TITLE
SULFONAMIDE DERIVATIVES TO TREAT
INFECTION WITH HEPATITIS C VIRUS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of United States Provisional
Application No. 60/771,904, filed February 8, 2006.
FIELD OF THE INVENTION
[0002] A series of sulfonamide compounds are effective pharmaceuticals for the
treatment of hepatitis C infection.
BACKGROUND OF THE INVENTION
[0003] Hepatitis C is a common 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).
[0004] 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.
[0005] There is no effective vaccine to prevent HCV infection. The only therapy
currently available is treatment with interferon-ct (DSTF-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.
[0006] 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 that is essential for viral
replication. Therefore, the inhibition of NS5B is a suitable target for the
development of therapeutic agents.
[0007] U.S. Patent No. 3,506,646 relates to compounds that are derivatives of 6-
aminosulfonyl compounds, in particular 1,2,5-benzothiadiazepine 1,1 -dioxides
with fused heterocycles, the intermediates used to synthesize them, and their use
as diuretic and hypotensive agents.
[0008] WO 98/08815 relates to substituted cyclic amine metalloprotease
inhibitors.
[0009] Biorganic and medicinal chemistry, 1996, 837-850 describes 5H-pyrrolo
[l.,2-b] [l,2,5]benzofhiadiazepines (PBTDs) as a novel class of non-nucleoside
reverse transcriptase inhibitors.
[0010] WO 03/043985 describes sulfonamides as peroxisome proliferator-
activated receptor agonists.
[0011] WO 02/02554 describes sulfonyl-pyrrolidine derivatives useful for the
treatment of neurological disorders.
SUMMARY OF THE INVENTION
[0012] This invention relates to a series of sulfonamide derivatives, processes for
their preparation, pharmaceutical compositions containing them, and their use in
therapy. The compounds are believed to be useful in the treatment of hepatitis C
by virtue of their ability to inhibit hepatitis C polymerase (NS5B).

[0013] This invention is directed to compounds of formula (I):

[0014] wherein:
[0015] R1 is H, -COOH, -CO2R4, cyano, tetrazole, a straight chain alkyl of 1 to 6
carbon atoms optionally substituted with OH, amine or -COOH, an optionally
substituted -C(O)-C1-C12-alkyl, or an optionally substituted -C(O)- C6-C12-aryl,
wherein R4 is a C1-C12-alkyl, C6-C12-aryl, C3-C12-cycloalkyl, or C2-C9-heteroaryl,
any of which may be optionally substituted;
[0016] R2 is an aryl or a heteroaryl group optionally substituted with one to five
substituents selected from the group consisting of halogen, -NO2, -CN, -N3,
-CHO, -CF3, -OCF3, -R3, -OR3, -S(O)mR3, -NR3R3, -NR3S(O)mR3, -NR3C(O)R3,
-C(O)R3, -C(O)OR3, -C(O)NR3R3, -OC(O)R3, -OC(O)OR3, -OC(O)NR3R3,
NR3C(O)R3, -NR3C(O)OR3, and -NR3C(O)NR3R3, wherein m is 0, 1, or 2;
[0017] R3 is H, an alkyl of 1-6 carbon atoms, a branched alkyl of 1-8 carbon
atoms, a cycloalkyl of 3 to 6 carbon atoms, phenyl, a C2-C9-heteroaryl, an alkenyl
of 2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms;
[0018] X is CH2,CHOR3,or S; and
[0019] n is 1 or 2;
[0020] and all crystalline forms and pharmaceutically acceptable salts thereof,
with the provisos that when X is CH2, n is 1, and R1 is -COOH, R2 cannot be


[0021] wherein:
[0022] A is CH3-, CH3CH2- or a haloalkyl of 1 to 2 carbon atoms; and
[0023] B is a halogen; and
[0024] when X is CH2, n is 2, and R1 is -COOH, R2 cannot be

[0025] The present invention is also directed to compounds of formula (11):

[0026] wherein:
[0027] R1 is H, -COOH, -CN, tetrazole, -C(O)R4, or a hydroxyalkyl of 1 to 4
carbon atoms, wherein R4 is an alkyl of 1 to 4 carbon atoms or an optionally
substituted phenyl;
[0028] Rs is H, OH or-OCH3; and
[0029] X1-X5 are independently H, a halogen, OH, NH2, an alkyl of 1 to 4
carbon atoms, -NH-C(O)-R3, wherein R3 is an alkyl of 1 to 4 carbon atoms, a C6-
C12-aryl, a cycloalkyl of 3 to 6 carbon atoms, or a C2-C9-heteroaryl;
[0030] and all crystalline forms or pharmaceutically acceptable salts thereof,
with the provisos that when R1 is -COOH, R5 is H, X3 is a halogen, and X4 is
-CH3 or -CF3, then X1 cannot be NH2; and

[0031] when R1 is -COOH, R5 is H, X2 is -CH3 or -CF3, and X3 is a halogen,
then X5 cannot be NH2.
[0032] Another aspect of the present invention are compounds of formula (III):

[00331 wherein:
[0034] R1 is H, -COOH, -CN, tetrazole, -C(O)R4, or a hydroxyalkyl of 1 to 4
carbon atoms, wherein R4 is an alkyl of 1 to 4 carbon atoms or an optionally
substituted phenyl; and
[0035] X1-X5 are independently H, a halogen, OH, NH2, an alkyl of 1 to 4
carbon atoms, -NH-C(O)R3, wherein R3 is an alkyl of 1 to 4 carbon atoms, a C6-
C12-aryl, a cycloalkyl of 3 to 6 carbon atoms, or a C2-C9-heteroaryl;
[0036] and all crystalline forms and pharmaceutical!y acceptable salt thereof,
with the provisos that when R1 is —COOH, X3 is a halogen, and X4 is -CH3 or
-CH2CH3, then X1 cannot be NH2; and
[0037] when R1 is -COOH, X2 is -CH3 or-CH2CH3, and X3 is a halogen, then
X5 cannot be NH2.
[0038] The present invention is also directed to compounds of formula (IV):

