EP2475254A1 - Inhibiteurs du virus de l'hépatite c - Google Patents

Inhibiteurs du virus de l'hépatite c

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Publication number
EP2475254A1
EP2475254A1 EP10816134A EP10816134A EP2475254A1 EP 2475254 A1 EP2475254 A1 EP 2475254A1 EP 10816134 A EP10816134 A EP 10816134A EP 10816134 A EP10816134 A EP 10816134A EP 2475254 A1 EP2475254 A1 EP 2475254A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
alkyl
compound
heteroaryl
ring
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP10816134A
Other languages
German (de)
English (en)
Other versions
EP2475254A4 (fr
Inventor
Yao-Ling Qiu
Ce Wang
Lu Ying
Xiaowen Peng
Yat Sun Or
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Enanta Pharmaceuticals Inc
Original Assignee
Enanta Pharmaceuticals Inc
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.)
Filing date
Publication date
Application filed by Enanta Pharmaceuticals Inc filed Critical Enanta Pharmaceuticals Inc
Publication of EP2475254A1 publication Critical patent/EP2475254A1/fr
Publication of EP2475254A4 publication Critical patent/EP2475254A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to novel antiviral agents. More specifically, the present invention relates to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, methods for inhibiting HCV viral replication, methods for treating or preventing HCV infection, and processes for making the compounds.
  • HCV Hepatitis C virus
  • HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants.
  • Chronic HCV infection accounts for 30%) of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.
  • Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection.
  • adverse side effects are commonly associated with this treatment: flulike symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology, 26 (suppl 1): 71S-77S).
  • HCV is now widely accepted as the most common causative agent of posttransfusion non-A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science, 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g.
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA - A Publication of the RNA
  • This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology, 2 nd Edition, p931-960; Raven Press, N.Y.).
  • host and virally-encoded proteinases There are three structural proteins, C, El and E2.
  • the P7 protein is of unknown function and is comprised of a highly variable sequence. There are several non- structural proteins.
  • NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • NS5A is a membrane-anchored phosphoprotein that is observed in basally phosphorylated (56 kDa) and hyperphosphorylated (58 kDa) forms.
  • NS5A While its function has not fully been elucidated, NS5A is believed to be important in viral replication.
  • the NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. , 151 2-22) encodes an R A-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases.
  • RdRp R A-dependent RNA polymerase
  • the NS5B protein is fairly well conserved both intra- typically (-95-98% amino acid (aa) identity across lb isolates) and inter-typically (-85% aa identity between genotype la and lb isolates).
  • 3' NTR which roughly consists of three regions: an -40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun., 215744-749; Tanaka, T. et al (1996) J. Virology, 70:3307-3312; Yamada, N. et al (1996) Virology, 223:255-261).
  • the 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • HCV NS5A protein is described, for example, in Tan, S.-L., Katzel, M.G. Virology, 2001, 284, 1; and in Rice, C. M. Nature, 2005, 435, 374.
  • the present invention relates to novel antiviral compounds represented herein below, pharmaceutical compositions comprising such compounds, and methods for the treatment or prophylaxis of viral (particularly HCV) infection in a subject in need of such therapy with said compounds.
  • Compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
  • the present invention provides a compound of Formula
  • Ring A is absent or a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;
  • Ring B is a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;
  • L is absent or selected from the group consisting of optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, and optionally substituted C 2 -C 4 alkynyl;
  • G is optionally substituted 5 -membered heteroaryl or optionally substituted 5/6- member fused heteroaryl; wherein the 5 -membered heteroaryl contains one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of Ring A, L, and Ring B, and is aryl or heteroaryl; preferably optionally substituted imidazolyl or optionally substituted benzimidazolyl;
  • J is selected from -N(R lc )-C(0)-, -N(R lc )-C(0)0- and -N(R lc )-C(0)-N(R lc )-; preferably -N(R lc )-C(0)-;
  • W at each occurrence is independently O or -N(R lb )-; preferably -N(R lb )-;
  • R 1 , R la , R lb , R lc , R 9 , and R 9a at each occurence are each independently hydrogen or optionally substituted C 1 -C 4 alkyl; alternatively R la and R 9a , R la and R 9 , R 1 and R 9a , or R 1 and R 9 can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C 3 -C 8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R lb and R 9a , or R lb and R 9 can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic ring;
  • R 6 at each occurence is independently selected from the group consisting of optionally substituted 0(C 1 -C 8 alkyl), optionally substituted amino, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C 1 -C 8 alkyl; more preferably C 1 -C8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl);
  • Q is selected from: and ;
  • X is absent, O, S, CH 2 , or CH 2 CH 2 ;
  • Y is absent, O, S, C(R , C(R 1 ) 2 C(R 7 ) 2 , C(R 1 ) 2 C(R 7 ) 2 C(R 7 ) 2 , C(R 1 ) 2 OC(R 1 ) 2 , or C(R ⁇ SC(R 1 ) 2 ;
  • At least one of X and Y is not O or S;
  • U is absent or independently selected from O, S, S(O), S0 2 , NC(0)-(C 1 -C 4 alkyl),
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 1 -C 4 alkyl; preferably hydrogen, halogen or hydroxy;
  • two geminal R 7 groups can be taken together with the cabon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl and 3- to 8- membered heterocyclic, each optionally substituted; preferably two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6-membered heterocyclic;
  • R 2 at each occurence is independently hydrogen, optionally substituted C 1 -C 8 alkyl, or -NR a R b ;
  • R a at each occurence is independently hydrogen or optionally substituted C 1 -C 8 alkyl;
  • R b at each occurence is -C(0)-R 6 ;
  • R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C1-C 4 alkyl; alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic;
  • R 5 is independently hydrogen, optionally substituted C 1 -C 8 alkyl, or optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C1-C 4 alkyl; and
  • the present invention provides a compound of Formula (2-1)
  • Ring A and Ring B are each independently a monocyclic or polycyclic group selected from aryl, heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl; L is absent or selected from the group consisting of optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, and optionally substituted C 2 -C 4 alkynyl; wherein taken together is not optionally substituted phenyl-thiazolyl or 3,4'-biphenyl;
  • J is selected from the group consisting of -N(R lc )-C( O)-, -N(R lc )-C(0)0- and
  • W at each occurrence is independently O or -N(R lb )-; preferably -N(R lb )-;
  • R 1 , R la , R lb , R lc , R 9 , and R 9a at each occurrence are each independently hydrogen or optionally substituted C 1 -C 4 alkyl; alternatively, R la and R 9a , R la and R 9 , R 1 and R 9a , or R J and R 9 can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C 3 -C 8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R lb and R 9a , or R lb and R 9 can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic;
  • R 6 at each occurrence is independently selected from the group consisting of optionally substituted 0(C 1 -C 8 alkyl); optionally substituted amino; C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C 1 -C 8 alkyl; more preferably C 1 -C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl);
  • G is selected from the group consisting of -N(R lc )-C(0)-, -N(R lc )-C(0)0- and -N(R lc )-C( -N(R lc )-; preferably -N(R lc )-C(0)-;
  • X is absent, O, S, CH 2 , or CH 2 CH 2 ;
  • Y at is absent, O, S, C(R , CCR ⁇ C(R 7 ⁇ , CCR ⁇ C ⁇ C ⁇ , C(R ⁇ OCCR 1 ⁇ , or C(R ⁇ SCCR 1 ⁇ ; Wherein at least one of X and Y is present;
  • At least one of X and Y is not O or S;
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 1 -C 4 alkyl; preferably hydrogen, halogen or hydroxy;
  • R 2 at each occurrence is independently hydrogen, optionally substituted C 1 -C 8 alkyl, or -NR a R b ;
  • R a at each occurrence is independently hydrogen or optionally substituted C 1 -C 8 alkyl
  • R b at each occurrence is -C(0)-R 6 ;
  • R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group.
  • the present invention provides a compound of Formula
  • Ring A and Ring B are each independently absent or a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C3-C8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;
  • L is absent or selected from the group consisting of optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, and optionally substituted C 2 -C 4 alkynyl;
  • Ring A, Ring B and L is present;
  • G and J are each independently optionally substituted 5-membered heteroaryl or optionally substituted 5/6-member fused heteroaryl; wherein the 5-membered heteroaryl contains one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of Ring A, Ring B and L, and is aryl or heteroaryl; preferably optionally substituted imidazolyl or optionally substituted benzimidazolyl; W at each occurrence is independently O or -N(R lb )-; preferably -N(R lb )-;
  • R 1 , R la , R lb , R 9 , and R 9a at each occurrence are each independently hydrogen or optionally substituted C 1 -C 4 alkyl; alternatively R la and R 9a , R la and R 9 , R 1 and R 9a , or R 1 and R 9 can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C 3 -C 8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R lb and R 9a , or R lb and R 9 can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic;
  • R 6 at each occurrence is independently selected from the group consisting of optionally substituted 0(C 1 -C 8 alkyl); optionally substituted amino; C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C8 cycloalkyl, C 3 -C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C 1 -C 8 alkyl; more preferably C 1 -C8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl);
  • Q is selected from: , and;
  • X is absent, O, S, CH 2 , or CH 2 CH 2 ;
  • Y is absent, O, S, C(R , C(R 1 ) 2 C(R 7 ) 2 , C(R 1 ) 2 C(R 7 ) 2 C(R 7 ) 2 , C(R 1 ) 2 OC(R 1 ) 2 , or C(R ⁇ SC(R 1 ) 2 ;
  • At least one of X and Y is not O or S;
  • U is absent or independently selected from O, S, S(O), S0 2 , NC(0)-(C 1 -C 4 alkyl), C(O), protected carbonyl, OCH 2 , OCH 2 CH 2 , SCH 2 , SCH 2 CH 2 , C(R 7 ) 2 , and C(R 7 ) 2 C(R 7 ) 2 ; preferably CH 2 ;
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 1 -C 4 alkyl; preferably hydrogen, halogen or hydroxy;
  • two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C 3 -C 8 cycloalkyl, C3-C 8 cycloalkenyl and 3- to 8- membered heterocyclic, each optionally substituted; preferably an optionally substituted cyclopropyl or an optionally substituted 5- to 6-membered heterocyclic;
  • R 2 at each occurrence is independently hydrogen, optionally substituted C 1 -C 8 alkyl, or -NR a R b ;
  • R a at each occurrence is independently hydrogen or optionally substituted C 1 -C 8 alkyl
  • R b at each occurrence is -C(0)-R 6 ;
  • R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C1-C 4 alkyl; alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic;
  • R 5 is independently hydrogen, optionally substituted C 1 -C 8 alkyl, or optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C1-C 4 alkyl; and
  • the present invention provides a compound of Formula (4-1):
  • Ring A is absent or a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;
  • Ring B is a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;
  • L is absent or selected from the group consisting of optionally substituted C1-C 4 alkyl, optionally substituted C2-C 4 alkenyl, and optionally substituted C2-C 4 alkynyl;
  • R 1 at each occurrence is independently hydrogen or optionally substituted C1-C 4 alkyl
  • R 6 at each occurrence is independently selected from the group consisting of optionally substituted 0(C 1 -C 8 alkyl); optionally substituted amino; C 1 -C 8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C 1 -C 8 alkyl; more preferably C 1 -C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl);
  • U is absent or independently selected from O, S, S(O), S0 2 , NC(0)-(C 1 -C 4 alkyl), C(O), protected carbonyl, OCH 2 , OCH 2 CH 2 , SCH 2 , SCH 2 CH 2 , C(R 7 ) 2 , and C(R 7 ) 2 C(R 7 ) 2 ; preferably CH 2 ;
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C1-C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C1-C 4 alkyl; preferably hydrogen, halogen or hydroxy;
  • two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl and 3- to 8- membered heterocyclic, each optionally substituted; preferably an optionally substituted C 3 -C 8 cyclopropyl or an optionally substituted 5- to 6-membered heterocyclic;
  • G is optionally substituted 5 -membered heteroaryl or optionally substituted 5/6- member fused heteroaryl; wherein the 5 -membered heteroaryl contains one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of Ring A, L and Ring B, and is aryl or heteroaryl; preferably optionally substituted imidazolyl or optionally substituted benzimidazolyl;
  • Q is selected from: ,
  • V is selected from the group consisting of -N(R lc )-, -N(R lc )-C(0)-, -N(R lc )- C(0)0- and -N(R lc )-C(0)-N(R lc )-; preferably -N(R lc )- or -N(R lc )-C(0)-;
  • W is O or -N(R lb )-; preferably -N(R lb )-;
  • R la , R lb , R lc , R ld , R 9 , and R 9a at each occurrence are each independently hydrogen or optionally substituted C 1 -C 4 alkyl; alternatively R la and R 9a , R la and R 9 , R ld and R 9a , or R ld and R 9 can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C 3 -C 8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R lb and R 9a , or R lb and R 9 can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic;
  • X is absent, O, S, CH 2 , or CH 2 CH 2 ;
  • Y is absent, O, S, C(R , C(R 1 ) 2 C(R 7 ) 2 , C(R 1 ) 2 C(R 7 ) 2 C(R 7 ) 2 , C(R 1 ) 2 OC(R 1 ) 2 , or C(R ⁇ SC(R 1 ) 2 ;
  • At least one of X and Y is not O or S;
  • R 2 is hydrogen, optionally substituted C 1 -C 8 alkyl, or
  • R a is hydrogen or optionally substituted C 1 -C 8 alkyl
  • R b at each occurrence is -C(0)-R 6 ;
  • R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl; alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic; and
  • R 5 is independently hydrogen, optionally substituted C 1 -C 8 alkyl, or optionally substituted C3-C8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl.
