ANTHRANILIC ACID DERIVATIVES USEFUL IN TREATING
INFECTION WITH HEPATITIS C VIRUS
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] This invention is directed to a series of anthranilic acid compounds that are
useful in the treatment of Hepatitis C viral infections.
Related Background Art
[0002] Hepatitis C is a common viral infection that can lead to chronic Hepatitis,
cirrhosis, liver failure, and hepatocellular carcinoma. Infection with the Hepatitis
C virus (HCV) leads to chronic Hepatitis in at least 85% of cases, is the leading
reason for liver transplantation, and is responsible for at least 10,000 deaths
annually in the United States (Hepatology, 1997, 26 (Suppl. 1), 2S-10S).
[0003] The Hepatitis C virus is a member of the Flaviviridae family, and the
genome of HCV is a single-stranded linear RNA of positive sense (Hepatology,

1997,26 (Suppl. 1), 11S-14S). HCV displays extensive genetic heterogeneity; at
least 6 genotypes and more than 50 subtypes have been identified.
[0004] There is no effective vaccine to prevent HCV infection. The only therapy
currently available is treatment with interferon-a (INF-α) or combination therapy
of INF-α with the nucleoside analog ribavirin (Antiviral Chemistry and
Chemotherapy, 1997, 8, 281-301). However, only about 40% of treated patients
develop a sustained response, so there is a need for more effective anti-HCV
therapeutic agents.
[0005] The HCV genome contains a number of non-structural proteins: NS2, NS3,
NS4A, NS4B, NS5A, and NS5B (J. General Virology, 2000, 81,1631-1648).
NS5B is an RNA-dependent RNA polymerase which is essential for viral
replication, and therefore, the inhibition of NS5B is a suitable target for the
development of therapeutic agents.
[0006] In US patent 5,741,926, aniline derivatives, including anthranilic acids, of
the below formula, are claimed and the compounds are stated to have
antihyperglycemic activity,

where R1, R2, R3, R4 and R5 are independently selected from the group
consisting of hydrogen, halogen, OR11, CX3, a C1-C6 alkyl group, (CH2)nCH2OH,
(CH2)nCO2R12- and (CH2)n-5-tetrazolyl, where one but not more than one of R1, R2,
R3, R4 or R5 is selected from the group consisting of (CH2)nCO2R12- and (CH2)n-5-
tetrazolyl; R11 and R12 are independently selected from the group consisting of
hydrogen and a C1-C6 alkyl group; X is a halogen; n is 0 or 1; R6, R7, R8, R9 and
R10 are independently selected from the group consisting of hydrogen, halogen,
OR13, SR14, C(Y)3, a C1-C6 alkyl group and phenyl; Y is halogen; A is C=O; and B
is selected from the group consisting of NH, oxygen and sulfur. This reference
does not teach or suggest that these compounds may be used to treat or prevent
Hepatitis C viral infections.

BRIEF SUMMARY OF THE INVENTION
[0007] The present invention is directed to compounds of formula (I):
wherein R1 is selected from the group consisting of-C(O)R6 and
wherein R6 and R7 are independently selected from H, C1-C12 alkyl, C3-C12
cycloalkyl, C1-C11 heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of which
may be optionally substituted, G is selected from H or hydroxyl, Y is O, NH or S,
X is selected from the group consisting of H, halo, C1-C12 alkyl, C3-C12 cycloalkyl,
C1-C12 perfluoroalkyl, C1-C12 alkoxy, C1-C12 alkylthio, amino, C1-C6 alkylamino,
C2-C12 dialkylamino, and CN, and n is 0, 1,2 or 3, or a prodrug, a pharmaceutically
acceptable salt, or a pharmaceutically active metabolite thereof.
[0008] This invention also includes the compounds of formula (H):



independently selected from C1-C6 alkyl, C3-C12 cycloalkyl, C1-C11
heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of which may be optionally
substituted, X is selected from the group consisting of H, halo, alkyl of 1 to 4
carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 6 carbon atoms, amino,
alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms, and CN,
and G is selected from H or hydroxyl, or a prodrug, a pharmaceutically acceptable
salt, or a pharmaceutically active metabolite thereof.
[0009] The present invention is also directed to the compounds of formula (III):

independently selected from C1-C6 alkyl, C3-C12 cycloalkyl, C1-C11
heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of which may be optionally
substituted, X is selected from the group consisting of H, halo, alkyl of 1 to 4
carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 6 carbon atoms, amino,
alkylamino 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, and CN, and

G is selected from H or hydroxyl, or a prodrug, a pharmaceutically acceptable salt,
or a pharmaceutically active metabolite thereof.
[0010] The present invention also includes compositions containing compounds of
formulas (I), (II) and (III), and methods of using these compounds and
compositions thereof to treat or prevent Hepatitis C virus infection, or to inhibit
replication of a Hepatitis C virus.
DETAILED DESCRIPTION OF THE INVENTION
[0011] For purposes of this invention the term "alkyl" includes both straight and
branched alkyl moieties, which can contain as many as 12 carbon atoms.
Preferably, the alkyl moiety contains between 1 to 6 carbon atoms, though 1 to 4
carbon atoms is more preferable. The term "cycloalkyl" refers to alicyclic
hydrocarbon groups having 3 to 12 carbon atoms, but more preferably contain 3 to
6 carbon atoms, and includes but is not limited to: cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, or adamantyl. These moieties may
be further substituted.
[0012] For the purposes of this invention the term "heterocycloalkyl" refers to a
non-aromatic heterocyclic ring system (monocyclic or bicyclic) where the moieties
contain 1 to 4 heteroatoms selected from the group consisting of S, N, and O, and
include but is not limited to: Pyrrolidine, pyrroline, 1,3-dioxolane, imidazoline,
imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, dioxane, morpholine,
dithioxane, thiomorpholine, piperazine, azetidinyl, hexahydroazepinyl,
dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl,
dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,
dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,
dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,
dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl,
dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydro-1,4-
dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl and indoline. A heterocycloalkyl moiety preferably
contains 1-11 carbon atoms. These moieties may be further substituted.

[0013] For purposes of this invention the term "aryl" is defined as an aromatic
hydrocarbon moiety and may be substituted or unsubstituted. An aryl group
preferably contains 6 to 12 carbon atoms and may be selected from, but not limited
to, the group: phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl,
acenaphthylenyl, or phenanthrenyl groups. An aryl group may be optionally mono-
, di-, tri- or tetra-substituted with substituents selected from, but not limited to, the
group consisting of alkyl, acyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, alkoxyalkoxy,
arylalkyl, alkylaryl, aryl, heteroaryl, heteroarylalkyl, cyano, halogen, hydroxy, nitro,
trifluoromethyl, trifluoromethoxy, trifiuoropropyl, amino, alkylamino,
dialkylamino, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, -SO3H, -
SO2NH2, -SO2NHalkyl, -SO2N(alkyl)2 , -CO2H, CO2NH2, CO2NHalkyl, and -
CO2N(alkyl)2. Preferred substituents for aryl moieties include: alkyl, alkoxy,
halogen, amino, alkylamino, dialkylamino, trifluoromethyl, and trifluoromethoxy.
[0014] For purposes of this invention the term "heteroaryl" is defined as an
aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl
moieties are five or six membered rings containing 1 to 4 heteroatoms selected
from the group consisting of S, N, and O, and include but is not limited to: (1)
furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole,
imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-
methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-
methyl-l,2,4-triazole, 1 H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole,
benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole,
azabenzimidazole, indazole, quinazoline, quinoline, pyrrolidinyl; (2) a bicyclic
aromatic heterocycle where a phenyl, pyridine, pyrimidine or pyridizine ring is: (i)
fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one
nitrogen atom; (ii) fused to a 5 or 6-membered aromatic (unsaturated) heterocyclic
ring having two nitrogen atoms; (iii) fused to a 5-membered aromatic (unsaturated)
heterocyclic ring having one nitrogen atom together with either one oxygen or one
sulfur atom; or (iv) fused to a 5-membered aromatic (unsaturated) heterocyclic ring
having one heteroatom selected from O, N or S. Preferably a heterocyclic group
contains 2 to 9 carbon atoms. These moieties may be further substituted from
substituents selected from the group consisting of alkyl, acyl, alkoxycarbonyl,

