Ci_ 4 aliphatic groups of R° is unsubstituted.
  • Non-aromatic nitrogen containing heterocyclic rings that are substituted on a ring nitrogen and attached to the remainder of the molecule at a ring carbon atom are said to be N substituted.
  • an N alkyl piperidinyl group is attached to the remainder of the molecule at the two, three or four position of the piperidinyl ring and substituted at the ring nitrogen with an alkyl group.
  • Non-aromatic nitrogen containing heterocyclic rings such as pyrazinyl that are substituted on a ring nitrogen and attached to the remainder of the molecule at a second ring nitrogen atom are said to be N' substituted-N-heterocycles.
  • an N' acyl N-pyrazinyl group is attached to the remainder of the molecule at one ring nitrogen atom and substituted at the second ring nitrogen atom with an acyl group.
  • two independent occurrences of R° may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring.
  • Exemplary rings that are formed when two independent occurrences of R° (or R + , or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°) 2 , where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-l-yl, piperazin-l-yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example
  • amino refers to -NH 2 .
  • hydroxyl'Or hydroxy or “alcohol moiety” refers to -OH.
  • alkoxy refers to an alkyl group, as previously defined, attached to the molecule through an oxygen (“alkoxy” e.g., -O-alkyl) or sulfur (“alkylthio” e.g., -S-alkyl) atom.
  • halogen means F, CI, Br, or I.
  • cyano or "nitrile” refer to -CN or -C ⁇ N.
  • alkoxyalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups.
  • haloalkyl haloalkenyl
  • haloaliphatic haloalkoxy
  • cyclo(haloalkyl) mean alkyl, alkenyl, aliphatic, alkoxy, or cycloalkyl, as the case may be, substituted with one or more halogen atoms.
  • This term includes perfluorinated alkyl groups, such as -CF 3 and -CF 2 CF 3 .
  • cyanoalkyl mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups.
  • the cyanoalkyl is (NC)-alkyl-.
  • aminoalkyl means alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups, wherein the amino group is as defined above.
  • hydroxyalkyl means alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups.
  • alkoxyalkyl means alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups.
  • alkoxyalkyl refers to an alkyl group such as (alkyl-O)-alkyl-, wherein alkyl has been defined above.
  • a protecting group and “protective group” as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites.
  • a protecting group has one or more, or specifically all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound.
  • the reagents may also react with other reactive groups in the compound.
  • protecting groups are detailed in Greene, T. W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book), the entire contents of which are hereby incorporated by reference.
  • the term "nitrogen protecting group”, as used herein, refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound.
  • Preferred nitrogen protecting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • the term "displaceable moiety” or “leaving group” refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure.
  • isomeric e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational
  • the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention, unless only one of the isomers is drawn specifically.
  • a substituent can freely rotate around any rotatable bonds.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Such compounds, especially deuterium (D) analogs can also be therapeutically useful.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • the compounds described herein can exist in free form, or, where appropriate, as salts. Those salts that are pharmaceutically acceptable are of particular interest since they are useful in administering the compounds described above for medical purposes. Salts that are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compounds of the invention or intermediates thereof.
  • the term "pharmaceutically acceptable salt” refers to salts of a compound, which are, within the scope of sound medical judgment, suitable for use in humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • compositions described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.
  • acid addition salts can be prepared by, for example, 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.
  • acid addition salts might be a more convenient form for use and use of the salt amounts to use of the free basic form.
  • Examples of pharmaceutically acceptable, non-toxic 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, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, ox
  • base addition salts can be prepared by, for example, 1) reacting the purified compound in its acid form with a suitable organic or inorganic base; and 2) isolating the salt thus formed.
  • base addition salt might be more convenient and use of the salt form inherently amounts to use of the free acid form.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N (Ci_ 4 alkyl)4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Basic addition salts include pharmaceutically acceptable metal and amine salts.
  • Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminium.
  • the sodium and potassium salts are usually preferred.
  • 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, lower alkyl sulfonate and aryl sulfonate.
  • Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like.