  • the present invention provides a compound of Formula
  • Ring A is absent or a monocyclic or polycyclic group independently selected from aryl, heteroaryl, heterocyclic, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl, each optionally substituted; preferably optionally substituted aryl or optionally substituted heteroaryl;
  • Ring B is an optionally substituted aryl or optionally substituted heteroaryl
  • L is absent or selected from the group consisting of optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, and optionally substituted C 2 -C 4 alkynyl;
  • W at each occurrence is independently O or -N(R lb )-; preferably -N(R lb )-;
  • R 1 , R la , R lb , R lc , R 9 , and R 9a at each occurrence are each independently hydrogen or optionally substituted C 1 -C 4 alkyl; alternatively R la and R 9a , R la and R 9 , R 1 and R 9a , or R 1 and R 9 can be taken together with the carbon atom(s) to which they are attached to form an optionally substituted C 3 -C 8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic; or yet alternatively R lb and R 9a , or R lb and R 9 can be taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic;
  • R 6 at each occurrence is independently selected from the group consisting of optionally substituted 0(C 1 -C 8 alkyl); optionally substituted amino; C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C 1 -C 8 alkyl; more preferably C 1 -C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl);
  • G is optionally substituted 5 -membered heteroaryl or optionally substituted 5/6- member fused heteroaryl; wherein the 5 -membered heteroaryl contains one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-fused membered heteroaryl is attached to one of Ring A, L and Ring B and is aryl or heteroaryl; preferably optionally substituted imidazolyl or optionally substituted benzimidazolyl;
  • Q is selected from: ;
  • V is selected from the group consisting of -N(R lc )-, -N(R lc )-C(0)-, -N(R lc )- C(0)0- and -N(R lc )-C(0)-N(R lc )-;
  • X is absent, O, S, CH 2 , or CH 2 CH 2 ;
  • Y is absent, O, S, C(R , C(R 1 ) 2 C(R 7 ) 2 , C(R 1 ) 2 C(R 7 ) 2 C(R 7 ) 2 , C(R 1 ) 2 OC(R 1 ) 2 , or C(R ⁇ SC(R 1 ) 2 ;
  • At least one of X and Y is not O or S;
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 1 -C 4 alkyl; preferably hydrogen, halogen or hydroxy;
  • U is absent or selected from O, S, S(O), S0 2 , NC(0)-(C C 4 alkyl), C(O), protected carbonyl, OCH 2 , OCH 2 CH 2 , SCH 2 , SCH 2 CH 2 , C(R 7 ) 2 , and C(R 7 ) 2 C(R 7 ) 2 ; preferably CH 2 ;
  • Optionally two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl and 3- to 8- membered heterocyclic, each optionally substituted; preferably an optionally substituted cyclopropyl or an optionally substituted 5- to 6-membered heterocyclic;
  • R 2 is hydrogen, optionally substituted C 1 -C 8 alkyl, or -NR a R b ;
  • R a is hydrogen or optionally substituted C 1 -C 8 alkyl
  • R b is -C(0)-R 6 ;
  • R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl; alternatively, R 3 and R 4 can be taken together with the carbon atom to which they are attached to form optionally substituted C 3 -C 8 cycloalkyl or optionally substituted heterocyclic;
  • R 5 is hydrogen, optionally substituted C 1 -C 8 alkyl, or optionally substituted C 3 -C 8 cycloalkyl; preferably hydrogen or optionally substituted C 1 -C 4 alkyl; and
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting the replication of a RNA-containing virus comprising contacting said virus with said pharmaceutical composition. Particularly, this invention is directed to methods of inhibiting the replication of HCV.
  • the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • this invention is directed to methods of treating or preventing infection caused by HCV.
  • Yet another aspect of the present invention provides the use of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof, as defined hereinafter, in the preparation of a medicament for the treatment or prevention of infection caused by RNA-containing virus, specifically HCV.
  • the compounds of the invention have utility in inhibiting the replication of RNA- containing virus, including, for example, HCV.
  • Other compounds useful for inhibiting the replication of RNA-containing viruses and/or for the treatment or prophylaxis of HCV infection have been described in copending U.S. Application Serial No. 12/702,673 filed February 9, 2010 entitled “Linked Dibenzimidiazole Derivatives"; U.S. Application Serial No. 12/702,692 filed February 9, 2010 entitled “Linked Dibenzimidiazole Derivatives"; U.S. Application Serial No. 12/702,802 filed February 9, 2010 entitled "Linked
  • Provisional Application Serial No. 61/241,578 filed September 11, 2009 entitled “Hepatitis C Virus Inhibitors”; U.S. Provisional Application Serial No. 61/241,595 filed September 11, 2009 entitled “Hepatitis C Virus Inhibitors”; U.S. Provisional Application Serial No. 61/241,617 filed September 11, 2009 entitled “Hepatitis C Virus Inhibitors”; U.S. Provisional Application Serial No. 61/241,577 filed September 11, 2009 entitled “Hepatitis C Virus Inhibitors”; U.S. Provisional Application Serial No. 61/241,598 filed September 11, 2009 entitled “Hepatitis C Virus Inhibitors”; U.S. Provisional Application Serial No.
  • a general strategy for the development of antiviral agents is to inactivate virally encoded proteins, including NS5A, that are essential for the replication of the virus.
  • the relevant patent disclosures describing the synthesis of HCV NS5A inhibitors are: US 2009/0202478; US 2009/0202483; WO 2004/014852; WO
  • the present invention relates to compounds of Formula (1-1) as illustrated above, and pharmaceutically acceptable salts thereof.
  • the present invention relates to compounds of Formula (1- I), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(O)-.
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(0)0-.
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(O)-
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein R la and R 9a , R la and R 9 , R 1 and R 9a , or R 1 and R 9 are taken together to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein R lb and R 9a , or R lb and R 9 are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein the moiety of is illustrated by one of the following core groups:
  • R 6 is as previously defined in Formula (1-1) and each of the above core groups is optionally substituted.
  • the invention relates to compounds of Formula (1-1) and pharmaceutically acceptable salts thereof; wherein R ⁇ is independently an optionally substituted C 1 -C 8 alkyl. In a further embodiment, the invention relates to compounds of Formula (1-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R 6 is an a-amino acid residue.
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted five-membered heteroaryl containing one or more nitrogen atoms, and is C-attached.
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen atoms and wherein the 5- membered ring is C-attached to group Q, and wherein the 6-membered ring of said 5/6- membered fused heteroaryl is aryl or heteroaryl and is C-attached to group one of Ring A, L and Ring B.
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein G is illustrated by one of the following heteroaryl groups:
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of
  • Ring A, Ring B, G, J, L, U, W, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R la , R lb , R 7a , R 7b , and R 9a are as previously defined in Formula (1-1).
  • the present invention relates to compounds of
  • Ring A, Ring B, G, J, L, R 1 , R 6 , R 9 , R la , R lb , and R 9a are as previously defined in Formula (1-1 ).
  • the present invention relates to compounds of Formula (l-Ia-7), and pharmaceutically acceptable salts thereof:
  • Ring A, Ring B, G, J, L, R 1 , R 6 , R 9 , R la , R lb , and R 9a are as previously defined in Formula (1-1).
  • the present invention relates to compounds of Formula (l-Ia-7), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.
  • the present invention relates to compounds of Formula (l-Ia-7), and pharmaceutically acceptable salts thereof; wherein R 6 at each independently occurrence is independently C 1 -C 8 alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formulae (1-Ib-l ⁇ l-Ib-4), and pharmaceutically acceptable salts thereof: (1-lb-4)
  • Ring B, G, J, Q, R 1 , R 6 , R 9 , R la , R lb , and R 9a are as previously defined in Formula (1-1); in Formula (1-Ib-l), Ring A and L are each present and as previously defined in Formula (1-1); in Formula (l-Ib-2), Ring A is present and as previously defined in Formula (1-1); in Formula (l-Ib-3), L is present and as previously defined in Formula (1- I)
  • the present invention relates to compounds of Formulae (1-Ib-l ⁇ l-Ib-4), and pharmaceutically acceptable salts thereof; wherein R 6 is independently C 1 -C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formula (1- Ib-1), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or optionally substituted monocyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (l-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or bicyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (l-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or bicyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (1-
  • Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (l-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted bicyclic aryl or bicyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (l-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (1- Ib-4), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted polycyclic aryl or polycyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein two geminal R 7 groups can be taken together with the carbon atoms to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6- membered heterocyclic.
  • the present invention relates to compounds of Formula (1-1), and pharmaceutically acceptable salts thereof; wherein R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 1 -C 4 alkyl; preferably hydrogen, halogen or hydroxyl.
  • the present invention relates to com ounds of
  • Representative compounds of the present invention are those selected from compounds 1-1 to 1-374 and 1-377 to 1-382 compiled in the following tables and/or shown below:
  • any substituent or variable e.g., R , R , etc.
  • a particular location in a molecule be independent of its definitions elsewhere in that molecule.
  • U is C(R 7 ) 2
  • each of the two R 7 groups may be the same or different.
  • the present invention relates to compounds of Formula (2-1) as illustrated above, and pharmaceutically acceptable salts thereof.
  • the present invention relates to compounds of Formula (2- I), and pharmaceutically acceptable salts thereof; wherein G is -NH-C(O)-.
  • the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein G is -NH-C(0)0-.
  • the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein G is -NH-C(O)- NH-.
  • the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(O)-.
  • the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein J is -NH-C(0)0-.
  • the present invention relates to compounds of
  • the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof;; wherein each of G and J is -NH-C(O)-.
  • the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein R la and R 9a , R la and R 9 , R 1 and R 9a , or R 1 and R 9 are taken together to form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula
  • R lb and R 9a , or R lb and R 9 are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula (2-1), and pharmaceutically acceptable salts thereof; wherein the moiety of is illustrated by the one of the following core groups:
  • R 6 is as previously defined in Formula (2-1) and each of the above core groups is optionally substituted.
  • the invention relates to compounds of Formula (2-1) and pharmaceutically acceptable salts thereof; wherein R6 is independently an optionally substituted C 1 -C 8 alkyl.
  • the invention relates to compounds of Formula (2-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R 6 is an a-amino acid residue.
  • the present invention relates to compounds of Formulae (2-Ia-l ⁇ 2-Ia-2), and pharmaceutically acceptable salts thereof:
  • Ring A, Ring B, G, J, L, ,W, X, Y, R 1 , R 2 , , R 6 , R 9 , R la , R lb , R lc , and R 9a are as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formulae (2-Ia-3 ⁇ 2-Ia-4),and pharmaceutically acceptable salts thereof:
  • Ring A, Ring B, G, J, L, Y, R 1 , R 2 , R 6 , R 9 , R la , R lb , R lc , and R 9a are as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2- Ia-5), and pharmaceutically acceptable salts thereof:
  • Ring A, Ring B, G, J, L, Y, R 1 , R 6 , R 9 , R a , R la , R lb , R lc , and R 9a are as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formula (2-Ia-5), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.
  • the present invention relates to compounds of Formula (2-Ia-5), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently C 1 -C 8 alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formulae (2-Ib-l ⁇ 2-Ib-2), and pharmaceutically acceptable salts thereof: ) (2-lb-2)
  • Ring A, Ring B, G, J, Q, R 1 , R 6 , R 9 , R la , R lb , and R 9a are as previously defined; and in Formula (2-lb-l), L is present and as previously defined in Formula (2-1).
  • the present invention relates to compounds of Formulae (2-Ib-l ⁇ 2-Ib-2), and pharmaceutically acceptable salts thereof; wherein R 6 is C 1 -C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formula (2-Ib-l), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • the present invention relates to compounds of
  • the present invention relates to compounds of Formula (2-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or heteroaryl.
  • the present invention relates to compounds of Formula (2- Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl.
  • Representative compounds of the present invention are those selected from compounds 2-1 to 2-295 compiled in the following tables and/or shown below:
  • any linker or spacer e.g., -NH- C(O)-, -OC(0)-NH-, etc.
