MACROCYCLIC COMPOUNDS AS INHIBITORS OF VIRAL REPLICATION

COMPOSES MACROCYCLIQUES INHIBITEURS DE REPLICATION VIRALE

English Abstract

The embodiments provide macrocylic compounds, as well as compositions,
including pharmaceutical compositions, comprising a subject compound. The
embodiments further provide treatment methods, including methods of treating
flaviviral infection, including hepatitis C virus infection and methods of
treating liver fibrosis, the methods generally involving administering to an
individual in need thereof an effective amount of a subject compound or
composition.

French Abstract

La présente invention concerne des composés représentés par les formules générales (I à XIX), ainsi que des compositions, et notamment des compositions pharmaceutiques à base d'un composé de l'invention. L'invention concerne également un procédé permettant de traiter des infections flavivirales, hépatite C comprise, ainsi que la fibrose hépatique, en administrant à l'individu atteint une quantité suffisante d'un composé ou d'une composition de l'invention.

Claims

WHAT IS CLAIMED IS:

1. A compound having the Formula I:
Image
or a pharmaceutically acceptable salt thereof,
wherein:
Q is a core ring selected from:
Image
wherein the core ring can be unsubstituted or substituted with H, halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, C1-6
alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy,
substituted
C1-6 alkoxy, C6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl,
oxazolyl,
phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl,
carbamyl,
sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl,
alkylamino,
alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl,
spirocyclic
cyclopentyl, or spirocyclic cyclohexyl,
or Q is R1-R2, wherein R1 is C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl,
phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene,
thiazole,
oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline,
isoquinoline,
quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or
benzimidazole, each
optionally substituted with up to three NR6R7 , halo, cyano, nitro, hydroxy,
C1-6 alkyl,
-389-


C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, or
C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally
substituted
with up to 5 fluoro; and R2 is H, phenyl, pyridine, pyrazine, pyrimidine,
pyridazine,
pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole,
isothiazole,
naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,

benzofuran, indole, or benzimidazole, each optionally substituted with up to
three
NR6R7, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-20
alkylcycloalkyl,
C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally
substituted with up to
fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, or
benzyl, said
phenyl or benzyl optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or
(CO)CHR21NH(CO)R22;

R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally
substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6
alkoxy, or
phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, C1-6
alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5
fluoro, or C1-6
alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl
optionally
substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked
through the
-390-


C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrahydropyran ring
linked
through the C4 position of the tetrahydropyran ring;
Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-6 alkyl, C3-7

cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted
from one to
three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl, or R9 is
C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, or
C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally
substituted
with up to 5 fluoro; or R9 is a C1-6 alkyl optionally substituted with up to 5
fluoro
groups, NR6R7, NR1aR1b, or (CO)OH, or R9 is a heteroaromatic ring optionally
substituted up to two times with halo, cyano, nitro, hydroxyl, or C1-6 alkoxy;
or Y is a
carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug
thereof;
wherein R1a and R1b are each independently H, C1-6 alkyl, C3-7
cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted
from
one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl,
or R1a and R1b are each independently H and C6 or 10 aryl which is
optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl,
C3-7
cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6
alkyl,
C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro,
or R1a and R1b are each independently H, heterocycle, which is a five-,
six-, or seven-membered, saturated or unsaturated heterocyclic molecule,
containing from one to four heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur,
or NR1a R1b is a three- to six- membered alkyl cyclic amine, which
optionally has one to three hetero atoms incorporated in the ring, and which
is
optionally substituted from one to three times with halo, cyano, nitro, C1-6
alkoxy, amido, or phenyl,
or NR1a R1b is a heteroaryl selected from the group consisting of:
-391-


Image
wherein R1c is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6
cycloalkoxy, NO2, N(R1d)2, NH(CO)R1d, or NH(CO)NHR1d, wherein each R1a is
independently H, C1-6 alkyl, or C3-6 cycloalkyl,
or R1c is NH(CO)OR1e, wherein R1e is C1-6 alkyl or C3-6 cycloalkyl;
p= 0 or 1;
V is selected from O, S, or NH;
when V is O or S, W is selected from 0, NR15, or CR15; when V is NH, W is
selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10

alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;
the dashed lines represent an optional double bond;
R21 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or
R21 is C6 or 10
aryl which is optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R21 is pyridyl, pyrimidyl, pyrazinyl,
thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
R22 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkyl optionally substituted with up to 5 fluoro, or phenyl;
with the proviso that the compound of Formula I does not include a compound
having the Formula II, III, or IV:

-392-


Image
wherein, with respect to Formula II, III, and IV:
(aa) R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1-6
alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, or
C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally
substituted
with up to 5 fluoro, C6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl,
thiazolyl, oxazolyl,
phenoxy, thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7, NHC(S)NR6R7, C(O)NR6R7,
NR6R7, C(O)R8, C(O)OR8, NHC(O)R8, NHC(O)OR8, SO m R8, NHS(O)2R8,
(CH2)n NR6R7, O(CH2)n NR6R7, or O(CH2)n R9 where R9 is imidazolyl or
pyrazolyl; said
thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R1
and R2 are
optionally substituted by up to two halo, cyano, nitro, hydroxy, C1-6 alkyl,
C3-7
cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6
alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro; said C6 or 10 aryl, pyridyl, phenoxy and thiophenoxy in
the definition
of R1 and R2 are optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
(bb) m= 0, 1, or 2;
(cc) R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl phenyl or
benzyl,
said phenyl or benzyl optionally substituted by up to three halo, cyano,
nitro, hydroxy,
-393-


C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
(dd) R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8,
or (CO)CHR21NH(CO)R22;

(ee) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;

(ff) R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by
up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted
with up to 5
fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6
alkyl
optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran
ring linked
through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a
tetrahydropyran ring
linked through the C4 position of the tetrahydropyran ring;
(gg) Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-6 alkyl,

C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally
substituted from one to
three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl, or R9 is
C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, or
C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally
substituted
with up to 5 fluoro; or R9 is a C1-6 alkyl optionally substituted with up to 5
fluoro
groups, NR6R7, or (CO)OH, or R9 is a heteroaromatic ring optionally
substituted up to
two times with halo, cyano, nitro, hydroxyl, or C1-6 alkoxy; or Y is a
carboxylic acid or
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pharmaceutically acceptable salt, solvate, or prodrug thereof;
(hh) R10 and R11 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally
substituted with
up to 5 fluoro, (CH2)N NR6R7, (CH2)N C(O)OR14 where R14 is H, C1-6 alkyl, C3-7

cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted
from one to
three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro; said C6 or 10 aryl, in the definition of R10 and R11 is
optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7
cycloalkyl, C4-10
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
or R10 and R11 are taken together with the carbon to which they are attached
to form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R10 and R11 are
combined as O;
(ii) p= 0 or 1;
(jj) R12 and R13 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally
substituted with
up to 5 fluoro, (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7

cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from
one to three
times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6
or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is
optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7
cycloalkyl, C4-10
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
or R12 and R13 are taken together with the carbon to which they are attached
to form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R12 and R13 are each
-395-


independently C1-6 alkyl optionally substituted with (CH2)n OR8;
(kk) R20 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10
aryl,
hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or
(CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which
is optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7
cycloalkyl, C4-10
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted
by up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted
with up to 5
fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro;
(11) n = 1-4;
(mm) V is selected from O, S, or NH;
(nn) when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W
is selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-
10
alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;
(oo) the dashed line represents an optional double bond;
(pp) R21 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or
R21 is C6 or 10
aryl which is optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R21 is pyridyl, pyrimidyl, pyrazinyl,
thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
(qq) R22 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkyl optionally substituted with up to 5 fluoro, or phenyl; and

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(rr) Z is a fused or appended aryl or heteroaryl ring system.

2. The compound or salt thereof of Claim 1, wherein the core ring is:
Image
3. The compound or salt thereof of Claim 1, wherein the core ring is:

Image
4. The compound or salt thereof of Claim 1, wherein the core ring is:
Image

5. The compound or salt thereof of Claim 1 of the formula Ia:
Image
6. The compound or salt thereof of Claim 1 of the formula Ib:

-397-


Image
7. The compound or salt thereof of Claim 1 of the formula Ic:

Image
8. The compound or salt thereof of Claim 1 of the formula Id:
Image

-398-


9. The compound or salt thereof of Claim 1 of the formula Ie:
Image

10. The compound or salt thereof of Claim 1 of the formula If:
Image
11. The compound or salt thereof of Claim 1 of the formula Ig:

-399-


Image
12. The compound or salt thereof of Claim 1 of the formula Ih:

Image
13. The compound or salt thereof of Claim 1 of the formula Ii:
-400-


Image
14. The compound or salt thereof of Claim 1 of the formula Ij:

Image
15. The compound or salt thereof of Claim 1 of the formula Iz:
Image

16. The compound or salt thereof of any one of Claims 1 to 15, wherein Y is
-401-


sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is selected from the group
consisting
of C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, and NR1a R1b, wherein
R1a and R1b are each
independently H, C1-6 alkyl, or C3-7 cycloalkyl.

17. The compound or salt thereof of any one of Claims 1 to 16, wherein the C13-

C14 double bond is cis.

18. The compound or salt thereof of any one of Claims 1 to 16, wherein the C13-

C14 double bond is trans.

19. A pharmaceutical composition comprising:
a) the compound or salt thereof of any one of Claims 1 to 18; and
b) a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of Claim 19 in a formulation free of any
alcohol and any poly-ol.

21. The pharmaceutical composition of Claim 20, wherein the formulation is
free of
any sugar alcohol and any poly (ethylene glycol) (PEG).

22. The pharmaceutical composition of Claim 19 in an aqueous formulation free
of
any excipient that reduces polarity in the aqueous formulation.

23. The pharmaceutical composition of any one of Claims 19 to 22 in a tablet
formulation.

24. The pharmaceutical composition of any one of Claims 19 to 22 in a caplet
formulation.

25. The pharmaceutical composition of any one of Claims 19 to 22 in a capsule
formulation.

26. Use of the compound or salt thereof of any one of Claims 1 to 18 for
treating a
hepatitis C virus infection in an individual.

-402-


27. Use of the compound or salt thereof of any one of Claims 1 to 18 for
preparation
of a medicament for treating a hepatitis C virus infection in an individual.

28. The use of Claim 26 or 27, wherein the compound is for achieving a
sustained
viral response.

29. The use of Claim 26, 27 or 28, wherein the compound is for use with a
nucleoside analog.

30. The use of Claim 29, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

31. The use of any one of Claims 26 to 30, wherein the compound is for use
with a
NS5B RNA-dependent RNA polymerase inhibitor.

32. The use of any one of Claims 26 to 31, wherein the compound is for use
with
thymosin-.alpha..

33. The use of Claim 32, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

34. The use of any one of Claims 26 to 33, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

35. The use of Claim 34, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µ about 300 µ

36. The use of any one of Claims 26 to 35, wherein the compound is for use
with
interferon-alpha (IFN-.alpha.).

37. The use of Claim 36, wherein the IFN-.alpha.oPEG (30 kD, linear)-ylated
consensus IFN-.alpha.ministration at a dosing interval of every 8 days to
every 14 days.

-403-


38. The use of Claim 36, wherein the IFN-.alpha. is monoPEG(30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of once every 7
days.

39. The use of Claim 36, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

40. The use of any one of Claims 26 to 39, wherein the compound is for use
with an
agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

41. Use of the compound or salt thereof of any one of Claims 1 to 18 for
treating
liver fibrosis in an individual.

42. Use of the compound or salt thereof of any one of Claims 1 to 18 for
preparation
of a medicament for treating liver fibrosis in an individual.

43. The use of Claim 41 or 42, wherein the compound is for use with a
nucleoside
analog.

44. The use of Claim 43, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

45. The use of any one of Claims 41 to 44, wherein the compound is for use
with a
NS5B RNA-dependent RNA polymerase inhibitor.

46. The use of any one of Claims 41 to 45, wherein the compound is for use
with
thymosin-.alpha..

47. The use of Claim 46, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

48. The use of any one of Claims 41 to 47, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

-404-


49. The use of Claim 48, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µg to about 300 µg.

50. The use of any one of Claims 41 to 49, wherein the compound is for use
with
interferon-alpha (IFN-.alpha.).

51. The use of Claim 50, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of every 8 days
to every 14 days.

52. The use of Claim 50, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of once every 7
days.

53. The use of Claim 50, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

54. The use of any one of Claims 41 to 53, wherein the compound is for use
with an
agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

55. Use of the compound or salt thereof of any one of Claims 1 to 18 for
increasing
liver function because of a hepatitis C virus infection.

56. Use of the compound or salt thereof of any one of Claims 1 to 18 for
preparation
of a medicament for increasing liver function because of a hepatitis C virus
infection.

57. The use of Claim 55 or 56, wherein the compound is for use with a
nucleoside
analog.

58. The use of Claim 57, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

59. The use of any one of Claims 55 to 58, wherein the compound is for use
with a
NS5B RNA-dependent RNA polymerase inhibitor.