alkoxy, alkoxyalkyl, alkoxyalkoxy, arylalkyl, alkylaryl, aryl, heteroaryl,
heteroarylalkyl, cyano, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy,
trifluoropropyl, amino, alkylamino, dialkylamino, dialkylaminoalkyl, hydroxyalkyl,
alkoxyalkyl, alkylthio, -SO3H, -SO2NH2, -SO2NHalkyl, -SO2N(alkyl)2 , -CO2H,
CO2NH2, CO2NHalkyl, and -CO2N(alkyl)2. Preferred substituents for heteroaryl
moieties include: alkyl, alkoxy, halogen, amino, alkylamino, dialkylamino,
trifluoromethyl, and trifluoromethoxy. Preferably a heteroaryl moiety contains 1 to
9 carbon atoms.
[0015] For the purposes of this invention the term "alkoxy" is defined as C1-C6-
alkyl-O-; the term "aryloxy" is defined as aryl-O-; the term "heteroaryloxy" is
defined as heteroaryl-O; wherein alkyl, aryl, and heteroaryl are as defined above.
[0016] For purposes of this invention the term "arylalkyl" is defined as aryl-C1-C6-
alkyl-; arylalkyl moieties include benzyl, 1-phenylethyl, 2-phenylethyl, 3-
phenylpropyl, 2-phenylpropyl and the like.
[0017] For purposes of this invention the term "alkylaryl" is defined as C1-C6-
alkyl-aryl, such as a tolyl group.
[0018] For purposes of this invention the term "alkylthio" is defined as C1-C6-
alkyl-S-. For the purpose of this invention the terms "thio" and mercapto" refer to
a -SH group.
[0019] For purposes of this invention "alkylthioalkyl," and "alkyloxyalkyl," denote
an alkyl group as defined above that is further substituted with an alkoxy or
alkylthio as defined above.
[0020] For purposes of this invention "arylthio" and "heteroarylthio," denote a thio
group that is further substituted with an aryl or heteroaryl group as defined above.
[0021] The terms "alkylamino" and "dialkylamino" refer to moieties with one or
two alkyl groups wherein the alkyl chain is 1 to 6 carbons or 1 to 4 carbons and the
groups may be the same or different. The term "aminoalkyl" refer to an alkyl
group, as defined herein, which is further substituted with an amino group. The
terms "monoalkylaminoalkyl" and "dialkylaminoalkyl" refer to monoalkylamino
and dialkylamino moieties with one or two alkyl groups (the same or different)
bonded to the nitrogen atom which is attached to an alkyl group of 1 to 6 carbon
atoms.

[0022] "Acyl" is a radical of the formula -(C=O)-alkyl or-(C=O)-perfluoroalkyl
wherein the alkyl radical or perfluoroalkyl radical is 1 to 6 carbon atoms; preferred
examples include, but are not limited to, acetyl, propionyl, butyryl, and
trifluoroacetyl.
[0023] For purposes of this invention the term "alkylsulfinyl" is defined as a R'SO-
radical, where R' is an alkyl radical of 1 to 6 carbon atoms. Alkylsulfonyl is a
R'SO2- radical, where R' is an alkyl radical of 1 to 6 carbon atoms.
[0024] For purposes of this invention the term "haloalkyl" is defined as an alkyl
group, as defined herein, which has been substituted with at least one halogen
atom. This moiety may also be fully substituted by halogen atoms, such as a
trifluoromethyl group.
[0025] For purposes of this invention the term "perfluoroalkyl" is defined as an
alkyl group, as defined herein, which has been fully substituted with fluorine
atoms, and thus, is defined by the formula -CnF2+1- Examples include -CF3 and -
CF2CF3.
[0026] For purposes of this invention the term "hydroxyalkyl" is defined as an
alkyl group, as defined herein, which has been substituted with at least one hydroxy
group.
[0027] For purposes of this invention the terms "haloalkoxy" and "haloalkylthio"
are defined as an alkoxy or alkylthio group, as defined herein, further substituted
by at least one halo atom.
[0028] For purposes of this invention the terms "alkoxyalkoxy" and
"alkylthioalkoxy" are defined as an alkoxy group further substituted by another
alkoxy group, such as CH3-O-CH2CH2-O-, or an alkylthio group. For purposes of
this invention the terms "alkoxyalkylthio" and "alkylthioalkylthio" are defined as
an alkylthio group further substituted by another alkoxy group or an alkylthio
group.
[0029] For purposes of this invention the term "oxo" is defined as a carbonyl group
(i.e. C=O).
[0030] The term "substituent" is used herein to refer to an atom radical, a
functional group radical or a moiety radical that replaces a hydrogen radical on a
molecule. Unless expressly stated otherwise, it should be assumed that any of the
moieties described herein may be optionally substituted with one or more groups

selected from: alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, nitro,
amino, hydroxy, cyano, aminoalkyl, alkylamino, dialkylamino,
monoalkylaminoalkyl, dialkylaminoalkyl, alkoxy, haloalkoxy, alkoxyalkyl,
alkoxyalkoxy, alkylthioalkoxy, alkoxyalkylthio, alkylthioalkylthio, oxo, alkylthio,
-SH, haloalkylthio, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio,
acyl, -CO2-alkyl, -SO3H, -SO2NH2, -SO2NH-alkyl, -SO2NH-(alkyl)2, -CO2H, -
CO2NH2, -CO2NH-alkyl and -CO2N-(alkyl)2.
[0031] For the purposes of this invention the term "substituted" refers to where a
hydrogen radical on a molecule has been replaced by another atom radical, a
functional group radical or a moiety radical; these radicals being generally referred
to as "substituents."
[0032] The compounds of this invention may contain an asymmetric carbon atom
and may thus give rise to stereoisomers, such as enantiomers and diastereomers.
The stereoisomers of the instant invention are named according to the Cahn-
Ingold-Prelog System. While shown without respect to stereochemistry in
formulas (I), (II) and (III), the present invention includes all the individual possible
stereoisomers; as well as the racemic mixtures and other mixtures of R and S
stereoisomers (scalemic mixtures which are mixtures of unequal amounts of
enantiomers) and prodrugs, pharmaceutically acceptable salts and pharmaceutically
active metabolites thereof. It should be noted that stereoisomers of the invention
having the same relative configuration at a chiral center may nevertheless have
different R and S designations depending on the substitution at the indicated chiral
center.
[0033] An embodiment of the present invention is where the compound of formula
(I) is defined by R6 and R7 being independently selected from H, C1-C6 alkyl, C3-
C12 cycloalkyl, C1-C11 heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of
which may be optionally substituted, X is selected from the group consisting of H,
halo, C1-C6 alkyl, C3-C12 cycloalkyl, C1-C11 heterocycloalkyl, C1-C6 perfluoroalkyl,
C1-C6 alkoxy, C1-C6 alkylthio, amino, C1-C6 alkylamino, C2-C12 dialkylamino, and
CN, and optional substituents are selected from the group consisting of C1-C6
alkyl, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, nitro, amino, hydroxy, cyano,
C1-C6 alkylamino, C2-C12 dialkylamino, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C12
alkoxyalkyl, C2-C12 alkoxyalkoxy, oxo, C1-C6 alkylthio, mercapto, C1-C6

haloalkylthio, C6-C12 aryl, C6-C12 aryloxy, C6-C12 arylthio, C2-C9 heteroaryl,
C2-C9 heteroaryloxy, C2-C9 heteroarylthio, acyl, -CO2-C1-C6 alkyl, -SO3H, -
SO2NH2, -SO2NH-C1-C6 alkyl, -SO2NH-(C1-C6 alkyl)2, -CO2H, -CO2NH2, -
CO2NH- C1-C6 alkyl and -CO2N-(C1-C6 alkyl)2.
[0034] Another embodiment of the compounds of formula (I) is wherein Y is O or
NH and X is selected from the group consisting of H, halo, C1-C4 alkyl, C1-C4
alkoxy, and C1-C44 haloalkyl.
[0035] A more specific embodiment of the compounds of formula (I) is wherein n
is 0, 1, or 2, and G is H. Another specific embodiment is wherein R6 and R7
(when present) are C1-C4 alkyl, wherein methyl is preferable, Y is NH. Another
more specific embodiment is wherein n is 2 and X is halo, preferably Cl or F.
Especially more preferable is wherein one X is Cl and the other X is F.
[0036] A embodiment of the compounds of formula (II) is wherein R6 and R7 are
independently selected from H, C1-C6 alkyl, C3-C12 cycloalkyl, or C6-C12 aryl, any
of which may be optionally substituted, though it is more preferred that R6 or R7 be
C1-C4 alkyl.
[0037] Another embodiment of the compounds of formula (II) is wherein G is H.
Another embodiment of the compound of formula (II) is wherein X is selected
from the group H, halo, C1-C4 alkyl, C1-C4 perfluoroalkyl and C1-C4 alkoxy, with
X being halo the most preferred. A more specific embodiment is where in n is 0,1,
or 2, and the most specific embodiments are where the compound of formula (II) is
either -{[N-(2-acetyl-5-chloro-4-fluorophenyl)glycyl]amino}benzoic acid or 2-(2-([5-
chloro-4-fluoro-2-(1-methoxyimino-ethyl)-phenylamino]acetylamino} benzoic acid.
[0038] An embodiment of the compounds of formula (III) is wherein R6 and R7 are
independently selected from H, C1-C6 alkyl, C3-C12 cycloalkyl, or C6-C12 aryl, any
of which may be optionally substituted, though it is more preferred that R6 or R7 be
C1-C4 alkyl.
[0039] A more specific embodiment of the compounds of formula (III) is wherein
G is H. Another embodiment of the compound of formula (III) is wherein X is
selected from the group H, halo, C1-C4 alkyl, C1-C4 perfluoroalkyl and C1-C4
alkoxy, with X being halo the most preferred. A more specific embodiment is
where in n is 1,2, or 3 and at least one X is halo, though it more preferable that n
be 1 or 2.