  • a linker e.g., -NH- C(O)-, it is meant to include -NH-C(O)- and -C(0)-NH- for attachments.
  • the present invention relates to compounds of Formula (3-1) as illustrated above, and pharmaceutically acceptable salts thereof.
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein R la and R 9a , R la and R 9 , R 1 and R 9a , or R 1 and R 9 are taken together to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein R lb and R 9a , or R lb and R 9 are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein the moiety of is illustrated by one of the following core groups:
  • R 6 is as previously defined and each of the above core groups is optionally substituted.
  • the invention relates to compounds of Formula (3-1) and pharmaceutically acceptable salts thereof; wherein R6 is independently an optionally substituted C 1 -C 8 alkyl.
  • the invention relates to compounds of Formula (3-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R 6 is an a-amino acid residue.
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein G and J are each
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein G and J are each
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein one of G and J is an optionally substituted five-membered heteroaryl containing one or more nitrogen, and is each C-attached; the other of G and J is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen atoms, and wherein the 6-membered ring of said 5/6-membered fused aryl is aryl or heteroaryl and is C-attached to one of Ring A, L and Ring B.
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein G and J are each
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein G and J are each
  • the present invention relates to compounds of F rmulae (3-Ia-l ⁇ 3-Ia-4), or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, G, J, L, U, W, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R la , R lb , R 7a and R 9a are as previously defined in Formula (3-1).
  • the present invention relates to compounds of F rmulae (3-Ia-5 ⁇ 3-Ia-6), and pharmaceutically acceptable salts thereof:
  • Ring A, Ring B, G, J, L, R 1 , R 6 , R 9 , R la , R lb , and R 9a are as previously defined in Formula (3-1).
  • the present invention relates to compounds of Formula (3-Ia-7), and pharmaceutically acceptable salts thereof:
  • Ring A, Ring B, G, J, L, R 1 , R 6 , R 9 , R la , R lb , and R 9a are as previously defined in Formula (3-1).
  • the present invention relates to compounds of Formula (3-Ia-7), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.
  • the present invention relates to compounds of Formula (3-Ia-7), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently C 1 -C 8 alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formulae 3-Ib-l ⁇ 3-Ib-6), and pharmaceutically acceptable salts thereof:
  • G, J, Q, R 1 , R 6 , R 9 , R la , R lb , and R 9a are as previously defined in Formula (3-1); in Formula (3-Ib-l), Ring A, Ring B, and L are each present and as previously defined; in Formula (3-Ib-2), Ring A and Ring B are each present and as previously defined in Formula (3-1); in Formula (3-Ib-3), Ring B and L are each present and as previously defined in Formula (3-1); in Formula (3-Ib-4), Ring A and L are each present and as previously defined in Formula (3-1); in Formula (3-Ib-5), Ring B is present and as previously defined in Formula (3-1); and in Formula (3-Ib-6), L is present and as previously defined in Formula (3-1).
  • the present invention relates to compounds of Formulae (3-Ib-l ⁇ 3-Ib-6), and pharmaceutically acceptable salts thereof; wherein R 6 is independently C 1 -C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formula (3-Ib-l), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (3-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (3-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or bicyclic heteroaryl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (3-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and G and J are each independently optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of
  • Ring B or Ring A is optionally substituted bicyclic aryl or bicyclic heteroaryl
  • L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl
  • G and J are each independently optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of
  • Ring B or Ring A is optionally substituted phenyl or monocyclic heteroaryl
  • L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl
  • G and J are each independently optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl and 3- to 8-membered heterocyclic, each optionally substituted.
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6- membered heterocyclic.
  • the present invention relates to compounds of Formula (3-1), and pharmaceutically acceptable salts thereof; wherein R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 1 - C 4 alkyl; preferably hydrogen, halogen or hydroxy.
  • the present invention relates to com ounds of
  • Representative compounds of the present invention are those selected from compounds 3-1 to 3-347compiled in the following tables and/or shown below:
  • any substituent or variable e.g., R , R , etc.
  • each of the two R 7 groups may be the same or different.
  • the drawn formula of any linker or spacer e.g., -NH- C(O)-, -OC(0)-NH-, etc.
  • linker e.g., -NH- C(O)-, -OC(0)-NH-, etc.
  • a linker is -NH- C(O)-, it is meant to include -NH-C(O)- and -C(0)-NH- for attachments.
  • the present invention relates to compounds of Formula (4-1) as illustrated above, and pharmaceutically acceptable salts thereof.
  • the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl and 3- to 8-membered heterocyclic, each optionally substituted.
  • the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted cyclopropyl or a spiro, optionally substituted 5- to 6- membered heterocyclic.
  • the present invention relates to com ounds of Formula (4-
  • R la and R 9a , R la and R 9 , R ld and R 9a , or R ld and R 9 are taken together with the carbon atom to which they are attached to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic.
  • R lb and R 9a are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula
  • R 6 is as previously defined in Formula (4-1) and each of the above core groups is optionally substituted.
  • the invention relates to compounds of Formula (4-1) and pharmaceutically acceptable salts thereof; wherein R ⁇ is independently an optionally substituted C 1 -C 8 alkyl.
  • the invention relates to compounds of Formula (4-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R 6 is an a-amino acid residue.
  • the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted five-membered heteroaryl containing one or more nitrogen atoms, and is C-attached.
  • the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen atoms and wherein the 5- membered ring is C-attached to group Q, and wherein the 6-membered ring of said 5/6- membered fused heteroaryl is aryl or heteroaryl and is C-attached to one of Ring A, L and Ring B.
  • the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein G is illustrated by one of the following heteroaryl groups:
  • the present invention relates to compounds of Formula (4-1), and pharmaceutically acceptable salts thereof; wherein G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of
  • Ring A, Ring B, G, J, L, U, W, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R la , R lb , R ld , R 7a , R 7b and R 9a are as previously defined in Formula (4-1).
  • the present invention relates to compounds of
  • Ring A, Ring B, G, J, L, U, W, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R la , R lb , R lc , R ld , R 7a , R 7b and R 9a are as previously defined in Formula (4-1).
  • the present invention relates to compounds of
  • Ring A, Ring B, G, L, R 6 , R 7a and R 7b are as previously defined in Formula (4-1).
  • the present invention relates to compounds of
  • Ring A, Ring B, G, L, R 6 , R 7a and R 7b are as previously defined in Formula (4-1).
  • the present invention relates to compounds of
  • R 6 at each occurrence is independently selected from the group consisting of C 1 -C 8 alkyl, C 2 - C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.
  • the present invention relates to compounds of Formula (4-Ia-13 ⁇ 4-Ia-16), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently C 1 -C 8 alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formulae (4-Ib- ⁇ 4-Ib-4), and pharmaceutically acceptable salts thereof;
  • Ring B, G, Q, U, R 1 , R 6 , R 7a and R 7b are as previously defined in Formula (4-1); in Formula (4-Ib-l), A and L are each present and as previously defined; in Formula (4-1). in Formula (4-Ib-2), Ring A is present and as previously defined in Formula (4-1); and in Formula (4-Ib-3), L is present and as previously defined in Formula (4-1).
  • the present invention relates to compounds of Formula (4-Ib-l ⁇ 4-Ib-4), and pharmaceutically acceptable salts thereof; wherein R 6 is independently C 1 -C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formula (4-Ib-l), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (4-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (4-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or heteroaryl; and G is optionally substituted imidazolyl.
  • the present invention relates to compounds of
  • Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and G is optionally substituted benzimidazolyl.
  • the present invention relates to compounds of Formula (4-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted bicyclic aryl or heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (4-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (4-Ib-4), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted polycyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (4-Ib- 4), and pharmaceutically acceptable salts thereof; wherein R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, 0(C 1 -C 4 alkyl), S(C 1 -C 4 alkyl), amino optionally substituted with one or two C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C 1 - C 4 alkyl; preferably hydrogen, halogen or hydroxyl.
  • Representative compounds of the present invention are those selected from compounds 4-1 to 4-348 compiled in the following tables and/or are shown below:
  • any substituent or variable e.g., R 3 , R 7 , etc.
  • each of the two R 7 groups may be the same or different.
  • the present invention relates to compounds of Formula (5-1) as illustrated above, and pharmaceutically acceptable salts thereof.
  • the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein R la and R 9a , R la and R 9 , R 1 and R 9a , or R 1 and R 9 are taken together to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein R lb and R 9a , or R lb and R 9 are taken together with the nitrogen or carbon atom(s) to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula (5-
  • R 6 is as previously defined and each of the above core groups is optionally substituted.
  • the invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein R ⁇ is independently an optionally substituted C 1 -C 8 alkyl.
  • the invention relates to compounds of Formula (5-1) and pharmaceutically acceptable salts thereof; wherein -C(0)R 6 is an a-amino acid residue.
  • the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; G is an optionally substituted five- membered heteroaryl containing one or more nitrogen atoms, and is C-attached. In yet another embodiment, the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein G is an optionally substituted 5/6-membered fused heteroaryl; wherein the 5-membered ring of said 5/6-membered fused heteroaryl is a heteroaryl containing one or more nitrogen and wherein the 5-membered ring is C-attached to group Q, and wherein the 6-membered ring of said 5/6-membered fused heteroaryl is aryl or heteroaryl and is C-attached to one of Ring A, L and Ring B.
  • the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein G is illustrated by one of the following heteroaryl groups:
  • the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of
  • Ring A, Ring B, G, L, U, W, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R la , R lb , R lc , and R 9a are as previously defined in Formula (5-1).
  • the present invention relates to compounds of
  • Ring A, Ring B, G, L, U, W, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R la , R lb , R lc , and R 9a are as previously defined in Formula (5-1).
  • the present invention relates to compounds of Formulae (5-Ia-8 ⁇ 5-Ia-9), and pharmaceutically acceptable salts thereof;
  • Ring A, Ring B, G, L, R 1 , R 6 , R 9 , R la , R lb , R lc , and R 9a are as previously defined in Formula (5-1).
  • the present invention relates to compounds of Formula (5-Ia-ll), and pharmaceutically acceptable salts thereof;
  • Ring A, Ring B, G, L, R 1 , R 6 , R 9 , R la , R lb , R lc , and R 9a are as previously defined in Formula (5-1).
  • the present invention relates to compounds of Formula (5-Ia-ll), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted.
  • the present invention relates to compounds of Formula (5-Ia-ll), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently C 1 -C 8 alkyl optionally substituted with amino, hydoxy, protected amino, or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formulae (5-Ib-l ⁇ 5-Ib-4), and pharmaceutically acceptable salts thereof;
  • Ring B, G, Q, R 1 , R 6 , R 9 , R la , R lb , R lc , and R 9a are as previously defined in Formula (5-1); in Formula (5-Ib-l), Ring A and L are each present and as previously defined in Formula (5-1); in Formula (5-Ib-2), Ring A is present and as previously defined in Formula (5-1); and in Formula (5-Ib-3), L is present and as previously defined in Formula (5-1).
  • the present invention relates to compounds of Formulae (5-Ib-l ⁇ 5-Ib-4), and pharmaceutically acceptable salts thereof; wherein R 6 at each occurrence is independently C 1 -C 8 alkyl optionally substituted with amino, hydroxy, protected amino or 0(C 1 -C 4 alkyl).
  • the present invention relates to compounds of Formula (5-Ib-l), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (5-Ib-2), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Rng B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (5-Ib-2), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted bicyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (5-Ib-2) and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (5-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted bicyclic aryl or heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (5-Ib-3), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formula (5-Ib-4), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted polycyclic aryl or heteroaryl; and G is optionally substituted imidazolyl or benzimidazolyl.
  • the present invention relates to compounds of Formulae (5-Ib-5 ⁇ 5-Ib-8), and pharmaceutically acceptable salts thereof:
  • Ring B, Q, V, R 1 , R 6 , R 9 , R la , R lb , R lc , and R 9a are as previously defined in Formula (5-1); in Formula (5-Ib-5), Ring A and L are each present and as previously defined in Formula (5-1); in Formula (5-Ib-6), Ring A is present and as previously defined in Formula (5-1); and in Formula (5-Ib-7), L is present and as previously defined in Formula (5-1).
  • the present invention relates to compounds of Formula (5-Ib-5), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • the present invention relates to compounds of Formula (5-Ib-6), and pharmaceutically acceptable salts thereof; wherein one of Ring A and Ring B is optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the other of Ring A and Ring B is optionally substituted bicyclic aryl or heteroaryl.
  • the present invention relates to compounds of Formula (5-Ib-6), and pharmaceutically acceptable salts thereof; wherein Ring A and Ring B are each independently optionally substituted phenyl or monocyclic heteroaryl.