-405-


60. The use of any one of Claims 55 to 59, wherein the compound is for use
with
thymosin-.alpha..

61. The use of Claim 60, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

62. The use of any one of Claims 55 to 61, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

63. The use of Claim 62, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µg to about 300 µg.

64. The use of any one of Claims 55 to 63, wherein the compound is for use
with
interferon-alpha (IFN-.alpha.).

65. The use of Claim 64, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of every 8 days
to every 14 days.

66. The use of Claim 64, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of once every 7
days.

67. The use of Claim 64, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

68. The use of any one of Claims 55 to 67, wherein the compound is for use
with an
agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

69. A compound having the Formula XI:
-406-


Image
or a pharmaceutically acceptable salt thereof,
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H and C6 or 10 aryl which is optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7
cycloalkyl, C4-10
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
or R1a and R1b are each independently H or heterocycle, which is a five-, six-
, or
seven-membered, saturated or unsaturated heterocyclic molecule, containing
from one
to four heteroatoms selected from the group consisting of nitrogen, oxygen and
sulfur;
or NR1a R1b is a three- to six- membered alkyl cyclic amine, which optionally
has
one to three hetero atoms incorporated in the ring, and which is optionally
substituted
from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or
phenyl;
or NR1a R1b is a heteroaryl selected from the group consisting of:
Image

wherein R1c is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6
cycloalkoxy,
NO2, N(R1d)2, NH(CO)R1d, or NH(CO)NHR1d, wherein each R1d is independently H,
C1-6 alkyl, or C3-6 cycloalkyl;
or R1c is NH(CO)OR1e wherein R1e is C1-6 alkyl, or C3-6 cycloalkyl;
-407-


(b) V is selected from O, S, or NH;
(c) when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W is
selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10

alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;

(d) R2 is a bicyclic amine with the structure of
Image

wherein R21 and R22 are each independently H, halo, cyano, nitro, hydroxy, C1-
6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy
optionally
substituted with up to 5 fluoro, C6 or 10 aryl, pyridyl, pyrimidyl, thienyl,
furanyl,
thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7,
NHC(S)NR6R7, C(O)NR6R7, NR6R7, C(O)R8, C(O)OR8, NHC(O)R8, NHC(O)OR8,
SO m R8 (m = 0, 1 or 2), or NHS(O)2R8; said thienyl, pyrimidyl, furanyl,
thiazolyl and
oxazolyl in the definition of R21 and R22 are optionally substituted by up to
two halo,
cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-
6 alkenyl,
C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to
5 fluoro, or
C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl,
pyridyl, phenoxy
and thiophenoxy in the definition of R21 and R22 are optionally substituted by
up to
three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted
with up to 5
fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
wherein R10 and R11 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-
10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally
substituted with
up to 5 fluoro, (CH2)n NR6R7, or (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl,
C3-7
cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted
from one to
three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
-408-


C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally
substituted with
up to 5 fluoro; said C6 or 10 aryl, in the definition of R10 and R11 is
optionally substituted
by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10

alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
or R10 and R11 are taken together with the carbon to which they are attached
to form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R10 and R11 are
combined as O;
wherein p = 0 or 1;
wherein R12 and R13 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-
10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally
substituted with
up to 5 fluoro, (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7

cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted
from one to
three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally
substituted with
up to 5 fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is
optionally substituted
by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10

alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
or R12 and R13 are taken together with the carbon to which they are attached
to form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
wherein R20 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10
aryl,
hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro,
(CH2)n NR6R7,
or (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, or C4-10
alkylcycloalkyl,
which are all optionally substituted from one to three times with halo, cyano,
nitro,
hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally
substituted by
up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl,
C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally
substituted with up to
-409-


fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or
10 aryl, in
the definition of R20 is optionally substituted by up to three halo, cyano,
nitro, hydroxy,
C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
wherein n = 0-4;
wherein R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10

alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
or R2 is R2a R2b when W = NH and V = O, wherein

R2a is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, pyridine,
pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole,
oxazole,
imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline,
isoquinoline,
quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or
benzimidazole, each
optionally substituted with up to three NR2c R2d, halo, cyano, nitro, hydroxy,
C1-6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro;
R2b is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan,
thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole,
naphthyl,
quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,
benzofuran,
indole, or benzimidazole, each optionally substituted with up to three NR2c
R2d, halo,
cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-
6 alkenyl,
C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to
5 fluoro, or
C1-6 alkoxy optionally substituted with up to 5 fluoro;
said R2c and R2d are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
-410-


alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R2c and R2d are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
(e) R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl,
said
phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6
alkyl, C3-7
cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6
alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro;
(f) R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, or S(O)2R8;
(g) R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all

optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by
up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted
with up to 5
fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; and
(h) the dashed line represents an optional double bond.
70. The compound of Claim 1 having the Formula XII:
Image

-411-


XII
or a pharmaceutically acceptable salt thereof,
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from the group
consisting of:

Image
wherein R1c is H;
or NR1a R1b is a three- to six- membered alkyl cyclic amine, which optionally
has
one to three hetero atoms incorporated in the ring, and which is optionally
substituted
from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or
phenyl;
(b) R21 and R22 are each independently H, halo, cyano, hydroxy, C1-3 alkyl, or

C1-3 alkoxy;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;
(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-
tetrahydrofuryl;
(f) R10 and R11 are each independently H, halo, C1-3 alkyl, or R10 and R11 are

taken together with the carbon to which they are attached to form cyclopropyl,

cyclobutyl, cyclopentyl, or cyclohexyl;
(g) R12 and R13 are each independently H, halo, C1-6 alkyl, C3-7 cycloalkyl,
C4-10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally
substituted with
up to 5 halo atoms; and
(h) the dashed line represents an optional double bond.
71. The compound of Claim 1 having the Formula XIII:
-412-


Image
or a pharmaceutically acceptable salt thereof,
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from the group
consisting of:

Image
wherein R10 is H;
or NR1a R1b is a three- to six- membered alkyl cyclic amine, which optionally
has
one to three hetero atoms incorporated in the ring, and which is optionally
substituted
from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or
phenyl;
(b) R21 and R22 are each independently H, halo, cyano, hydroxy, C1-3 alkyl, or

C1-3 alkoxy;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;
(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-
tetrahydrofuryl;
and

-413-


(f) the dashed line represents an optional double bond.
72. The compound of Claim 1 having the Formula XIV:

Image
or a pharmaceutically acceptable salt thereof,
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from a group
consisting of:

Image
wherein R1c is H;
or NR1a R1b is a three- to six- membered alkyl cyclic amine, which optionally
has
one to three hetero atoms incorporated in the ring, and which is optionally
substituted
from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or
phenyl;
(b) R2a is C6 or C10 aryl optionally substituted with up to three NR2c R2d,
halo,
cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-
6 alkenyl,
C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up
to 5 fluoro,
C1-6 alkoxy optionally substituted with up to 5 fluoro;
said R2c and R2d are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
-414-


nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R2c and R2d are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;
(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-
tetrahydrofuryl;
and
(f) the dashed line represents an optional double bond.
73. A pharmaceutical composition comprising:
a) the compound or salt thereof of any one of Claims 69 to 72; and
b) a pharmaceutically acceptable carrier.

74. The pharmaceutical composition of Claim 73 in a formulation free of any
alcohol and any poly-ol.

75. The pharmaceutical composition of Claim 74, wherein the formulation is
free of
any sugar alcohol and any poly (ethylene glycol) (PEG).

76. The pharmaceutical composition of Claim 73 in an aqueous formulation free
of
any excipient that reduces polarity in the aqueous formulation.

77. The pharmaceutical composition of any one of Claims 73 to 76 in a tablet
formulation.

78. The pharmaceutical composition of any one of Claims 73 to 76 in a caplet
formulation.

79. The pharmaceutical composition of any one of Claims 73 to 76 in a capsule
formulation.

-415-


80. Use of the compound or salt thereof of any one of Claims 69 to 72 for
treating a
hepatitis C virus infection in an individual.

81. Use of the compound or salt thereof of any one of Claims 69 to 72 for
preparation of a medicament for treating a hepatitis C virus infection in an
individual.

82. The use of Claim 80 or 81, wherein the compound is for achieving a
sustained
viral response.

83. The use of Claim 80 or 82, wherein the compound is for use with a
nucleoside
analog.

84. The use of Claim 83, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

85. The use of any one of Claims 80 to 84, wherein the compound is for use
with a
NS5B RNA-dependent RNA polymerase inhibitor.

86. The use of any one of Claims 80 to 84, wherein the compound is for use
with
thymosin-.alpha..

87. The use of Claim 86, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

88. The use of any one of Claims 80 to 87, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

89. The use of Claim 88, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µg to about 300 µg.

90. The use of any one of Claims 80 to 89, wherein the compound is for use
with
interferon-alpha(IFN-.alpha.).

-416-


91. The use of Claim 90, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of every 8 days
to every 14 days.

92. The use of Claim 90, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of once every 7
days.

93. The use of Claim 90, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

94. The use of any one of Claims 80 to 93, wherein the compound is for use
with an
agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

95. Use of the compound or salt thereof of any one of Claims 69 to 72 for
treating
liver fibrosis in an individual.

96. Use of the compound or salt thereof of any one of Claims 69 to 72 for
preparation of a medicament for treating liver fibrosis in an individual.

97. The use of Claim 95 or 96, wherein the compound is for use with a
nucleoside
analog.

98. The use of Claim 97, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

99. The use of any one of Claims 95 to 98, wherein the compound is for use
with a
NS5B RNA-dependent RNA polymerase inhibitor.

100. The use of any one of Claims 95 to 99, wherein the compound is for use
with
thymosin-.alpha..

101. The use of Claim 100, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

-417-


102. The use of any one of Claims 95 to 101, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

103. The use of Claim 102, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µg to about 300 µg.

104. The use of any one of Claims 95 to 103, wherein the compound is for use
with
interferon-alpha (IFN-.alpha.).

105. The use of Claim 104, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of every 8 days
to every 14 days.

106. The method of Claim 104, wherein the IFN-.alpha. is monoPEG (30 kD,
linear)-
ylated consensus IFN-.alpha. for administration at a dosing interval of once
every 7 days.

107. The use of Claim 104, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

108. The use of any one of Claims 95 to 107, wherein the compound is for use
with
an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

109. Use of the compound or salt thereof of any one of Claims 69 to 72 for
increasing
liver function because of a hepatitis C virus infection.

110. Use of the compound or salt thereof of any one of Claims 69 to 72 for
preparation of a medicament for increasing liver function because of a
hepatitis C virus
infection.

111. The use of Claim 109 or 110, wherein the compound is for use with a
nucleoside
analog.

112. The use of Claim 111, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

-418-


113. The use of any one of Claims 109 to 112, wherein the compound is for use
with
a NS5B RNA-dependent RNA polymerase inhibitor.

114. The use of any one of Claims 109 to 113, wherein the compound is for use
with
thymosin-.alpha..

115. The use of Claim 114, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

116. The use of any one of Claims 109 to 115, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

117. The use of Claim 116, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µg to about 300 µg.

118. The use of any one of Claims 109 to 117, wherein the compound is for use
with
interferon-alpha (IFN-.alpha.).

119. The use of Claim 118, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of every 8 days
to every 14 days.

120. The use of Claim 118, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of once every 7
days.

121. The use of Claim 118, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

122. The use of any one of Claims 109 to 121, wherein the compound is for use
with
an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

123. A compound having the Formula XVIII:
-419-


Image
wherein
(a) R1 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl,
pyridine,
pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole,
oxazole,
imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline,
isoquinoline,
quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or
benzimidazole, each
optionally substituted with up to three NR5R6, halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro;
(b) R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,
furan,
thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole,
naphthyl,
quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,
benzofuran,
indole, or benzimidazole, each optionally substituted with up to three NR5R6,
halo,
cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-
6 alkenyl,
C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to
5 fluoro, or
C1-6 alkoxy optionally substituted with up to 5 fluoro;
(c) R3 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl,
said
phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6
alkyl, C3-7
cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6
alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
-420-


with up to 5 fluoro;
(d) R4 is C1-6 alkyl, C(O)NR5R6, C(S)NR5R6, C(O)R7, C(O)OR7, or S(O)2R7;
(e) R5 and R6 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R5 and R6 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
(f) R7 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, or phenyl; or R7 is C6 or 10 aryl which is optionally substituted by
up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted
with up to 5
fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
(g) R8 is C1-3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally
substituted by
up to two halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy; and
(h) the dashed line represents an optional double bond;
or a pharmaceutically acceptable salt thereof.

124. The compound or salt thereof of Claim 123, wherein
R1 is phenyl, benzothiazole, benzothiophene, benzofuran, or benzimidazole,
each optionally substituted with up to 1-2 NR5R6, halo, cyano, nitro, hydroxy,
C1-2
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C1-6 alkoxy, hydroxy-C1-6
alkyl, C1-6 alkyl
optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted with up
to 5 fluoro;
R2 is H, phenyl, pyridine, pyrimidine, thiazole, oxazole, isoxazole, or
pyrazole,
each optionally substituted with up to 1-2 NR5R6, halo, cyano, nitro, hydroxy,
C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;

-421-


R3 is H;
R4 is C1-6 alkyl, C(O)NR5R6, C(S)NR5R6, C(O)R, C(O)OR7, or S(O)2R7;
R5 and R6 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to two
halo, cyano,
hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl,
hydroxy-C1-6
alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R5 and R6 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
R7 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally
substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6
alkoxy, or
phenyl; or R7 is C6 or 10 aryl which is optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, C1-6
alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5
fluoro, or C1-6
alkoxy optionally substituted with up to 5 fluoro;
R8 is C1-3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally substituted
by up
to two halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy; and the dashed line
represents an
optional double bond.

125. The compound or salt thereof of Claim 123, wherein
R1 is phenyl, benzothiazole, or benzothiophene each optionally substituted
with
up to 1-2 halo, hydroxy, C1-2 alkyl, C1-6 alkyl optionally substituted with up
to 5 fluoro,
or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R2 is H or phenyl optionally substituted with up to 1-2 halo, hydroxy, C1-3
alkyl,
alkyl, or C1-3 alkyl optionally substituted with up to 5 fluoro, or C1-6
alkoxy optionally
substituted with up to 5 fluoro;
R3 is H;
R4 is C1-6 alkyl, C(O)NR5R6, C(O)R7, or C(O)OR7;
R5 is H and R6 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or
phenyl,
said phenyl optionally substituted by up to two halo, cyano, hydroxy, C1-6
alkyl, C3-7
cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, or C1-6
alkyl
-422-


optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted
with up to 5
fluoro;
R7 is C1-6 alkyl or C3-7 cycloalkyl, which are all optionally substituted from
one
to three times with halo or phenyl; or R7 is C6 or 10 aryl which is optionally
substituted
by up to one halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
R8 is C1-3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally substituted
by up
to two halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy; and the dashed line
represents an
optional double bond.

126. A pharmaceutical composition comprising:
a) the compound or salt thereof of Claim 123, 124 or 125; and
b) a pharmaceutically acceptable carrier.

127. The pharmaceutical composition of Claim 126 in a formulation free of any
alcohol and any poly-ol.

128. The pharmaceutical composition of Claim 127, wherein the formulation is
free
of any sugar alcohol and any poly (ethylene glycol) (PEG).

129. The pharmaceutical composition of Claim 126 in an aqueous formulation
free of
any excipient that reduces polarity in the aqueous formulation.

130. The pharmaceutical composition of any one of Claims 126 to 129 in a
tablet
formulation.

131. The pharmaceutical composition of any one of Claims 126 to 129 in a
caplet
formulation.

132. The pharmaceutical composition of any one of Claims 126 to 129 in a
capsule
formulation.

-423-


133. Use of the compound or salt thereof of Claim 123, 124 or 125 for treating
a
hepatitis C virus infection in an individual.

134. Use of the compound or salt thereof of Claim 123, 124 or 125 for
preparation of
a medicament for treating a hepatitis C virus infection in an individual.

135. The use of Claim 133 or 134, wherein the compound is for achieving a
sustained
viral response.

136. The use of Claim 133, 134 or 135, wherein the compound is for use with a
nucleoside analog.

137. The use of Claim 136, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

138. The use of any one of Claims 133 to 137, wherein the compound is for use
with
a NS5B RNA-dependent RNA polymerase inhibitor.

139. The use of any one of Claims 133 to 138, wherein the compound is for use
with
thymosin-.alpha..

140. The use of Claim 139, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

141. The use of any one of Claims 133 to 140, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

142. The use of Claim 141, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µg to about 300 µg.

143. The use of any one of Claims 133 to 142, wherein the compound is for use
with
interferon-alpha (IFN-.alpha.).

144. The use of Claim 143, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
-424-


consensus IFN-.alpha. for administration at a dosing interval of every 8 days
to every 14 days.