  • Suitable amine base addition salts are prepared from amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine,
  • the methods of the invention can be employed for preparing pharmaceutically acceptable solvates (e.g., hydrates) and clathrates of these compounds.
  • solvate is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds described herein.
  • solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • hydrate means a compound described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound described herein or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • the compounds in accordance with the present invention can contain a chiral center.
  • the compounds of formula may thus exist in the form of two different optical isomers (i.e. (+) or (-) enantiomers). All such enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
  • the single optical isomer or enantiomer can be obtained by method well known in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary.
  • the compounds of the invention are provided in the form of a single enantiomer at least 95%, at least 97% and at least 99% free of the corresponding enantiomer.
  • the compounds of the invention are in the form of the (+) enantiomer at least 95% free of the corresponding (-) enantiomer.
  • the compounds of the invention are in the form of the (+) enantiomer at least 97% free of the corresponding (-) enantiomer.
  • the compounds of the invention are in the form of the (+) enantiomer at least 99% free of the corresponding (-) enantiomer.
  • the compounds of the invention are in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer.
  • the compounds of the invention are in the form of the (-) enantiomer at least 97% free of the corresponding (+) enantiomer.
  • the compounds of the invention are provided as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts can be derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • acids examples include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene -2-sulphonic and benzenesulphonic acids.
  • Other acids such as oxalic, while not themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Salts derived from amino acids are also included (e.g. L-arginine, L-Lysine).
  • Salts derived from appropriate bases include alkali metals (e.g. sodium, lithium, potassium), alkaline earth metals (e.g. calcium, magnesium), ammonium, NR 4+
  • alkali metals e.g. sodium, lithium, potassium
  • alkaline earth metals e.g. calcium, magnesium
  • ammonium NR 4+
  • R is C 1 4 alkyl
  • the pharmaceutically acceptable salt is a sodium salt.
  • the pharmaceutically acceptable salt is a potassium salt.
  • the pharmaceutically acceptable salt is a lithium salt.
  • the pharmaceutically acceptable salt is a tromethamine salt.
  • the pharmaceutically acceptable salt is an
  • polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
  • a polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
  • Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds.
  • Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process.
  • the terms "subject,” “host,” or “patient” includes an animal and a human (e.g., male or female, for example, a child, an adolescent, or an adult).
  • a human e.g., male or female, for example, a child, an adolescent, or an adult.
  • the "subject,” “host,” or “patient” is a human.
  • the present invention provides methods for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to the invention described herein.
  • the viral infection is chosen from Flavivirus infections.
  • the Flavivirus infection is Hepatitis C virus (HCV), bovine viral diarrhea virus (BVDV), hog cholera virus, dengue fever virus, Japanese encephalitis virus or yellow fever virus.
  • HCV Hepatitis C virus
  • BVDV bovine viral diarrhea virus
  • hog cholera virus dengue fever virus
  • Japanese encephalitis virus yellow fever virus.
  • the Flaviviridea viral infection is hepatitis C viral infection (HCV).
  • the methods of the invention are directed for treatment of HCV genotype 1 infection.
  • the HCV is genotype la or genotype lb.
  • the present invention provides a method for treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to the invention described herein, and further comprising administering at least one additional agent chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • IRS internal ribosome entry site
  • a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound according to the invention described herein.
  • a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound according to the invention described herein and further comprising administering one or more viral polymerase inhibitors.
  • viral polymerase is a Flaviviridae viral polymerase.
  • viral polymerase is a RNA-dependant RNA- polymerase.
  • viral polymerase is HCV polymerase.
  • the compounds described above can be formulated in pharmaceutically acceptable formulations that optionally further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention described herein and at least one pharmaceutically acceptable carrier, adjuvant, or vehicle, which includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • compositions and known techniques for the preparation thereof are contemplated to be within the scope of this invention.
  • side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky.
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject.
  • Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropyl
  • compositions thereof can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • compositions are administered orally, intraperitoneally or intravenously.
  • any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions, can be used for the oral administration.
  • carriers commonly used include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • Liquid dosage forms for oral administration include, but are not limited to, 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 emulsifiers 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.