  • the present invention relates to compounds of Formula (5-Ib-7), and pharmaceutically acceptable salts thereof; wherein Ring B is optionally substituted bicyclic aryl or heteroaryl; L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • the present invention relates to compounds of
  • Ring B is optionally substituted phenyl or monocyclic heteroaryl
  • L is optionally substituted C 2 -C 4 alkenyl or optionally substituted C 2 -C 4 alkynyl.
  • the present invention relates to compounds of Formula (5-Ib-8), or a pharmaceutically acceptable salt thereof; wherein Ring B is optionally substituted polycyclic aryl or heteroaryl.
  • the present invention relates to compounds of Formula (5-1), and pharmaceutically acceptable salts thereof; wherein two geminal R 7 groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 8-membered ring selected from the group consisting of C 3 -C 8 cycloalkyl, C3-C 8 cycloalkenyl and 3- to 8-membered heterocyclic, each optionally substituted.
  • the present invention relates to compounds of
  • the present invention relates to compounds of Formula
  • R 7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy,
  • the present invention relates to com ounds of
  • Representative compounds of the present invention are those selected from compounds 5-1 to 5-394 compiled in the following tables and/or shown below:
  • any substituent or variable e.g., R 3 , R 7 , etc.
  • each of the two R 7 groups may be the same or different.
  • any linker or spacer e.g., -NH- C(O)-, -OC(0)-NH-, etc.
  • a linker e.g., -NH- C(O)-, it is meant to include -NH-C(O)- and -C(0)-NH- for attachments.
  • the description of the present invention herein should be construed in congruity with the laws and principals of chemical bonding. In some instances it may be necessary to remove a hydrogen atom in order to accommodate a substitutent at any given location. It will be yet appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
  • the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent.
  • references herein to therapy and/or treatment includes, but is not limited to, prevention, retardation, prophylaxis, therapy and/or cure of the disease. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection includes treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.
  • a further embodiment of the present invention includes pharmaceutical compositions comprising any single compound a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or excipient.
  • Yet a further embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising any single compound or a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, in combination with one or more agents known in the art, with a pharmaceutically acceptable carrier or excipient.
  • compounds of the present invention can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection.
  • agents to be administered in combination with a compound or combination of compounds of the present invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms.
  • agents include, but are not limited to, host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma, CpG oligonucleotides and the like); antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like); cytokines that modulate immune function (for example, interleukin 2, interleukin 6, and interleukin 12); a compound that enhances the development of type 1 helper T cell response; interfering R A; anti-sense R A; vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV; agents that interact with host cellular components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated translation step of HCV viral replication or to block viral particle maturation and release with agents targeted toward the viroporin family of membrane proteins such as, for
  • compositions of the present invention may further comprise other inhibitor(s) of targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • one embodiment of the present invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising co- administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second or more antiviral agents, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • Examples of the host immune modulator include, but are not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • An example of the RNA-containing virus includes, but is not limited to, hepatitis C virus (HCV).
  • a further embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • An example of the RNA-containing virus includes, but is not limited to, hepatitis C virus (HCV).
  • Yet another embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.
  • An example of the R A-containing virus includes, but is not limited to, hepatitis C virus (HCV).
  • a further embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • HIV human immunodeficiency virus
  • the agent that treats patients for disease caused by human immunodeficiency virus (HIV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combination thereof.
  • An example of the RNA- containing virus includes, but is not limited to, hepatitis C virus (HCV).
  • a patient may be co-infected with hepatitis C virus and one or more other viruses, including but not limited to, human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV).
  • HAV human immunodeficiency virus
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • combination therapy to treat such co-infections by co-administering a compound according to the present invention with at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • the present invention provides the use of a compound or a combination of compounds of the invention, or a pharmaceutically acceptable salt thereof, and one or more agents selected from the group consisting of a host immune modulator and a second or more antiviral agents, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, particularly hepatitis C virus.
  • the host immune modulator examples include, but are not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • combination of compound or compounds of the present invention, together with one or more agents as defined herein above can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt thereof.
  • such combination of therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their
  • compositions can be used for inhibiting the replication of an R A-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition.
  • R A-containing virus particularly Hepatitis C virus (HCV)
  • HCV Hepatitis C virus
  • compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).
  • a still further embodiment of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt thereof, and one or more agents as defined hereinabove, with a pharmaceutically acceptable carrier.
  • an RNA-containing virus particularly a hepatitis C virus (HCV)
  • HCV hepatitis C virus
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
  • agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.
  • cytochrome P450 monooxygenase inhibitor also referred to herein as a CYP inhibitor
  • the cytochrome P450 monooxygenase inhibitor would be in an amount effective to inhibit metabolism of the compounds of this invention.
  • the CYP inhibitor is administered in an amount such that the bioavailiablity of the protease inhibitor is increased in comparison to the bioavailability in the absence of the CYP inhibitor.
  • the invention provides methods for improving the
  • one embodiment of this invention provides a method for administering an inhibitor of CYP3 A4 and a compound of the invention.
  • Another embodiment of this invention provides a method for administering a compound of the invention and an inhibitor of isozyme 3A4 ("CYP3A4"), isozyme 2C19 (“CYP2C19”), isozyme 2D6 (“CYP2D6"), isozyme 1 A2 (“CYP1 A2”), isozyme 2C9 (“CYP2C9”), or isozyme 2E1 ("CYP2E1").
  • the CYP inhibitor preferably inhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics of the relevant NS3/4A protease may be used in a method of this invention.
  • CYP inhibitors include, but are not limited to, ritonavir (see, for example, WO 94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfmavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.
  • Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.
  • the pharmaceutical pack further comprises one or more of additional agent as described herein.
  • the additional agent or agents may be provided in the same pack or in separate packs.
  • kits for a patient to use in the treatment of HCV infection or in the prevention of HCV infection comprising: a single or a plurality of pharmaceutical formulation of each pharmaceutical component; a container housing the pharmaceutical formulation(s) during storage and prior to administration; and instructions for carrying out drug administration in a manner effective to treat or prevent HCV infection.
  • kits for the simultaneous or sequential administration of a compound of the invention and a CYP inhibitor (and optionally an additional agent) or derivatives thereof are prepared in a conventional manner.
  • a kit will comprise, e.g. a composition of each inhibitor and optionally the additional agent(s) in a pharmaceutically acceptable carrier (and in one or in a plurality of pharmaceutical formulations) and written instructions for the simultaneous or sequential administration.
  • a packaged kit contains one or more dosage forms for self administration; a container means, preferably sealed, for housing the dosage forms during storage and prior to use; and instructions for a patient to carry out drug administration.
  • the instructions will typically be written instructions on a package insert, a label, and/or on other components of the kit, and the dosage form or forms are as described herein.
  • Each dosage form may be individually housed, as in a sheet of a metal foil- plastic laminate with each dosage form isolated from the others in individual cells or bubbles, or the dosage forms may be housed in a single container, as in a plastic bottle.
  • the present kits will also typically include means for packaging the individual kit components, i. e., the dosage forms, the container means, and the written instructions for use.
  • Such packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.
  • viral infection refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication. Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.
  • HCV hepatitis C virus
  • immune modulator refers to any substance meant to alter the working of the humoral or cellular immune system of a subject.
  • immune modulators include inhibitors of mast cell-mediated inflammation, interferons, interleukins, prostaglandins, steroids, cortico-steroids, colony-stimulating factors, chemotactic factors, etc.
  • aryl refers to a mono- or polycyclic carbocyclic ring system including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and idenyl.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a
  • heteroaryl refers to a mono- or polycyclic ring system comprising at least one aromatic ring having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, and quinoxalinyl.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group.
  • Aromatic groups can be substituted or unsubstituted.
  • bicyclic aryl or "bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and they can be fused or covalently attached.
  • tricyclic aryl or "tricyclic heteroaryl” refers to a ring system consisting of three rings wherein at least one ring is aromatic.
  • C 1 -C 4 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals containing between one and four, one and six, one and eight carbon atoms, or the like, respectively.
  • Examples of C 1 -Cs alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
  • C 2 -C 8 alkenyl refers to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • C 2 -C 8 alkynyl refers to straight- or branched-chain hydrocarbon radicals containing from two to eight, or two to four carbon atoms, or the like, having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • C 3 -C8-cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo-substituted.
  • C 3 -C8-cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of Cs-Cycycloalkyl include, but not limited to, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and the like.
  • C 3 -C 8 cycloalkenyl or “C5-C7 cycloalkenyl,” as used herein, refers to monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond, and the carbon atoms may be optionally oxo-substituted.
  • C 3 -C 8 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C5-C7 cycloalkenyl include, but not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • arylalkyl refers to an aryl-substituted alkyl group. More preferred arylalkyl groups are aryl-C 1 -C 6 -alkyl groups.
  • heteroarylalkyl refers to a heteroaryl-substituted alkyl group. More preferred heteroarylalkyl groups are heteroaryl-C 1 -C6-alkyl groups.
  • any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
  • an "aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
  • Examples of aliphatic groups are functional groups, such as, O, OH, NH, NH 2 , C(O), S(0) 2 , C(0)0, C(0)NH, OC(0)0, OC(0)NH, OC(0)NH 2 , S(0) 2 NH, S(0) 2 NH 2 , NHC(0)NH 2 , NHC(0)C(0)NH, NHS(0) 2 NH, NHS(0) 2 NH 2 , C(0)NHS(0) 2 ,
  • C(0)NHS(0) 2 NH or C(0)NHS(0) 2 NH 2 groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
  • Carbon atoms of an aliphatic group can be optionally oxo- substituted.
  • An aliphatic group may be straight chained, branched, cyclic, or a
  • aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and
  • Aliphatic groups may be optionally substituted.
  • a linear aliphatic group is a non-cyclic aliphatic group. It is to be understood that when an aliphatic group or a linear aliphatic group is said to "contain” or “include” or “comprise” one or more specified functional groups, the aliphatic group can be selected from one or more of the specified functional groups or a combination thereof, or a group wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a specified functional group.
  • the linear aliphatic group can be represented by the formula M-V'-M', where M and M' are each independently absent or an alkyl, alkenyl or alkynyl, each optionally substituted, and V is a functional group.
  • V is selected from the group consisting of C(O), S(0) 2 , C(0)0,
  • an exemplary linear aliphatic group is an alkyl, alkenyl or alkynyl, each optionally substituted, which is interrupted or terminated by a functional group such as described herein.
  • alicyclic denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom, and the carbon atoms may be optionally oxo-substituted. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo
  • heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible).
  • any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).
  • substituted when used with alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, or aliphatic as described herein refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, - OH, protected hydroxy, -N0 2 , -N 3 , -CN, -NH 2 , protected amino, oxo, thioxo, -NH-C1-C12- alkyl, -NH-C 2 -C 8 -alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -C 12 -cycloalkyl, -NH-aryl, -NH- heteroaryl, -NH-hetero
  • halogen refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • hydrox includes hydrogen and deuterium.
  • recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate and the like.
  • activated hydroxyl refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl,
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl,
  • carbonyl protecting group refers to a labile chemical moiety which is known in the art to protect a carbonyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the carbonyl protecting group as described herein may be selectively removed.
  • Carbonyl protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • carbonyl protecting groups include acetals, ketals, cyclic acetals, cyclic ketals, mono- or dithio acetals, mono- or dithioketals, optionally substituted hydrazones or oximes.
  • protected carbonyl refers to a carbonyl group protected with a carbonyl protecting group, as defined above, including dimethyl acetal, 1,3- dioxolane, 1,3-dioxane, S,S'-dimethylketal, 1,3-dithiane, 1,3-dithiolane, 1,3-oxathiolane, N,N-dimethylhydrazone, oxime, for example.
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t- butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • substituted amino refers to substitution by replacement of one or two hydrogen atoms of -NH 2 with substituents independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclic; alternatively, when disubstituted, the two substitutents can be optionally taken together with the nitrogen atom to which they are attached to form an optionallysubstituted heterocyclic group.
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; hydroxy; imidazolyl; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • alcohol for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid
  • subject refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of these compounds and mixtures thereof.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • suitable organic acid examples include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention.
  • Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed).
  • the present invention also relates to solvates of the compounds of Formula (1-1),
  • This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically acceptable prodrugs of compounds of the invention.
  • compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention.
  • the amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • compositions of the present invention comprise a
  • the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; algin
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and 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.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated 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 and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
  • Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter et al, U.S. Pat. No.
  • An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 0.1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • viral infections are treated or prevented in a patient such as a human or another animal by administering to the subject a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • An additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of composition of the present invention in such amounts and for such time as is necessary to achieve the desired result.