145. The use of Claim 143, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of once every 7
days.

146. The use of Claim 143, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

147. The use of any one of Claims 133 to 146, wherein the compound is for use
with
an agent selected from 3'-.azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

148. Use of the compound or salt thereof of Claim 123, 124 or 125 for treating
liver
fibrosis in an individual.

149. Use of the compound or salt thereof of Claim 123, 124 or 125 for
preparation of
a medicament for treating liver fibrosis in an individual.
150. The use of Claim 148 or 149, wherein the compound is for use with a
nucleoside
analog.

151. The use of Claim 150, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

152. The use of any one of Claims 148 to 151, wherein the compound is for use
with
a NS5B RNA-dependent RNA polymerase inhibitor.

153. The use of any one of Claims 148 to 152, wherein the compound is for use
with
thymosin-.alpha..

154. The use of Claim 153, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

155. The use of any one of Claims 148 to 154, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

-425-


156. The use of Claim 155, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µg to about 300 µg.

157. The use of any one of Claims 148 to 156, wherein the compound is for use
with
interferon-alpha (IFN-.alpha.).

158. The use of Claim 157, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of every 8 days
to every 14 days.

159. The use of Claim 157, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of once every 7
days.

160. The use of Claim 157, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

161. The use of any one of Claims 148 to 160, wherein the compound is for use
with
an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

162. Use of the compound or salt thereof of claim 123, 124 or 125 for
increasing liver
function because of a hepatitis C virus infection.

163. Use of the compound or salt thereof of claim 123, 124 or 125 for
preparation of
a medicament for increasing liver function because of a hepatitis C virus
infection.

164. The use of Claim 162 or 163, wherein the compound is for use with a
nucleoside
analog.

165. The use of Claim 164, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

166. The use of any one of Claims 162 to 165, wherein the compound is for use
with
a NS5B RNA-dependent RNA polymerase inhibitor.

-426-


167. The use of any one of Claims 162 to 166, wherein the compound is for use
with
thymosin-.alpha..

168. The use of Claim 167, wherein the thymosin-.alpha. is for administration
subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

169. The use of any one of Claims 162 to 168, wherein the compound is for use
with
interferon-gamma (IFN-.gamma.).

170. The use of Claim 169, wherein the IFN-.gamma. is for administration
subcutaneously in
an amount of from about 10 µg to about 300 µg.

171. The use of any one of Claims 162 to 170, wherein the compound is for use
with
interferon-.alpha (IFN-.alpha.).

172. The use of Claim 171, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of every 8 days
to every 14 days.

173. The use of Claim 171, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration at a dosing interval of once every 7
days.

174. The use of Claim 171, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

175. The use of any one of Claims 162 to 174, wherein the compound is for use
with
an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

176. A compound of the formula:

-427-


Image
or a pharmaceutically acceptable salt thereof,
wherein:
(a) Z is a group configured to hydrogen bond to an NS3 protease His57
imidazole moiety and to hydrogen bond to a NS3 protease Gly137 nitrogen atom;
(b) P1' is a group configured to form a non-polar interaction with at least
one
NS3 protease S1' pocket moiety selected from the group consisting of Lys136,
Gly137,
Ser139, His57, G1y58, Gln41, Ser42, and Phe43;
(c) L is a linker group consisting of from 1 to 5 atoms selected from the
group
consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
(d) P2 is selected from the group consisting of unsubstituted aryl,
substituted
aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted
heterocyclic and
substituted heterocyclic; P2 being positioned by L to form a non-polar
interaction with
at least one NS3 protease S2 pocket moiety selected from the group consisting
of His57,
Arg155, Va178, Asp79, Gln80 and Asp81;
(e) the dashed line represents an optional double bond;
(f) R5 is selected from the group consisting of H, C(O)NR6R7 and C(O)OR8;
(g) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl; and

-428-


(h) R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all

optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by
up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted
with up to 5
fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-
6 alkyl
optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran
ring linked
through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a
tetrahydropyran ring
linked through the C4 position of the tetrahydropyran ring;
with the proviso that the compound does not include a compound having the
Formula II, III, or IV:

Image
wherein, with respect to Formula II, III, and IV:
(aa) R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1-6
alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, or
C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally
substituted
with up to 5 fluoro, C6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl,
thiazolyl, oxazolyl,
phenoxy, thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7 , NHC(S)NR6R7, C(O)NR6R7,
NR6R7, C(O)R8, C(O)OR8, NHC(O)R8, NHC(O)OR8, SO m R8, NHS(O)2R8
(CH2)n NR6R7, O(CH2)n NR6R7, or O(CH2)n R9 where R9 is imidazolyl or
pyrazolyl; said
thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R1
and R2 are
-429-


optionally substituted by up to two halo, cyano, nitro, hydroxy, C1-6 alkyl,
C3-7
cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6
alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro; said C6 or 10 aryl, pyridyl, phenoxy and thiophenoxy in
the definition
of R1 and R2 are optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
(bb)m=0, 1,or 2;
(cc) R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl phenyl or
benzyl,
said phenyl or benzyl optionally substituted by up to three halo, cyano,
nitro, hydroxy,
C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
(dd) R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8,
or (CO)CHR21NH(CO)R22;
(ee) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
(ff) R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by
up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted
with up to 5
fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6
alkyl
optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran
ring linked
-430-


through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a
tetrahydropyran ring
linked through the C4 position of the tetrahydropyran ring;
(gg) Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-6 alkyl,

C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally
substituted from one to
three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl, or R9 is
C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, or
C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally
substituted
with up to 5 fluoro; or R9 is a C1-6 alkyl optionally substituted with up to 5
fluoro
groups, NR6R7, or (CO)OH, or R9 is a heteroaromatic ring optionally
substituted up to
two times with halo, cyano, nitro, hydroxyl, or C1-6 alkoxy; or Y is a
carboxylic acid or
pharmaceutically acceptable salt, solvate, or prodrug thereof;
(hh) R10 and R11 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally
substituted with
up to 5 fluoro, (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7

cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted
from one to
three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro; said C6 or 10 aryl, in the definition of R10 and R11 is
optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7
cycloalkyl, C4-10
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
or R10 and R11 are taken together with the carbon to which they are attached
to form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R10 and R11 are
combined as O;
(ii) p= 0 or 1;
(jj) R12 and R13 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally
substituted with
up to 5 fluoro, (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7

-431-


cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from
one to three
times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6
or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-
6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is
optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7
cycloalkyl, C4-lo
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
or R12 and R13 are taken together with the carbon to which they are attached
to form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R12 and R13 are each
independently C1-6 alkyl optionally substituted with (CH2)n OR8;
(kk) R20 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10
aryl,
hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or
(CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which
is optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7
cycloalkyl, C4-10
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted
by up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted
with up to 5
fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro;
(ll) n = 1-4;
(mm) V is selected from O, S, or NH;
(nn) when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W
is selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-
10
alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;
(oo) the dashed line represents an optional double bond;
-432-


(pp) R21 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or
R21 is C6 or 10
aryl which is optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R21 is pyridyl, pyrimidyl, pyrazinyl,
thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
(qq) R22 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkyl optionally substituted with up to 5 fluoro, or phenyl; and
(rr) Z is a fused or appended aryl or heteroaryl ring system;
with the proviso that the compound does not include a compound having the
formula:

Image
-433-


Image
-434-


Image
177. The compound or salt thereof of Claim 176 of the formula

Image
-435-


178. The compound or salt thereof of Claim 176 of the formula
Image

179. The compound or salt thereof of Claim 176, 177 or 178, in which L
consists of
from 2 to 5 atoms.

180. The compound or salt thereof of Claim 176, 177 or 178, in which L
comprises a
-W-C(=V)- group, where V and W are each individually selected from O, S or NH.

181. The compound or salt thereof of Claim 176, 177 or 178, in which L is
selected
from the group consisting of ester, amide, carbamate, thioester, and
thioamide.

182. The compound or salt thereof of Claim 176, 177 or 178, wherein L is a
linker
group consisting of from 1 to 5 atoms selected from the group consisting of
nitrogen, hydrogen
and sulfur.

183. The compound or salt thereof of any one of Claims 176 to 182 in which P2
is
further positioned by L to form a hydrogen bonding interaction with at least
one NS3 protease
S2 pocket moiety selected from the group consisting of His57, Arg155, Va178,
Asp79, Gln80,
and Asp81.

184. The compound or salt thereof of Claim 179 in which L is selected from the

group consisting of -OCH2- and -NHCH2-.

185. The compound or salt thereof of Claim 179 in which L is selected from the

group consisting of -CH=CH- and -C.ident.C-.

-436-


186. The compound or salt thereof of Claim 179 in which L is selected from the

group consisting of -SCH2-, -SO2-, and -CH2SO-.

187. The compound or salt thereof of Claim 179 in which L is selected from the

group consising of -WC(=V)-NH- and -WC(=V)-O-, where V and W are each
individually
selected from O, S or NH.

188. The compound or salt thereof of any one of Claims 176 to 186, wherein the

C13-C14 double bond is cis.

189. The compound or salt thereof of any one of Claims 176 to 186, wherein the

C13-C14 double bond is trans.

190. The compound or salt thereof of any one of Claims 176 to 189, wherein P2
is
selected from the group consisting of unsubstituted heterocycle and
substituted heterocycle.
191. The compound or salt thereof of anyone of Claims 176 to 189, in which P2
is
Image

192. A compound having the formula:
Image
-437-


or a pharmaceutically acceptable salt thereof,
wherein:

Image
Q is a core ring selected from:
wherein the core ring can be unsubstituted or substituted with H, halo, cyano,

nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, C1-6
alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy,
substituted
C1-6 alkoxy, C6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl,
oxazolyl,
phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl,
carbamyl,
sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl,
alkylamino,
alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl,
spirocyclic
cyclopentyl, or spirocyclic cyclohexyl,
or Q is R1-R2, wherein R1 is C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl,
phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene,
thiazole,
oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline,
isoquinoline,
quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole,
each
optionally substituted with up to three NR6R7 , halo, cyano, nitro, hydroxy,
C1-6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro; and R2 is H, phenyl, pyridine, pyrazine, pyrimidine,
pyridazine,
pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole,
isothiazole,
naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,

benzofuran, indole, benzimidazole, each optionally substituted with up to
three NR6R7,
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted
with up to 5
fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, or
benzyl, said
phenyl or benzyl optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
-438-


alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
R5 is C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or
(CO)CHR21NH(CO)R22;
R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally
substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6
alkoxy, or
phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, C1-6
alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5
fluoro, or C1-6
alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl
optionally
substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked
through the
C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrahydropyran ring
linked
through the C4 position of the tetrahydropyran ring;
Y is COOR9, wherein R9 is C1-6 alkyl;
V is selected from O, S, or NH;
when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W is
selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10

alkylcycloalkyl or C1-6 alkyl optionally substituted with up to 5 fluoro;
the dashed line represents an optional double bond;
R21 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or
R21 is C6 or 10
aryl which is optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
-439-


alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R21 is pyridyl, pyrimidyl, pyrazinyl,
thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
R22 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkyl optionally substituted with up to 5 fluoro, or phenyl; and
with the proviso that the compound does not include a compound having the
formula

Image
193. The compound or salt thereof of Claim 192 of the formula:
Image

194. A compound having the formula:
-440-


Image
or a pharmaceutically acceptable salt thereof,
wherein:
R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, or
benzyl, said
phenyl or benzyl optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
R5 is C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or
(CO)CHR21NH(CO)R22;
R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally
substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6
alkoxy, or
phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, C1-6
alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5
fluoro, or C1-6
alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl
optionally
substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked
through the
-441-


C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrahydropyran ring
linked
through the C4 position of the tetrahydropyran ring;
Y is a sulfonimide of the formula -C(O)NHS(O)2R9;
R9 is C1-3 alkyl, C3-7 cycloalkyl, or phenyl which is optionally substituted
by up
to two halo, cyano, nitro, hydroxy, C1-3 alkyl, C3-7 cycloalkyl, or C1-3
alkoxy, or Y is a
carboxylic acid;

V is selected from OH, SH, or NH2;
the dashed line represents an optional double bond;
R21 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or
R21 is C6 or 10
aryl which is optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R21 is pyridyl, pyrimidyl, pyrazinyl,
thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy,or thiophenoxy;
R22 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkyl optionally substituted with up to 5 fluoro, or phenyl; and
with the proviso that the compound does not include a compound having the
formula:

Image
195. The compound or salt thereof of Claim 194 of the formula
-442-


Image
or a pharmaceutically acceptable salt thereof.

196. The compound or salt thereof of Claim 194 or 195, wherein Y is a
sulfonimide
of the formula -C(O)NHS(O)2R9, and wherein V is selected from OH and NH2.

197. A compound having the formula:

Image
or a pharmaceutically acceptable salt thereof,
wherein:

Image
Q is a core ring selected from:
wherein the core ring can be unsubstituted or substituted H, halo, cyano,
nitro,
hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-
6 alkoxy,
hydroxy-C1-6 alkyl, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy,
substituted C1-6
alkoxy, C6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl,
oxazolyl, phenoxy,
thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl,
sulphide,
-443-


sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino,
alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl,
spirocyclic
cyclopentyl, or spirocyclic cyclohexyl,
or Q is R1-R2, wherein R1 is C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl,
phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene,
thiazole,
oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline,
isoquinoline,
quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole,
each
optionally substituted with up to three NR6R7 , halo, cyano, nitro, hydroxy,
C1-6 alkyl,
C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-
6 alkyl, C1-6
alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally
substituted
with up to 5 fluoro; and R2 is H, phenyl, pyridine, pyrazine, pyrimidine,
pyridazine,
pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole,
isothiazole,
naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,

benzofuran, indole, benzimidazole, each optionally substituted with up to
three NR6R7,
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, C2-6
alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted
with up to 5
fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, or
benzyl, said
phenyl or benzyl optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro;
R5 is C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or
(CO)CHR21NH(CO)R22;

R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6
alkoxy optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
-444-


morpholinyl;
R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally
substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6
alkoxy, or
phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, C1-6
alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5
fluoro, or C1-6
alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl
optionally
substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked
through the
C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrahydropyran ring
linked
through the C4 position of the tetrahydropyran ring;
Y is COOR9, wherein R9 is C1-6 alkyl; or Y is a sulfonimide of the formula
-C(O)NHS(O)2R9, where R9 is C1-3 alkyl, C3-7 cycloalkyl, or phenyl which is
optionally
substituted by up to two halo, cyano, nitro, hydroxy, C1-3 alkyl, C3-7
cycloalkyl, or C1-3
alkoxy, or Y is a carboxylic acid;
V and W are each individually selected from O, S, or NH;
the dashed line represents an optional double bond;
R21 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or
R21 is C6 or 10
aryl which is optionally substituted by up to three halo, cyano, nitro,
hydroxy, C1-6
alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy,
hydroxy-C1-6
alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R21 is pyridyl, pyrimidyl, pyrazinyl,
thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy,or thiophenoxy;
R22 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1-6
alkyl optionally substituted with up to 5 fluoro, or phenyl; and
with the proviso that the compound does not include a compound having the
formula:

-445-


Image
198. The compound or salt thereof of Claim 1 having the Formula XII:

Image
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from the group
consisting of:

-446-


Image
wherein R1c is H;
or NR1aR1b is a three- to six- membered alkyl cyclic amine, which optionally
has
one to three hetero atoms incorporated in the ring, and which is optionally
substituted
from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or
phenyl;
(b) R21 and R22 are each independently H, halo, cyano, hydroxy, C1-3 alkyl, or

C1-3 alkoxy;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;
(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-
tetrahydrofuryl;
(f) R10 and R11 are each independently H, halo, C1-3 alkyl, or R10 and R11 are

taken together with the carbon to which they are attached to form cyclopropyl,

cyclobutyl, cyclopentyl, or cyclohexyl;
(g) R12 and R13 are each independently H, halo, C1-6 alkyl, C3-7 cycloalkyl,
C4-10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally
substituted with
up to 5 halo atoms; and
(h) the dashed line represents an optional double bond.