  • inert diluents such as, for example, water or other solvents, solubilizing agents
  • 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
  • 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. 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 polethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • 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.
  • 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.
  • Sterile injectable forms may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the active compound with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Dosage forms for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • transdermal patches which have the added advantage of providing controlled delivery of a compound to the body, can also be used.
  • Such 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.
  • compositions described above and pharmaceutically acceptable compositions thereof may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
  • the amount of the active compound in a unit dosage form will vary depending upon, for example, the host treated, and the particular mode of administration, for example, from 0.01 mg/kg body weight/day to 100 mg/kg body weight/day.
  • a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, for example, in the range of 0.5 to 60 mg/kg/day, or, for example, in the range of 1 to 20 mg/kg/day.
  • the desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention described herein, and further comprising one or more additional agents chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • additional agents chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • additional agents chosen from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomudulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agent, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).
  • compositions and combinations include, for example, ribavirin, amantadine, merimepodib, Levovirin, Viramidine, and maxamine.
  • the compound and additional agent are administered sequentially.
  • the compound and additional agent are administered simultaneously.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier therefore comprise a further aspect of the invention.
  • viral serine protease inhibitor means an agent that is effective to inhibit the function of the viral serine protease including HCV serine protease in a mammal.
  • Inhibitors of HCV serine protease include, for example, those compounds described in WO 99/07733 (Boehringer Ingelheim), WO 99/07734 (Boehringer Ingelheim), WO 00/09558 (Boehringer Ingelheim), WO 00/09543 (Boehringer Ingelheim), WO
  • viral polymerase inhibitors as used herein means an agent that is effective to inhibit the function of a viral polymerase including an HCV polymerase in a mammal.
  • Inhibitors of HCV polymerase include non-nucleosides, for example, those compounds described in: WO 03/010140 (Boehringer Ingelheim), WO 03/026587 (Bristol Myers Squibb); WO 02/100846 Al , WO 02/100851 A2, WO 01 /85172 AI (GSK), WO 02/098424 Al (GSK), WO 00/06529 (Merck), WO 02/06246 Al (Merck), WO 01 /47883 (Japan Tobacco), WO 03/000254 (Japan Tobacco) and EP 1 256 628 A2 (Agouron).
  • inhibitors of HCV polymerase also include nucleoside analogs, for example, those compounds described in: WO 01 /90121 A2 (Idenix), WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.), and WO 02/057287 A2 (Merck/ Isis) and WO 02/057425 A2 (Merck/lsis).
  • nucleoside inhibitors of an HCV polymerase include R1626, R1479 (Roche), R7128 (Roche), MK-0608 (Merck), R1656, (Roche-Pharmasset) and Valopicitabine (Idenix).
  • Specific examples of inhibitors of an HCV polymerase include JTK-002/003 and JTK- 109 (Japan Tobacco), HCV-796 (Viropharma), GS-9190(Gilead), and PF-868,554 (Pfizer).
  • viral NS5A inhibitor means an agent that is effective to inhibit the function of the viral NS5 A protease in a mammal.
  • Inhibitors of HCV NS5 A include, for example, those compounds described in WO2010/117635, WO2010/117977, WO2010/117704, WO2010/1200621, WO2010/096302, WO2010/017401, WO2009/102633, WO2009/102568, WO2009/102325, WO2009/102318, WO2009020828, WO2009020825, WO2008144380, WO2008/021936, WO2008/021928, WO2008/021927, WO2006/133326, WO2004/014852, WO2004/014313, WO2010/096777, WO2010/065681, WO2010/065668, WO2010/065674, WO2010/062821, WO2010/099527, WO2010/09
  • HCV NS5A inhibitors include: EDP-239 (being developed by Enanta); ACH-2928 (being developed by Achillion); PPI-1301 (being developed by Presido Pharmaceuticals); PPI-461 (being developed by Presido
  • AZD-7295 being developed by AstraZeneca
  • GS-5885 being developed by Gilead
  • BMS-824393 being developed by Bristol-Myers Squibb
  • BMS-790052 being developed by Bristol-Myers Squibb
  • nucleoside or nucleotide polymerase inhibitors such as PSI-661 (being developed by Pharmasset), PSI-938 (being developed by
  • RO-5303253 being developed by Hoffmann-La Roche
  • IDX-184 being developed by Idenix Pharmaceuticals
  • viral helicase inhibitors as used herein means an agent that is effective to inhibit the function of a viral helicase including a Flaviviridae helicase in a mammal.