  • terapéuticaally effective amount of a compound of the invention means an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • inhibitory amount of a compound of the present invention means a sufficient amount to decrease the viral load in a biological sample or a subject (e.g., resulting in at least 10%, preferably at least 50%, more preferably at least 80%, and most preferably at least 90%> or 95%, reduction in viral load). It is understood that when said inhibitory amount of a compound of the present invention is administered to a subject it will be at a reasonable benefit/risk ratio applicable to any medical treatment as determined by a physician.
  • biological sample(s), as used herein, means a substance of biological origin intended for administration to a subject.
  • biological samples include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, and the like; sperm and ova; bone marrow and components thereof; or stem cells.
  • another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention.
  • Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • compositions of this invention comprise a combination of a compound of the Formula (1-1), Formula (2-1), Formula (3-1), Formula (4-1) and Formula (5-1), described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally
  • agents administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention.
  • those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • additional therapeutic or prophylactic agents include, but are not limited to, immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta- 2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti- muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g.
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • Drug resistance most typically occurs by mutation of a gene that encodes for a protein such as an enzyme used in viral replication, and most typically in the case of HCV, RNA polymerase, protease, or helicase.
  • a compound of the present invention can also be administered in combination or alternation with antiviral agent.
  • Examplary antiviral agents include ribavarin, interferon, interleukin or a stabilized prodrug of any of them. More broadly described, the compound can be administered in combination or alternation with any of the anti-HCV drugs listed in Table 53 below.
  • cyanoborohydride NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodium hydride; NaHC0 3 for sodium bicarbonate or sodium hydrogen carbonate; Na 2 C0 3 sodium carbonate; NaOH for sodium hydroxide; Na 2 S0 4 for sodium sulfate; NaHS0 3 for sodium bisulfite or sodium hydrogen sulfite; Na 2 S 2 0 3 for sodium thiosulfate; NH 2 NH 2 for hydrazine; NH 4 HC0 3 for ammonium bicarbonate; NH 4 C1 for ammonium chloride; NMMO for N-methylmorpholine N-oxide; NaI0 4 for sodium periodate; Ni for nickel; OH for hydroxyl; Os0 4 for osmium tetroxide; Pd for palladium; Ph for phenyl; PMB for p-methoxybenzyl; POPd for dihydrogen dichlorobis(di
  • PPh 3 for triphenyl-phosphine
  • Troc for 2,2,2-trichloroethyl carbonyl
  • Ts for tosyl or -S0 2 - C 6 H 4 CH 3
  • Ts 2 0 for tolylsulfonic anhydride or tosyl-anhydride
  • TsOH for p-tolylsulfonic acid
  • TMS for trimethylsilyl
  • TMSC1 trimethylsilyl chloride.
  • the compounds of the present invention may be prepared via several different synthetic routes from a variety of 5/6-membered fused heteroaryl, 5-membered heteroaryl, and related intermediates.
  • a retro-synthesis of the compounds include direct formation of a suitably linked core structure (5/6-membered fused heteroaryl or 5-membered heteroaryl) followed by attachment of a suitable capping group (such as -C(0)R 6 ), plus some functional group manipulations in between and/or after.
  • a suitable capping group such as -C(0)R 6
  • Various 5/6-membered fused heteroaryl or 5-membered heteroaryl intermediates are known to those skilled in the art, for example see the encyclopedic volumns edited by A. R. Katrizky, et al,
  • imidazopyridine or benzimidazole 1-2 which may be obtained by condensation of an amino acid or its derivative 1-1.1 or 1-1.2 and a 2,3-diaminopyridine or 1,2- diaminobenzene 1-1 under the conditions to those skilled in the art.
  • the imidazole ring closure may be realized either in one pot by heat, optionally in the presence of an acid and/or with a dehydration reagent such as polyphosphoric acid; or in two steps: 1) amide formation between diamine 1-1 and amino acid 1-1.1 or 1-1.2 in the presence of a condensation reagent such as EDC C1 , DCC or the like; or through mixed anhydride approach by reacting acid 1-1.1 or 1-1.2 with a chloroformate such as methyl
  • chloroformate isobutyl chloroformate, or the like, in the presence of a base such as TEA, DIPEA, DMAP, N-methylmorpholine, or the like, followed by treating the mixed anhydride with diamine 1-1; and 2) the heterocyclic ring closure in the presence of an acid such as acetic acid, sulfuric acid or the like or a dehydration reagent such as HATU or the like, optionally with heat.
  • a base such as TEA, DIPEA, DMAP, N-methylmorpholine, or the like
  • the NH group in the newly formed imidazopyridine or benzimidazole ring of 1-2 may be protected with an amino protecting group, such as SEM (i.e. SEM-C1, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • SEM i.e. SEM-C1, NaH
  • Boc Boc
  • Cbz Boc
  • Teoc Teoc
  • Troc Troc
  • the protected imidazopyridine or benzimidazole 1-2 may be subjected to lithium-halogen exchange with various (n-, s-, or t-) butyl lithium and the resulting lithiate can be trapped with a nucleophile, i.e. a halide such as various allyl halide to give the allylated 1-6 as a key intermediate.
  • a nucleophile i.e. a halide such as various allyl halide
  • 1-6 may be obtained from the Stille reaction conditions to those skilled in the art (see reviews: A. Anastasia, et al, Handbook of Organopalladium Chemistry for Organic Synthesis, 2002, 1, 311; F. Bellina, et al, Synthesis 2004, 2419; M. G. Organ, et al, Synthesis 2008, 2776; A. T. Lindhardt, et al, Chem. - A European J., 2008, 14, 8756; E. A. B. Kantchev, et al, Angew. Chem. Int. Ed., 2007, 46, 2768; V.
  • allylstanne such as allyltributylstanne
  • allyltributylstanne an allylstanne
  • a key vinyl intermediates 1-3 may be prepared by Stille reaction from bromide 1-2 with tributylvinylstanne.
  • Sonogashira coupling between bromide 1-2 and propargyl alcohol or trimethylsilyl-acetylene can generate propargyl alcohol 1-4 or alkyne 1-5 after removal of TMS. Further bromination of intermediate 1-4 may form the propargyl bromide 1-9.
  • the bromide 1-2 may be converted to methyl ketone 1-7 by coupling with tributyl(l-ethoxyvinyl)tin under Stille coupling conditions followed by acidic hydrolysis.
  • bromination procedure which can be further functionalized to amine 1-20 through azide substitution followed by reduction.
  • Aldehyde 1-8 can then either be reduced to alcohol 1- 11, or be converted to a, ⁇ -unsatuated acid 1-10 through Horner- Wadsworth-Emmons aldehyde homologation reaction followed by saponification.
  • Alcohol 1-11 may be similarly converted to the correponding amine intermediate 1-14 and bromide intermediate 1-13 as described previously.
  • Bromide 1-13 can be homologated to alkyne intermediate 1- 19 with a metal acetylide.
  • bromide 1-13 may be also tranformed to thiol 1-16 through nucleophilic substitution, which can be further oxidized to sulfonic acid 1-17.
  • Sulfonamide 1-18 may then be derived from 1-17 through the sulfonyl chloride activation process.
  • the NH group of all the imidazopyridine or benzimidazole related intermediates listed above may be protected with an amino protecting group, such as SEM (i.e. SEM-C1, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • SEM i.e. SEM-C1, NaH
  • Boc Boc
  • Cbz Boc
  • Teoc Teoc
  • Troc Troc
  • bromo- imidazole 2-4 can be synthesized in a three-step sequence: 1) condensation between amino acid derived aldehyde 2-1.1 or 2-1.2 and glyoxal 2-1.3 in the presence of methanolic ammonia to generate imidazole 2-2; 2) bromination of 2-2 with excess amount of bromination reagent such as 2,4,4,6-tetrabromo-2,5-cyclohexadienone, NBS, etc. to afford dibromide 2-3; and 3) selective reduction of the dibromide 2-3 by heating in aq. Na 2 S03 or aq. NaHS0 3 . 2-4 then may be served as a universal intermediate further elaborable to many other imidazole derivatives using the chemistry discussed in Scheme 1, some of which are listed in the table 54 below.
  • the NH group of imidazole related intermediates listed above may be protected with an amino protecting group (shown in Scheme 2 as PG, theoretically the reaction will generate two regio-isomers, but only one is drawn for clarity), such as SEM (i.e. SEM-C1, NaH), Boc, Cbz, Teoc, Troc, or the like.
  • an amino protecting group shown in Scheme 2 as PG, theoretically the reaction will generate two regio-isomers, but only one is drawn for clarity
  • SEM i.e. SEM-C1, NaH
  • Boc Boc
  • Cbz Boc
  • Teoc Teoc
  • Troc Troc
  • the protected imidazole 2-5 may be deprotonated with a strong base such as LDA, BuLi, etc to generate a carbon anion, which may either undergo a nucleophilic substitution with an activated halide such as 2- 5.2 to afford aryl or heteroaryl substituted imidazole 2-6 or couple with an aryl or heteroaryl halide 2-5.1 in the presence appropriate transition metal salt to generate bicyclic heteroaryl 2-7.
  • the protected bromo imidazole 2-8 may be subjected to lithium- halogen exchange with various (n-, s-, or t-) butyl lithium, the resulting lithiate may undergo similar reactions to afford 2-6 and 2-7.
  • aryl or heteroaryl bromide 2-5.1 may be converted to methyl ketone 2-9 under Stille coupling conditions with tributyl(l-ethoxyvinyl)tin 2-9.1.
  • 2-9 may be brominated under conditions to those skilled in the art to afford bromide 2-10, which may be either converted to the corresponding amine 2-11, or coupled with protected amino acid 1-1.1 or 1-1.2 in the presence of a base such as Et 3 N and DIPEA to afford keto-ester 2-12.
  • amine 2-11 may be converted to the corresponding keto-amide 2-13 via condensation with appropriate amino acid under standard amide formation conditions.
  • 2- 12 and 2-13 may be tranformed to key intermediate 2-14 via heating with (NH 4 )OAc under thermal or microwave conditions.
  • requisite buiding blocks for the syntheses of the molecule of the present invention are various amide, carbamate or urea-related intermediates, which can be prepared from a suitable, commercially available amine through standard amide, carbamate or urea formation by direct condensation of an carboxylic acid with a dehydration and/or condensation reagent, such as HATU, DCC, BtOH, EDC or the like; or a chloroformate; or an isocyanate; in the presence of a suitable base such as pyridine, TEA, DIPEA, DMAP, NaHC0 3 , K 2 C0 3 or the like.
  • a suitable base such as pyridine, TEA, DIPEA, DMAP, NaHC0 3 , K 2 C0 3 or the like.
  • the Boc-protected ⁇ -amino acid 3- la can be condensed with 4-bromoaniline 3-2a in the presence of HATU and DIPEA in CH 2 C1 2 to afford amide 3-3a.
  • heteroaryl or aryl amine related intermediates which can be prepared from a suitable, commercially available amine through standard nucleophilic substitution by direct condensation of a heteroaryl halide such as 5-bromo-2-chloropyrimidine, 2,6-dibromoquinazoline, 6-bromo- 2-chlorobenzothiazole, or the like; with an appropriate amine such as 2-aminomethyl-N- Boc-pyrrolidine, l-Boc-3-aminopyrrolidine, trans-N-Boc1,2-cyclopentanediamine or the like; in the presence of a suitable base such as pyridine, TEA, DIPEA, DMAP, NaHC0 3 , K 2 C0 3 or the like; under thermal or microwave conditions.
  • a heteroaryl halide such as 5-bromo-2-chloropyrimidine, 2,6-dibromoquinazoline, 6-bromo- 2-chlorobenzothiazole, or the like
  • heteroaryl or aryl amino related intermediates can be prepared through transition metal catalyzed amination process between an suitable amine as mentioned above and an aryl or heteroaryl iodide or bromide such as 5-bromo-2-iodopyridine, 1 ,4-diiodobenzene, or the like; in the presence of a suitable base such as Cs 2 C0 3 , K 3 P0 4 , K 2 C0 3 or the like; and an appropriate transition metal catalyst such as Cul or various Pd related catalysts; and an related ligand according to the used transition metal catalyst; under inert atmosphere.
  • a suitable base such as Cs 2 C0 3 , K 3 P0 4 , K 2 C0 3 or the like
  • an appropriate transition metal catalyst such as Cul or various Pd related catalysts
  • an related ligand according to the used transition metal catalyst
  • the Boc-protected ⁇ -diamine 3-lb can be condensed with 5-bromo-2-chloropyrimidine 3-2b in the presence of DIPEA in 1,4-dioxane under thermal or microwave conditions to afford pyrimidynyl amine 3-3b.
  • 3-lb can be reacted with 5-bromo-2-iodopyridine 3-4b in the presence of Cs 2 C0 3 , catalytic amount of Cul, and 2-isobutyrylcyclohexanone as ligand, in DMF under N 2 atmosphere to yield the desired pyridinyl amine 3-5b as described by S. L. Buchwald (J. Am. Chem. Soc. 2006, 128, 8742).