199. The compound or salt thereof of Claim 1 having the Formula XIII:
-447-


Image
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from the group
consisting of:

Image
wherein R1c is H;
or NR1a R1b is a three- to six- membered alkyl cyclic amine, which optionally
has
one to three hetero atoms incorporated in the ring, and which is optionally
substituted
from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or
phenyl;
(b) R21 and R22 are each independently H, halo, cyano, hydroxy, C1-3 alkyl, or

C1-3 alkoxy;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;
(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-
tetrahydrofuryl;
-448-



and
(f) the dashed line represents an optional double bond.

200. The compound or salt thereof of Claim 1 having the Formula XIV:
Image
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from a group
consisting of:

Image
wherein R1c is H;
or NR1a R1b is a three- to six- membered alkyl cyclic amine, which optionally
has
one to three hetero atoms incorporated in the ring, and which is optionally
substituted
from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or
phenyl;
(b) R2a is C6 or C10 aryl optionally substituted with up to three NR2c R2d,
halo,
cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-
6 alkenyl,
C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up
to 5 fluoro,
C1-6 alkoxy optionally substituted with up to 5 fluoro;


-449-



said R2c and R2d are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6
alkenyl, hydroxy-
C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy
optionally
substituted with up to 5 fluoro; or R2c and R2d are taken together with the
nitrogen to
which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;
(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-
tetrahydrofuryl;
and
(f) the dashed line represents an optional double bond.

201. The compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176
to
200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition containing
either entity for use in the treatment of a hepatitis C virus infection in an
individual.

202. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125,
and
176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition
containing either entity for the treatment of a hepatitis C virus infection in
an individual.

203. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125,
and
176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition
containing either entity in the preparation of a medicament for the treatment
of a hepatitis C
virus infection in an individual.

204. The use of Claim 202 or 203, wherein the treatment achieves a sustained
viral
response.

205. The use of Claim 202, 203 or 204, wherein the use further comprises use
of a

-450-



nucleoside analog.

206. The use of Claim 205, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

207. The use of any one of Claims 202 to 206, wherein the use further
comprises use
of a NS5B RNA-dependent RNA polymerase inhibitor.

208. The use of any one of Claims 202 to 207, wherein the use further
comprises use
of thymosin-.alpha..

209. The use of Claim 208, wherein the thymosin-.alpha. is for subcutaneous
delivery
twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

210. The use of any one of Claims 202 to 209, wherein the use further
comprises use
of interferon-gamma (IFN-.gamma.).

211. The use of Claim 210, wherein the IFN-.gamma. is for subcutaneous
delivery in an
amount of from about 10 µg to about 300 µg.

212. The use of any one of Claims 202 to 211, wherein the use further
comprises use
of interferon-alpha (IFN-.alpha.).

213. The use of Claim 212, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration in a dosing interval of every 8 days
to every 14 days.

214. The use of Claim 212, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration in a dosing interval of once every 7
days.

215. The use of Claim 212, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

216. The use of any one of Claims 202 to 215, wherein the use further
comprises use
of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an

-451-



inosine monophosphate dehydrogenase inhibitor.

217. The compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176
to
200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition containing
either entity for use in the treatment of liver fibrosis in an individual.

218. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125,
and
176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition
containing either entity for the treatment of liver fibrosis in an individual.

219. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125,
and
176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition
containing either entity in the preparation of a medicament for the treatment
of liver fibrosis in
an individual.

220. The use of Claim 218 or 219, wherein the use further comprises use of a
nucleoside analog.

221. The use of Claim 220, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

222. The use of any one of Claims 218 to 221, wherein the use further
comprises use
of a NS5B RNA-dependent RNA polymerase inhibitor.

223. The use of any one of Claims 218 to 222, wherein the use further
comprises use
of thymosin-.alpha..

224. The use of Claim 223, wherein the thymosin-.alpha. is for subcutaneous
delivery
twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

225. The use of any one of Claims 218 to 224, wherein the use further
comprises use
of interferon-gamma (IFN-.gamma.).


-452-



226. The use of Claim 225, wherein the IFN-.gamma. is for subcutaneous
delivery in an
amount of from about 10 µg to about 300 µg.

227. The use of any one of Claims 218 to 226, wherein the use further
comprises use
of interferon-alpha (IFN-.alpha.).

228. The use of Claim 227, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN- .alpha. for administration in a dosing interval of every 8 days
to every 14 days.

229. The use of Claim 227, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration in a dosing interval of once every 7
days.

230. The use of Claim 227, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

231. The use of any one of Claims 218 to 230, wherein the use further
comprises use
of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine, 2-,3-
didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

232. The compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176
to
200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition containing
either entity for use in increasing liver function in an individual having a
hepatitis C virus
infection.

233. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125,
and
176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition
containing either entity for increasing liver function in an individual having
a hepatitis C virus
infection.

234. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125,
and
176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition
containing either entity in the preparation of a medicament for the increasing
liver function in

-453-



an individual having a hepatitis C virus infection.

235. The use of Claim 233 or 234, wherein the use further comprises use of a
nucleoside analog.

236. The use of Claim 235, wherein the nucleoside analog is selected from
ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.

237. The use of any one of Claims 233 to 236, wherein the use further
comprises use
of a NS5B RNA-dependent RNA polymerase inhibitor.

238. The use of any one of Claims 233 to 237, wherein the use further
comprises use
of thymosin-.alpha..

239. The use of Claim 238, wherein the thymosin-.alpha. is for subcutaneous
delivery
twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

240. The use of any one of Claims 233 to 239, wherein the use further
comprises use
of interferon-gamma (IFN-.gamma.).

241. The use of Claim 240, wherein the IFN-.gamma. is for subcutaneous
delivery in an
amount of from about 10 µg to about 300 µg.

242. The use of any one of Claims 223 to 241, wherein the use further
comprises use
of interferon-alpha (IFN-.alpha.).

243. The use of Claim 242, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration in a dosing interval of every 8 days
to every 14 days.

244. The use of Claim 242, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-
ylated
consensus IFN-.alpha. for administration in a dosing interval of once every 7
days.

245. The use of Claim 242, wherein the IFN-.alpha. is INFERGEN consensus IFN-
.alpha..

-454-



246. The use of any one of Claims 233 to 245, wherein the use further
comprises use
of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-
dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil,
cidofovir, and an
inosine monophosphate dehydrogenase inhibitor.

247. A pharmaceutical composition for curative or prophylactic treatment of a
hepatitis C virus infection, comprising the compound of any one of Claims 1 to
18, 69 to 72,
123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof,
together with a
pharmaceutically acceptable diluent or carrier.

248. The pharmaceutical composition of any one of Claims 19 to 25, 73 to 79
and
126 to 132, for curative or prophylactic treatment of a hepatitis C virus
infection.

249. A commercial package containing, as active pharmaceutical ingredient, the

compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200,
or a
pharmaceutically acceptable salt thereof, together with instructions for its
use for curative or
prophylactic treatment of a hepatitis C virus infection in an animal.

250. A pharmaceutical composition for curative or prophylactic treatment of
liver
fibrosis, comprising the compound of any one of Claims 1 to 18, 69 to 72, 123
to 125, and 176
to 200, or a pharmaceutically acceptable salt thereof, together with a
pharmaceutically
acceptable diluent or carrier.

251. The pharmaceutical composition of any one of Claims 19 to 25, 73 to 79
and
126 to 132, for curative or prophylactic treatment of liver fibrosis.

252. A commercial package containing, as active pharmaceutical ingredient, the

compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200,
or a
pharmaceutically acceptable salt thereof, together with instructions for its
use for the curative
or prophylactic treatment of liver fibrosis in an animal.


-455-



253. A pharmaceutical composition for increasing liver function in an
individual
having a hepatitis C virus infection, comprising the compound of any one of
Claims 1 to 18, 69
to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt
thereof, together with a
pharmaceutically acceptable diluent or carrier.

254. The pharmaceutical composition of any one of Claims 19 to 25, 73 to 79
and
126 to 132, for increasing liver function in an individual having a hepatitis
C virus infection.
255. A commercial package containing, as active pharmaceutical ingredient, the
compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200,
or a
pharmaceutically acceptable salt thereof, together with instructions for its
use for increasing
liver function in an individual having a hepatitis C virus infection in an
animal.


-456-

Description

CA 02560897 2007-08-08

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

CECI EST LE TOME 1 DE 2

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des
Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

THIS IS VOLUME OF _2

NOTE: For additional volumes please contact the Canadian Patent Office.


CA 02560897 2010-03-26

MACROCYCLIC COMPOUNDS AS INHIBITORS OF VIRAL REPLICATION
Background of the Inventi
on
Field of the Invention
[00021 The present invention relates to compounds, processes for their
syntheses, pharmaceutical compositions, and methods for the treatment of
flaviviral
infections, such as hepatitis C virus (HCV) infection. In particular, the
present invention
provides novel peptide analogs, pharmaceutical compositions containing such
analogs and
methods for using these analogs in the treatment of flaviviral infection.

Description of the Related Art
[00031 Hepatitis C virus (HCV) infection is the most common chronic blood
borne infection in the United States. Although the numbers of new infections
have
declined, the burden of chronic infection is substantial, with Centers for
Disease Control
estimates of 3.9 million (1.8%) infected persons in the United States. Chronic
liver disease
is the tenth leading cause of death among adults in the United States, and
accounts for
approximately 25,000 deaths annually, or approximately 1 % of all deaths.
Studies indicate
that 40% of chronic liver disease is HCV-related, resulting in an estimated
8,000-10,000
deaths each year. HCV-associated end-stage liver disease is the most frequent
indication
for liver transplantation among adults.

-1-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[vuu4) Antiviral therapy of chronic hepatitis C has evolved rapidly over the
last
decade, with significant improvements seen in the efficacy of treatment.
Nevertheless,
even with combination therapy using pegylated IFN-a plus ribavirin, 40% to 50%
of
patients fail therapies, i.e., are nonresponders or relapsers. These patients
currently have no
effective therapeutic alternative. In particular, patients who have advanced
fibrosis or
cirrhosis on liver biopsy are at significant risk of developing complications
of advanced
liver disease, including ascites, jaundice, variceal bleeding, encephalopathy,
and
progressive liver failure, as well as a markedly increased risk of
hepatocellular carcinoma.

[00051 The high prevalence of chronic HCV infection has important public
health implications for the future burden of chronic liver disease in the
United States. Data
derived from the National Health and Nutrition Examination Survey (NHANES III)
indicate that a large increase in the rate of new HCV infections occurred from
the late
1960s to the early 1980s, particularly among persons between 20 to 40 years of
age. It is
estimated that the number of persons with long-standing HCV infection of 20
years or
longer could more than quadruple from 1990 to 2015, from 750,000 to over 3
million. The
proportional increase in persons infected for 30 or 40 years would be even
greater. Since
the risk of HCV-related chronic liver disease is related to the duration of
infection, with the
risk of cirrhosis progressively increasing for persons infected for longer
than 20 years, this
increase in the number of persons with long-standing HCV infection could
result in a
substantial increase in cirrhosis-related morbidity and mortality among
patients infected
between the years of 1965-1985.

[0006) HCV is an enveloped positive strand RNA virus in the Flaviviridae
family. The single strand HCV RNA genome is approximately 9500 nucleotides in
length
and has a single open reading frame (ORF) encoding a single large polyprotein
of about
3000 amino acids. In infected cells, this polyprotein is cleaved at multiple
sites by cellular
and viral proteases to produce the structural and non-structural (NS) proteins
of the virus.
In the case of HCV, the generation of mature nonstructural proteins (NS2, NS3,
NS4,
NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first
viral protease
cleaves at the NS2-NS3 junction of the polyprotein. The second viral protease
is serine
protease contained within the N-terminal region of NS3 (herein referred to as
"NS3
protease"). NS3 protease mediates all of the subsequent cleavage events at
sites
downstream relative to the position of NS3 in the polyprotein (i.e., sites
located between
the C-terminus of NS3 and the C-terminus of the polyprotein). NS3 protease
exhibits
-2-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
activity both in cis, at the N93-NS4 cleavage site, and in trans, for the
remaining NS4A-
NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is believed to serve
multiple functions, acting as a cofactor for the NS3 protease and possibly
assisting in the
membrane localization of NS3 and other viral replicase components. Apparently,
the
formation of the complex between NS3 and NS4A is necessary for NS3-mediated
processing events and enhances proteolytic efficiency at all sites recognized
by NS3. The
NS3 protease also exhibits nucleoside triphosphatase and RNA helicase
activities. NS5B is
an RNA-dependent RNA polymerase involved in the replication of HCV RNA.
Literature
[0007] METAVIR (1994) Hepatology 20:15-20; Brunt (2000) Hepatol. 31:241-
246; Alpini (1997) J. Hepatol. 27:371-380; Baroni et al. (1996) Hepatol.
23:1189-1199;
Czaja et al. (1989) Hepatol. 10:795-800; Grossman et al. (1998) J.
Gastroenterol. Hepatol.
13:1058-1060; Rockey and Chung (1994) J. Invest. Med. 42:660-670; Sakaida et
al. (1998)
J Hepatol. 28:471-479; Shi et al. (1997) Proc. Natl. Acad. Sci. USA 94:10663-
10668;
Baroni et al. (1999) Liver 19:212-219; Lortat-Jacob et al. (1997) J. Hepatol.
26:894-903;
Llorent et al. (1996) J. Hepatol. 24:555-563; U.S. Patent No. 5,082,659;
European Patent
Application EP 294,160; U.S. Patent No. 4,806,347; Balish et al. (1992) J.
Infect. Diseases
166:1401-1403; Katayama et al. (2001) J. Viral Hepatitis 8:180-185; U.S.
Patent No.
5,082,659; U.S. Patent No. 5,190,751; U.S. Patent No. 4,806,347; Wandl et al.
(1992) Br.
J. Haematol. 81:516-519; European Patent Application No. 294,160; Canadian
Patent No.
1,321,348; European Patent Application No. 276,120; Wandl et al. (1992) Sena.
Oncol.
19:88-94; Balish et al. (1992) J. Infectious Diseases 166:1401-1403; Van Dijk
et al. (1994)
Int. J. Cancer 56:262-268; Sundmacher et al. (1987) Current Eye Res. 6:273-
276; U.S.
Patent Nos. 6,172,046; 6,245,740; 5,824,784; 5,372,808; 5,980,884; published
international
patent applications WO 96/21468; WO 96/11953; WO 00/59929; WO 00/66623;
W02003/064416; W02003/064455; W02003/064456; WO 97/06804; WO 98/17679; WO
98/22496; WO 97/43310; WO 98/46597; WO 98/46630; WO 99/07733; WO 99/07734,
WO 00/09543; WO 00/09558; WO 99/38888; WO 99/64442; WO 99/50230; WO
95/33764; Torre et al. (2001) J. Med. Virol. 64:455-459; Bekkering et al.
(2001) J. Hepatol.
34:435-440; Zeuzem et al. (2001) Gastroenterol. 120:1438-1447; Zeuzem (1999)
J.
Hepatol. 31:61-64; Keeffe and Hollinger (1997) Hepatol. 26:1015-107S; Wills
(1990) Clin.
Pharmacokinet. 19:390-399; Heathcote et al. (2000) New Engl. J. Med. 343:1673-
1680;
Husa and Husova (2001) Bratisl. Lek. Listy 102:248-252; Glue et al. (2000)
Clin.