[0039] wherein:
[0040] R1 is H, -COOH, -CN, tetrazole, -C(O)R4, or a hydroxyalkyl of 1 to 4
carbon atoms, wherein R4 is an alkyl of 1 to 4 carbon atoms or an optionally
substituted phenyl; and
[0041] X1 to X5 are independently H, a halogen, OH, NH2, an alkyl of 1 to 4
carbon atoms, -MH-C(O)R3, wherein R3 is an alkyl of 1 to 4 carbon atoms, a C6-
C12-aryl, a cycloalkyl of 3 to 6 carbon atoms, or a C2-C9-heteroaryl;
[0042] and all crystalline forms and pharmaceutically acceptable salts thereof.
[0043] The present invention is also directed to pharmaceutical compositions
comprising a compound of the present invention and a pharmaceutically
acceptable carrier.
[0044] The present invention also includes methods of treating or preventing a
hepatitis C infection in humans, comprising administering an effective amount of
a compound of formula (1a):

[0045] wherein:
[0046] R1 is H, -COOH, -CO2R4, cyano, tetrazole, a straight chain alkyl of 1 to 6
carbon atoms optionally substituted with OH, amine, or -COOH, an optionally
substituted -C(O)-C1-C12-alkyl, or an optionally substituted -C(O)-C6-C12-aryl,
wherein R4 is a C1-C12-alkyl. C6-C12-aryl, C3-C12-cycloalkyl, or C2-C9-heteroaryl;

[0047] R2 is a C6-C12-aryl or a C2-C9-heteroaryl group optionally substituted
with one to five substituents selected from the group consisting of halogen, -NO2,
-CN, -N3, -CHO, -CF3, -OCF3, -R3, -OR3, -S(O)mR3, -NR3R3, -NR3S(O)mR3,
-NR3C(O)R3, -C(O)R3, -C(O)OR3, -C(O)NR3R3, -OC(O)R3, -OC(O)OR3,
-OC(O)NR3R3, NR3C(O)R3, -NR3C(O)R3, and -NR3C(O)NR3R3, wherein m is
0,1, or 2;
[0048] R3 is H, an alkyl of 1-6 carbon atoms, a branched alkyl of 1-8 carbon
atoms, a cycloalkyl of 3 to 6 carbon atoms, phenyl, a C2-C9-heteroaryl, an alkenyl
of 2-6 carbon atoms, or an alkynyl of 2-6 carbon atoms;
[0049] X is CH2, CHOR3, or S; and
[0050] n is 1 or 2;
[0051] and all crystalline forms and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0052] For purposes of this invention the term "alkyl" includes straight chain
moieties with a length of up to 12 carbon atoms, but preferably 1 to 6 carbon
atoms, and more preferably 1 to 4 carbons. The term "alkyl" also includes
branched moieties of 3 to 12 carbon atoms, but preferably 1 to 8 carbon atoms.
'The term "alkenyl" refers to a radical aliphatic hydrocarbon containing one
double bond and includes both straight and branched alkenyl moieties of 2 to 7
carbon atoms. Such alkenyl moieties may exist in the E or Z configurations; the
compounds of this invention include both configurations. The term "alkynyl"
includes both straight chain and branched moieties containing 2 to 7 carbon
atoms having at least one triple bond. The term "cycloalkyl" refers to alicyclic
hydrocarbon groups having 3 to 12 carbon atoms and includes but is not limited
to: cyclopropyl, cycloburyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, or
adamantyl. Preferably cycloalkyl groups are 3 to 6 carbon atoms.
[00S3] For purposes of this invention the term "aryl" is defined as an aromatic
hydrocarbon moiety having at least one aromatic ring, is mono-, bi- or tri-cyclic,
and may be substituted or unsubstituted. An aryl group may be selected from but
is not limited to: phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl,

acenaphthylenyl, or phenanthrenyl. An aryl group may be optionally substituted
with substituents selected from, but not limited to, the group consisting of alkyl,
haloalkyl, acyl, alkoxycarbonyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy,
cyano, halogen, hydroxy, nitro, trifluoromethyl, trifiuoromethoxy,
trifluoropropyl, amino, alkylamino, dialkylamino, dialkylaminoalkyl,
hydroxyalkyl, alkoxyalkyl, alkylthio, mercapto, haloalkylthio, aryl, aryloxy,
arylthio, heterocycloalkoxy, heterocycloalkylthio, -SO3H, -SO2NH2, -O2NHalkyl,
-SO2N(alkyl)2 , -CO2H, CO2NH2, CO2NHalkyl, and -CO2N(alkyl)2. Preferred
substituents for aryl and heterocycloalkyl include: alkyl, halogen, amino,
alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, arylalkyl, and
alkylaryl. Preferably an aryl group consists of 6 to 12 carbon atoms, though
phenyl is the most preferred moiety.
[0054] For purposes of this invention, the term "heteroaryl" is defined as: (1) an
aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl
moieties are selected from 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-1,2,4-triazole, lH-tetrazole, 1-
methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole,
benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole,
quinazoline, quinoline, and isoquinoline; and (2) a bicyclic aromatic heterocycle
where a phenyl, pyridine, pyrimidine or pyridizine ring is: (a) fused to a 6-
membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom;
(b) fused to a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having
two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated)
heterocyclic ring having one nitrogen atom together with either one oxygen or
one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated)
heterocyclic ring having one heteroatom selected from O, N or S. Preferably a
heteroaryl group consists of 2 to 9 carbon atoms.
[0055] For the purposes of this invention the term "hydroxyalkyl" is defined as
an alkyl, as defined above, substituted with a hydroxyl group.