  • the compounds of the present invention may be prepared through various coupling strategy or a combination of strategies to connect two fragments, optionally with a suitable cyclic or acyclic linker or formation of a cyclic or acyclic linker.
  • the said strategy includes, but not limited to, Stille coupling, Suzuki coupling, Sonogashira coupling, Heck coupling, Buchwald amidation, Buchwald amination, alkylation, pericyclic reaction with different variations, or the like.
  • bromides 4-1 and 4-2 can be prepared using similar procedures described in Schemes 1-3 and 3a.
  • Bromide 4-2 can be converted to the corresponding metallated aryl 4-3 (boronate or stanne) under Suzuki or Stille conditions with bis(pinacolato)diboron, hexamethylditin or hexabutylditin in the presence of Pd- catalyst.
  • the latter may be further coupled with imidazopyridine bromide 4-1 under similar conditions to generate a core structure 4-4.
  • Compound 4-4 then may be served as a common intermediate for further derivatizations to 4-5 in two steps: 1) mono-deprotection of the linear or cyclic amine moiety may be accomplished, for example, treatment to hydrogenolytic conditions under Pd catalyst to remove the Cbz protection group; and 2) the released amine functionality may be acylated with an carboxylic acid under standard acylation conditions, for example a coupling reagent such as HATU in combination with an organic base such as DIPEA can be used in this regard; alternatively, the released amine may be reacted with an isocyanate, carbamoyl chloride or chloroformate to provide an urea or carbamate.
  • Various carboxylic acids including amino acids in racemic or optical form are commercially available, and/or can be synthesized in racemic or optical form, see references cited in reviews by D.
  • the compounds of the present invention may also be derived from bromoimidazopyridine or bromobenzimidazole 4- la and amide 4-2a using the procedures described previously.
  • the intermediates 4- la and 4-2a have the desired acyl groups already installed using similar sequences shown in Scheme 4.
  • the compounds of the present invention containing five-membered heteroaryl other than imidazole may be prepared using similar procedures described above in Schemes 1-4 and 4a.
  • some intermediates containing a desired, suitably substituted five-membered heteroaryl have been published in US 2008/0311075A1 by C. Bachand, et al from Bristol-Myers Squibb, Co., which is incorporated by reference.
  • the synthesis of the compounds of the present invention involves 5/6-membered fused heteroaryl intermediates other than imidazopyridines or benzimidazoles, various 5/6-membered fused heteroaryl are known in the literature.
  • the synthesis of other 5/6-membered fused heteroaryl intermediates depends on the chemical features of each structure. For example, a typical synthesis of indole intermediate is illustrated in Scheme 5.
  • the commercially available bromoiodoaniline 5-1 may be coupled to the commercially available acetylene 5-1.1 under the Sonogashira conditions to give phenylacetylene 5-2.
  • the latter may be cyclized to indole 5-3 under heat or microwave condition in the presence of a copper catalyst.
  • the invention encompasses a process of making a compound of the invention comprising:
  • Ring A 1 is absent, optionally substituted aryl or optionally substituted heteroaryl
  • Ring B 1 is optionally substituted aryl or optionally substituted heteroaryl
  • L 1 is absent, optionally substituted C 2 -C 4 alkenyl or C 2 -C 4 alkynyl;
  • Z a and Z b are each independently an amino protecting group or -C(0)-R 6 ; wherein R 6 is as defined above;
  • Z c is hydrogen, an amino protecting group or -C(0)-R 6 ;
  • Z d is an amino protecting group -C(0)-R 6 ;
  • the invention is a process of making a compound according to Formula (l-I) comprising:
  • Ring A 1 is absent, optionally substituted aryl or optionally substituted heteroaryl; Ring B 1 is optionally substituted aryl or optionally substituted heteroaryl;
  • L 1 is absent, optionally substituted C2-C 4 alkenyl or C2-C 4 alkynyl;
  • Z a and Z b are each independently an amino protecting group or -C(0)-R 6 ; wherein R 6 is as defined in in Formula (1-1);
  • Z c is hydrogen, an amino protecting group or -C(0)-R 6 ;
  • Z d is an amino protecting group -C(0)-R 6 ;
  • the invention is a process of making a compound accordingormula (2-1) comprising:
  • Ring A 1 and Ring B 1 are each independently optionally substituted aryl or optionally substituted heteroaryl;
  • L 1 is absent, optionally substituted C2-C 4 alkenyl or C2-C 4 alkynyl; and Z a and Z b are each independently an amino protecting group or -C(0)-R 6 ; wherein R 6 is as defined in Formula (2-1);
  • Z c is hydrogen, an amino protecting group or -C(0)-R 6 ;
  • Z d is an amino protecting group -C(0)-R 6 ;
  • the invention is a process of making a compound of Formula (3-1) comprising:
  • R 1 , R la , R lb , R 7a , R 7b , R 9 , and R 9a are as defined in Formula (3-1);
  • Ring A 1 and Ring B 1 are each independently absent or an optionally substituted aryl or optionally substituted heteroaryl;
  • L 1 is absent, optionally substituted C 2 -C 4 alkenyl or C 2 -C 4 alkynyl;
  • Z a and Z b are each independently an amino protecting group or -C(0)-R 6 ; wherein R 6 is as defined in Formula (3-1); ii) when Z a or Z b is an amino protecting group, fully or selectively deprotecting a compound of Formula (3 -II) to give the corresponding amine of Formula (3 -III):
  • Z c is hydrogen, an amino protecting group or -C(0)-R 6 ;
  • Z d is an amino protecting group -C(0)-R 6 ;
  • the invention is a process of making a compound of Formula (4-omprising:
  • R 1 , R la , R lb , R lc , R 7a , R 7b , R 9 , and R 9a are as defined in Formula (4-1);
  • Ring A 1 is absent, or optionally substituted aryl or optionally substituted heteroaryl
  • Ring B 1 is optionally substituted aryl or optionally substituted heteroaryl
  • L 1 is absent, or optionally substituted C2-C 4 alkenyl or C2-C 4 alkynyl
  • Z a or Z b are each independently an amino protecting group or -C(0)-R 6 ; wherein R 6 is as defined in Formula (4-1); ii) when Z a or Z b is an amino protecting group, fully or selectively deprotecting a compound of Formula (4-II) to give the corresponding amine of Formula (4-III):
  • Z c is hydrogen, an amino protecting group or -C(0)-R 6 ;
  • Z d is an amino protecting group or -C(0)-R 6 ;
  • the invention is a process of making a compound of Formula (5-1) comprising:
  • Ring B, G, U, R 1 , R la , R lb , R lc , R 7a , R 7b , R 9 , and R 9a are as defined in Formula (5-1);
  • Ring A 1 is absent, optionally substituted aryl or optionally substituted heteroaryl
  • L 1 is absent, optionally substituted C 2 -C 4 alkenyl or C 2 -C 4 alkynyl;
  • Z a and Z b are each independently an amino protecting group or -C(0)-R 6 ; wherein R 6 is as defined in Formula (5-1);
  • Z c is hydrogen, an amino protecting group or -C(0)-R 6 ;
  • Z d is an amino protecting group or -C(0)-R 6 ;
  • Step l-257a A solution of the compound from example 1-353 (32.5 ⁇ at most) in
  • Step l-257b A mixture of the crude compound from step l-257a (32.5 ⁇ at most) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step l-348a A mixture of 4-bromoaniline (0.500 g, 2.91 mmol) and trans (+/-) 2-(tert- butoxycarbonylamino)-cyclopentanecarboxylic acid (0.733 g, 3.20 mmol) in DMF (12 mL) were added EDC HCl (0.724 g, 3.78 mmol), HOBt (0.646 g, 3.78 mmol) and DIPEA (0.54 mL, 4.36 mmol). The mixture was stirred at room temperature until the
  • Step l-348b A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol) and N-Boc-L- proline (3.87 g, 18.0 mmol) in CH 3 CN (60 mL) was added TEA (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-348c A solution of the compound from step l-348b (6.73 g, 16.3 mmol) in toluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol) and the resultant mixture was heated up to 100 °C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHC0 3 ). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%).
  • Step l-348d A mixture of the compound from step 348c (1.00 g, 2.55 mmol), bis-
  • Step l-348e A mixture of the compound from step l-348a (0.200 g, 0.522 mmol), the compound from step 348d (0.229 g, 0.522 mmol) and NaHC0 3 (0.175 g, 2.09 mmol) in DME (12 mL) and H 2 0 (4 mL) was added Pd(PPh 3 ) 4 (30.2 mg, 26.1 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated. The residue was purified by
  • Step l-349b A mixture of the crude compound from step l-348a (97.5 ⁇ at most) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step l-350a A mixture of 2-amino-6-bromonaphthalene (0.500 g, 2.25 mmol) and trans (+/-) 2-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (0.567 g, 2.48 mmol) in DMF (10 mL) were added EDC C1 (0.561 g, 2.93 mmol), HOBt (0.500 g, 2.93 mmol) and DIPEA (0.42 mL, 3.38 mmol). The mixture was stirred at room temperature until the disappearence of the starting material.
  • Step l-350b A mixture of the compound from step l-350a (0.200 g, 0.462 mmol), the compound from step 348d (0.184 g, 0.420 mmol) and NaHC0 3 (0.141 g, 1.68 mmol) in DME (12 mL) and H 2 0 (4 mL) was added Pd(PPh 3 ) 4 (24.2 mg, 20.9 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-351a A solution of the compound from example 1-350 (50.0 mg, 75.1 ⁇ ) in CH 2 CI 2 (5 mL) was treated with C1 in 1,4-dioxane (4 M, 1 mL) for 30 min. The volatiles 5 were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 466.24 [M+H] + .
  • Step l-351b A mixture of the crude compound from step 1-35 la (75.1 ⁇ at most) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step l-352a A mixture of (i?)-(+)-tert-butyl pyrrolidin-3-ylcarbamate (0.100 g, 0.537 mmol) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO 2008/021927, 0.103 g, 0.590 mmol) in DMF (3 mL) was treated with HATU (0.204 g, 0.537 mmol) in the presence of DIPEA (0.13 mL, 1.07 mmol) for 2 hours at rt and the 20 volatiles were evaporated off to provide a brown syrup.
  • Step l-352a A solution of the compound from step l-352a (0.537 mmol at most) in CH 2 CI 2 (6 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) for 30 min. The volatiles 25 were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 244.24 [M+H] + .
  • Step l-352d A solution of the compound from step l-348c (1.500 g, 3.824 mmol) in 1,4- dioxane (12 mL) was treated with C1 in 1,4-dioxane (4 M, 24 mL) at room temperature for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.
  • ESIMS m/z 292.06, 294.06
  • Step l-352e A mixture of the crude compound from step l-352d (3.824 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 0.670 g, 3.824 mmol) in DMF (12 mL) was treated with HATU (1.381 g, 3.633 mmol) in the presence of DIPEA (6.66 mL, 38.24 mmol) for 1 hour at room temperature and the volatiles were evaporated off. The residue was purified by
  • Step l-352f A mixture of the compound from step l-352e (1.50 g, 3.34 mmol), bis-
  • Step l-352g A mixture of the compound from step l-350c (39.8 mg, 84.1 ⁇ ), the compound from step l-352f (54.2 mg, 0.109 mmol) and NaHC0 3 (28.3 g, 0.336 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (4.9 mg, 4.2 ⁇ ). The resultant mixture were degassed and heated to 85 °C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-353b A mixture of the compound from step l-353a (49.0 mg, 0.114 mmol), the compound from step l-348d (60.0 mg, 0.137 mmol) and NaHC0 3 (38.3 mg, 0.456 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (6.5 mg, 5.6 ⁇ ). The resultant mixture were degassed and heated to 85 °C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-354b A mixture of the compound from step l-354a (50.3 mg, 0.136 mmol), the compound from step l-348d (65.8 mg, 0.150 mmol) and NaHC0 3 (45.8 mg, 0.545 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (7.9 mg, 6.8 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-355a A solution of the compound from example 1-354 (20.0 mg, 33.2 ⁇ ) in CH 2 C1 2 (4 mL) was treated with C1 in 1,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 402.38 [M+H] + .
  • Step l-355b A mixture of the crude compound from step l-355a (max. 33.2 ⁇ ) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step l-356a A mixture of trans-N-Boc-1,2-cyclopentanediamine (60.0 mg, 0.300 mmol) and 3-iodobenzoic acid (74.3 mg, 0.300 mmol) in CH 2 C1 2 (6 mL) was treated with HATU (0.114 g, 0.300 mmol) in the presence of DIPEA (75 ⁇ ⁇ , 0.600 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.120 g, 93%).