-3-


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WO 2005/095403 PCT/US2005/010494
Pharmacol. 6$:556-567; Bailon et al. (2001) Bioconj. Chena. 12:195-202; and
Neumann et
al. (2001) Science 282:103; Zalipsky (1995) Adv. Drug Delivery Reviews S. 16,
157-182;
Mann et al. (2001) Lancet 358:958-965; Zeuzem et al. (2000) New Engl. J. Med.
343:1666-
1672; U.S. Patent Nos. 5,633,388; 5,866,684; 6,018,020; 5,869,253; 6,608,027;
5,985,265;
5,908,121; 6,177,074; 5,985,263; 5,711,944; 5,382,657; and 5,908,121; Osborn
et al.
(2002) J. Pharmacol. Exp. Therap. 303:540-548; Sheppard et al. (2003) Nat.
Immunol.
4:63-68; Chang et al. (1999) Nat. Biotechnol. 17:793-797; Adolf (1995)
Multiple Sclerosis
1 Suppl. 1:544-S47; Chu et al., Tet. Lett. (1996), 7229-7232; Ninth Conference
on
Antiviral Research, Urabandai, Fukyshima, Japan (1996) (Antiviral Research,
(1996), 30:
1, A23 (abstract 19)); Steinkuhler et al., Biochena., 37: 8899-8905;
Ingallinella et al.,
Biochem., 37: 8906-8914.

Summary of the Invention

[0008] The embodiments provide a compound having the Formula I:
Q
v=~
W
O N
NH I
R4RSN 8 O
7
9 14
12
13
11
[0009] wherein:

[0010] Q is a core ring selected from:

I
( p I \ fN

/ [0011] wherein the core ring can be unsubstituted or substituted with H,
halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2_6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl, substituted C1_6 alkyl, C1_6 alkoxy,
substituted C1_6
alkoxy, C6 or to aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl,
oxazolyl, phenoxy,
thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl,
sulphide,
-4-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino,
alkylcarboxy,
carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic
cyclopentyl, or
spirocyclic cyclohexyl,

[0012] or Q is R1-R2, wherein R1 is C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,
furan,
thiophene, thiazole, oxazole, ilnidazole, isoxazole, pyrazole, isothiazole,
napthyl, quinoline,
isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole,
or
benzimidazole, each optionally substituted with up to three NR6R7, halo, cyan,
nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, .C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro; and R2 is H, phenyl, pyridine,
pyrazine,
pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole,
imidazole, isoxazole,
pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline,
benzothiazole,
benzothiophene, benzofuran, indole, or benzimidazole, each optionally
substituted with up
to three NR6R7, halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl,
C4.10
alkylcycloalkyl, C2.6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl
optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;
[0013] R4 is H, C1_6 alkyl, C3.7 cycloalkyl, 04.10 alkylcycloalkyl, phenyl, or
benzyl, said phenyl or benzyl optionally substituted by up to three halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, 04.10 alkylcycloalkyl, C2.6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0014] R5 is H, C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8,
S(O)2R8, or (CO)CHR21NH(CO)R22;

[0015] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up,to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, C1.6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;
[0016] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
-5-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
nitro flydroxy, C1_6 alkyl, C3_7 cycloalkyl, C¾-lo alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1.6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring;

[0017] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_6
alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are all optionally
substituted from one
to three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl, or R9
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, or C1.6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; or R9 is a C1_6 alkyl optionally substituted with up to 5 fluoro
groups, NR6R7,
NR1aRlb, or (CO)OH, or R9 is a heteroaromatic ring optionally substituted up
to two times
with halo, cyano, nitro, hydroxyl, or C1_6 alkoxy; or Y is a carboxylic acid
or
pharmaceutically acceptable salt, solvate, or prodrug thereof;
[0018] wherein Rla and Rlb are each independently H, C1_6 alkyl, C3_7
cycloalkyl, or C4_10 alkylcycloalkyl, which are all optionally substituted
from one to three
times with halo, cyano, nitro, C1.6 alkoxy, amido, or phenyl,

[0019] or Rla and Rlb are each independently H and C6 or 10 aryl which is
optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl,
C3_7 cycloalkyl,
C4_10 alkylcycloalkyl, C2_6 alkenyl, C1.6 alkoxy, hydroxy-C1_6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, or C1.6 alkoxy optionally substituted with up
to 5 fluoro,

[0020] or Rla and Rlb are each independently H, heterocycle, which is a five-,
six-, or seven-membered, saturated or unsaturated heterocyclic molecule,
containing from
one to four heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur,
[0021] or NRlaRlb is a three- to six- membered alkyl cyclic secondary amine,
which optionally has one to three hetero atoms incorporated in the ring, and
which is
optionally substituted from one to three times with halo, cyano, nitro, C1.6
alkoxy, amido, or
phenyl,
[0022] or NR1aRlb is a heteroaryl selected from the group consisting of-
-6-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
-`N^N `-N~N
ANN
R1c ~'\R1c and Rtc

[0023] wherein Rle is H, halo, C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3_6
cycloalkoxy, NO2, N(RId)2, NH(CO)RId, or NH(CO)NHRId, wherein each Rld is
independently H, C1_6 alkyl, or C3_6 cycloalkyl,

[0024] or Ric is NH(CO)OR", wherein Rle is C1_6 alkyl or C3_6 cycloalkyl;
[0025] p= 0 or 1;

[0026] V is selected from 0, S, or NH;

[0027] when V is 0 or S, W is selected from 0, NR15, or CR15; when V is NH,
W is selected from NR15 or CR15, where R15 is H, C1_6 alkyl, C3_7 cycloalkyl,
C4-10
alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;

[0028] the dashed lines represent an optional double bond;

[0029] R21 is C1_6 alkyl, C3_7 cycloalkyl, C4_i0 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
C1_6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6
or 10 aryl which
is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2.6 alkenyl, C1.6 alkoxy, hydroxy-C1.6
alkyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; or or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl,
thiazolyl, oxazolyl,
phenoxy, or thiophenoxy; and

[0030] R22 is C1.6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkyl
optionally substituted with up to 5 fluoro, or phenyl; with the proviso that
the compound
having the Formula I does not include a compound having the Formula II, III,
or IV as
defined below.

[0031] The embodiments provide a compound having the Formula II, III, or
IV:

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R11 R11 R11 \1
R10 -I~ R10 R1 R10 Z-R2

R20 20 20
1 \ \ R2 R I \" R
N R13 N \~ N 13
V=< R12 V=< Ra V=~ R12
W W W
ON NH Y O N N N 7r ~
NH Y O r NH Y
:7,

9 14 9 14 g 14
R4R5N 8 O R4R5N 3 O R4R5N 8 0
12 12 12
13 13 13
11 10 11 10 11

II III IV
[0032] wherein:
[0033] a) R1 and R2 are each independently H, halo, cyano, nitro, hydroxy,
C1_6
alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, or
C1_6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally
substituted with
up to 5 fluoro, C6 or 1o aryl, pyridal, pyrimidal, thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy,
thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7, NHC(S)NR6R7, C(O)NR6R7, NR6R7, C(O)R8,
C(O)ORS, NHC(O)R8, NHC(O)OR8, SO,,,R8, NHS(O)2R8, CH INR6R7, OCHõNR6R7, or
OCHIR9 where R9 is imidazolyl or pyrazolyl; said thienyl, pyrimidal, furanyl,
thiazolyl and
oxazolyl in the definition of R1 and R2 are optionally substituted by up to
two halo, cyano,
nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; said C6 or 10 aryl, pyridal,
phenoxy and
thiophenoxy in the definition of R1 and R2 are optionally substituted by up to
three halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2_6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro;

[0034] b) m = 0, 1, or 2;
[0035] c) R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl phenyl
or
benzyl, said phenyl or benzyl optionally substituted by up to three halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
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CA 02560897 2006-09-20
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nyaroxy-U1_6 alkyl, c;1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0036] d) R5 is H, C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8,
S(O)2R8, or (CO)CHR21NH(CO)R22;

[0037] e) R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl,
C4.10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0038] f) R8 is C1.6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which
are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1.6 alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring;

[0039] g) Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_6
alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are all optionally
substituted from one
to three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl, or R9
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; or R9 is a CI-6 alkyl optionally substituted with up to 5 fluoro
groups, NR6R7, or
(CO)OH, or R9 is a heteroaromatic ring optionally substituted up to two times
with halo,
cyano, nitro, hydroxyl, or C1_6 alkoxy; or Y is a carboxylic acid or
pharmaceutically
acceptable salt, solvate, or prodrug thereof;
[0040] h) R10 and R11 are each independently H, C1.6 alkyl, C3_7 cycloalkyl,
C4-
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1.6 alkyl, C1.6 alkyl optionally
substituted with up
to 5 fluoro, (CH2).NR6R7, (CH2)õC(O)OR14 where R14 is H, Cl_6 alkyl, C3_7
cycloalkyl, or
C4-1o alkylcycloalkyl, which are all optionally substituted from one to three
times with halo,
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WO 2005/095403 PCT/US2005/010494
cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which
is optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3-7
cycloalkyl, C4-10
alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1.6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
said C6 or 10 aryl, in the definition of R10 and R'1 is optionally substituted
by up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3_7 cycloalkyl, C4-io
alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to
5 fluoro, or C1-6
alkoxy optionally substituted with up to 5 fluoro; or R10 and R11 are taken
together with the
carbon to which they are attached to form cyclopropyl, cyclobutyl,
cyclopentyl, or
cyclohexyl; or R10 and R11 are combined as 0;

[0041] i) p= 0 or 1;

[0042] j) Ri2 and R13 are each independently H, C1-6 alkyl, C3.7 cycloalkyl,
C4-10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1-6 alkyl optionally
substituted with up to
fluoro, (CH2)õNR6R7, (CH2)õC(O)OR14 where R14 is H, C1-6 alkyl, C3-7
cycloalkyl, C4-i0
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which
is optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3_7
cycloalkyl, C4-10
alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl
optionally
substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up
to 5 fluoro;
said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted
by up to three
halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-1o
alkylcycloalkyl, C2-6 alkenyl,
C1-6 alkoxy, hydroxy-C1-6 alkyl, C1.6 alkyl optionally substituted with up to
5 fluoro, or CI-6
alkoxy optionally substituted with up to 5 fluoro; or R12 and R13 are taken
together with the
carbon to which they are attached to form cyclopropyl, cyclobutyl,
cyclopentyl, or
cyclohexyl; or R12 and R13 are each independently C1.6 alkyl optionally
substituted with
(CH2)õ ORB;
[0043] k) R20 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or
10 aryl,
hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or
(CH2)õNR6R7,
(CH2)õ C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-lo
alkylcycloalkyl, which
are all optionally substituted from one to three times with halo, cyano,
nitro, hydroxy, C1-6
alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by
up to three halo,
cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-
6 alkenyl, C1-6
alkoxy, hydroxy-C1-6 alkyl, CI-6 alkyl optionally substituted with up to 5
fluoro, or CI-6
-10-


CA 02560897 2007-08-08

alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the
definition of R12
and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1.6 alkyl, C3.7
cycloalkyl, C4-lo alkylcycloalkyl, C2_6 alkenyl, CI-6 alkoxy, hydroxy-C1_6
alkyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, CI -6 alkoxy optionally
substituted with up to 5
fluoro;
[0044] 1) n = 1-4;
[0045] m) V is selected from 0, S, or NH;
[0046] n) when V is 0 or S, W is selected from 0, NR15, or CR'5; when V is
NH, W is selected from NO or CR15, where R15 is H, C1.6 alkyl, C3_7
cycloalkyl, C4-io
alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;
[0047] o) the dashed line represents an optional double bond;
[0048] p) R21 is C1.6 alkyl, C3-7 cycloalkyl, C4_10 alkylcycloalkyl, which are
all optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1.6
alkoxy, C1_6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or
R21 is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4-1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1.6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C,.6 alkoxy optionally
substituted with up to 5
fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl,
oxazolyl, phenoxy,
or thiophenoxy; and
[0049] q) R22 is C1_6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, which are
all optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1.6 alkyl
optionally substituted with up to 5 fluoro, or phenyl.
[0050] The embodiments provide a compound having the Formula XI:
R2
V=<
W
18-
17 19
1s 1 O
O N 2 NH O~ 0
13N~S\NR1aR1b
R4RSN O H
13
12 7
9
11 10
XI

[0051] wherein:
-11-


CA 02560897 2007-08-08

[0052] a) Rh and Rib are each independently H, C1_6 alkyl, C3_7 cycloalkyl, or
C4.10 alkylcycloalkyl, which are all optionally substituted from one to three
times with halo,
cyano, nitro, C1_6 alkoxy, amido, or phenyl;
[0053] or Rla and Rib are each independently H and C6 or 10 aryl which is
optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl,
C3_7 cycloalkyl,
C4.10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1.6
alkyl optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;
[0054] or Rla and RIb are each independently H or heterocycle, which is a
five-, six-, or seven-membered, saturated or unsaturated heterocyclic
molecule, containing
from one to four heteroatoms selected from the group consisting of nitrogen,
oxygen and
sulfur;
[0055] or NRIaRlb is a three- to six- membered alkyl cyclic secondary amine,
which optionally has one to three hetero atoms incorporated in the ring, and
which is
optionally substituted from one to three times with halo, cyano, nitro, C1_6
alkoxy, amido, or
phenyl;
[0056] or NR1aR]b is a heteroaryl selected from the group consisting of:
'IN
ENV N ~N > \
LJ~R1c ~~R1c and R1c