[0040] Preferred compounds of this invention are:
2-{[N-(6-acetyl-l,3-benzodioxol-5-yl)glycyl]amino}benzoic acid;
2-({[N-[2-acetyl-4-chloro-5-(methylthio)phenyl]glycyl}amino) benzoic acid;
2-({[N-[2-acetyl-4-chloro-5-(dimetheylamino)phenyl]glycyl} amino)benzoic
acid;
2-({[N-[2-acetyl-4-chloro-5-(methylamino)phenyl]glycyl}amino) benzoic acid;
2-{[N-(2-acetyl-5-chloro-4-fluorophenyl-N-methylglycyl] amino } benzoic acid;
2-({[N-[2-acetyl-4-chloro-5-(methylsulfinyl)phenyl]glycyl}amino) benzoic acid;
2-{[N-(2-acetylphenyl)glycyl]amino}benzoic acid;
2-{[N-(5-chloro-4-methyl-2-propionylphenyl)glycy]amino} benzoic acid;
2-{[N-(2-acetyl-4,5-dimethylphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4-bromo-5-choloro phenyl)glycyl]amino}benzoic acid;
2-{[N-(5-chloro-4-fluoro-2-propionylphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4,5-difluorophenyl)glycyl]amino}benzoic acid;
2-{[N-(2-aceryl-4-chloro-5-ethoxyphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4-chloro-5-fluorophenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4,5-dichlorophenyl)glycyl]amino}benzoicacid;
2-{[N-(2-acetyl-4-chloro-5-methoxyphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4-fluoro-5-methylphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-5-chloro-4-fluorophenyl)glycyl]amino}benzoic acid;
2-{[N-(4-chloro-2-propionylphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4-chlorophenyl)glycyl]amino}benzoic acid;
2-(2-([5-chloro-4-fluoro-2-(l-methoxyimino-ethyl)-phenylamino]-acetylamino}-
benzoic acid;
2-({[4,5-dimethyl-2-(trifluoroacetyl)phenoxy]acetyl}amino} benzoic acid;
2-{[(2-acetyl-4,5-dimethoxyphenoxy)acetyl]amino}benzoic acid;
2-[2-(2-acetyl-5-methylphenoxy)acetylamino]-benzoic acid;
2-{[(2-acetyl-4-ethylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4-methylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-5-fluorophenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-5-methoxyphenoxy)acetyl]amino}benzoic acid;
2- {[(2-acetyl-5-chlorophenoxy)acetyl]amino}benzoic acid;
2- {[(2-benzoyl4-methylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acety]-4,5-dimethylphenoxy)acetyl]amino}-5-hydroxybenzoic acid;
2- {[(2-acetyl-4,5-dimethylphenoxy)acetyl]amino}benzoic acid;

2-{[(2-isobutyryl-4,5-dimethylphenoxy)acetyl]amino}benzoic acid;
2- {[(2-acetyl-5-ethylphenoxy)acetyl]amino}benzoic acid;
2-{[(4,5-dimethyl-2-pentanoyphenoxy)acetyl]amino}benzoic acid;
2-{[(2-butyiyl-4,5-dimethylphenoxy)acetyl]amino}benzoic acid;
2-{[(4,5-dimethyl-2-propionyphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4-chloro-5-fluorophenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-5-chloro-4-fluorophenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4-fluoro-5-methylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4,5-difluorophenoxy)acetyl]amino}benzoic acid;
2-{[(4-chloro-2-propionylphenoxy)acetyl]amino} benzoic acid
2-{[(2-acetyl-4-chloro-5-methylphenoxy)acetyl]amino}benzoic acid
2-{[(2-acetyl-4-fluorophenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4-chlorophenoxy)acetyl]amino}benzoic acid;
2-{[N-(2-acetyl-4-bromophenyl)glycyl]amino}benzoic acid; and
2-{[(2-acetyl-4-ethyl-3-hydroxphenoxy)acetyl]amino}benzoic acid.
[0041] The inventive compounds are acids and a desired salt may be prepared by
any suitable method known to the art, including treatment of the free acid with an
inorganic or organic base, such as an amine (primary, secondary, or tertiary); an
alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of
suitable salts include organic salts derived from amino acids such as glycine and
arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines,
such as piperidine, morpholine, and piperazine; as well as inorganic salts derived
from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,
aluminum, and lithium.
[0042] If an inventive compound is a base, a desired salt may be prepared by any
suitable method known in the art, including treatment of the free base with an
inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid,
maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,
oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid
or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino
acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or

cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,
or the like.
[0043] A "prodrug" is intended to mean a compound that is converted under
physiological conditions or by solvolysis or metabolically to a specified compound
that is pharmaceutically active. A prodrug may be a derivative of one of the
compounds of this invention that contains a moiety, such as for example -CO2R, -
PO(OR)2 or -C=NR, that may be cleaved under physiological conditions or by
solvolysis. Any suitable R substituent may be used that provides a
pharmaceutically acceptable solvolysis or cleavage product. A prodrug containing
such a moiety may be prepared according to conventional procedures by treatment
of a compound of this invention containing, for example, an amido, carboxylic
acid, or hydroxyl moiety with a suitable reagent. A "pharmaceutically active
metabolite" is intended to mean a pharmacologically active compound produced
through metabolism in the body of a specified compound. Prodrugs and active
metabolites of compounds of this invention of the above-described Formulas may
be determined using techniques known in the art, for example, through metabolic
studies. See, e.g., "Design of Prodrugs," (Bundgaard, ed.), 1985, Elsevier
Publishers B.V., Amsterdam, The Netherlands. A "pharmaceutically acceptable
salt" is intended to mean a salt that retains the biological effectiveness of the free
acids and bases of a specified compound and that is not biologically or otherwise
undesirable. Examples of pharmaceutically acceptable salts include sulfates,
pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates,
dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides,
iodides, acetates, propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates,
suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates,
benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates,
phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates,
glycollates, tartrates, methane-sulfonates (mesylates), propanesulfonates,
naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. In the case of
compounds or salts that are solids it is understood by those skilled in the art that

the inventive compounds or salts may exist in different crystal forms, all of which
are intended to be within the scope of the present invention and specified formulas.
[0044] In one embodiment, the present invention also provides for a method of
inhibiting the Hepatitis C RNA-dependent RNA polymerase NS5B. The method
comprises contacting a cell with an amount of a compound of formulas (I), (II) or
(III) effective to decrease or prevent NS5B function. The cell may be a mammalian
cell and more specifically a human cell. The cell may also be a bacterial cell such
as for example E coli. The cell may include but is not limited to, a neuronal cell,
an endothelial cell, a glial cell, a microglial cell, a smooth muscle cell, a somatic
cell, a bone marrow cell, a liver cell, an intestinal cell, a germ cell, a myocyte, a
mononuclear phagocyte, an endothelial cell, a tumor cell, a lymphocyte cell, a
mesangial cell, a retinal epithelial cell, a retinal vascular cell, a ganglion cell or a
stem cell. The cell may be a normal cell, an activated cell, a neoplastic cell, a
diseased cell, or an infected cell.
[0045] The present invention further provides a compound of the invention for use
as an active therapeutic substance for treating or preventing Hepatitis C infection.
Compounds of formulas (I), (II) and (III) are of particular use for the treatment or
prevention of infection with Hepatitis C virus.
[0046] A preferred embodiment of the method of the present invention involves
treating or preventing a Hepatitis C viral infection in a mammal comprising
providing the mammal with an effective amount of at least one compound of
formula (I), (II), or (EH). This embodiment can further comprise providing the
mammal with at least one biologically active agent, which can be selected from the
group consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors,
polymerase inhibitors, small interfering RNA compounds, anti-sense compounds,
nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators,
hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-
infective compounds. This list only provides examples and is not meant to be
exhaustive.
[0047] In another embodiment of the method of the present invention involves
inhibiting replication of a Hepatitis C virus comprising contacting the Hepatitis C
virus with an effective amount of at least one compound of formula (I), (II), or (III).
This embodiment can further comprise providing the mammal with at least one