  • Immunomodulatory agent as used herein means those agents that are effective to enhance or potentiate the immune system response in a mammal.
  • Immunomodulatory agents include, for example, class I interferons (such as alpha-, beta-, delta- and omega- interferons, x-interferons, consensus interferons and asialo-interferons), class II interferons (such as gamma-interferons) and pegylated interferons.
  • Exemplary immunomudulating agents include, but are not limited to:
  • interferon including natural interferon (such as OMNIFERON, Viragen and SUMIFERON, Sumitomo, a blend of natural interferon's), natural interferon alpha (ALFERON, Hemispherx Biopharma, Inc.), interferon alpha nl from lymphblastoid cells (WELLFERON, Glaxo Wellcome), oral alpha interferon, Peg-interferon, Peg-interferon alfa 2a (PEGASYS, Roche), recombinant interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX, Aradigm), Peg-interferon alpha 2b (ALBUFERON, Human Genome Sciences/Novartis, PEGINTRON, Schering), recombinant interferon alfa 2b
  • natural interferon such as OMNIFERON, Viragen and SUMIFERON, Sumitomo, a blend of natural interferon's
  • VIRAFERONPEG Schering
  • interferon beta- la REBIF, Serono, Inc. and Pfizer
  • consensus interferon alpha INFERGEN, Valeant Pharmaceutical
  • interferon gamma- lb ACTIMMUNE, Intermune, Inc.
  • un-pegylated interferon alpha alpha interferon, and its analogs
  • synthetic thymosin alpha 1 ZADAXIN, SciClone Pharmaceuticals Inc.
  • class I interferon as used herein means an interferon selected from a group of interferons that all bind to receptor type 1. This includes both naturally and synthetically produced class I interferons. Examples of class I interferons include alpha-, beta-, delta- and omega- interferons, tau-interferons, consensus interferons and asialo- interferons.
  • class II interferon as used herein means an interferon selected from a group of interferons that all bind to receptor type II. Examples of class II interferons include gamma-interferons .
  • Antisense agents include, for example, ISIS- 14803.
  • Specific examples of inhibitors of HC V NS3 protease include BILN-2061 (Boehringer Ingelheim) SCH-6 and SCH-503034/Boceprevir(Schering-Plough), VX- 950/telaprevir( Vertex) and ITMN-B (InterMune), GS9132 (Gilead), TMC- 435350(Tibotec/Medivir), ITMN-191 (InterMune), MK-7009 (Merck).
  • ISIS- 14803 ISIS- 14803
  • the additional agent is interferon alpha, ribavirin, silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.
  • the additional agent is interferon alpha 1 A, interferon alpha 1 B, interferon alpha 2A, or interferon alpha 2B.
  • Interferon is available in pegylated and non pegylated forms. Pegylated interferons include PEGASYSTM and Peg-intronTM.
  • the recommended dose of PEGASYSTM monotherapy for chronic hepatitis C is 180 mg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.
  • the recommended dose of PEGASYSTM when used in combination with ribavirin for chronic hepatitis C is 180 mg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly.
  • Ribavirin is typically administered orally, and tablet forms of ribavirin are currently commercially available.
  • General standard, daily dose of ribavirin tablets e.g., about 200 mg tablets
  • ribavirn tablets are administered at about 1000 mg for subjects weighing less than 75 kg, or at about 1200 mg for subjects weighing more than or equal to 75 kg. Nevertheless, nothing herein limits the methods or combinations of this invention to any specific dosage forms or regime.
  • ribavirin can be dosed according to the dosage regimens described in its commercial product labels.
  • the recommended dose of PEG-lntronTM regimen is 1.0 mg/kg/week
  • the dose should be administered on the same day of the week.
  • the recommended dose of PEG- lntron is 1.5 micrograms/ kg/ week.