[0056] The compounds of this invention may contain an asymmetric carbon
atom and one or more asymmetric centers, and may thus give rise to optical
isomers and diastereomers. While shown without respect to stereochemistry in
formulas (I), (II), (HI), and (TV), the present invention includes all optical isomers
and diastereomers, racemic and resolved, enantiomerically pure R and S
stereoisomers, and other mixtures of the R and S stereoisomers and
pharmaceutically acceptable salts thereof.
[0057] Pharmaceutically acceptable salts of the compounds of formulas (I), (II),
(III), and (IV) with an acidic moiety can be formed from both organic and
inorganic bases. For example, alkali metal salts such as sodium, lithium, and
potassium, and N-tetraalkylammonium salts such as N-tetrabutylammonium salts.
Similarly, when a compound of this invention contains a basic moiety, salts can
be formed from organic and inorganic acids. For example, salts can be formed
from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,
mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,
camphorsulfonic, and similarly known acceptable acids.
[0058] A preferred embodiment of the compounds of formula (I) is wherein X is
CH2 or S, especially where X is S and n is 1.
[0059] Another preferred embodiment of the compounds of formula (I) is
wherein X is CH2OR3 and R3 is H or CH3, especially where n is 1.
[0060] Another preferred embodiment of the compounds of formula (I) is
wherein R, is H, -COOH, -CN, tetrazole, -CH2OH, -C(O)-CH3 or -C(O)-phenyl,
but even more preferred is where R1 is -COOH.
[0061] Yet another preferred of the compounds of formula (I) is wherein R2 is
optionally substituted phenyl, especially where the phenyl ring is substituted by
at least one substituent selected from OH, halogen, C1-C12-alkyl, amino, and -
NR3C(O)R3.
[0062] A preferred embodiment of the compounds of formula (II) is wherein R5
is H, OH, or -OCH3.
[0063] Another preferred embodiment of the compounds of formula (II) is
wherein R, is -COOH.

[0064] Yet another preferred embodiment of the compounds of formula (II) is
wherein at least one of X1-X5 is OH or -NH-C(O)-R3.
[0065] A preferred embodiment of the compounds of formula (III) is wherein R1
is-COOH.
[0066] Another preferred embodiment of the compounds of formula (III) is
wherein X1-X5 are independently selected from H, NH2, OH, halogen and alkyl,
especially where at least one of X1-X5 is OH.
[0067] A preferred embodiment of the compounds of formula (IV) is wherein R1
is -COOH or H.
[0068] Another preferred embodiment of the compounds of formula (TV) is
wherein X1-X5 are independently selected from H, halogen, NH2, alkyl and OH.
[0069] Preferred compounds of the present invention include:
2,4-dichloro-6-{[(2S)-2-(2H-tetrazol-5-yl)pyrrolidin-1-yl]sulfonyl}phenol;
(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidine-2-carbonitrile;
(4R)-4-hydroxy-l-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-L-proline;
1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-L-prolme;
1-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]-L-proline;
(4R)-1-[(3,5-dibromo-2-hydroxyphenyl)sulfonyl]-4-hydroxy-L-proline;
(4R)-1-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]-4-hydroxy-L-
proline;
1-[(5-bromo-3-chloro-2-hydroxyphenyl)sulfonyl]-L-proline;
1-[(3,5-dibromo-2-hydroxyphenyI)sulfonyl]-L-proline;
(4R)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-4-hydroxy-L-proline;
1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-L-proline;
(4R)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-4-methoxy-L-proline;
1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-D-proline;
1-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyl]-L-proline;
(4S)-4-hydroxy-1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-D-proline;
1-{(2S)-1 -[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidin-2-
yl}ethanone;
1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-D-proline;

(4R)-1-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyl]-4-hydroxy-L-
proline;
(4S)-1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-4-hydroxy-D-proline;
1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-L-proline;2,4-dichloro-6-
{[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]sulfonyl}phenol;
1-[(5-bromo-3-chloro-2-hydroxyphenyl)sulfonyl]-D-proline;
2,4-dichloro-6-(pyrrolidin-1-ylsulfonyl)phenol;
(4S)-1-[(2-amino-4-chloro-5-methylphenyl)sulfonyl]-4-hydroxy-D-proline;
(4R)-1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-4-hydroxy-L-proline;
1-({5-chloro-4-methyl-2-[(2-thienylcarbonyl)amino]phenyl}sulfonyl)-L-
proline; 1-[(3,5-dioromo-2-hydroxyphenyl)sulfonyl]-D-proline;
(4R)-1-[(2-amino-4-chloro-5-methylphenyl)sulfonyl]-4-hydroxy-L-proline;
l-{(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidin-2-
yl}propan-1-one;
{(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidin-2-
yl} (phenyl)methanone;
1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-D-proline;
1-[(2,4,6-trichlorophenyl)sulfonyl]-L-proline;
1-({5-chloro-2-[(cyclopropylcarbonyl)amino]-4-methylphenyl} sulfonyl)-L
proline;
1-{[2-(benzoylamino)-5-chloro-4-methylphenyl]sulfonyl}-L-proline;
1-[(3-chloro-4-methylphenyl)sulfonyl]-L-proline;
1-[(2,4,5-trichlorophenyl)su1fonyl]-L-proline;
(2S)-1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic
acid;
(2R)-1-[(3,4,5-tricholoro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic
acid;
(2S)-1-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]piperidine-2-
carboxylic acid;
(2R)-1-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]piperidine-2-
carboxylic acid;

(2S)-1-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyl]piperidine-2-
carboxylic acid;
(2R)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic
acid;
(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfony1]piperidine-2-carboxylic
acid;
(2R)-1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]piperidine-2-
carboxylic acid;
(4R)-3-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-
carboxylic acid;
(4S)-3-[(3,4,5-trichloro-2-hydroxyphenyl)sulfbnyl]-1,3-thiazolidine-4-
carboxylic acid;
(4R)-3-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-
carboxylic acid;
(4R)-3-[(3,5-dibromo-2-hydroxyphenyl)sulfonyl]-l,3-thiazolidine-4-
carboxylic acid;
(4R)-3-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyI]-1,3-thiazolidine-4-
carboxylic acid;
(4S)-3-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-
carboxylic acid;
(4S)-3-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-l,3-thiazolidine-4-
carboxylic acid;
2,4-dichloro-6-( 1,3-thiazolidin-3-ylsulfonyl)phenol;
(4S)-3-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-1,3-thiazolidine-4-
carboxylic acid;
(4R)-3-[(2-amino-4-chloro-5-methylphenyl)sulfonyl]-l,3-thiazolidine-4-
carboxylic acid;
(4S)-3-[(2-amino-4-chloro-S-methylphenyl)sulfonyl]-l,3-thiazolidine-4-
carboxylic acid;
(4R)-3-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-
carboxylic acid;