  • Step l-356c The compound from step l-356b (2.89 g, 11.6 mmol) in acetic acid (60 mL) was treated with bromine (0.59 mL, 11.6 mmol) dropwise for 1 hour. The volatiles were evaporated and the residue was partitioned (EtOAc - saturated aqueous NaHC0 3 ). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated to give the crude desired compound as a light yellow solid (3.898 g).
  • Step l-356e A mixture of the compound from step l-356d (0.200 g, 0.452 mmol), bis(pinaco-lato)diboron (0.144 g, 0.565 mmol), PdCl 2 (dppf) 2 (36.9 mg, 0.0452 mmol) and potassium acetate (88.7 mg, 0.904 mmol) in DMSO (5 mL) was degassed and heated at 80°C under N 2 for 17 hours. The reaction mixture was allowed to cool down and partitioned (EtOAc - water). The organic layer was washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-356f A mixture of the compound from step l-356a (29.4 mg, 68.3 ⁇ ), the compound from step l-356e (40.0 mg, 81.9 ⁇ ) and NaHC0 3 (22.9 mg, 0.273 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (3.9 mg, 3.4 ⁇ ). The resultant mixture were degassed and heated to 85 °C under N 2 for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-357a A solution of the compound from example 1-356 (20.0 mg, 30.0 ⁇ ) in CH 2 CI 2 (4 mL) was treated with C1 in 1,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 466.43 [M+H] + .
  • Step l-357b A mixture of the crude compound from step l-357a (max. 30.0 ⁇ ) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step l-358a A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20 °C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-1,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20°C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water).
  • Step l-358b A solution of the crude compound from step l-358a (10.7 g, 26.7 mmol at most) in glacial acetic acid (100 mL) was heated at 50°C for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc - aqueous NaHC0 3 ). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-358c A mixture of the compound from step l-358b (2.010 g, 5.488 mmol), trimethylsilyl-acetylene (2.33 ml, 16.46 mmol), Cul (0.110 g, 0.576 mmol) and
  • Step l-358e A mixture of the compound from step l-354a (52.6 mg, 0.143 mmol), the compound from step l-358d (48.8 mg, 0.157 mmol) in Et 3 N (6 mL) was added Cul (0.8 mg, 4.2 ⁇ ) and Pd(PPh 3 ) 4 (16.4 mg, 14.2 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 20 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-359a A solution of the compound from example 1-358 (27.4 mg, 45.7 ⁇ ) in CH 2 C1 2 (4 mL) was treated with C1 in 1,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 400.35 [M+H] + .
  • Step l-359b A mixture of the crude compound from step l-359a (max. 45.7 ⁇ ) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step l-360b A solution of the compound from step l-356d (0.120 g, 0.271 mmol) in 1,4- dioxane (3 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) at rt for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was used directly in the next step.
  • Step l-360c A mixture of the crude compound from step l-360b (0.271 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (47.5 mg, 0.271 mmol) in DMF (2 mL) was treated with HATU (98.0 mg, 0.258 mmol) in the presence of DIPEA (0.47 mL, 2.713 mmol) for 1.5 hours at rt and the volatiles were evaporated off . The residue was patitioned (EtOAc/CH 2 Cl 2 - H 2 0). The organic layer was washed with saturated NaHC0 3 , brine, dried (Na 2 S0 4 ), filtered and concentrated.
  • Step l-360d A mixture of the compound from step l-360c (0.130 g, 0.260 mmol), bis(pinacolato)diboron (79.3 mg, 0.312 mmol), PdCl 2 (dppf) 2 (21.3 mg, 26.0 ⁇ ) and potassium acetate (51.0 mg, 0.521 mmol) in DMSO (4 mL) was degassed and heated at 80 °C under N 2 overnight. The mixture was allowed to cool down and partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-360e A mixture of the compound from step l-360a (18.4 mg, 43.9 ⁇ ), the compound from step 360d (20.0 mg, 36.6 ⁇ ) and NaHC0 3 (12.3 mg, 0.146 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (2.1 mg, 1.8 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-362a A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20°C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-1,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 °C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water).
  • Step l-362c A mixture of the compound from step l-362b (1 g, 2.73 mmol), bis- (pinacolato)-diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 1,4- dioxane (9.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.14 mmol). The resulting solution was degased and then heated at 80°C under N 2 overnight before being evaporated.
  • Step l-362d A mixture of the compound from step l-354a (20.0 mg, 54.2 ⁇ ), the compound from step l-362c (24.6 mg, 59.6 ⁇ ) and NaHC0 3 (18.2 mg, 0.217 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (3.1 mg, 2.7 ⁇ ). The resultant mixture were degassed and heated to 90°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-364a A mixture of ( ⁇ ) -l-N-Boc-3 ⁇ 4eto-proline (0.100 g, 0.465 mmol) and 2-amino- 6-bromonaphthalene (0.103 g, 0.465 mmol) in CH 2 CI 2 (6 mL) was treated with HATU (0.177 g, 0.465 mmol) in the presence of DIPEA (0.12 mL, 0.929 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.191 g, 98%).
  • Step l-364b A mixture of the compound from step l-364a (30.0 mg, 71.5 ⁇ ), the compound from step l-348d (34.5 mg, 78.6 ⁇ ) and NaHC0 3 (24.0 mg, 0.286 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (4.0 mg, 3.5 ⁇ ). The resultant mixture were degassed and heated to 95°C under N 2 for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-367a To a suspension of trans- 1 ,2-cyclopentanediamine dihydrochloride
  • Step l-367b A mixture of the crude compound from step l-367a (0.578 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 101.2 mg, 0.578 mmol) in DMF (3 mL) was treated with HATU (0.220 g, 0.578 mmol) in the presence of DIPEA (1.00 mL, 5.778 mmol) for 1 hours at room temperature and the volatiles were evaporated off. The residue was taken up in
  • Step l-367c A mixture of compound from step l-367b (17.0 mg, 34.9 ⁇ ), the compound from step 352f (17.2 mg, 34.9 ⁇ ), Pd(PPh 3 ) 4 (4.0 mg, 3.49 ⁇ ) and NaHC0 3 (10.3 mg, 0.122 mmol) in DME (2.1 mL) and H 2 0 (0.7 mL) was degassed and heated at 97 °C under N 2 for 15 hours. The mixture was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-368b A mixture of compound from step l-368a (45.0 mg, 0.105 mmol), the compound from step l-348d (46.0 mg, 0.105 mmol), Pd(PPh 3 ) 4 (12.1 mg, 10.5 ⁇ ) and NaHC0 3 (30.8 mg, 0.366 mmol) in DME (3 mL) and H 2 0 (1 mL) was degassed and heated at 97°C under N 2 for 15 hours. The mixture was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-369a A solution of the compound of example 1-368 (63.2 mg, 0.103 mmol) in 1,4-dioxane (1.25 mL) was treated with C1 in 1,4-dioxane (4 M, 5 mL) at 30°C for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.
  • Step l-368b A mixture of the crude compound from step l-369a (0.103 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 36.0 mg, 0.205 mmol) in DMF (3 mL) was treated with HATU (74.1 mg, 0.195 mmol) in the presence of DIPEA (0.36 mL, 2.053 mmol) for 30 minutes at rt and the volatiles were evaporated off.
  • Step l-370b A mixture of the compound from step l-362c (0.250 g, 0.605 mmol), 1- bromo-4-iodobenzene (0.257 g, 0.908 mmol), NaHC0 3 (0.203 g, 2.42 mmol) and
  • Step l-370c To a mixture of the compound from step l-370b (50.0 mg, 0.113 mmol), bis-(pinacolato)-diboron (35.9 mg, 0.141 mmol), potassium acetate (22.2 mg, 0.226 mmol) in DMSO (2 mL) was added PdCl 2 (dppf) 2 (9.2 mg, 11.3 ⁇ ). The resulting solution was degased and then heated at 80 °C under N 2 overnight before being partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-370d A mixture of compound from step l-370a (32.0 mg, 74.4 ⁇ ), the compound from step l-370c (36.4 mg, 74.4 ⁇ ), Pd(PPh 3 ) 4 (8.6 mg, 7.4 ⁇ ) and NaHC0 3 (21.9 mg, 0.260 mmol) in DME (2.1 mL) and H 2 0 (0.7 mL) was degassed and heated at 97 °C under N 2 for 15 hours. The mixture was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-371a A solution of the compound of example 1-370 (31.7 mg, 47.6 ⁇ ) in 1,4- dioxane (1 mL) was treated with C1 in 1,4-dioxane (4 M, 4 mL) at 30 °C for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.
  • Step l-371b A mixture of the crude compound from step 1-37 la (47.6 ⁇ at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 16.7 mg, 95.2 ⁇ ) in DMF (3 mL) was treated with HATU (34.4 mg, 90.5 ⁇ ) in the presence of DIPEA (0.17 mL, 0.952 mmol) for 30 minutes at rt and the volatiles were evaporated off.
  • Step l-372a A mixture of (5)-3-(Boc-amino)pyrrolidine (0.150 g, 0.805 mmol) and (S)- 2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO
  • Step l-372b A solution of the compound from step l-372a (0.680 g, 0.805 mmol at most) in 1,4-dioxane (1.5 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) at rt for 1 hours. The volatiles were evaporated off to give the crude desired compound as a yellow oil, which was used directly in the next step.
  • ESIMS m/z 244.17 [M+H] + .
  • Step l-372d A mixture of compound from step l-372c (30.0 mg, 63.4 ⁇ ), the compound from step l-352f (40.9 mg, 82.4 ⁇ ), Pd(PPh 3 ) 4 (7.3 mg, 6.34 ⁇ ) and NaHC0 3 (21.3 mg, 0.254 mmol) in DME (3 mL) and H 2 0 (1 mL) was degassed and heated at 98 °C under N 2 for 2.5 hours. The mixture was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et 3 N and 20% MeOH in EtOAc) to give the title compound as a light brown solid (42.7 mg, 94%).
  • Step l-373a A mixture of (i?)-N-Boc-pyrrolidine-3-carboxylic acid (1.000 g, 4.646 mmol) and 4-bromoaniline (0.799 g, 4.646 mmol) in CH 2 CI 2 (20 mL) was treated with HATU (1.766 g, 4.646 mmol) in the presence of DIPEA (1.62 mL, 9.292 mmol) for 1 hours at rt and the volatiles were evaporated off. The residue was purified by
  • Step l-373b A mixture of compound from step l-373a (0.100 g, 0.271 mmol), the compound from step l-348d (0.131 g, 0.298 mmol), Pd(PPh 3 ) 4 (31.2 mg, 27.1 ⁇ ) and NaHC0 3 (91.0 mg, 1.083 mmol) in DME (3 mL) and H 2 0 (1 mL) was degassed and heated at 97°C under N 2 for 15 hours. The mixture was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-374a A solution of the compound of example 1-373 (0.111 g, 0.184 mmol) in 1,4- dioxane (2 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) at room temperature for 1 hour. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.
  • Step l-374b A mixture of the crude compound from step l-374a (0.184 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 64.6 mg, 0.369 mmol) in DMF (4 mL) was treated with HATU (0.133 g, 0.351 mmol) in the presence of DIPEA (0.64 mL, 3.689 mmol) for 1 hour at room temperature and the volatiles were evaporated off. The residue was purified by
  • Step l-375a A mixture of trans-aminocyclopentanol hydrochloride (racemic, 0.100 g, 0.727 mmol) and 4-iodobenzoic acid (0.180 g, 0.727 mmol) in CH 3 CN (10 mL) was treated with HATU (0.276 g, 0.727 mmol) in the presence of DIPEA (1.27 mL, 7.266 mmol) for 30 minutes at rt and the volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate with 1% EtOH) to give the desired compound as a white solid (0.226 g, 94%).
  • ESIMS m/z 332.04 [M+H] + .
  • Step l-375b A mixture of compound from step l-375a (45.0 mg, 0.136 mmol), the compound from step l-348d (46.0 mg, 0.105 mmol), Pd(PPh 3 ) 4 (15.7 mg, 13.6 ⁇ ) and NaHC0 3 (45.7 mg, 0.544 mmol) in DME (3 mL) and H 2 0 (1 mL) was degassed and heated at 97°C under N 2 for 15 hours. The mixture was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step l-376a A solution of the compound of example 1-375 (54.2 mg, 0.105 mmol) in 1,4-dioxane (1.25 mL) was treated with C1 in 1,4-dioxane (4 M, 5 mL) at room temperature for 1 hour. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.
  • Step l-376b A mixture of the crude compound from step l-376a (0.103 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 36.8 mg, 0.210 mmol) in DMF (4 mL) was treated with HATU (37.9 mg, 0.100 mmol) in the presence of DIPEA (0.18 mL, 1.049 mmol) for 15 minutes at rt and the volatiles were evaporated off.