biologically active agent, which can be selected from the group consisting of
interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase
inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide
analogs, nucleoside analogs, immunoglobulins, immunornodulators,
hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-
infective compounds. This list only provides examples and is not meant to
exhaustive.
[0048] The compounds, or the prodrugs, the pharmaceutically active metabolites or
the pharmaceutically acceptable salts thereof, and the pharmaceutical compositions
of the present invention are preferably provided orally or subcutaneously. The
compounds may be provided by intralesional, intraperitoneal, intramuscular or
intravenous injection; infusion; liposome-mediated delivery; topical, nasal, anal,
vaginal, sublingual, uretheral, transdermal, intrathecal, ocular or otic delivery. In
order to obtain consistency in providing the compound of this invention it is
preferred that a compound of the invention is in the form of a unit dose. Suitable
unit dose forms include tablets, capsules and powders in sachets or vials. Such unit
dose forms may contain from 0.1 to 100 mg of a compound of the invention and
preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to
25 mg of a compound of the present invention. The compounds of the present
invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or
preferably at a dose range of 0.1 to 10 mg/kg. Such compounds may be
administered from 1 to 6 times a day, more usually from 1 to 4 times a day. The
effective amount will be known to one of skill in the art; it will also be dependent
upon the form of the compound. One of skill in the art could routinely perform
empirical activity tests to determine the bioactivity of the compound in bioassays
and thus determine what dosage to administer.
[0049] The compounds or the prodrugs, the pharmaceutically active metabolites or
the pharmaceutically acceptable salts thereof, and the pharmaceutical compositions
of the invention may be formulated with conventional excipients, such as a filler, a
disintegrating agent, a binder, a lubricant, a flavoring agent, a color additive, or a
carrier. The carrier may be for example a diluent, an aerosol, a topical carrier, an
aqueous solution, a nonaqueous solution or a solid carrier. The carrier may be a
polymer or a toothpaste. A carrier in this invention encompasses any of the

Standard pharmaceutically accepted carriers, such as phosphate buffered saline
solution, acetate buffered saline solution, water, emulsions such as an oil/water
emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated
tablets and capsules.
[0050] When provided orally or topically, such compounds would be provided to a
subject by delivery in different carriers. Typically, such carriers contain excipients
such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc,
vegetable fats or oils, gums, or glycols. The specific carrier would need to be
selected based upon the desired method of delivery, for example, phosphate
buffered saline (PBS) could be used for intravenous or systemic delivery and
vegetable fats, creams, salves, ointments or gels may be used for topical delivery.
[0051] The compounds, or the prodrugs, the pharmaceutically active metabolites or
the pharmaceutically acceptable salts thereof, and the pharmaceutical compositions
of the present invention may be delivered together with suitable diluents,
preservatives, solubilizers, emulsifiers, adjuvants and/or carriers useful in treatment
or prevention of Hepatitis C viral infection. Such compositions are liquids or
lyophilized or otherwise dried formulations and include diluents of various buffer
content (for example, Tris-HCl, acetate, phosphate), pH and ionic strength,
additives such as albumins or gelatin to prevent absorption to surfaces, detergents
(for example, TWEEN 20, TWEEN 80, PLURONIC F68, bile acid salts),
solubilizing agents (for example, glycerol, polyethylene glycerol), anti-oxidants
(for example ascorbic acid, sodium metabisulfate), preservatives (for example,
thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (for
example, lactose, mannitol), covalent attachment of polymers such as polyethylene
glycol, complexation with metal ions, or incorporation of the compound into or
onto particulate preparations of hydrogels or liposomes, micro-emulsions, micelles,
unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such
compositions will influence the physical state, solubility, stability, rate of in vivo
release, and rate of in vivo clearance of the compound or composition. The choice
of compositions will depend on the physical and chemical properties of the
compound capable of treating or preventing a Hepatitis C viral infection.
[0052] The compound, or the prodrugs, the pharmaceutically active metabolites or
the pharmaceutically acceptable salts thereof, and the pharmaceutical compositions

of the present invention may be delivered locally via a capsule that allows a
sustained release of the compound over a period of time. Controlled or sustained
release compositions include formulation in lipophilic depots (for example, fatty
acids, waxes, oils).
[0053] The present invention further provides controlled-release therapeutic
dosage forms for the pharmaceutical composition in which the composition is
incorporated into a delivery system. The dosage form controls release of the
pharmaceutical composition in such a manner that an effective concentration of the
composition in the blood can be maintained over an extended period of time, but
also the release of the composition should be such that the concentration in the
blood remains relatively constant over the extended period of time to improve
therapeutic results and/or minimize side effects. Additionally, a controlled release
system would affect minimal peak to trough fluctuations in blood plasma levels of
the pharmaceutical composition.
[0054] The present invention further provides a method of treating Hepatitis C
infection in humans, which comprises administering to the infected individual an
effective amount of a compound or a pharmaceutical composition of the invention.
[0055] The present invention is also directed to a pharmaceutical composition that
contains a compound of formula (I):

wherein R and R7 are independently selected from H, alkyl, cycloalkyl,
heterocycloalkyl, heteroaryl or aryl, any of which maybe optionally substituted, G
is selected from H or hydroxyl, Y is O, NH or S, X is selected from the group

consisting of H, halo, alkyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylthio, amino,
alkylamino, dialkylamino, and CN, and n is 0,1, 2 or 3, or a prodrug, a
pharmaceutically acceptable salt, or a pharmaceutically active metabolite thereof,
and a pharmaceutically acceptable carrier.
[0056] The present invention is also directed to a pharmaceutical composition that
contains a compound of formula (II):

R7 are independently selected from C1-C6 alkyl, C3-C12 cycloalkyl, C1-C11
heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of which may be optionally
substituted, X is selected from the group consisting of H, halo, alkyl of 1 to 4
carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl, alkoxy of 1 to 4
carbon atoms, alkylthio of 1 to 6 carbon atoms, amino, alkylamino of 1 to 4 carbon
atoms, dialkylamino of 2 to 8 carbon atoms, and CN, and G is selected from H or
hydroxyl, or a prodrug, a pharmaceutically acceptable salt, or a pharmaceutically
active metabolite thereof, and a pharmaceutically acceptable carrier.
[0058] The present invention is also directed to a pharmaceutical composition that
contains a compound of formula (III):



independently selected from C1-C6 alkyl, C3-C12 cycloalkyl, C1-C11
heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of which may be optionally
substituted, X is selected from the group consisting of H, halo, alkyl of 1 to 4
carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl, alkoxy of 1 to 4
carbon atoms, alkylthio of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon
atoms, dialkylamino of 2 to 12 carbon atoms, and CN, and G is selected from H or
hydroxyl, or a prodrug, a pharmaceutically acceptable salt, or a pharmaceutically
active metabolite thereof, and a pharmaceutically acceptable carrier.
[00591 The present invention provides a method of treating or preventing a
Hepatitis C viral infection in a mammal comprising providing the mammal with an
effective amount of at least one pharmaceutical composition, wherein the at least
one pharmaceutical composition includes a compound of formula (I), (II), or (III).
[0060] The method of the present invention further comprises providing the
mammal with an effective amount of at least one biologically active agent.
In an embodiment of the method of the present invention, the at least one
biologically active agent is provided prior to the at least one pharmaceutical
composition, concurrently with the at least one pharmaceutical composition or after
the at least one pharmaceutical composition, wherein the biologically active agent
is selected from the group consisting of interferon, a pegylated interferon, ribavirin,
protease inhibitors, polymerase inhibitors, small interfering RNA compounds, anti-
sense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins,
immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics,
antivirals, and anti-infective compounds.
[0061] The compounds of the present invention, or the prodrugs, the
pharmaceutically active metabolites or the pharmaceutically acceptable salts
thereof, or the isomers thereof are also useful in treating and preventing viral
infections, in particular hepatitis C infection, and diseases in living hosts when