(4S)-3-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyl]-l,3-thiazolidine-4-
carboxylic acid; and
(4R)-3-[(2-ammo-5-chloro-4-methylphenyl)sulfonyl]-l,3-thiazolidine-4-
carboxylic acid.
[0070] Compounds of the present invention inhibit the hepatitis C RNA-
dependent RNA polymerase NS5B, and are therefore useful for the treatment of
hepatitis C infection. The present invention accordingly provides a
pharmaceutical composition that comprises a compound selected from formulas
(I), (II), (HI) and (IV) in combination or association with a pharmaceutically
acceptable carrier. The compositions are preferably adapted for oral or
subcutaneous administration. However, they may be adapted for other modes of
administration. In order to obtain consistency of administration, it is preferred
that a composition 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 compositions may be
administered from 1 to 6 times a day, more usually from 1 to 4 times a day. The
compositions of the invention may be formulated with conventional excipients,
such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and
the; like.
[0071] The present invention further provides a compound of the invention for
use as an active therapeutic substance. Compounds of formulas (Ia), (II), (III),
and (TV) are of particular use for the treatment of infection with hepatitis C virus.
[0072] 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 of formulas (Ia), (II), (III), and (IV) or a
pharmaceutical composition of the invention.

General Synthetic Schemes for Preparation of Compounds of the Present Invention

Reagents: (a) EDCI, HOBT, DIEA, DMF, RT, 6h; (b) 20% piperidine in DMF,
RT, 20 min; (c) Pyridine, RT, ON; (d) 1:1 TFA-DCM, RT, 2h.
[0073] Scheme 1 shows how compounds of formula (I) can be prepared on a
solid support using a resin, for example Wang resin. The Fmoc protected amino
acid of interest 2 was attached to the resin using coupling agents, for example
EDCI, HOBT in the presence of a base, and DIEA in a polar solvent. DMF may
be used as the polar solvent, but one skilled in the art would be aware of other
appropriate solvents. After washing the excess reagents and solvent, the amino
acid attached to the resin was deprotected using base in DMF. Appropriate bases
include alkylamine bases, for example piperidine, but skilled artisans would be
aware of other possible bases to use. The free amino acid was reacted with the
sulfonyl chloride of interest 5 in a solvent such as pyridine. Depending on the
nature of the groups on the sulfonyl chloride, a deprotection step was employed
before cleaving the product from the resin using trifluoroacetic acid and DCM.
One skilled in the art would of be aware of the possible protecting groups that can
be used to protect various functional groups from the acidic cleavage conditions.


Reagents: (g) Pyridine, THF, RT, 8 h; (h) aq. NaOH, EtOH, RT, 8 h.
[0074] Alternately, the analogs can also be obtained by following Scheme 2. In
this solution phase method, the amino acid ester of interest 8 was reacted with the
sulfonyl chloride of choice 9 in pyridine, but other solvents may be used. The
ester was hydrolyzed using a base like sodium hydroxide or lithium hydroxide to
provide the required acid.
[0075] The reagents used in the preparation of the compounds of this invention
can be either commercially obtained or can be prepared by standard procedures
described in the literature. In accordance with this invention, the compounds
described are produced by the reaction schemes shown above.
[0076] One skilled in the art would also understand how the methods of
preparation detailed in Schemes 1 and 2 would also apply to compounds of
formulas (II). (III) and (IV).
Specific Synthesis of Compounds of the Present Invention
[0077] Examples 1,2, 11 and 23 were synthesized in solution as shown in
Scheme 2.
Example 1
2,4-dichloro-6-{[(2S)-2-(2H-tetrazol-5-yl)pyrrolidin-l-yl]sulfonyl}phenol
[0078] A mixture of (2S)-1-[(3,5-dichloro-2-hydroxyphenyl) sulfonyl]
pyrrolidine-2-carbonitrile (37mg, 0.12mmol), sodium azide (24mg, 0.36 mmol),
and triethylamine hydrochloride (25mg, 0.18 mmol) in 1.5 mL of DMF was
stirred at 120°C for 6 hours. The reaction was then cooled to room temperature,
acidified by adding 2 mL of 1N HCl, and concentrated. 2,4-dichloro-6- {[(2S)-2-
(2H-tetrazol-5-yl) pyrrolidin-1-yl] sulfonyl} phenol (31mg, 71% yield) was
obtained after reverse phase chromatography. 1H NMR (DMSO-d6) δ 7.89 (d,

J=3.5 HZ, 1H), 7.60 (d, J=3.5 Hz, 1H), 5.46 (dd, 1H), 3.56 (m, 1H), 3.33 (m, 1H),
2.30 (m, 1H), 1.96 (m, 3H). HRMS: calcd for C11H11Cl2N5O3S, 364.00325;
found (ESI-, [M-H]), 364.00349.
Example 2
(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidine-2-carbonitrile
[0079] A mixture of (2S)-pyrolidine-2-carbonitrile hydrochloride (34mg, 0.2
mmol) and 3,5-dichloro-2-hydroxy-benzenesulfonyl chloride (57mg, 0.22mmol)
in 2 mL of CH^CVpyridine (1:1) was stirred at room temperature for 16 hours.
Then the reaction mixture was concentrated and purified by reverse phase
chromatography to give (2S)-l-{3,5-Dichloro-2-hydroxy-benzenesulfonyl)-
pyrrolidine-2-carbonitrile (37mg, 58% yield). 1H NMR (DMSO-d6) δ 7.86 (d,
J=2.8 HZ, 1H), 7.63 (d, J=2.8 Hz, 1H), 5.08 (br., 1H), 3.44(m, 1H), 3.18 (m, 1H),
2.54(m, 1H), 2.17 (m, 2H), 1.93 (m, 2H). HRMS: calcd for C11H10Cl2N2O3S,
320.9862; found (ESI-, [M-H]), 320.98639.
[0080] Example 23 was prepared following the same procedure described for
Example 2, except pyrolidine was substituted for (2S)-pyrolidine-2-carbonitrile
hydrochloride.
Example 11
1-['(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-L-proIine
[0081] Step 1. To a solution of L-proline methyl ester hydrochloride (8.24 g;
50.1 mmol) in pyridine (100 mL) was added 3, 5 dichloro-2-hydroxybenzene
sulfonyl chloride (15 g; 57.3 mmol) at 0°C. The reaction mixture was warmed to
room temperature and stirred for additional 4 h. The mixture was concentrated
and purified by flash chromatography on silica gel (25% ethyl acetate in hexane)
to yield 1-(3,5-Dichloro-2-hydroxy-benzenesulfonyl)-pynrolidine-2-carboxylic
acid methyl ester (8.6 g; 49%).
[0082] Step 2: The ester from step 1 was taken up in ethanol (175 mL) and 1 N
sodium hydroxide was added and stirred overnight. The reaction mixture was
then concentrated, diluted with water and extracted with ethyl acetate. The
aqueous layer was acidified with 2N HCl to yield the desired compound as white
solid (7.3 g; 89%). mp 107.4 °C; 1H NMR (CDC13) δ 7.6 (d, 1H), 7.5 (d, 1H),