[0057] wherein Ric is H, halo, Cl-6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3-6
cycloalkoxy, NO2, N(RId)2, NH(CO)RII, or NH(CO)NHRId, wherein each Rid is
independently H, Ci_6 alkyl, or C3_6 cycloalkyl;
[0058] or R1c is NH(CO)OR" wherein Rle is C1_6 alkyl, or C3.6 cycloalkyl;
[0059] b) W is 0 or NH;
[0060] c) V is selected from 0, S, or NH;
[0061] d) when V is 0 or S, W is selected from 0, NR's, or CR15; when V is
NH, W is selected from NR15 or CRIS, where R15 is H, C1_6 alkyl, C3-7
cycloalkyl, C4-10
alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;
[0062] e) R2 is a bicyclic secondary amine with the structure of:
R21
R11
R10 -I

R20 ~R22
P
N 13
~! R12

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
fõ~=õ,aaõ.t. ,,,,,n ,: ,~,r, ,,r ....i~ 2~1 22
[0063] wherein R and R are each independently H, halo, cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro, C6 or 10 aryl, pyridal, pyrimidal,
thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7,
NHC(S)NR6R7,
C(O)NR6R7, NR6R7, C(O)R8, C(O)OR8, NHC(O)R8, NHC(O)OR8, SO1õ R8 (m = 0, 1 or
2),
or NHS(O)2R8; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the
definition of
R21 and R22 are optionally substituted by up to two halo, cyano, nitro,
hydroxy, C1_6 alkyl,
C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-
C1_6 alkyl, C1_6
alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with
up to 5 fluoro; said C6 or 10 aryl, pyridal, phenoxy and thiophenoxy in the
definition of R21
and R22 are optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;

[0064] wherein R10 and R'1 are each independently H, C1_6 alkyl, C3_7
cycloalkyl, C4-1o alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, (CH2)nNR6R7, or (CH2)nC(O)OR14 where R14 is
H, CI-6
alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are all optionally
substituted from one
to three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; or
R14 is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is optionally
substituted by up to
three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted
with up to 5
fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro; or R10 and
R1' are taken
together with the carbon to which they are attached to form cyclopropyl,
cyclobutyl,
cyclopentyl, or cyclohexyl; or R10 and R" are combined as 0;

[0065] wherein p = 0 or 1;

[0066] wherein R12 and R13 are each independently H, C1.6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, (CH2)nNR6R7, (CH2)nC(O)OR14 where R14 is H,
C1.6 alkyl,
-13-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
" C3"~ 'cyclo`alky~ 'or` C4-io"alky cycloalkyl, which are all optionally
substituted from one to
three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; or R14
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2.6 alkenyl, C1_6 alkoxy, hydroxy-CI.6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is optionally
substituted by up to
three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-lo
alkylcycloalkyl, C2_6
alkenyl, CI-6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted
with up to 5
fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro; or R12 and
R13 are taken
together with the carbon to which they are attached to form cyclopropyl,
cyclobutyl,
cyclopentyl, or cyclohexyl;

[0067] wherein R20 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_Io alkylcycloalkyl,
C6 or 10
aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, (CH2)1NR6R7,
or (CH2)I,C(O)OR14 where R14 is H, CI-6 alkyl, C3_7 cycloalkyl, or C4_1o
alkylcycloalkyl,
which are all optionally substituted from one to three times with halo, cyano,
nitro,
hydroxy, CI.6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally
substituted by up
to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-10
alkylcycloalkyl, C2_6
alkenyl, CI-6 alkoxy, hydroxy-CI.6 alkyl, C1_6 alkyl optionally substituted
with up to 5
fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro; said C6 or
10 aryl, in the
definition of R12 and R13 is optionally substituted by up to three halo,
cyano, nitro, hydroxy,
C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, C2_6 alkenyl, CI.6 alkoxy,
hydroxy-CI.6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro;

[0068] wherein n = 0-4;

[0069] wherein R6 and R7 are each independently H, C1_6 alkyl, C3_7
cycloalkyl,
C4_10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to
three halo,
cyano, nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2.6 alkenyl,
hydroxy-CI.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R6 and R7 are taken together
with the nitrogen
to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
[0070] or R2 is R2aR2b when W = NH and V = O, wherein
-14-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
:,.,:.R`"is C16 `alk 1 C3_7 cYcloalkY1, C4-lo alkYlcYcloalkY1, phenyl,
pyridine,
OD7Y
pyrazine, pyrilnidine, pyridazine, pyrrole, furan, thiophene, thiazole,
oxazole, imidazole,
isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline,
quinoxaline,
benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each
optionally
substituted with up to three NR2CR2d, halo, cyano, nitro, hydroxy, C1_6 alkyl,
C3_7 cycloalkyl,
C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1.6
alkyl optionally
substituted with up to 5 fluoro, or C1.6 alkoxy optionally substituted with up
to 5 fluoro;

[0072] R2b is H, phenyl, pyridine, pyrazine, pyriunidine, pyridazine, pyrrole,
furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole,
isothiazole, naphthyl,
quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,
benzofuran, indole, or
benzimidazole, each optionally substituted with up to three NR2oR2d, halo,
cyano, nitro,
hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, CI-6 alkyl optionally substituted with up to 5 fluoro, or
C1.6 alkoxy
optionally substituted with up to 5 fluoro;

[0073] said R2o and Red are each independently H, C1_6 alkyl, C3_7 cycloalkyl,
C4_
to alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2.6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R2o and Red are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0074] f) R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or
phenyl,
said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1.6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;

[0075] g) R5 is H, C1.6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, or
S(O)2R8;
[0076] h) R8 is C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which
are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; and

-15-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
i) Elie "dashed line represents an optional double bond.

[0078] The embodiments provide a compound having the Formula XVIII:
R2

R1
O=<
NH

O O O
O N I ~S
NH .~`k N~ Rs
R~ :T7r
N a H
R4
9 14
12
13
11
XVIII
[0079] wherein
[0080] a) R1 is C1.6 alkyl, C3.7 cycloalkyl, C4_1o alkylcycloalkyl, phenyl,
pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene,
thiazole, oxazole,
imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline,
quinoxaline,
benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each
optionally
substituted with up to three NR5R6, halo, cyano, nitro, hydroxy, C1_6 alkyl,
C3_7 cycloalkyl,
C4_1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;
[0081] b) R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine,
pyrrole,
furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole,
isothiazole, napthyl,
quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,
benzofuran, indole, or
benzimidazole, each optionally substituted with up to three NR5R6, halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-lo alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;
[0082] c) R3 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl or
phenyl,
said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;

-16-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
. ` "Irisf 1.6' alkyl, C(O)NR5R6, C(S)NR5R6, C(O)R7, C(O)OR7 or
S(O)2R7;

[0084] e) R5 and R6 are each independently H, C1_6 alkyl, C3_7 cycloalkyl,
C4_10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_lo alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R5 and R6 are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0085] f) R7 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R7 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0086] g) R8 is C1_3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally
substituted by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy; and

[0087] h) the dashed line represents an optional double bond;
[0088] or a pharmaceutically acceptable salt thereof.

[0089] The embodiments provide a compound of the formula:
P2
L
O N O
7 jNH Z'P1,
R5N 8 O
H 9 14
12
13
11

[0090] wherein:

[0091] a) Z is a group configured to hydrogen bond to an NS3 protease His57
imidazole moiety and to hydrogen bond to a NS3 protease Gly137 nitrogen atom;

[0092] b) Pi' is a group configured to form a non-polar interaction with at
least
one NS3 protease Si' pocket moiety selected from the group consisting of
Lys136, Gly137,
Ser139, His57, G1y58, Gln41, Ser42, and Phe43;

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
~b93 c I, is anlinker group consisting of from 1 to 5 atoms selected from the
group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;

[0094] d) P2 is selected from the group consisting of unsubstituted aryl,
substituted aryl, unsubstituted heteroaryl, substituted heteroaryl,
unsubstituted heterocyclic
and substituted heterocyclic; P2 being positioned by L to form a non-polar
interaction with
at least one NS3 protease S2 pocket moiety selected from the group consisting
of His57,
Argl55, Va178, Asp79, G1n80 and Asp81;

[0095] e) the dashed line represents an optional double bond;

[0096] f) R5 is selected from the group consisting of H, C(O)NR6R7 and
C(O)ORS;

[0097] g) R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4-
10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy
optionally substituted
with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to
which they are
attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or
morpholinyl; and
[0098] h) R8 is C1_6 alkyl, C3_7 cycloalkyl, C44o alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6 o,= 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, C2.6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring; with the proviso that the compound does not include a
compound having
the Formula II, III, or IV as defined above.

[0099] The embodiments provide a compound having the formula:
-18-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
V V
O N O N
NH Y NH Y
7 7
R4R5N 8 O R4R5N 8
9 14 9 14
12 12
13 13
11 or 10 11
[0100] wherein:
[0101] R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4-1o alkylcycloalkyl, phenyl, or
benzyl, said phenyl or benzyl optionally substituted by up to three halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0102] R5 is C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8,
or (CO)CHR21NH(CO)R22;

[0103] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, 04.10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0104] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring;

-19-


CA 02560897 2007-08-08

[0105] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-3
alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two
halo, cyano,
nitro, hydroxy, C1_3 alkyl, C3_7 cycloalkyl, or C1_3 alkoxy, or Y is a
carboxylic acid
[0107] V is selected from OH, SH, or NH2;
[0108] the dashed line represents an optional double bond;
[0109] R21 is C1_6 alkyl, C3_7 cycloalkyl, C410 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6
or 10 aryl which is
optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl,
C3_7 cycloalkyl,
C4_10 alkylcycloalkyl, C2_6 alkenyl, C1.6 alkoxy, hydroxy-Cl-6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, C1.6 alkoxy optionally substituted with up to
5 fluoro; or or
R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl,
phenoxy,or
thiophenoxy; and
[0110] R22 is C1_6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1.6 alkyl
optionally substituted with up to 5 fluoro, or phenyl.
[0111] The embodiments provide a compound having the formula:
Q
v
W
O N
N H 1 ~~Y
R4RSN`~~ O

12

11
[0112] wherein:
[0113] Q is a core ring selected from:
,Na
[0114] wherein the core ring can be unsubstituted or substituted H, halo,
cyano,
nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
-20-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
hydroxy- p1_6'a1kT,` Ci='6 alkyl, substituted C1_6 alkyl, C1_6 alkoxy,
substituted C1_6 alkoxy C6
or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl,
phenoxy, thiophenoxy,
sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide,
sulphoxide,
sulphone, amino, alkoxyainino, alkyoxyheterocyclyl, alkylainino, alkylcarboxy,
carbonyl,
spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or
spirocyclic
cyclohexyl,

[0115] or Q is R1-R2, wherein R1 is C1.6 alkyl, C3_7 cycloalkyl, C4.10
alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,
furan,
thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole,
napthyl, quinoline,
isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole,
benzimidazole, each optionally substituted with up to three NR6R7, halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; and R2 is H, phenyl, pyridine,
pyrazine,
pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole,
imidazole, isoxazole,
pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline,
benzothiazole,
benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted
with up to
three NR6R7, halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl,
C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally
substituted with up to 5
fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro;
[0116] R4 is H, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, phenyl, or
benzyl, said phenyl or benzyl optionally substituted by up to three halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0117] R5 is C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)ORB, S(O)2R8,
or (CO)CHR21NH(CO)R22;
[0118] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, 04.10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

-21-


CA 02560897 2007-08-08

[0119] R8 is C1_6 alkyl, C3.7 cycloalkyl, C4-lo alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1.6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1.6 alkyl, C3.7 cycloalkyl, C4.1o alkylcycloalkyl, C2.6
alkenyl, C1.6 alkoxy,
hydroxy-C1.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1.6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring;
[0120] Y is COOR9, wherein R9 is C1_6 alkyl; or Y is a sulfonimide of the
formula -C(O)NHS(O)2R9, where R9 is CI-3 alkyl, C3.7 cycloalkyl, or phenyl
which is
optionally substituted by up to two halo, cyano, nitro, hydroxy, C1_3 alkyl,
C3.7 cycloalkyl,
or C1.3 alkoxy, or Y is a carboxylic acid
[0122] V and W are each individually selected from 0, S, or NH;
[0123] the dashed line represents an optional double bond;
[0124] R21 is C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
C1.6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6
o, to aryl which
is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7
cycloalkyl, C4_1o alkylcycloalkyl, C2.6 alkenyl, C1_6 alkoxy, hydroxy-C1.6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; or or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl,
thiazolyl, oxazolyl,
phenoxy,or thiophenoxy; and
[0125] R22 is C1_6 alkyl, C3_7 cycloalkyl, C4-lo alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkyl
optionally substituted with up to 5 fluoro, or phenyl.
[0126] The embodiments provide pharmaceutical compositions comprising
preferred compounds and pharmaceutically acceptable carriers.
[0127] The embodiments provide a method of treating a hepatitis C virus
infection in an individual, the method comprising administering to the
individual an
effective amount of the preferred compounds.

-22-


CA 02560897 2010-03-26

[0128] The embodiments provide a method of treating liver fibrosis in an
individual,
the method comprising administering to the individual an effective amount of
the preferred
compounds.
[0129] The embodiments provide a method of increasing liver function in an
individual
having a hepatitis C virus infection, the method comprising administering to
the individual an
effective amount of the preferred compounds.
[0130] The chemical formulas representing the compounds described herein also
represent pharmaceutically acceptable salts, solvates, esters, and prodrug
derivatives thereof.
[0130A] Various embodiments of this invention provide use of a compound or
composition of this invention for curative or prophylactic treatment of a
hepatitis C virus
infection or for preparation of a medicament for such treatment.
[0130B] Various embodiments of this invention provide use of a compound or
composition of this invention for curative or prophylactic treatment of liver
fibrosis or for
preparation of a medicament for such treatment.
[0130C] Various embodiments of this invention provide use of a compound or
composition of this invention for curative or prophylactic treatment for
increasing liver function
in an individual having a hepatitis C virus infection or for preparation of a
medicament for such
treatment.
[0130D] Various embodiments of this invention provide a commercial package
containing as an active pharmaceutical ingredient a compound or composition of
this invention
together with instructions for use of the compound or composition.

Detailed Description of the Preferred Embodiment
Definitions
[0131] As used herein, the term "hepatic fibrosis," used interchangeably
herein with
"liver fibrosis," refers to the growth of scar tissue in the liver that may
occur in the context of a
chronic hepatitis infection.
[0132] The terms "individual," "host," "subject," and "patient" are used
interchangeably herein, and refer to a mammal, including, but not limited to,
primates, including
simians and humans.
[0133] As used herein, the term "liver function" refers to a normal function
of the liver,
including, but not limited to, a synthetic function, including, but not
limited to, synthesis of proteins
such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase,
aminotransferases (e.g.,
alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-
glutaminyltranspeptidase, etc.),
synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids;
a liver metabolic
-23-


CA 02560897 2012-01-20

function, including, but not limited to, carbohydrate metabolism, amino acid
and ammonia metabolism,
hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a
hemodynamic
function, including splanchnic and portal hemodynamics; and the like.
[0134] As used herein, the terms "HCV NS3 protease inhibitor" and "NS3
protease
inhibitor" refer to any agent that inhibits the protease activity of HCV
NS3/NS4A complex. Unless
specifically stated otherwise, the term "NS3 inhibitor" is used
interchangeably with the terms "HCV
NS3 protease inhibitor" and "NS3 protease inhibitor."
[0134A] Various embodiments of this invention may exclude from their scope, a
compound
disclosed in W02005/03 7214 having the following formula.