  • viral serine protease inhibitor is a flaviviridae serine protease inhibitor.
  • viral polymerase inhibitor is a flaviviridae polymerase inhibitor.
  • viral helicase inhibitor is a flaviviridae helicase inhibitor.
  • viral serine protease inhibitor is HCV serine protease inhibitor
  • viral polymerase inhibitor is HCV polymerase inhibitor
  • viral helicase inhibitor is HCV helicase inhibitor.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention described herein, one or more additional agents select from non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626, R1479), HCV NS3 protease inhibitors (e.g., VX-950/telaprevir and ITMN-191), interferon and ribavirin, and at least one pharmaceutically acceptable carrier or excipient.
  • non-nucleoside HCV polymerase inhibitors e.g., HCV-796
  • nucleoside HCV polymerase inhibitors e.g., R7128, R1626, R147
  • HCV NS3 protease inhibitors e.g., VX-950/telaprevir and ITMN-191
  • interferon and ribavirin interferon and ribavirin
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier therefore comprise a further aspect of the invention.
  • the individual components for use in the method of the present invention or combinations of the present invention may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the present invention provides the use of a compound according to the invention described herein for treating or preventing Flaviviridae viral infection in a host.
  • the present invention provides the use of a compound according to the invention described herein for the manufacture of a medicament for treating or preventing a viral Flaviviridae infection in a host.
  • the present invention provides the use of a compound according to the invention described herein for inhibiting or reducing the activity of viral polymerase in a host.
  • the composition or combination according to the invention further comprises at least one compound according to the invention described herein; one or more additional agents select from non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626, R1479), and HCV NS3 protease inhibitors (e.g., VX-950/telaprevir and ITMN-191); and interferon and/or ribavirin.
  • the additional agent is interferon a 1A, interferon a IB, interferon a 2A, or interferon a 2B, and optionally ribavirin.
  • the present invention provides a method for treating or preventing a HCV viral infection in a host comprising administering to the host a combined therapeutically effective amounts of at least one compound according to the invention described herein, and one or more additional agents select from non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626, R1479), HCV NS3 protease inhibitors (e.g., VX-950/telaprevir and ITMN-191), interferon and ribavirin.
  • non-nucleoside HCV polymerase inhibitors e.g., HCV-796
  • nucleoside HCV polymerase inhibitors e.g., R7128, R1626, R147
  • HCV NS3 protease inhibitors e.g., VX-950/telaprevir and ITMN-191
  • interferon and ribavirin
  • the compound and additional agent are administered sequentially.
  • the compound and additional agent are administered simultaneously.
  • a method for inhibiting or reducing the activity of HCV viral polymerase in a host comprising administering to the host a combined therapeutically effective amounts of at least one compound of the invention, and one or more additional agents select from non-nucleoside HCV polymerase inhibitors (e.g., HCV-796) and nucleoside HCV polymerase inhibitors (e.g., R7128, R1626, R1479), interferon and ribavirin.
  • non-nucleoside HCV polymerase inhibitors e.g., HCV-796
  • nucleoside HCV polymerase inhibitors e.g., R7128, R1626, R1479
  • compositions or compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier therefore comprise a further aspect of the invention.
  • the present invention provides the use of at least one compound of the invention, in combination with the use of one or more additional agents select from non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626, R1479), HCV NS3 protease inhibitors (e.g., VX- 950/telaprevir and ITMN-191), interferon and ribavirin, for the manufacture of a medicament for treating or preventing a HCV infection in a host.
  • non-nucleoside HCV polymerase inhibitors e.g., HCV-796
  • nucleoside HCV polymerase inhibitors e.g., R7128, R1626, R147
  • HCV NS3 protease inhibitors e.g., VX- 950/telaprevir and ITMN-191
  • interferon and ribavirin interferon and
  • the dose of each compound may be either the same as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • the ratio of the amount of a compound according to the invention described herein administered relative to the amount of the additional agent will vary dependent on the selection of the compound and additional agent.