4.5 (dd, 1H), 3.4(m, 2H), 2.3 (m, 2H), 2.0 (m, 2H); MS (ESI) m/z 337.82;
HRMS: calcd for C11H111C12NO5S, 337.96622; found (ESI-, [M-H]),
337.96619.
[0083] Examples 3-10,12-17,18-19, 20-22, 24-58 were prepared in solid phase
as described below for Example 20, using appropriately protected amino acids
and sulfonyl chlorides, as shown in Scheme 1.
Example 20
1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-L-proline
[0084] Step 1. 5-Chloro-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methyl-
benzenesulfonic acid. To a solution of S-Chloro-2-amino-4-methyl-
benzenesulfonic acid (3.3 g; 15.13 mmol) in water (40 mL) and sodium
bicarbonate (2.8 g) was added a solution of 9-fluorenylmethoxycarbonyl chloride
(4.3 g; 16.7 mmol) in dioxane (40 mL) at 0°C. The reaction mixture was stirred
overnight and the volatiles were removed under reduced pressure. The aqueous
layer was acidified with 2 N HCl, extracted with ethyl acetate, dried and
concentrated. The residue was purified by flash column on silica gel (10%
MeOH in EtOAc) to give a white solid (89%). 1H NMR (DMSO-d6) δ 9.9 (s,
1H), 7.9 (d, J 8 Hz, 3H), 7.7 (d, J= 8 Hz, 2H), 7.6 (s, 1H), 7.4 (m, 2H), 7.3 (m,
2H), 4.4 (d, J= 7 Hz, 2H), 4.0 (t, J= 7 Hz 1H), 2.3 (s, 3H).
[008S] Step 2. (4-Chloro-2-chlorosulfonyl-5-methyl-phenyl)-carbamic acid 9H-
fluoren-9-ylmethyl ester. Sulfonic acid (3.0 g; 6.7 mmol) from step 1 was
dissolved in 3 mL of DMF, and 2.5 mL of thionyl chloride was added dropwise at
room temperature. The resulting solution was stirred at room temperature for an
additional 4 hours and then quenched with ice and water. The white solid
precipitate was filtered and dried, and used without further purification.
[0086] Step 3. Attachment of N-Fmoc-L-Proline to Wang Resin. Wang Resin
(Ana Spec 100-200 mesh, 1% crosslinked; loading: 1.1 mmol/g; 5 g, 5.5 mmol)
was swollen in anhydrous DMF (20 ml). A solution of N-Fmoc-L-Proline (7.4 g,
22 mmol), HOBT (3.37 g, 22 mmol), DMAP (268.8 mg, 2.2 mmol) and DIC (3.4
ml, 22 mmol) in anhydrous DMF (30 ml) was added to the resin. The mixture
was shaken at room temperature on an orbital shaker overnight The mixture was

filtered and the resin was washed with DMF (3 x 50 ml), MeOH (3 x 50ml),
CH2Cl2 (3 x 50ml), and dried.
[0087] Step 4. Deprotection of Fmoc Group. The resin (5.5 mmol), prepared as
described in step 1 above, was treated with a solution of 20% piperidine in DMF
(2 x 50 ml, 10 min for the first time and 30 min for the second time) to remove
the Fmoc protecting group from the resin. The mixture was filtered and the resin
was washed with DMF (3 x 50 ml), MeOH (3 x 50ml), and CH2C12 (3 x 50ml).
[0088] Step 5. Reaction with (4-Chloro-2-chlorosulfonyl-5-methyl-phenyl)-
carbamic acid 9H-fluoren-9-ylmethyl ester. To the L-proline on Wang resin (5.5
mmol) was added a solution of (4-Chloro-2-chlorosulfonyl-5-methyl-phenyl)-
carbamic acid 9H-fluoren-9-ylmethyl ester (5.1 g, 11 mmol) in 1:1 anhydrous
CH2Cl2 and pyridine (50 ml). After shaking at room temperature overnight, the
mixture was filtered, washed with MeOH (3 x 50 ml) and CH2C12 (5 x 50 ml).
[0089] Step 6. Deprotection of Fmoc group. The resin (5.5 mmol) obtained from
step 5 was reacted again with a solution of 20% piperidine in DMF (2 x 50 ml, 10
min for the first time and 30 min for the second time). The mixture was filtered
and the resin was washed with DMF (3 x 50 ml), MeOH (3 x 50ml), CH2C12 (3 x
50 ml), and dried.
[0090] Step 7. Cleavage from resin. The above resin was treated with 1:1
TFA:CH2C12 (50ml) and was shaken at room temperature for 4 h. The mixture
was filtered and the resin was washed with CH2Cl2 (3 x 10ml). The combined
CH2Cl2 was concentrated and purified by HPLC. 1H NMR (DMSO-d6) δ 7.4 (s,
1H), 6.8 (s, 1H), 6.3 (s, 2H), 4.3 (m, 1H), 3.2 (t, 2H), 2.2 (s, 3H), 2.1 (m, 1H), 1.9
(m, 1H), 1.65-1.8 (m, 2H). HRMS: calcd for Cl2H15CIN2O4S, 319.05139; found
(ESI-FTMS, [M+H]), 319.05179.
EXAMPLES
[0091] Examples of compounds of the present invention are listed in Table 1.