O N

O O P
0
N 0
0 H

-23a-


CA 02560897 2007-08-08

[0135] As used herein, the term "polyol" or "poly-ol" denotes a hydrocarbon
including at least two hydroxyls bonded to carbon atoms, and includes sugars
(reducing and
nonreducing sugars), sugar alcohols and sugar acids. Polyols may include other
functional
groups. Examples of polyols include sugar alcohols such as mannitol and
trehalose, and
polyethers. A "reducing sugar" is one which contains a hemiacetal group that
can reduce
metal ions or react covalently with lysine and other amino groups in proteins
and a
"nonreducing sugar" is one which does not have these properties of a reducing
sugar.
Examples of reducing sugars are fructose, mannose, maltose, lactose,
arabinose, xylose,
ribose, rhamnose, galactose and glucose. Nonreducing sugars include sucrose,
trehalose,
sorbose, melezitose and raffinose. Mannitol, xylitol, erythritol, threitol,
sorbitol and
glycerol are examples of sugar alcohols. As to sugar acids, these include L-
gluconate and
metallic salts thereof.
[0136] The term "polyether" as used herein denotes a hydrocarbon containing
at least three ether bonds. Polyethers may include other functional groups.
Polyethers
include polyethylene glycol (PEG).
[0137] The term "sustained viral response" (SVR; also referred to as a
"sustained response" or a "durable response"), as used herein, refers to the
response of an
individual to a treatment regimen for HCV infection, in terms of serum HCV
titer.
Generally, a "sustained viral response" refers to no detectable HCV RNA (e.g.,
less than
about 500, less than about 200, or less than about 100 genome copies per
milliliter serum)
found in the patient's serum for a period of at least about one month, at
least about two
months, at least about three months, at least about four months, at least
about five months,
or at least about six months following cessation of treatment.
[0138] "Treatment failure patients" as used herein generally refers to HCV-
infected patients who failed to respond to previous therapy for HCV (referred
to as "non-
responders") or who initially responded to previous therapy, but in whom the
therapeutic
response was not maintained (referred to as "relapsers"). The previous therapy
generally
may include treatment with IFN-a monotherapy or 1FN-a combination therapy,
where the
combination therapy may include administration of IFN-a and an antiviral agent
such as
ribavirin.
[0139] As used herein, the terms "treatment," "treating," and the like, refer
to
obtaining a desired pharmacologic and/or physiologic effect. The effect may be
prophylactic in terms of completely or partially preventing a disease or
symptom thereof
-24-


CA 02560897 2007-08-08

and/or may be therapeutic in terms of a partial or complete cure for a disease
and/or adverse
affect attributable to the disease. "Treatment," as used herein, covers any
treatment of a
disease in a mammal, particularly in a human, and includes: (a) preventing the
disease from
occurring in a subject which may be predisposed to the disease but has not yet
been
diagnosed as having it; (b) inhibiting the disease, i.e., arresting its
development; and (c)
relieving the disease, i.e., causing regression of the disease.
[0140] The terms "individual," "host," "subject," and "patient" are used
interchangeably herein, and refer to a mammal, including, but not limited to,
murines,
simians, humans, mammalian farm animals, mammalian sport animals, and
mammalian pets.
[0141] As used herein, the term "pirfenidone" refers to 5-methyl-l-phenyl-2-
(1H)-pyridone. As used herein, the term "pirfenidone analog" refers to any
compound of
Formula I, IIA or IIB in the section entitled "Pirfenidone and Analogs
Thereof" below. A
"specific pirfenidone analog," and all grammatical variants thereof, refers
to, and is limited
to, each and every pirfenidone analog shown in Table I in the section entitled
"Pirfenidone
and Analogs Thereof" below.
[0142] As used herein, the term "a Type I interferon receptor agonist" refers
to any naturally occurring or non-naturally occurring ligand of human Type I
interferon
receptor, which binds to and causes signal transduction via the receptor. Type
I interferon
receptor agonists include interferons, including naturally-occurring
interferons, modified
interferons, synthetic interferons, pegylated interferons, fusion proteins
comprising an
interferon and a heterologous protein, shuffled interferons; antibody specific
for an
interferon receptor; non-peptide chemical agonists; and the like.
[0143] As used herein, the term "Type II interferon receptor agonist" refers
to
any naturally occurring or non-naturally occurring ligand of human Type II
interferon
receptor that binds to and causes signal transduction via the receptor. Type
II interferon
receptor agonists include native human interferon-y, recombinant IFN-y
species,
glycosylated IFN-y species, pegylated IFN-y species, modified or variant IFN-y
species,
IFN-y fusion proteins, antibody agonists specific for the receptor, non-
peptide agonists, and
the like.
[0144] As used herein, the term "a Type III interferon receptor agonist"
refers
to any naturally occurring or non-naturally occurring ligand of humanlL-28
receptor c ("IL-
-25-


CA 02560897 2007-08-08

28R"), the amino acid sequence of which is described by Sheppard, et al.,
infra., that binds
to and causes signal transduction via the receptor.
[0145] As used herein, the term "interferon receptor agonist" refers to any
Type I interferon receptor agonist, Type II interferon receptor agonist, or
Type III
interferon receptor agonist.
[0146] The term "dosing event" as used herein refers to administration of an
antiviral agent to a patient in need thereof, which event may encompass one or
more
releases of an antiviral agent from a drug dispensing device. Thus, the term
"dosing
event," as used herein, includes, but is not limited to, installation of a
continuous delivery
device (e.g., a pump or other controlled release injectible system); and a
single
subcutaneous injection followed by installation of a continuous delivery
system.
[0147] "Continuous delivery" as used herein (e.g., in the context of
"continuous delivery of a substance to a tissue") is meant to refer to
movement of drug to a
delivery site, e.g., into a tissue in a fashion that provides for delivery of
a desired amount of
substance into the tissue over a selected period of time, where about the same
quantity of
drug is received by the patient each minute during the selected period of
time.
[0148] "Controlled release" as used herein (e.g., in the context of
"controlled
drug release") is meant to encompass release of substance (e.g., a Type I or
Type III
interferon receptor agonist, e.g., IFN-(x) at a selected or otherwise
controllable rate,
interval, and/or amount, which is not substantially influenced by the
environment of use.
"Controlled release" thus encompasses, but is not necessarily limited to,
substantially
continuous delivery, and patterned delivery (e.g., intermittent delivery over
a period of time
that is interrupted by regular or irregular time intervals).
[0149] "Patterned" or "temporal" as used in the context of drug delivery is
meant to encompass delivery of drug in a pattern, generally a substantially
regular pattern,
over a pre-selected period of time (e.g., other than a period associated with,
for example a
bolus injection). "Patterned" or "temporal" drug delivery is meant to
encompass delivery of
drug at an increasing, decreasing, substantially constant, or pulsatile, rate
or range of rates
(e.g., amount of drug per unit time, or volume of drug formulation for a unit
time), and
further encompasses delivery that is continuous or substantially continuous,
or chronic.
[0150] The term "controlled drug delivery device" is meant to encompass any
device wherein the release (e.g., rate, timing of release) of a drug or other
desired substance
contained therein is controlled by or determined by the device itself and not
substantially.
-26-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
i1 luericec]` by `Th6 environment of use, or releasing at a rate that is
reproducible within the
environment of use.

[0151] By "substantially continuous" as used in, for example, the context of
"substantially continuous infusion" or "substantially continuous delivery" is
meant to refer
to delivery of drug in a manner that is substantially uninterrupted for a pre-
selected period
of drug delivery, where the quantity of drug received by the patient during
any 8 hour
interval in the pre-selected period never falls to zero. Furthermore,
"substantially
continuous" drug delivery may also encompass delivery of drug at a
substantially constant,
pre-selected rate or range of rates (e.g., amount of drug per unit time, or
volume of drug
formulation for a unit time) that is substantially uninterrupted for a pre-
selected period of
drug delivery.

[0152] By "substantially steady state" as used in the context of a biological
parameter that may vary as a function of time, it is meant that the biological
parameter
exhibits a substantially constant value over a time course, such that the area
under the curve
defined by the value of the biological parameter as a function of time for any
8 hour period
during the time course (AUC8hr) is no more than about 20% above or about 20%
below,
and preferably no more than about 15% above or about 15% below, and more
preferably no
more than about 10% above or about 10% below, the average area under the curve
of the
biological parameter over an 8 hour period during the time course (AUC8hr
average). The
AUC8hr average is defined as the quotient (q) of the area under the curve of
the biological
parameter over the entirety of the time course (AUCtotal) divided by the
number of 8 hour
intervals in the time course (total/3days), i.e., q = (AUCtotal)/
(total/3days). For example,
in the context of a serum concentration of a drug, the serum concentration of
the drug is
maintained at a substantially steady state during a time course when the area
under the
curve of serum concentration of the drug over time for any 8 hour period
during the time
course (AUC8hr) is no more than about 20% above or about 20% below the average
area
under the curve of serum concentration of the drug over an 8 hour period in
the time course
(AUC8hr average), i.e., the AUC8hr is no more than 20% above or 20% below the
AUC8hr
average for the serum concentration of the drug over the time course.
[0153] As used herein, "hydrogen bond" refers to an attractive force between
an
electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a
hydrogen atom
which is linked covalently to another electronegative atom (such as oxygen,
nitrogen, sulfur
or halogen). See, e.g., Stryer et. al. "Biochemistry", Fith Edition 2002,
Freeman & Co.
-27-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
ypically, "ihe 11yc1r"ogeri." bond is between a hydrogen atom and two unshared
electrons
of another atom. A hydrogen bond between hydrogen and an electronegative atom
not
covalently bound to the hydrogen may be present when the hydrogen atom is at a
distance
of about 2.5 angstroms to about 3.8 angstroms from the not-covalently bound
electronegative atom, and the angle formed by the three atoms (electronegative
atom
covalently bound to hydrogen, hydrogen, and electronegative atom not-
covalently bound
electronegative atom) deviates from 180 degrees by about 45 degrees or less.
The distance
between the hydrogen atom and the not-covalently bound electronegative atom
may be
referred to herein as the "hydrogen bond length," and the the angle fonned by
the three
atoms (electronegative atom covalently bound to hydrogen, hydrogen, and
electronegative
atom not-covalently bound electronegative atom) may be referred to herein as
the
"hydrogen bond angle." In some instances, stronger hydrogen bonds are formed
when the
hydrogen bond length is shorter; thus, in some instances, hydrogen bond
lengths may range
from about 2.7 angstroms to about 3.6 angstroms, or about 2.9 angstroms to
about 3.4
angstroms. In some instances, stronger hydrogen bonds are formed when the
hydrogen
bond angle is closer to being linear; thus, in some instances, hydrogen bond
angles may
deviate from 180 degrees by about 25 degrees or less, or by about 10 degrees
or less.

[0154] As used herein, "non-polar interaction" refers to proximity of non-
polar
molecules or moieties, or proximity of molecules or moieties with low
polarity, sufficient
for van der Waals interaction between the moieties and/or sufficient to
exclude polar
solvent molecules such as water molecules. See, e.g., Stryer et. al.
"Biochemistry", Fith
Edition 2002, Freeman & Co. N.Y. Typically, the distance between atoms
(excluding
hydrogen atoms) of non-polar interacting moieties may range from about 2.9
angstroms to
about 6 angstroms. In some instances, the space separating non-polar
interacting moieties
is less than the space that would accommodate a water molecule. As used herein
a non-
polar moiety or moiety with low polarity refers to moieties with low dipolar
moments
(typically dipolar moments less than the dipolar moment of 0-H bonds of H2O
and N-H
bonds of NH3) and/or moieties that are not typically present in hydrogen
bonding or
electrostatic interactions. Exemplary moieties with low polarity are alkyl,
alkenyl, and
unsubstituted aryl moieties.
[0155] As used herein, an NS3 protease S1' pocket moiety refers to a moiety of
the NS3 protease that interacts with the amino acid positioned one residue C-
terminal to the
cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the
NS3 protease
-28-


CA 02560897 2010-03-26

muienes that interact with amino acid S in the polypeptide substrate DLEVVT-
STWVLV).
Exemplary moieties include, but are not limited to, atoms of the peptide
backbone or side
chains of amino acids Lys136, G1y137, Ser139, His57, G1y58, G1n41, Ser42, and
Phe43,
see Yao. et. al., Structure 1999, 7, 1353.
[0156) As used herein, an NS3 protease S2 pocket moiety refers to a moiety of
the NS3 protease that interacts with the amino acid positioned two residues N-
terminal to
the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g.,
the NS3
protease moieties that interact with amino acid V in the polypeptide substrate
DLEVVT-
STWVLV). Exemplary moieties include, but are not limited to, atoms of the
peptide
backbone or side chains of amino acids His57, Arg155, Va178, Asp79, G1n80 and
Asp81,
see Yao. et. al., Structure 1999, 7, 1353.
[0157] As used herein, a first moiety "positioned by" a second moiety refers
to
the spatial orientation of a first moiety as determined by the properties of a
second moiety
to which the first atom or moiety is covalently bound. For example, a phenyl
carbon may
position an oxygen atom bonded to the phenyl carbon in a spatial position such
that the
oxygen atom hydrogen bonds with a hydroxyl moiety in an NS3 active site.
[0158] Before the embodiments are fur her described, it is to be understood
that
this invention is not limited to particular embodiments described, as such
may, of course,
vary. It is also to be understood that the terminology used herein is for the
purpose of
describing particular embodiments only, and is not intended to be limiting.
[0159] Where a range of values is provided, it is understood that each
intervening value, to the tenth of the unit of the lower limit unless the
context clearly
dictates otherwise, between the upper and lower limit of that range and any
other stated or
intervening value in that stated range is encompassed within the embodiments.
The upper
and lower limits of these smaller ranges may independently be included in the
smaller
ranges is also encompassed within the embodiments, subject to any specifically
excluded
limit in the stated range. Where the stated range includes one or both of the
limits, ranges
excluding either both of those included limits are also included in the
embodiments.
[0160] Unless defined otherwise, all technical and scientific terms used
herein
have the same meaning as commonly understood by one of ordinary skill in the
art to which
the embodiments belong. Although any methods and materials similar or
equivalent to
those described herein may also be used in the practice or testing of the
embodiments, the
preferred methods and materials are now described.