used in combination with each other (i.e. pharmaceutical compositions comprising
the compounds, or the prodrugs or pharmaceutically acceptable salts thereof, are
administered concurrently with each or sequentially, in either order). The
combination of compounds provided herein may further be provided to a subject in
respective pharmaceutical compositions, concurrently with or sequentially to other
biologically active agents, including but not limited to the group consisting of
interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase
inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide
analogs, nucleoside analogs, immunoglobulins, immunomodulators,
hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-
infective compounds. The present invention further provides combination therapy
with one or more anthranilic acid derivatives, i.e., at least two pharmaceutical
compositions, each comprising a different compound, or prodrug or a
pharmaceutically acceptable salt thereof, of the present invention, are provided to a
subject in need thereof either concurrently with each other or sequentially, and such
therapy may further comprise providing concurrently or sequentially other
medicinal agents or potentiators, such as acyclovir, famicyclovir, valgancyclovir
and related compounds, ribavirin and related compounds, amantadine and related
compounds, various interferons such as, for example, interferon-alpha, interferon-
beta, interferon-gamma and the like, as well as alternative forms of interferons such
as pegylated interferons. Additionally, combinations of, for example ribavirin and
interferon, may be administered as an additional combination for a multiple
combination therapy with at least one of the compounds of the present invention.
[0062] The combination therapy with any of the above-described biologically
active agents may also be sequential, that is the treatment with a first
pharmaceutical composition comprising a compound, or prodrug or a
pharmaceutically acceptable salt thereof, of the invention followed by treatment
with a second pharmaceutical composition comprising a second compound of the
invention, wherein the second compound is different than the first compound;
alternatively, treatment may be with both two or more pharmaceutical
compositions, wherein each pharmaceutical composition comprises a different
compound, or prodrug or a pharmaceutically acceptable salt thereof, of the
invention, at the same time. The sequential therapy can be within a reasonable

time after the completion of the first therapy with the pharmaceutical composition.
Treatment with the respective pharmaceutical compositions, each comprising a
different compound, or prodrug or a pharmaceutically acceptable salt thereof, of
the present invention, at the same time may be provided in the same daily dose or
in separate doses. Combination therapy may also be provided wherein a
pharmaceutical composition comprising at least one compound, or prodrug or a
pharmaceutically acceptable salt thereof, of the present invention is administered in
a composition further comprising at least one biologically active agent, i.e. in a
single dose. The dosages for both concurrent and sequential combination therapy
(for combined pharmaceutical compositions comprising at least two compounds, or
the prodrugs or a pharmaceutically acceptable salts thereof, of the invention or
compositions comprising at least one compound, or prodrug or a pharmaceutically
acceptable salt thereof, of the invention and at least one biologically active agent),
will depend on absorption, distribution, metabolism and excretion rates of the
components of the pharmaceutical composition as well as other factors known to
one of skill in the art. Dosage values of the pharmaceutical composition will also
vary with the severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage regimens and schedules
may be adjusted over time according to the individual's need and the professional
judgment of the person administering or supervising the administration of the
pharmaceutical compositions.
[0063] In a further embodiment, the compounds of the invention may be used for
the treatment of HCV in humans in combination therapy mode with other
inhibitors of the HCV polymerase.
[0064] In yet a further embodiment, the compounds, or the prodrugs, the
pharmaceutically active metabolites or the pharmaceutically acceptable salts
thereof, of the present invention may be used for the treatment of HCV in humans
in combination therapy mode with other inhibitors of the HCV life cycle such as,
for example, inhibitors of HCV cell attachment or virus entry, HCV translation,
HCV RNA transcription or replication, HCV maturation, assembly or virus release,
or inhibitors of HCV enzyme activities such as the HCV nucleotidyl transferase,
helicase, protease or polymerase.

[0065] It is intended that combination therapies of the pharmaceutical
compositions include any chemically compatible combination of a compound, or
prodrug or a pharmaceutically acceptable salt thereof, of this inventive group with
other compounds, or the prodrugs or pharmaceutically acceptable salts thereof, of
the inventive group or other compounds outside of the inventive group, as long as
the combination does not eliminate the anti-viral activity of the compound of this
inventive group or the anti-viral activity of the pharmaceutical composition itself.
[0066] The term "interferon-alpha" as used herein means the family of highly
homologous species-specific proteins that inhibit viral replication and cellular
proliferation and modulate immune response. Typical suitable interferon-alphas
include, but are not limited to, recombinant interferon alpha-2b such as INTRON-
A INTERFERON available from Schering Corporation, Kenilworth, NJ,
recombinant interferon alpha-2a such as Roferon interferon available from
Hofman-La Roche, Nutley, NJ, a recombinant interferon alpha-2C, such as
BEROFOR ALPHA 2 INTERFERON available from Boehringer Ingelheim
Pharmaceutical, Inc., Ridgefield, Conn., interferon alpha-nl, a purified blend of
natural alpha interferons such as SUMIFERON available from Sumitomo, Japan or
as Wellferon interferon alpha-nl (INS) available from Glaxo-Wellcome Ltd.,
London, Great Britain, or a consensus alpha interferon such as those described in
U.S. Patent Nos. 4,897,471 and 4,695,623 (the contents of which are hereby
incoprpoated by reference in their entireties, specifically examples 7, 8 or 9
thereof) and the specific product available from Amgen, Inc., Newbury Park,
Calif., or interferon alpha-n3 a mixture of natural interferons made by Interferon
Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the
ALFERON trademark. The use of interferon alpha-2a or alpha 2b is preferred.
Since interferon alpha 2b, among all interferons, has the broadest approval
throughout the world for treating chronic hepatitis C infection, it is most preferred.
The manufacture of interferon alpha 2b is described in U.S. Pat. No. 4,503,901.
[0067] The term "pegylated interferon" as used herein means polyethylene glycol
modified conjugates of interferon, preferably interferon alpha-2a and alpha-2b.
The preferred polyethylene-glycol-interferon alpha-2b conjugate is
PEG.sub.l2000-interferon alpha 2b. The phrase "PEG.sub.l2000-IFN alpha" as
used herein means conjugates such as are prepared according to the methods of

International Application No. WO 95/13090 and containing urethane linkages
between the interferon alpha-2a or alpha-2b amino groups and polyethylene glycol
having an average molecular weight of 12000.
[0068] The following experimental details are set forth to aid in an understanding
of the invention, and are not intended, and should not be construed, to limit in any
way the invention set forth in the claims that follow thereafter.
[0069] The compounds of the present invention can be readily prepared according
to the following reaction schemes or modification thereof.
[0070] Compounds of the present invention, wherein R1 is carbonyl containing
moiety, can be synthesized as described in the schemes below (Scheme 1 and 2).
Subsequently, these compounds can be converted to the corresponding oximes,

by other methods know by skilled practitioners of the art.

[0071] The phenylamine derivatives of this invention are prepared by Method 1, as
described in Scheme 1. Accordingly, a methyl anthranilate derivative is acylated
with a reagent of formula L1-CH2C(O)L2 to give compound 2, wherein L1 is a
leaving group such as halo, O-mesyl, O-tolyl or 0-triflate, and L2 is a leaving
groups such as halo. Preferably the reagent is bromoacetyl bromide. The ortho
acylation of compound 3 is accomplished according to the method of Sugasawa,
(Sugasawa, Tsuotomu, Toyoda, Tatsuo, Adachi, Makoto; Sasakura, Kazuyuki.
Aminohaloborane in Organic Synthesis. 1. Specific Ortho Substitution Reaction
of Anilines. J. Am. Chem. Soc. (1978), 100(15), 4842-52) by treating the
compound with a Lewis acid, or a combination of Lewis acids, such as boron
tribomide, aluminum trichloride, and the corresponding nitrile, followed by acid
hydrolysis to give the aminoketone 4. Reaction of methyl N-acetyl anthranilate 2
with aminoketone 4 in the presence of a base, preferably a tertiary amine base, such
as N, N-diethylisopropylamine, triethylamine and pyridine, gives alkylation
product 5. A skilled artisan would be knowledgeable of other bases that could be
used to effect this alkylation. Hydrolysis of the ester under standard conditions
affords final product 1. These compounds can be further derivatized to form the
corresponding oximes (See Schemes 3 and 4).
[0072] The phenoxy and thiophenyl derivates of this invention are prepared by
Method 2, as illustrated in Scheme 2. Accordingly, ortho-acylphenol or ortho-
acylthiophenol derivative 7 is prepared by reacting the corresponding acid chloride
and a Lewis acid with a substituted phenol or thiophenol 6. This methodology is
described in Mewshaw, et al (Mewshaw, R.E.; Marquis, K.L.; Shi, X.;
McGaughey, G.; Stack, G.; et al.; Tetrahedron; EN; 54; 25; 1998; 7081-7108).
Alkylation with a reagent of formula R'OC(O)L2, wherein R' is selected from alkyl
or aryl and L2 is halo, affords ester 8. Preferably the reagent is ethyl iodoacetate.
Ester 8 is then converted to acid 9 by basic hydrolysis. Compound 9 is then
coupled to an anthranilic acid derivative using standard peptide coupling methods
to yield final product 10. An example of a standard coupling method is converting
compound 9 into the corresponding acid halide which can then reacted the
anthranilic acid derivative in a non-reactive solvent. This conversion can be
effected with reagents like oxalyl chloride, thionyl chloride, phosphorus trichloride,
phosphorus pentachloride, Ph3PBr2, Ph3P/CBrCl3, Ph3P/CCLt and the like. One

skilled in the art would be aware of other similar reagents that could be used to
form an acid halide from a carboxylic acid. These compounds can then be
derivatized further to form the corresponding oximes, as shown in Schemes 5 and
6.