Brief Description of Biological Test Procedure(s) and Text Summary of Results
[0092] The ability of the compounds of the present invention to inhibit hepatitis
C polymerase was established by the following experimental procedure:
[0093] NS5B from the BK strain (1b subtype) 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). The purified protein is mixed with radioactive
nucleotides and allowed to replicate a heteropolymeric KNA 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 UTP (Promega # p116B)
10 mM ATP (Promega # p113B)
10 mM CTP (Promega # p114B)
10 mM GTP (Promega # p115B)
BSA 10 mg/ml NEB (100X at 10 mg/ml) #007-BSA
RNaseIn (Promega #N251X) 40 U/l
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 96-well filtration plate #MADE NOB 50
Optiphase Supermix (Wallac) formulated by Fisher
Millipore Multiscreen liner for use in MicroBeta 1450-106 cassette (Wallac)
PerkinElmer #1450-433
1 M HEPES, pH 7.3

Amersham Pharmacia Biotec (US16924-500 ml)
1 MMgCl2 (SIGMA #M1028)
DTT (solid) (SIGMA # D9779)
RNAse-free water (GESCO-BRL #10977-023)
Dimethyl sulfoxide (Aldrich #27685-5)
Basilen Blue (Sigma, B5520)
0.5M EDTA, pH 8 (GIBCO-BRL #15575-020)
Dibasic sodium phosphate 7-hydrate (Na2HPO4.7H2O; Baker#3824-07)
Phosphoric acid (Baker, #0262.02)
Further reagent preparation:
[0094] 0.5 M Na Phosphate buffer. Per liter, weigh 134 g. Na2HPO4.7H2O; add
water to 900 ml. Adjust pH to 7.0 with phosphoric acid. Top off with water to 1
L.
[0095] Dilute nucleotides 1:1000 to 10 μM (GTP and CTP) or 1:100 to 100 μM
(ATP and UTP) into RNAse-free water.
Procedure:
(1) Compounds 10 μl at 10 μg/ml in 15 % DMSO
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.
When starting from 50 μg/ml compound stock in 15 % DMSO:
Add 10 μl compound per well.
(2) Enzyme Mix:



[0096] 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.
[0097] Spin down a tube of RNA (5μg/tube stored in 75°/o ethanol and 0.3 M
sodium acetate) in a microcentrifuge for 20 min. at 4 °C. One tube is enough for
1 to 1½ 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 foT -60 min. and
gently vortex. Spin briefly to ensure all RNA solution is down to the bottom of
the 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).
[0098] Add the following volumes of reagents.


[0099] Add 20 μl template mix per reaction (i.e. 20 ng of POF per reaction or ~3
nM)
[00100] (4) Incubate reaction at room temperature (22-25°C) for 2 hours.
[00101] (5) Stop reaction by adding 50 μl of 170 mM EDTA.
[00102] Final concentration of EDTA is 85 mM.
[00103] (6) Prewet filters of Millipore Multiscreen filter 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 min.
[00104] (7) Place the Multiscreen filter plate onto a Millipore Manifold and turn
on vacuum to allow buffer to flow through. Turn off vacuum. Transfer 80 μl of
the reaction product into each well of the filter plate. Let stand for 2-3 min. Turn
on vacuum to filter reaction product.
[00105] (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.
[00106] Repeat step (8) three more times.
[00107] (9) Remove polypropylene bottom. Spot dry filter at the bottom with
paper towel. Air dry filter plate on a bench for 1 hr. Add 40 μl Super Mix
scintillant. Seal top of the plate with a tape. Place plate into a Packard carrier or
MicroBeta carrier.
[00108] (10) Count plate using a Packard Topcount or MicroBeta counter.
Program 10 for 33P in Top count or 33P program in micro-beta.
ANALYSIS OF RESULTS
[00109] 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.
[00110] Table 2 shows the in vitro inhibitory activity for the compounds of the
present invention towards HCV polymerase.
Table 2

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

wherein:
R1 is H, -COOH, -CO2R4, cyano, tetrazole, a straight chain alkyl of 1 to 6 carbon
atoms optionally substituted with OH, amine or -COOH, an optionally substituted
-C(O)-C1-C12-alkyl, or an optionally substituted -C(O)- C6-C12-aryl, wherein R4 is
a C1-C12-alkyl, C6-C12-aryl, C3-C12-cycloalkyl, or C2-C9-heteroaryl, any of which
may be optionally substituted;
R2 is an aryl or a heteroaryl group optionally substituted with one to five
substituents selected from the group consisting of halogen, -NO2, -CN, -N3,
-CHO, -CF3, -OCF3, -R3, -OR3, -S(O)mR3, -NR3R3, -NR3S(O)mR3, -NR3C(O)R3,
-C(O)R3, -C(O)OR3, -C(O)NR3R3, -OC(O)R3, -OC(O)OR3, -OC(O)NR3R3,
NR3C(O)R3, -NR3C(O)OR3, and -NR3C(O)NR3R3, wherein m is 0, 1, or 2;
R3 is H, an alkyl of 1-6 carbon atoms, a branched alkyl of 1-8 carbon atoms, a
cycloalkyl of 3 to 6 carbon atoms, phenyl, a C2-C9-heteroaryl, an alkenyl of 2-6
carbon atoms, or an alkynyl of 2-6 carbon atoms;
X is CH2, CHOR3, or S; and
n is 1 or 2;
and all crystalline forms and pharmaceutically acceptable salts thereof, with the
provisos that when X is CH2, n is 1, and R1 is -COOH, R2 cannot be

wherein:
A is CH3-, CH3CH2- or a haloalkyl of 1 to 2 carbon atoms; and

B is a halogen; and
when X is CH2, n is 2, and R1 is -COOH, then R2 cannot be

2. The compound of claim 1, wherein R2 is an optionally substituted phenyl.
3. The compound of claim 1, wherein X is CH2.
4. The compound of claim 1, wherein X is CH2OR3 and R3 is H or CH3.
5. The compound of claim 4, wherein n is 1.
6. The compound of claim 1, wherein X is S.
7. The compound of claim 6, wherein n is 1.
8. The compound of claim 1, wherein R1 is H, -COOH, -CN, tetrazole,
-CH2OH, -C(O)-CH3, or -C(O)-phenyl.
9. The compound of claim 8, wherein R1 is -COOH.
10. The compound of claim 2, wherein the phenyl ring is substituted by at least
ones substituent selected from OH, halogen, alkyl, amino, and -NR3C(O)R3.
11. The compound of claim 3, wherein R2 cannot be phenyl substituted with NH2,
an alkyl, and a halogen when R1 is -COOH.