  • HATU 37.9 mg, 0.100 mmol
  • Step l-378a A mixture of (5)-N-Boc-pyrrolidine-3-carboxylic acid (80.0 mg, 0.372 mmol) and 2-amino-5-bromopyridine (64.3 mg, 0.372 mmol) in CH 2 CI 2 (3 mL) was treated with HATU (0.141 g, 0.372 mmol) in the presence of DIPEA (0.13 mL, 0.743 mmol) for 1 hours at rt. More (5)-N-Boc-pyrrolidine-3-carboxylic acid (40.0 mg, 0.186 mmol), DIPEA (0.065 mL, 0.372 mmol) and HATU (70.5 mg, 0.186 mmol) were added.
  • Step l-378b A mixture of compound from step l-378a (48.0 mg, 0.130 mmol), the compound from step l-370c (62.7 mg, 0.143 mmol), Pd(PPh 3 ) 4 (15.0 mg, 13.0 ⁇ ) and NaHC0 3 (38.1 mg, 0.454 mmol) in DME (3 mL) and H 2 0 (1 mL) was degassed and heated at 97°C under N 2 for 15 hours. The volatiles were evaporated off. The residue was purified by chromatography (silica, hexanes-ethyl acetate, with 1% Et 3 N in EtOAc) to give the title compound as a yellow solid (61.8 mg, 79%).
  • ESIMS m/z 603.15 [M+H] + .
  • Step l-379a A solution of the compound of example 1-378 (61.8 mg, 0.102 mmol) in 1,4-dioxane (1 mL) was treated with C1 in 1,4-dioxane (4 M, 4mL) at room temperature for 1.5 hours. The volatiles were evaporated off to give the crude desired compound as a yellow solid, which was used directly in the next step.
  • Step l-379b A mixture of the crude compound from step l-379a (0.102 mmol at most) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 35.9 mg, 0.205 mmol) in DMF (2 mL) was treated with HATU (74.1 mg, 0.195 mmol) in the presence of DIPEA (0.36 mL, 2.051 mmol) for 15 minutes at room temperature and the volatiles were evaporated off.
  • Step l-381a Into a mixture of (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 90 mg, 0.5 mmol) and (R)-tert-butyl 2- (aminomethyl)pyrrolidine-1-carboxylate (100 mg, 0.50 mmol) in acetonitrile (2 mL) was added diisopropylethylamine (0.11 mL, 0.6 mmol) and HATU (200 mg, 0.55 mmol). The resulting mixture was stirred at room temperature for 1 hour before being partitioned between water and EtOAc. The organic phase was separated, dried (Na 2 S0 4 ) and concentrated to afford a brown slurry, which was purified by flash column
  • Step l-381b Into a mixture of compound firm step l-381a (144 mg, 0.4 mmol) was added hydrochloric acid in 1,4-dioxane (4M, 2 mL). The resulting mixture was stirred at room temperature for 1 hour before all volatiles were removed to afford the crude desired compound, which was used directly for the next step without further purification.
  • ESIMS m/z 258.28 [M+H] + .
  • Step l-381c The title compound was prepared from 4-iodobenzoic acid and the compound from step l-348d using procedures similar to that described in example 1-348.
  • ESIMS m/z 730.45 [M+H] + .
  • Examples 2-1 to 2-293 may be prepared using procedures similar to those described in examples 2-294 and 2-295 (described below), and/or as described in the Synthetic Methods.
  • Step 2-294a A mixture of l-Boc-pyrrolidine-3-carboxylic acid (0.100 g, 0.465 mmol) and 4-bromoaniline (79.9 mg, 0.465 mmol) in CH 2 CI 2 (6 mL) was treated with HATU (0.177 g, 0.465 mmol) in the presence of DIPEA (0.12 mL, 0.929 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a colorless oil (0.156 g, 91%).
  • Step 2-294b A mixture of the compound from step 2-294a (0.184 g, 0.499 mmol), bis- (pinacolato) diboron (0.253 g, 0.997 mmol) and potassium acetate (0.122 g, 1.25 mmol) in 1,4-dioxane (8 mL) was added Pd(PPh 3 ) 4 (28.8 mg, 24.9 ⁇ ). The resultant mixture were degassed for three times and heated up to 85°C under N 2 for 13 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water).
  • Step 2-294c A mixture of the compound from step 2-294a (30.0 mg, 81.3 ⁇ ), the compound from step 2-294b (40.6 mg, 97.5 ⁇ ) and NaHC0 3 (27.3 mg, 0.325 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (4.6 mg, 4.0 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 16 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 2-295a A solution of the compound from example 2-294 (23.5 mg, 40.6 ⁇ ) in CH 2 C1 2 (4 mL) was treated with C1 in 1 ,4-dioxane (4 M, 3 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 379.35 [M+H] + .
  • Step 2-295b A mixture of the crude compound from step 2-295 a (40.6 ⁇ at most) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step 3-336a A mixture of 2,4'-dibromoacetophenone (1.00 g, 3.60 mmol) and trans (+/-) 2-(fert-butoxycarbonylamino)-cyclopentanecarboxylic acid (0.825 g, 3.60 mmol) in CH 3 CN (12 mL) was added DIPEA (0.94 mL, 7.55 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-336c A mixture of 2,4'-dibromoacetophenone (5.00 g, 18.0 mmol) and N-Boc-L- proline (3.87 g, 18.0 mmol) in CH 3 CN (60 mL) was added TEA (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-336d A solution of the compound from step 3-336c (6.73 g, 16.3 mmol) in toluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol) and the resultant mixture was heated up to 100°C for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - aq. NaHC0 3 ). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a yellow foam (6.10 g, 95%).
  • Step 3-336e A mixture of the compound from step 3-336d (1.00 g, 2.55 mmol), bis-
  • Step 3-336f A mixture of the compound from step 3_ 336b (0.315 g, 0.777 mmol), the compound from step 3 ⁇ 3366 (0.310 g, 0.706 mmol) and NaHC0 3 (0.237 g, 2.82 mmol) in DME (12 mL) and H 2 0 (4 mL) was added Pd(PPh 3 ) 4 (40.8 mg, 35.3 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-337a A solution of the compound of example 3-336 (80.0 mg, 0.125 mmol) in CH 2 C1 2 (3 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 439.23 [M+H] + .
  • Step 3-337b A mixture of the crude compound from step 3 ⁇ 337a (theo 0.125 mmol) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step 3-338a A mixture of N-Boc-L-proline (5.754 g, 26.7 mmol) and TEA (3.73 mL, 26.7 mmol) in THF (60 mL) at -20°C was treated with ethyl chloroformate (2.55 mL, 26.7 mmol) for 30 minutes before a slow addition of 4-bromo-1,2-diaminobenzene (5.00 g, 26.7 mmol) in THF (20 mL). It was then kept at -20 °C for 1 hour and then slowly warmed up to rt and stirred at rt overnight. The volatiles were evaporated and the residue was partitioned (EtOAc - water).
  • Step 3-338c A mixture of the compound from 3_ 2 338b (0.559 g, 1.425 mmol), trimethylsilyl acetylene (0.60 ml, 4.275 mmol), Cul (28.5 mg, 0.150 mmol) and
  • Step 3-338e A mixture of the compound from step 3 ⁇ 336b (150 mg, 0.369 mmol), the compound from step 3 ⁇ 338(1 (127 mg, 0.406 mmol) in Et 3 N (4 mL) and CH 3 CN (4 mL) were added Cul (2.1 mg, 11.0 ⁇ ) and Pd(PPh 3 ) 4 (21.3 mg, 18.4 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-339a A solution of the compound of example 3 ⁇ 338 (0.137 g, 0.215 mmol) in CH 2 C1 2 (3 mL) was treated with C1 in 1,4-dioxane (4 M, 6 mL) for 30 min. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step.
  • ESIMS m/z 437.20 [M+H] + .
  • Step 3-339b A mixture of the crude compound from step 3_-339a (theo 0.215 mmol) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step 3-340a A mixture of the compound from step 3_ 338b (1 g, 2.73 mmol), bis- (pinacolato)-diboron (763 mg, 3.0 mmol), potassium acetate (402 mg, 4.0 mmol) in 1,4- dioxane (9.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.14 mmol). The resulting solution was degased and then heated at 80°C under N 2 overnight before being evaporated.
  • Step 3-340b A mixture of the compound from step 3 2 338b (0.100 g, 0.246 mmol), the compound from step 3-340a (0.102 g, 0.246 mmol) and NaHC0 3 (82.8 mg, 0.985 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (14.2 mg, 12.3 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 20 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-341b A mixture of the crude compound from step 3-34 la (theo 0.183 mmol) and (S)-(methoxycarbonyl)amino-3 -methyl-butyric acid (prepared according to WO
  • Step 3-342a A mixture of l-Boc-pyrrolidine-3-carboxylic acid (0.159 g, 0.739 mmol), 4-bromo-1,2-diaminobenzene (0.142 g, 0.739 mmol) in DMF (6 mL) were added
  • Step 3-342c A mixture of the compound from step 3 ⁇ 342b (30.2 mg, 82.5 ⁇ ), the compound from step 3 ⁇ 3366 (36.2 mg, 82.5 ⁇ ) and NaHCOs (27.7 mg, 0.330 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (4.7 mg, 4.1 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-344a A mixture of 2,4'-dibromoacetophenone (0.258 g, 0.929 mmol) and 1-Boc- pyrrolidine-3-carboxylic acid (0.200 g, 0.929 mmol) in CH3CN (9 mL) was added DIPEA (0.23 mL, 1.86 mmol) slowly. The mixture was stirred at room temperature until the disappearence of the starting material. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-344c A mixture of the compound from step 3-344b (0.115 g, 0.293 mmol), bis- (pinacolato) diboron (0.149 g, 0.587 mmol) and potassium acetate (71.8 mg, 0.733 mmol) in 1,4-dioxane (8 mL) was added Pd(PPh 3 ) 4 (16.9 mg, 14.6 ⁇ ). The resultant mixture were degassed for three times and heated up to 85°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - water). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-344f A mixture of the compound from step 3-344c (30.0 mg, 68.3 ⁇ ), the compound from step 3 ⁇ 3446 (30.0 mg, 68.3 ⁇ ) and NaHC0 3 (22.9 mg, 0.273 mmol) in DME (6 mL) and H 2 0 (2 mL) was added Pd(PPh 3 ) 4 (3.9 mg, 3.4 ⁇ ). The resultant mixture were degassed and heated to 85°C under N 2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.
  • Step 3-346a To a solution of Boc-trans-2-aminocyclopentane carboxylic acid (racemic, 0.350 g, 1.526 mmol) in THF (8 mL) at 0°C was added iodomethane (0.76 mL, 12.21 mmol), followed by NaH (60% in mineral oil, 0.244 g, 6.106 mmol). The milky solution was stirred at 0°C for 15 minutes and then at room temperature for 3 hours before being quenched carefully with H 2 0. The volatiles were evaporated. The residue was diluted with H 2 0, washed with Et 2 0 (* 1). The aqueous layer was acidified with citric acid to pH ⁇ 3, extracted with dichloromethane.
  • Step 3-346d A mixture of compound from step 3-346c (89.0 mg, 0.212 mmol), the compound from step 3 ⁇ 3366 (93.0 mg, 0.212 mmol), Pd(PPh 3 ) 4 (24.5 mg, 21.2 ⁇ ) and NaHC0 3 (62.3 mg, 0.741 mmol) in DME (3 mL) and H 2 0 (1 mL) was degassed and heated at 98°C under N 2 for 15 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H 2 0). The organics were washed with brine, dried (Na 2 S0 4 ), filtered and evaporated.

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Abstract

Cette invention concerne des composés ou leurs sels, esters ou promédicaments pharmaceutiquement acceptables, qui inhibent les virus à ARN, en particulier le virus de l'hépatite C (VHC). Les composés de l'invention agissent donc sur le cycle de vie du virus de l'hépatite C et sont aussi utilisés en tant qu'agents antiviraux. L'invention concerne par ailleurs des compositions pharmaceutiques comprenant lesdits composés à administrer à un sujet infecté par le VHC. L'invention concerne des méthodes de traitement d'une infection à VHC chez un sujet, par administration d'une composition pharmaceutique comprenant les composés de l'invention. L'invention concerne également de nouveaux composés antiviraux indiqués ci-dessus, des compositions pharmaceutiques comprenant ces composés et des méthodes de traitement ou de prophylaxie de l'infection virale (en particulier l'infection à VHC) chez un sujet.
EP10816134.0A 2009-09-11 2010-09-10 Inhibiteurs du virus de l'hépatite c Withdrawn EP2475254A4 (fr)

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US24157809P 2009-09-11 2009-09-11
US24159509P 2009-09-11 2009-09-11
US24161709P 2009-09-11 2009-09-11
US24148909P 2009-09-11 2009-09-11
US24157709P 2009-09-11 2009-09-11
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