[0073] Scheme 3 illustrates a general method of preparing oxime derivatives 13
starting from the corresponding aminoketone 4. The aminoketone 4 is reacted
with hydroxylamine, or a derivative thereof, such as an alkoxyamine (i.e.
CH3ONH2), H2NOSO3H or HON(S03Na), in the presence of an acid or a base to

obtain oxime 11. Use of an acid is preferable, such as HCl. The oxime is then
reacted with benzyl ester 2 under basic conditions, as described previously herein,
to form oxime ester 12, which is then saponified to yield the final product 13.
[0074] Scheme 4 shows alternative methods of yielding final product 13 by
introducing the oxime functionality at different points of the synthesis described in
Scheme 1. Thus, ester 5 can be first reacted with hydroxylamine, or a derivative
thereof, as described herein, to form the oxime, which can then be saponified to
obtain the final compound 13. Alternatively, acid compound 1 (which was the
final product shown in Scheme 1), can be reacted with hydroxylamine, or a
derivative thereof, as described herein, to form the oxime final product.
[0075] Scheme 5 shows a method of preparing the corresponding oximes of the
phenol or thiophenol derivatives of the present invention. The 2-acylphenol or 2-
acylthiophenol 7 is reacted with hydroxylamine, or a derivative thereof, such as an
alkoxyamine (i.e. CH3ONH2), H2NOSO3H or HON(SO3Na), in the presence of an
acid or a base, and then is reacted with the appropriate acid halide in the presence
of a Lewis acid, as described previously herein, to obtain oxime 14. Use of an acid
is preferable, such as HCl. The oxime is then hydrolyzed under basic conditions,
as described previously herein, to form oxime acid 15, which is then coupled to a
anthranilic acid derivative using standard peptide coupling methods, as described
herein, to yield the final product 16.
[0076] Scheme 6 illustrates a method of preparing the oxime 16 from the
corresponding acid 10 (which was the final product in Scheme 2) by reacting it
with hydroxylamine, or a derivative thereof, such as an alkoxyamine, H2NOSO3H
or HON (SO3NA), in the presence of an acid or base. Use of an acid, such HCl, is
preferable.
[0077] Scheme 7 shows the specific synthesis of 2-{[N-(2-acetyl-5-chloro-4-
fluorophenyl)glycl]amino}benzoic acid using the general methodology described in
Scheme 1.
[0078] The following are examples of the compounds of the present invention.
These examples are not intended to encompass the entire scope of this invention
and should not be viewed as a limitation of the scope of the invention.

BIOLOGY
[00791 The ability of the compounds of the present invention to inhibit Hepatitis C
Polymerase was established by the following experimental procedure:
[0080] NS5B from the BK strain (genotype 1b) is expressed in E. coli as a protein
in which the 21 C-terminal amino acids are replaced with a short linker and a
hexahistidine tag (GSHHHHHH; SEQ ID NO:1). The purified protein is mixed
with radioactive nucleotides and allowed to replicate a heteropolymeric RNA
substrate, primed by an endogenous short hairpin, resulting in an approximately
760 nt product. The radioactive product is captured on a filter and quantitated after
removal of the unincorporated nucleotides.
Reagents:
10 mM uridine 5'-triphosphate (UTP) (Promega # p116B)
10 mM adenine 5'-triphosphate (ATP) (Promega # p113B)
10 mM cytidine 5'-triphosphate (CTP) (Promega # p114B)
10 mM guanine 5'-triphosphate (GTP) (Promega # p115B)
Bovine Serum Albumin (BSA) 10 mg/ml NEB (100X at 10 mg/ml) #007-BSA
RNasein (Promega #N251X) 40 U/μl
A-[33P]-GTP (NEN-easytides NEG/606H 3000 Ci/mmol, 370 MBq/ml, 10
mCi/ml)
Falcon polypropylene 96 well plates (Becton Dickinson # 351190)
Millipore Multiscreen assasy system-96 well-filtration plate #MADE NOB 50
Optiphase Supermix (Wallac) formulated by Fisher

Millipore Multiscreen liner for use in microbeta 1450-106 casette [(Wallac) Perkin
Elmer #1450-433]
1 M (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]) (HEPES), pH 7.3
Amersham Pharmacia Biotec (US 16924-500 ml)
1 M MgCl2 (SIGMA #M1028)
Dithiothreitol (DTT) (solid) (SIGMA # D9779)
RNase free water (GIBCO-BRL #10977-023)
Dimethyl sulfoxide (Aldrich #27685-5)
Basilen Blue (Sigma, B5520)
0.5M ethylenediaminetetraacetic acid (EDTA), pH 8 (GIBCO-BRL #15575-020)
Dibasic sodium phosphate (7-hydrate) (Na2HPO4.7H2O; Baker#3 824-07)
Phosphoric acid (Baker, #0262.02)
[0081] Further reagent preparation:
- 0.5 M Na Phosphate buffer. Per liter, weigh 134 gr Na2HPO4.7H2O, add water
to 900 ml. Adjust pH to 7.0 with phosphoric acid. Top off with water to 1 L.
- Dilute nucleotides 1:1000 to 10 μM (GTP and CTP) or 1:100 to 100 μM (ATP
and UTP) into RNase free water.
[0082] Procedure:
(1) Compounds 10μl at 10 μg/ml in 15 % dimethylsulfoxide (DMSO)
[0083] When starting from 100 μg/ml compound stock in 1% DMSO:
Dispense 5 μl 30 % DMSO per well
Dispense 5 μl compound (100 μg/ml) per well.
[0084] When starting from 50 μg/ml compound stock in 15 % DMSO:
Add 10μl compound per well.


[0085] Add 20 μl enzyme mix into each well of the assay plate. Incubate
compound and enzyme at room temperature for 15 minutes
(3) Template mix - prepare ahead
[0086] Spin down a tube of RNA (5μg/tube stored in 75% ethanol and 0.3 M
sodium acetate) in a microcentrifuge for 20 minutes at 4 °C. One tube is enough
for 1 - 1.5 plates. Remove as much ethanol from the tube as possible by inverting
the tube. Be gentle, pellet RNA may not adhere to the tube. Vacuum dry the RNA.
Resuspend the RNA by adding 1 ml of DEPC water, close the cap of the tube
tightly. To dissolve RNA, incubate RNA solution on ice for -60 minutes and
gently vortex. Spin briefly to ensure all RNA solution is down to the bottom of thf
tube before opening cap. Gently transfer RNA solution into a 5 ml or larger tube.
Add another 3 ml of DEPC water (total 4 ml of volume).

[0087] Add the following volumes of reagents

[0088] Add 20 μl template mix per reaction (i.e. 20 ng of pOF per reaction or ~3
nM)
(4) Incubate reaction at room temperature (22-25°C) for 2 hours.
(5) Stop reaction by adding 50 μl of 170 mM EDTA.
Final concentration of EDTA is 85 mM.
(6) Prewet filters of Millipore multiscreen assay plate by adding 200 μl of 0.5 M
sodium phosphate buffer, pH 7.0 into each well. Let stand at room temperature
for 2-3 minutes.
(7) Place the multiscreen filter plate onto a Millipore Manifold and turn on vacuum
to allow buffer to flow through. Tum off vacuum. Transfer 80 μl of the
reaction product into each well of the filter plate. Let stand for 2 - 3 minutes.
Turn on vacuum to filter reaction product.
(8) Turn off vacuum. Add 200 μl of 0.5 M sodium phosphate buffer, pH 7.0 into
each well to wash filter. Turn on vacuum.
Repeat step (8) three more times.