12. A compound of formula (II):

wherein:
R1 is H, -COOH, -CN, tetrazole, -C(O)R4, or a hydroxyalkyl of 1 to 4 carbon
atoms, wherein R4 is an alkyl of 1 to 4 carbon atoms or an optionally substituted
phenyl;
R5 is H, OH or -OCH3; and
X1-X5 are independently H, a halogen, OH, NH2, an alkyl of 1 to 4 carbon atoms,
-NH-C(O)-R3, wherein R3 is an alkyl of 1 to 4 carbon atoms, a C6-C12-aryl, a
cycloalkyl of 3 to 6 carbon atoms, or a C2-C9-heteroaryl;
and all crystalline forms or pharmaceutically acceptable salts thereof, with the
provisos that when R1 is -COOH, R5 is H, X3 is a halogen, and X4 is -CH3 or
-CF3, then X1 cannot be NH2, and
when R1 is -COOH, R5 is H, X2 is -CH3 or -CF3, and X3 is a halogen, then X5
cannot be NH2.
13. The compound of claim 12, wherein R5 is H.
14. The compound of claim 12, wherein R5 is OH.
15. The compound of claim 12, wherein R5 is -OCH3.
16. The compound of claim 12, wherein R\ is -COOH.
17. The compound of claim 12, wherein at least one of X1-X5 is OH.

18. The compound of claim 12, wherein at least one of X1-X5 is -NH-C(O)-R3.
19. A compound of formula (III):

wherein:
R1 is H, -COOH, -CN, tetrazole, -C(O)R4, or a hydroxyalkyl of 1 to 4 carbon
atoms, wherein R4 is an alkyl of 1 to 4 carbon atoms or an optionally substituted
phenyl; and
X1-X5 are independently H, a halogen, OH, NH2, an alkyl of 1 to 4 carbon atoms,
-NH-C(O)R3, wherein R3 is an alkyl of 1 to 4 carbon atoms, a C6-C12-aryl, a
cycloalkyl of 3 to 6 carbon atoms, or a C2-C9-heteroaryl;
and all crystalline forms and pharmaceutically acceptable salt thereof, with the
provisos that when R1 is -COOH, X3 is a halogen, and X4 is -CH3 or -CH2CH3 ,
then X1 cannot be NH2; and
when R1 is -COOH, X2 is -CH3 or -CH2CH3, and X3 is a halogen, then X5
cannot be NH2.
20. The compound of claim 19, wherein R1 is -COOH.
21. The compound of claim 19, wherein X1-X5 are independently selected from
H, NH2, OH, halogen, and alkyl.
22. The compound of claim 21, wherein at least one of X1-X5 is OH.


23. A compound of formula (IV):
wherein:
R1 is H, -COOH, -CN, tetrazole, -C(O)R4 , or a hydroxyalkyl of 1 to 4 carbon
atoms, wherein R4 is an alkyl of 1 to 4 carbon atoms or an optionally substituted
phenyl; and
X1 to X5 are independently H, a halogen, OH, NH2, an alkyl of 1 to 4 carbon
atoms, -NH-C(O)R3:, wherein R3 is an alkyl of 1 to 4 carbon atoms, a C6-C12-aryl,
a cycloalkyl of 3 to 6 carbon atoms, or a C2-C9-heteroaryl;
and all crystalline forms and pharmaceutically acceptable salts thereof.
24. The compound of claim 23, wherein R1 is -COOH or H.
25. The compound of claim 23, wherein X1-X5 are independently selected from
H, halogen, NH2, alkyl, and OH.
26. The compound of claim 1, wherein the compound is selected from:
2,4-dichloro-6-{[(2S)-2-(2H-tetrazol-5-yl)pyrrolidin-1-yl]sulfonyl}phenol;
(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidine-2-carbonitrile;
(4R.)-4-hydroxy-1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-L-proline;
1-[(3,4,5-trichloro-2-hydroxyphenyl]sulfonyl]-L-proline;
1-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]-L-proline;
(4R)-1-[(3,5-dibromo-2-hydroxyphenyl)sulfonyl]-4-hydroxy-L-proline;
(4R)-1-[(3-bromo-5-chloro-2-hydroxyphenyl)su]fonyl]-4-hydroxy-L-proline;

1-[(5-bromo-3-chloro-2-hydroxyphenyl)sulfonyl]-L-proline;
1-[(3,5-dibromo-2-hydroxyphenyl)sulfonyl]-L-proline;
(4R)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-4-hydroxy-L-proline;
1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-L-proline;
(4R)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-4-methoxy-L-proline;
1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-D-proline;
1-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyl]-L-proline;
(4S)-4-hydroxy-1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-D-proline;
1-{(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidin-2-yl}ethanone;
1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-D-proline;
(4R)-1-[(3-chIoro-5-fluoro-2-hydroxyphenyl)sulfonyl]-4-hydroxy-L-proline;
(4S)-1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-4-hydroxy-D-proline;
1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-L-proline;
2,4-dichloro-6-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl}phenol;
1-[(5-bromo-3-chloro-2-hydroxypheny])su]fonyl]-D-proline;
2,4-dichloro-6-(pyrrolidin-1 -ylsulfonyl)phenol;
(4S)-1-[(2-amino-4-chloro-5-methylphenyl)sulfonyl]-4-hydroxy-D-proline;
(4R)-1-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-4-hydroxy-L-proline;
1-[(5-chloro-4-methyl-2-[(2-thienylcarbonyl)aminolphenyl}sulfonyl)-L-proline;
1-[(3,5-dibromo-2-hydroxyphenyl)sulfonyl]-D-proline;
(4B.)-1-[(2-amino-4-chloro-5-methylphenyl)sulfonyl]-4-hydroxy-L-proline;
1-{(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidin-2-yl}propan-1-one;
{(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]pyrrolidin-2-
yl}(phenyl)methanone;
1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl] -D-proline;
1 -[{2,4,6-trichlorophenyl)sulfonyl]-L-proline; 1-({5-chloro-2-
[(cyclopropylcarbonyl)amino]-4-methylphenyl}sulfonyl)-L-proline;
l-{[2-(benzoylamino)-5-chloro-4-methylphenyl]sulfonyl}-L-proline;
1-[(3-chloro-4-methylphenyl)sulfonyl]-L-proline; 1-[(2,4,5-
trichlorophenyl)sulfonyl]-L-proline;
(2S)-1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]piperidinc-2-carboxylic acid;
(2R)-1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic acid;