  • the additional agent non-nucleoside HCV polymerase inhibitors (e.g., HCV-796), nucleoside HCV polymerase inhibitors (e.g., R7128, R1626, R1479), HCV NS3 protease inhibitors (e.g., VX-950/telaprevir and ITMN-191), interferon or ribavirin) will vary dependent on the selection of the compound and additional agent.
  • the compounds according to the invention described herein can be prepared by any suitable method known in the art, for example, US 6,881,741, US 2005/0009804, US 2006/0276533, WO 2002/100851, and WO 08/58393. Preparation details of some exemplary compounds are described below. Syntheses of certain exemplary compounds of the invention are described below. Generally, the compounds of the invention can be prepared as shown in those syntheses optionally with any desired appropriate modification.
  • RT refers to the LCMS retention time, in minutes, associated with the compound. Unless otherwise indicated, the method employed to obtain the reported retention times is as follows:
  • RT refers to the LCMS retention time, in minutes, associated with the compound.
  • NMR and Mass Spectroscopy data of certain specific compounds are summarized in Table 1.
  • the resulting reaction mixture was stirred for 14 h at ambient temperature, then cooled to 0 °C and hydrogen peroxide added dropwise (30 % w/v solution, 1.90 mL, 16.8 mmol). The solution was stirred for 2 h, then quenched slowly with saturated aqueous sodium sulfite while the temperature was maintained at 0 °C. The resulting mixture was extracted with dichloromethane (2 x 20 mL), the combined organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the prodrug whose PK parameters are to be determined can be formulated as a solution in 0.5%MC/0.5%Tween 80/99% water and administered orally by gavage to rats at a dose of 3 mg/kg. Rats are weighed the day before the study. Rat plasma is sampled predose and at 15, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 hrs post dose using Instech automatic blood sampling equipment. Blood is collected in tubes containing K2-EDTA and 110 uL plasma are extracted for analysis. Rats are fed ad lib and standard IACUC and SOP protocols are followed. Plasma samples and dose samples are analyzed using LC/MS/MS for both the prodrug compound and the active metabolite. PK parameters for both analytes for each subject are calculated using the measured dose of prodrug.
  • PK parameters of a prodrug of the invention was measured as described in the preceding paragraph, and are depicted in FIG. 3. As shown in FIG. 3, the -O-alaninyl group of compound 10 in vivo converted into the -OH active metabolite.
  • PK parameters of compound 11 and 1, which were measured as described in the preceding paragraph, are also depicted in FIGs. 4 and 5, respectively. As shown in FIGs. 4 and 5, compounds 11 and 1 were in vivo converted into their active metabolites.

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Abstract

L'invention concerne un composé représenté par la formule structurale (I): ou un sel pharmaceutiquement acceptable de ce composé, les variables de la formule structurale (I) étant décrites dans la spécification et les revendications. La composition pharmaceutique comprend un composé représenté par la formule structurale (I) ou un sel pharmaceutiquement acceptable de ce composé, et un support d'excipient pharmaceutiquement acceptable. L'invention concerne une méthode de traitement, chez un patient, d'une infection par le VHC, qui comprend l'administration audit patient d'une quantité thérapeutiquement efficace d'un composé représenté par la formule structurale (I) ou d'un sel pharmaceutiquement acceptable de ce composé. L'invention concerne un procédé visant à inhiber ou à réduire l'activité de la polymérase du VHC chez un patient ou dans un échantillon biologique in vitro, et qui comprend l'administration, audit patient ou échantillon, d'une quantité thérapeutiquement efficace du composé représenté par la formule structurale (I) ou d'un sel pharmaceutiquement efficace de ce composé.
PCT/US2011/042119 2010-06-28 2011-06-28 Composés et méthodes de traitement ou de prévention d'infections à flavovirus WO2012006060A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2013518559A JP2013531011A (ja) 2010-06-28 2011-06-28 フラビウイルス感染の処置または予防のための化合物および方法
EP11730823.9A EP2585448A1 (fr) 2010-06-28 2011-06-28 Composés et méthodes de traitement ou de prévention d'infections à flavovirus
US13/724,014 US20130203706A1 (en) 2011-06-28 2012-12-21 Compounds and methods for the treatment or prevention of flavivirus infections

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