(9) Remove polypropylene bottom. Spot dry filter at the bottom with paper towel.
Air dry filter plate on a bench for 1 hour. Add 40 μl Super Mix scintillant.
Seal top of the plate with a tape. Place plate into a Packard carrier or micro-
beta carrier.
(10) Count plate using a Packard Topcount or micro-beta counter. Count (for
example using Program 10) for 33P in Top count or 33P program in micro-beta.
[0089] Percent inhibition is calculated after background subtraction as a percent
reduction of activity relative to the positive control (average value of the plate
excluding the negative controls). For the primary screen hits were chosen as
showing >75 % inhibition.
[0090] See, Ferrari et al. 1999. J. Virology 73:1649-1654: "Characterization of
soluble Hepatitis C virus RNA-dependent RNA polymerase expressed in E. coli
and Takamizawa et al 1991" and J. Virology 65:1105-1113: "Structure and
characterization of the Hepatitis C virus genome isolated from human carriers,"
both references are hereby incorporated by reference.
[0091] The compounds of the present invention inhibited Hepatitis C polymerase
as summarized in Table II:



[0092] The ability of the compounds of the present invention to inhibit Hepatitis C
virus replicon constitutively expressed in a human liver cell line was established by
the following experimental procedure:
[0093] Clone A cells (licensed from Apath, LLC) are derived from Huh-7 cells
(human hepatoma cell line) and constitutively express of the HCV replication
proteins with concomitant amplification the HCV replicon (1b) genome. Cells are
maintained and passaged in DMEM/10% FCS/1 mg/ml G418 (Geneticin from

Gibco #11811-023; other media components as described below in "elisa media").
Care should be taken to maintain cell monolayers at a subconfluent state by 1:3 or
1:4 passages every 3-4 days. The replicon is extremely sensitive to the cellular
metabolism/proliferation state and replicon copy number will rapidly decline in
confluent monolayers (resting cells). Under ideal conditions each cell has, on
average, 1000 copies of the HCV replicon genome.
[0094] Reagents:
Elisa media:
Dulbecco's Modified Eagle Media (DMEM) (Gibco #12430-047)
2% Fetal Calf Serum (FCS) (HyClone #SH30070.03)
lXpen/strep (Gibco #15140-122)
IX Non-essential amino acids (NEAA) (Gibco #11140-050)
no G418
Glutaraldehyde (Fisher #02957-4)
TWEEN-20, 10% (Roche #1332465)
TRITON X-100 (Sigma #T-8787)
Superblock in Phosphate Buffered Saline (PBS) (Pierce #37515)
NS5a monoclonal antibody (Virostat #1873)
Goat antimouse-HRP monoclonal antibody (BioRad #172-1011)
3,3',5,5' tetramethylbenzidine (TMB) substrate (Sigma #T-0440)
[0095] Compound Dilution/Cell Plating:
Drug Plate Preparation (Mother Plate)
10 μl of compounds (in DMSO) are added to column 3 of the mother plate. 5 μl of
DMSO are added to the remaining columns. Mother plates are set aside until ready
for serial dilution to be performed.
[0096] Control Drugs
Drug and Cell Addition:
The process for each plate involves:
Prepare cell plates (daughter plates) by adding 52μl of Elisa media to each well.
In Mother plates, serially transfer 50 μlwell from column 3 through column 12.

Transfer 8 μl from mother plate to daughter plates (all 96 wells).
Place daughter plates in incubator until cells are prepared.
Harvest Clone A cells and plate directly into daughter plates at 0.7x105 cells/ml,
100 μl/well.
All plates are incubated at 37°C in 5% CO2 for 3 days.
[0097] Elisa Assay:
Remove media from 96-well plates (cells should be ca 80% confluent) by flicking
into sink.
Add 130 μl/well IX PBS + 0.05% glutaraldehyde.
Incubate 37°C for 1 hour.
Remove by flicking into sink.
Wash 3X with 300 μl/well PBS, shaking 5 min each wash. Remove by flicking
into sink.
Add 130 μl/well PBS + 0.05% TWEEN-20 + 0.1% TRITON X-100.
Incubate 37°C for 10 minutes.
Remove by flicking into sink.
Add 300 μl/well Superblock in PBS.
Incubate 37°C for 1 hour.
Remove by flicking into sink.
Wash 3x with 300 μl/well PBS, shaking 5 minutes each wash. Remove by flicking
into sink.
During last wash, make a 1:100 dilution of NS5a Monoclonal-antibody (Mab) in
Superblock + 0.02% TWEEN-20.
After last wash, add 50 μl/well diluted Mab.
Incubate 37°C for 1 hour.
Remove by flicking into sink.
Wash 3X with 300 μl/well PBS + 0.02% TWEEN-20, shaking 5 minutes each
wash.
Remove by flicking into sink.
During last wash, make a 1:500 dilution of goat antimouse-HRP Mab in
Superblock + 0.02% TWEEN-20.
After last wash, add 50 μl/well diluted Mab.

Incubate 37°C for 1 hour.
Remove by flicking into sink.
Wash 5X with 300 μl/well PBS + 0.02% TWEEN-20, shaking 5 minutes each
wash. Remove by flicking into sink.
Wash 3X with 300 μl/well PBS, shaking 5 minutes each wash. Remove by flicking
into sink.
After last wash, add 130 μl/well room temperature TMB substrate.
Incubate until blue color develops.
Add 130 μl/well 1N HCl to stop reaction (color turns from blue to yellow).
Read plates with optical density (O.D.) 450 filter.
ANALYSIS OF RESULTS: IC50 (μM); IC50 (μg/ml); % Inhibition
REFERENCE COMPOUNDS: Interferons; 4-30 U/ml IC50

WHAT IS CLAIMED:
1. A compound of formula (I):

wherein R6 and R7 are independently selected from H, C1-C12 alkyl,
C3-C12 cycloalkyl, C1-C11 heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of
which may be optionally substituted;
G is selected from H or hydroxyl;
Y is O, NH or S;
X is selected from the group consisting of H, halo, C1-C12 alkyl,
C3-C12 cycloalkyl, C1-C12 perfluoroalkyl, C1-C12 alkoxy, C1-C12 alkylthio, amino,
C1-C6 alkylamino, C2-C12 dialkylamino, and CN; and
n is 0, 1, 2 or 3;
or a prodrug, a pharmaceutically acceptable salt, or a pharmaceutically
active metabolite thereof.
2. The compound of claim 1, wherein:
R6 and R7are independently selected from H, C1-C6 alkyl, C3-C12
cycloalkyl, C1-C11 heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of which
may be optionally substituted;

X is selected from the group consisting of H, halo, C1-C6 alkyl, C3-C12
cycloalkyl, C1-C11 heterocycloalkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, C1-C6
alkylthio, amino, C1-C6 alkylamino, C2-C12 dialkylamino, and CN; and
optional substituents are selected from the group consisting of C1-C6 alkyl,
halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, nitro, amino, hydroxy, cyano,
C1-C6 alkylamino, C2-C12 dialkylamino, C1-C6 alkoxy, C1-C6 haloalkoxy,
C2-C12 alkoxyalkyl, C2-C12 alkoxyalkoxy, oxo, C1-C6 alkylthio, mercapto,
C1-C6 haloalkylthio, C6-C12 aryl, C6-C12 aryloxy, C6-C12 arylthio, C2-C9 heteroaryl,
C2-C9 heteroaryloxy, C2-C9 heteroarylthio, C2-C7 acyl, -CO2- C1-C6 alkyl, -SO3H, -
SO2NH2, -SO2NH-C1-C6 alkyl, -SO2NH-(C1-C6 alkyl)2, -CO2H, -CO2NH2, -
CO2NH-C1-C6 alkyl and -CO2N-(C1-C6 alkyl)2.
3. The compound of claim 2, wherein:
Y is O or NH;and
X is selected from the group consisting of H, halo, C1-C4 alkyl, C1-C4 alkoxy,
and C1-C4 haloalkyl.
4. The compound of claim 3, wherein n is 0, 1 or 2 and G is H.
5. The compound of claim 4, wherein:
R6 is C1-C4 alkyl;
R7 is C1-C4 alkyl, when present; and
Y is NH.
6. The compound of claim 5, wherein n is 2 and X is halo.
7. The compound of claim 6, wherein R is CH3 and, when present, R7 is CH3.
8. The compound of claim 7, wherein X is selected from Cl and F.
9. The compound of claim 8, wherein one X is Cl and the other X is F.
10. A compound of formula (II):


independently selected from C1-C6 alkyl, C3-C12 cycloalkyl, C1-C11
heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of which may be optionally
substituted;
X is selected from the group consisting of H, halo, alkyl of 1 to 4 carbon
atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 4 carbon atoms,
alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, amino, alkylamino
of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms, and CN; and
G is selected from H or hydroxyl;
or a prodrug, a pharmaceutically acceptable salt, or a pharmaceutically
active metabolite thereof.
11. The compound of claim 10, wherein R6 and R7 are independently selected
from C1-C6 alkyl, C3-C12 cycloalkyl, or C6-C12 aryl, any of which may be
optionally substituted.
12. The compound of claim 11, wherein G is H.
13. The compound of claim 12, wherein the compound is:
2-{[N-6-acetyl-l,3-benzodioxol-5-yl)glycyl]amino}benzoic acid;