(2S)-1-[3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic
acid;
(2R)-1-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic
acid;
(2S)-1-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic acid;
(2R)-1-[(3,5-dichloro-2-hydioxyphenyl)sulfonyl]piperidine-2-carboxylic acid;
(2S)-1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]piperdine-2-carboxylic acid;
(2R)-1 -[(2-amino-5-chloro-4-methylphenyl)sulfonyl]piperidine-2-carboxylic acid;
(4R)-3-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-l,3-thiazolidine-4-carboxylic
acid;
(4S)-3-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic
acid;
(4R)-3-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic
acid;
(4R.)-3-[(3,5-dibrorao-2-hydroxypheny])sulfonyl]-l,3-thiazolidine-4-carboxylic
acid;
(4R.)-3-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-
carboxylic acid;
(4S)-3-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-
carboxylic acid;
(4S)-3-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic
acid;
2,4-dichloro-6-(1,3-thiazolidin-3-ylsulfonyl)phenol;
(4S)-3-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-l,3-thiazolidine-4-carboxylic
acid;
(4B:)-3-[(2-amino-4-chloro-5-methylphenyl)sulfonyl]-l,3-thiazolidine-4-carboxylic
acid;
(4S)-3-[(2-amino-4-chloro-5-methylphenyl)sulfonyl]-1,3 -thiazolidine-4-carboxylic
acid;
(4R)-3-[(3-bromo-5-chloro-2-hydroxyphenyl)sulfonyl3-1,3-thiazolidine-4-
cafboxylic acid;

(4S)-3-[(3-chloro-5-fluoro-2-hydroxyphenyl)sulfonyl]-l,3-thiazolidine-4-
carboxylic acid; and
(4R)-3-[(2-amino-5-chloro-4-methylphenyl)sulfonyl]-l,3-thiazolidine-4-carboxylic
acid.
27. The compound of claim 12, wherein the compound of is (4R)-4-hydroxy-1-
[(3,4,5-trichloro-1-hydroxyphenyl)sulfonyl]-L-proline.
28. The compound of claim 12, wherein the compound is l-[(3,4,5-trichloro-2-
hydroxyphenyl)sulfonyl]-L-proline.
29. The compound of claim 19, wherein the compound is (2S)-1-[(3,4,5-
trichloro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic acid.
30. The compound of claim 23, wherein the compound is (4R)-3-[(3,4,5-
trichloro-2-hydroxypheayl)sulfonyl]-1,3-thiazolidine-4-carboxylic acid.
31. A pharmaceutical composition comprising a compound selected from one of
claims 1, 12, 19, or 23, and a pharmaceutically acceptable carrier.
32. The pharmaceutical composition of claim 31, wherein the compound is (4R)-
4-hydroxy-1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-L-proline.
33. The pharmaceutical composition of claim 31, wherein the compound is 1-
[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-L-proline.
34. The pharmaceutical composition of claim 31, wherein the compound is (2S)-
1-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]piperidine-2-carboxylic acid.
35. The pharmaceutical composition of claim 31, wherein the compound is (4R)-
3-[(3,4,5-trichloro-2-hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic acid.

36. A method of treating or preventing a hepatitis C infection in humans, which
comprises administering an effective amount of a compound of formula (Ia):

wherein:
R1 is H, -COOH, -CO2R4, cyano, tetrazole, a straight chain alkyl of 1 to 6 carbon
atoms optionally substituted with OH, amine, or -COOH, an optionally
substituted -C(O)-C1-C12-alkyl, or an optionally substituted-C(O)-C6-C12-aryl,
wherein R4 is a C1-C12-alkyl, C6-C12-atyl, C3-C12-cycloalkyl, or C2-C9-heteroaryl;
R2 is a C6-C12-aryl or a C2-C9-heteroaryl group optionally substituted with one to
five substituents selected from the group consisting of halogen, -NO2, -CN, -N3, -
CHO, -CF3, -OCF3, -R3, -OR3, -S(O)R3. -NR3R3, -NR3S(O)mR3,
-NR3C(O)R3, -C(O)R3, -C(O)OR3, -C(O)NR3R3, -OC(O)R3, -OC(O)OR3,
-OC(O)NR3R3, NR3C(O)R3, -NR3C(O)OR3, and -NR3C(O)NR3R3, wherein m is
0,1, or 2;
R3 is H, an alkyl of 1-6 carbon atoms, a branched alkyl of 1-8 carbon atoms, a
cycloalkyl of 3 to 6 carbon atoms, phenyl, a C2-C9-heteroaryl, an alkenyl of 2-6
carbon atoms, or an alkynyl of 2-6 carbon atoms;
X is CH2, CHOR3, or S; and
n is 1 or 2;
and all crystalline forms and pharmaceutically acceptable salts thereof.
37. The method of claim 36, wherein the compound is (4R)-4-hydroxy-1-[(3,4,5-
trichloro-2-hydroxyphenyl)sulfonyl]-L-proline.
38. The method of claim 36, wherein the compound is l-[(3,4,5-trichloro-2-
hydroxyphenyl)sulfonyl]-L-proline.
39. The method of claim 36, wherein the compound is (2S)-1-[(3,4,5-trichloro-2-
hydroxyphenyl)sulfonyl]piperidine-2-carboxylic acid.

40. The method of claim 36, wherein the compound is (4R)-3-[(3,4,5-trichloro-2-
hydroxyphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic acid.

This invention is directed to compounds of formula (I): wherein R1, R2, X, and n are as defined herein, including all crystalline forms and pharmaceutically acceptable salts thereof, with the provisos that when X is CH2, n is 1, and R1 is -COOH, then R2 cannot be formula (A) wherein A is CH3-, CH3CH2- or a haloalkyl of 1 to 2 carbon atoms, and B is a halogen; and when
X is CH2, n is 2, and R1 is -COOH, then R2 cannot be formula (A) or formula (B). The invention is also directed to compositions
containing compounds of the invention and methods of using the compounds to treat or prevent hepatitis C virus infections.