2-({[N-[2-acetyl-4-chloro-5-(methylthio)phenyl]glycyl}amino) benzoic acid;
2-({[N-[2-acetyl4-chloro-5-(dimetheylamino)phenyl]glycyl} amino)benzoic acid;
2-({[N-[2-acetyl-4-chloro-5-(methylamino)pheny]]glycyl} amino) benzoic acid;
2-{[N-(2-acetyl-5-chloro-4-(fluorophenyl)-N-methylglycyl]amino} benzoic acid; and
2-({[N-[2-acetyl-4-chloro-5-(methylsulfinyl)phenyl]glycy]}aniino) benzoic acid.
14. The compound of claim 12, wherein X is selected from the group H, halo,
C1-C4 alkyl, C1-C4 perfluoroalkyl and C1-C4 alkoxy.
15. The compound of claim 14, wherein R6 and R7 are C1-C4 alkyl.
16. The compounds of claim 15, wherein the compound is:
2- {[N-(2-acetyl-4-chloro-5-ethoxyphenyl)glycyl]amino}benzoic acid;
2- {[N-(2-acetyl-4-chloro-5-methoxyphenyl)glycyl]amino}benzoic acid;
2- {[N-(2-acetyl-4-fluoro-5-methylphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetylphenyl)glycyl]amino}benzoic acid;
2-{[N-(5-chloro-4-methyl-2-propionylphenyl)glycyl]amino} benzoic acid;
2-[2-(4,5-dimethyl-2-propionyl-phenylamino)-acetylamino]-benoic acid;
2-{[N-(2-acetyl-5-chloro-4-methylphenyl)glycyl]amino}benzoic acid; and
2-{[N-(2-acetyl-4,5-dimethylphenyl)glycyl]amino}benzoic acid.
17. The compound of claim 15, wherein X is halo, if present.
18. The compound of claim 17, wherein n is 0, 1, or 2.
19. The compound of claim 18, wherein the compound is:
2-{[N-(2-acetyl-4-bromo-5-choloro phenyl)glycyl]amino}benzoic acid;
2-{[N-(5-chloro-4-fluoro-2-propionylphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4,5-difluorophenyl)glycyl]amino} benzoic acid;
2-{[N-(2-acetyl-4-chloro-5-fluorophenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4,5-dichlorophenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-5-chloro-4-fluorophenyl)glycyl]amino}benzoic acid;
2-{[N-(4-chloro-2-propionylphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4-chloro-5-methylphenyl)glycyl]amino}benzoic acid;
2-{[N-(2-acetyl-4-chlorophenyI)glycyl]amino}benzoic acid; and
2-{[N-(2-acetyl-4-bromophenyl)glycyl]amino}benzoic acid.

20. The compound of claim 15, wherein the compound is 2-{[N-(2-acetyl-5-
chloro-4-fluorophenyl)glycyl]amino}benzoic acid.
21. The compound of claim 15, wherein the compound is 2-(2-([5-chloro-4-
fluoro-2-(1-methoxyimino-ethyl)-phenylamino]acetylamino}benzoic acid.
22. A compound of formula (III):

independently selected from C1-C6 alkyl, C3-C12 cycloalkyl, C1-C11
heterocycloalkyl, C2-C9 heteroaryl or C6-C12 aryl, any of which may be optionally
substituted;
X is selected from the group consisting of H, halo, alkyl of 1 to 4 carbon
atoms, cycloalkyl of 3 to 6 carbon atoms, C perfluoroalkyl of 1 to 4 carbon atoms,
alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 6 carbon atoms, amino,
alkylaminol to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, and CN; and
G is selected from H or hydroxyl;
or a prodrug, a pharmaceutically acceptable salt, or a pharmaceutically
active metabolite thereof.

23. The compound of claim 22, wherein R6 and R7 are independently selected
from C1-C6 alkyl, C3-C12 cycloalkyl and C6-C12 aryl, any of which may be
optionally substituted.
24. The compound of claim 23, wherein G is H.
25. The compound of claim 24, wherein the compound is 2-{[(2-acetyl-5-
methylphenoxy)acetyl]amino}benzoic acid.
26. The compound of claim 24, wherein X is selected from the group consisting
of H, halo, C1-C4 alkyl, C1-C4 perfluoroalkyl and C1-C4 alkoxy.
27. The compound of claim 26, wherein R6 and R7 are C1-C4 alkyl.
28. The compounds of claim 27, wherein the compound is:
2-{[(2-acetyl-5-ethylphenoxy)acetyl]amino}benzoic acid;
2-{[(4,5-dimethyl-2-pentanoyphenoxy)acetyl]amino}benzoic acid;
2-{[(2-butyryl-4,5-dimethylphenoxy)acetyl]amino}benzoic acid;
2-{[(4,5-dimethyl-2-propionyphenoxy)acetyl]amino}benzoic acid;
2-({[4,5-dimethyl-2-(trifluoroacetyl)phenoxy]acetyl}amino} benzoic acid;
2-{[(2-acetyl-4,5-dimethoxyphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-5-methylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4-ethylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4-methylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-5-methoxyphenoxy)aceryl]amino}benzoic acid;
2-{[(2-benzoyl4-methylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4,5-dimethylphenoxy)acetyl]amino}-5-hydroxybenzoic acid;
2-{[(2-acetyl-4,5-dimethylphenoxy)acetyl]amino}benzoic acid; and
2-{[(2-isobutyryl-4,5-dimethylphenoxy)acetyl]amino}benzoic acid.
29. The compound of claim 27, wherein n is 1, 2 or 3 and at least one X is halo.
30. The compound of claim 29, wherein n is 1 or 2.

31. The compound of claim 30, wherein the compound is:
2-{[(2-acetyl-4-chloro-5-fluorophenoxy)acetyl]amino}benzoicacid;
2- {[(2-acetyl-5-chloro-4-fluorophenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4-fluoro-5-methylphenoxy)acetyl]amino}benzoicacid;
2-{[(2-acetyl-4,5-difluorophenoxy)acetyl]amino}benzoic acid;
2- {[(4-chloro-2-propionylphenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-4-chloro-5-methylphenoxy)acetyl]amino}benzoic acid;
2- {[(2-acetyl-5-fluorophenoxy)acetyl]amino}benzoic acid;
2-{[(2-acetyl-5-chlorophenoxy)acetyl]amino}benzoicacid;
2-{[(2-acetyl-4-fluorophenoxy)acetyl]amino}benzoic acid; and
2- {[(2-acetyl-4-chlorophenoxy)acetyl]aniino}benzoic acid.
32. A method of inhibiting replication of a Hepatitis C virus comprising
contacting a Hepatitis C virus with an effective amount of at least one compound
from one of claims 1, 10 or 22.
33. The method of claim 32, further comprising contacting the Hepatitis C
virus with at least one biologically active agent selected from the group consisting
of interferon, apegylated interferon, ribavirin, protease inhibitors, polymerase
inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide
analogs, nucleoside analogs, immunoglobulins, immunomodulators,
hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-
infective compounds.
34. A method of treating or preventing a Hepatitis C viral infection in a
mammal comprising providing the mammal with an effective amount of at least
one compound from one of claims 1, 10 or 22.
3 5. The method of claim 34, further comprising providing the mammal with at
least one biologically active agent selected from the group consisting of interferon,
a pegylated interferon, ribavirin, protease inhibitors, polymerase inhibitors, small
interfering RNA compounds, anti-sense compounds, nucleotide analogs,

nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-
inflammatory agents, antibiotics, antivirals, and anti-infective compounds.
36. A method of inhibiting the Hepatitis C RNA-dependent RNA polymerase
NS5B, comprising contacting a cell with an effective amount of a compound of
claim 1 to decrease or prevent NS5B function.
37. A pharmaceutical composition, comprising a compound from one of claims
1, 10 or 22, and a pharmaceutically acceptable carrier.
38. A method of treating or preventing a Hepatitis C viral infection in a
mammal, comprising providing the mammal with an effective amount of at least
one pharmaceutical composition of claim 37.
39. The method of claim 38, further comprising providing the mammal with an
effective amount of at least one biologically active agent selected from the group
consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors,
polymerase inhibitors, small interfering RNA compounds, anti-sense compounds,
nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators,
hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-
infective compounds.

The present
invention is directed to compounds
of formula (I): wherein R1 is
selected from the group consisting
of -C(O)R and (a), wherein
R6 and R7 are independently
selected from H, alkyl, cycloalkyl,
heterocycloalkyl, heteroaryl
or aryl, any of which may be
optionally substituted, G is
selected from H or hydroxyl, Y is
O, NH or S, X is selected from the
group consisting of H, halo, alkyl,
cycloalkyl, perfluoroalkyl, alkoxy,
alkylthio, amino, alkylamino,
dialkylamino, and CN, and n
is 0, 1, 2 or 3, or a prodrug, a
pharmaceutically acceptable salt,
or a pharmaceutically active
metabolite thereof. This invention
is also directed to compositions
containing compounds of the
invention and methods of using both the inventive compounds and compositions thereof to treat or prevent Hepatitis C virus infection, or to inhibit replication of a Hepatitis C virus