-29-


CA 02560897 2010-03-26

[0161] It must be noted that as used herein and in the appended claims, the
singular forms "a," "and," and "the" include plural referents unless the
context clearly
dictates otherwise. Thus, for example, reference to "a method" includes a
plurality of such
methods and reference to "a dose" includes reference to one or more doses and
equivalents
thereof known to those skilled in the art, and so forth.
[0162] The publications discussed herein are provided solely for their
disclosure
prior to the filing date of the present application. Nothing herein is to be
construed as an
admission that the present invention is not entitled to antedate such
publication by virtue of
prior invention. Further, the dates of publication provided may be different
from the actual
publication dates which may need to be independently confirmed.
[0163] The embodiments provide compounds of Formulas I-XIX, as well as
pharmaceutical compositions and formulations comprising any compound of
Formulas I-
XIX. A subject compound is useful for treating flaviviral infection, such as
HCV infection.
and other disorders, as discussed below.

Compositions
[0164] Various embodiments of compositions are described below. For ease of
discussion, the description of these embodiments is divided into Sections A,
B, C, D and E.
Various terms that may be defined within a particular Section are understood
to apply
within that Section, and also to apply elsewhere herein when reference to that
particular
Section is made, Likewise, any references within a Section to a particular
number or label
should be understood in the context of the corresponding numbering or labeling
scheme
used within that Section, rather than in the context of a possibly similar or
identical
numbering or labeling scheme used in an unrelated section, unless otherwise
indicated.
Section A
[0165] Section A embodiments provide compounds having the general Formula
I:

-30-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
Q
V
W
O N
NY
R4F25N O
14
12
13
11

[0166] wherein:

[0167] Q is a core ring selected from:

)P P
fN / and /N

[0168] wherein the core ring can be unsubstituted or substituted with H, halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl,
C2_6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl, substituted C1_6 alkyl, C1_6 alkoxy,
substituted C1_6
alkoxy, C6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl,
oxazolyl, phenoxy,
thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl,
sulphide,
sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino,
alkylcarboxy,
carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic
cyclopentyl, or
spirocyclic cyclohexyl,

[0169] or Q is R1-R2, wherein R1 is C1_6 alkyl, C3_7 cycloalkyl, C4-10
alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,
furan,
thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole,
napthyl, quinoline,
isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole,
or
benzimidazole, each optionally substituted with up to three NR6R7, halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro,
or C1_6 alkoxy
optionally substituted with up to 5 fluoro; and R2 is H, phenyl, pyridine,
pyrazine,
pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole,
imidazole, isoxazole,
pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline,
benzothiazole,
benzothiophene, benzofuran, indole, or benzimidazole, each optionally
substituted with up
-31-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
to f~iree""` IRst' halo; `cyano, nitro, hydroxy, G1_6 alkyl, C3_7 cycloalkyl,
G¾_io
alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl
optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;
[0170] R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, phenyl, or
benzyl, said phenyl or benzyl optionally substituted by up to three halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0171] R5 is H, C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8,
S(O)2R8, or (CO)CHR21NH(CO)R22;

[0172] R6 and R7 are each independently H, C1.6 alkyl, C3_7 cycloalkyl, C4.10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2.6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0173] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2.6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring;

[0174] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_6
alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are all optionally
substituted from one
to three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl, or R9
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1.6
alkyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; or R9 is a C1_6 alkyl optionally substituted with up to 5 fluoro
groups, NR6R7,
NRlaRlb, or (CO)OH, or R9 is a heteroaromatic ring optionally substituted up
to two times
-32-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
L.. +6ur 7F .: 'i ~i5ud= 'nnir u"ur r' rrriwx ri,õn a :r
with halo,,xcyano, nitro, hydroxyl, or C1_6 alkoxy; or Y is a carboxylic acid
or
pharmaceutically acceptable salt, solvate, or prodrug thereof,

[0175] wherein Rla and Rlb are each independently H, C1_6 alkyl, C3_7
cycloalkyl, or C4-1o alkylcycloalkyl, which are all optionally substituted
from one to three
times with halo, cyano, nitro, C1_6 alkoxy, amido, or phenyl,

[0176] or Rla and Rib are each independently H and C6 or 10 aryl which is
optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl,
C3_7 cycloalkyl,
C4_1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro,

[0177] or Rla and Rib are each independently H, heterocycle, which is a five-,
six-, or seven-membered, saturated or unsaturated heterocyclic molecule,
containing from
one to four heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur,
[0178] or NRiaRib is a three- to six- membered alkyl cyclic secondary amine,
which optionally has one to three hetero atoms incorporated in the ring, and
which is
optionally substituted from one to three times with halo, cyano, nitro, C1_6
alkoxy, amido, or
phenyl,

[0179] or NRiaRib is a heteroaryl selected from the group consisting of:
-'K--N _"~_N -N~N -'*-N
~'\Rlc R1c and C_z R1c

[0180] wherein Rio is H, halo, C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3_6
cycloalkoxy, NO2, N(Rid)2, NH(CO)Rid, or NH(CO)NHRid, wherein each Rid is
independently H, C1_6 alkyl, or C3_6 cycloalkyl,

[0181] or Rio is NH(CO)ORie, wherein Rie is C1_6 alkyl or C3_6 cycloalkyl;
[0182] p= 0 or l;

[0183] V is selected from 0, S, or NH;

[0184] when V is 0 or S, W is selected from 0, NR15, or CR15; when V is NH,
W is selected from NR15 or CR15, where R15 is H, C1.6 alkyl, C3_7 cycloalkyl,
C4-10
alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;
[0185] the dashed lines represent an optional double bond;
[0186] R21 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
C1_6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6
o,. 10 aryl which
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
if if ' is optionall y subs'tituted' byup to three halo, cyano, nitro,
hydroxy, C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; or or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl,
thiazolyl, oxazolyl,
phenoxy, or thiophenoxy; and

[0187] R22 is C1_6 alkyl, C3_7 cycloalkyl, or C4-lo alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkyl
optionally substituted with up to 5 fluoro, or phenyl.

[0188] In preferred embodiments, Section A embodiments provide compounds
( p I ~

having the general Formula I, in which the core ring is

[0189] In preferred embodiments, Section A embodiments provide compounds
fN
I ~ having the general Formula I, in which the core ring is

[0190] In preferred embodiments, Section A embodiments provide compounds

( p f
N
having the general Formula I, in which the core ring is

[0191] In preferred embodiments, Section A embodiments provide compounds
Q
v=~
W
O N

NH 1
F24R5N s O
14
12
13
11
having the general Formula Ia: la
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
In pre erred embodiments, Section A embodiments provide compounds
Q
v=~
w
O N7 NH1 Y

R4R5N (-; 9 14
r
13
11 Ib

having the general Formula lb:

[0193] In preferred embodiments, Section A embodiments provide compounds
v
w
O N
NHY
7
R4R5N $ O

9 14
12
13
10 11
Ic
having the general Formula Ic:

[0194] In preferred embodiments, Section A embodiments provide compounds
Q
v=<
w
O N
NH Y
7
R4R5N 8 O

9 14
12
13
10 11 Id
having the general Formula Id:

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[0`I'0~ 'f iii preferre embodiments, Section A embodiments provide compounds
v
==< Q
w
O N
NY
7 r R4R5N 8 O

9 14
12
13
11 16
having the general Formula le:

[0196] In preferred embodiments, Section A embodiments provide compounds
Q
v=~
w
O N
f NH 1 Y
R4R5N 7 8 O
9 14
12
13
10 11
If
having the general Formula If:

[0197] In preferred embodiments, Section A embodiments provide compounds
v
=~ Q
w
O N

NH 1 Y
j 1
R4R5N 8 O
7
4
12 13

10 11
9
having the general Formula Ig:

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
Tnpreterred embodiments, Section A embodiments provide compounds
Q
v=<
w
o N
NH 1 Y
R4R5N a O

9 12 14
13
11 Ih
having the general Formula Ih:

[0199] In preferred embodiments, Section A embodiments provide compounds
Q
v=<
w
O N

NH 1
7
R4R5N a O
14
9 12 j 13

10 11 II
having the general Formula Ii:

[0200] In preferred embodiments, Section A embodiments provide compounds
v
w
O N
jNY
... R4R5N 3 O

9 14
12
13
10 11
having the general Formula Ij:

-37-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
iii' pre` er`r`ed embodiments, Section A embodiments provide compounds
v=~
W
O N
NH \Y
R4R5N ~ , a O

14
9 12
13
11 IZ
having the general Formula Iz:

[0202] In preferred embodiments, Section A embodiments provide compounds
having the general Formula I, in which Y is sulfonimide of the formula -
C(O)NHS(O)2R9,
where R9 is selected from the group consisting of C1_6 alkyl, C3_7 cycloalkyl,
C4.10
alkylcycloalkyl, and NRiaRlb, wherein Rla and Rib are each independently H,
C1_6 alkyl, or
C3_7 cycloalkyl.

[0203] In preferred embodiments, Section A embodiments provide compounds
having the general Formula I, in which the C13-C14 double bond is cis.

[0204] In preferred embodiments, Section A embodiments provide compounds
having the general Formula I, in which the C13-C14 double bond is trans.

[0205] In certain embodiments, the compounds of general Formula I do not
include the compounds disclosed in PCT/USO4/33970. For example, in certain
embodiments, the compounds of general Formula I do not include the compounds
of
Formulas II, III, and IV in Section B below.

Section B

[0206] Section B embodiments provide compounds having the general
Formulas II, III, and IV:

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R1+r= R
R11 R11 R11 \1
R10 d= Rio R1 R10 Z-R
R20 P R2 R20 )P I i) R20 )P
N R13 N \ N-~ R13
V=< R12 V= R2 V=~ R12
W W W

O N O N O N
NH 1 Y
1
NH 1 Y NH Y
:7r
R4R5N 8 O R4R5N ""8 O R4R5N 8 O
9 j 14 9 14 14
12 12 DI 12 1
13 13 13
11 10 11 10 11

II III IV
[0207] wherein:

[0208] R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7 cycloalkyl, C4.1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy,
hydroxy-Cl_6 alkyl, or
C1_6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally
substituted with
up to 5 fluoro, C6 or to aryl, pyridal, pyrimidal, thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy,
thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7, NHC(S)NR6R7, C(O)NR6R7, NR6R7, C(O)R8,
C(O)ORS, NHC(O)R8, NHC(O)OR8, SO,,,R8, NHS(O)2R8, CHõNR6R7, OCHINR 6R7, or
OCHõ R9 where R9 is imidazolyl or pyrazolyl; said thienyl, pyrimidal, furanyl,
thiazolyl and
oxazolyl in the definition of R1 and R2 are optionally substituted by up to
two halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; said C6 or 10 aryl, pyridal,
phenoxy and
thiophenoxy in the definition of R1 and R2 are optionally substituted by up to
three halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-1o alkylcycloalkyl,
C2.6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro;

[0209] m = 0, 1, or 2;

[0210] R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl phenyl or
benzyl, said phenyl or benzyl optionally substituted by up to three halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1.6 alkoxy,
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
hydroxy- 1.6 alkyl, Ci_6 alkyl` optionally substituted with up to 5 fluoro,
or C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0211] R5 is H, C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8,
S(O)2R8, or (CO)CHR21NH(CO)R22;

[0212] R6 and R7 are each independently H, C1_6 alkyl, C3.7 cycloalkyl, C4.10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, or C1.6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R6 and R7 are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0213] R8 is C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1.6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2.6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro,
Cl_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring;

[0214] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_6
alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are all optionally
substituted from one
to three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl, or R9
is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4-lo alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; or R9 is a C1_6 alkyl optionally substituted with up to 5 fluoro
groups, NR6R7, or
(CO)OH, or R9 is a heteroaromatic ring optionally substituted up to two times
with halo,
cyano, nitro, hydroxyl, or C1.6 alkoxy; or Y is a carboxylic acid or
pharmaceutically
acceptable salt, solvate, or prodrug thereof;
[0215] R10 and R11 are each independently H, C1.6 alkyl, C3_7 cycloalkyl,
C4.1o
alkylcycloalkyl, C6 or to aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally
substituted with up to
fluoro, (CH2)õNR6R7, (CH2)õ C(O)OR14 where R14 is H, C1_6 alkyl, C3_7
cycloalkyl, or C4-
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
-40-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
7i=== inm= ii = ' F v":tt 41 f: i dt r irt6. r f; ..-ff ' - rz
cyano, intro, hydroxy, 1.6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is
optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7
cycloalkyl, C4.1o
alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl
optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;
said C6 or 10 aryl, in the definition of R10 and R11 is optionally substituted
by up to three
halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to
5 fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro; or R10 and R11 are taken
together with the
carbon to which they are attached to form cyclopropyl, cyclobutyl,
cyclopentyl, or
cyclohexyl; or R10 and R11 are combined as 0;

[0216] p= 0 or 1;

[0217] R12 and R13 are each independently H, C1.6 alkyl, C3_7 cycloalkyl,
C4_10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally
substituted with up to
fluoro, (CH2)nNR6R7, (CH2)nC(O)OR14 where R14 is H, Cl_6 alkyl, C3_7
cycloalkyl, C4-10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which
is optionally
substituted by up to three halo, cyan, nitro, hydroxy, C1_6 alkyl, C3_7
cycloalkyl, C4-10
alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl
optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;
said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted
by up to three
halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to
5 fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro; or R12 and R13 are taken
together with the
carbon to which they are attached to form cyclopropyl, cyclobutyl,
cyclopentyl, or
cyclohexyl; or R12 and R13 are each independently CI-6 alkyl optionally
substituted with
(CH2)nOR8;

[0218] R20 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C6 or 10
aryl,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
(CH2)0NR6R7,
(CH2)nC(O)OR14 where R14 is H, C1.6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, which
are all optionally substituted from one to three times with halo, cyano,
nitro, hydroxy, C1_6
alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by
up to three halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2_6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, or C1_6
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
ail oxy optionall"y subst tuted `wit`h up to 5 fluoro; said C6 o to aryl, in
the definition of R12
and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4-1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
allcyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro;

[0219] n = 1-4;

[0220] V is selected from 0, S, or NH;

[0221] when V is 0 or S, W is selected from 0, NR15, or CR15; when V is NH,
W is selected from NR15 or CR15, where R15 is H, C1_6 alkyl, C3_7 cycloalkyl,
C4.10
alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;

[0222] the dashed line represents an optional double bond;

[0223] R21 is C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
C1_6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6
or 10 aryl which
is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl,
oxazolyl, phenoxy,
or thiophenoxy; and

[0224] R22 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkyl
optionally substituted with up to 5 fluoro, or phenyl.

[0225] Section B embodiments provide compounds having the general Formula
II,

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R1
R11
R1o
R20 ) P R2
N R13
V~ R12
W
O N
7
NH i
R4R5N s 0
9 14
12
13
11
II
[0226] wherein:

[0227] R1 is H, halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl,
C4.10
alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl
optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;

[0228] R2 is H, OCH11NR6R7, OCH11R16, halo, cyano, nitro, hydroxy, Cl_6 alkyl,
C3_7 cycloalkyl, C4-1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-
C1_6 alkyl, C1_6
alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with
up to 5 fluoro; said R6 and R7 in the definition of R2 being each
independently H, C1_6
alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl; or said R6 and R7 in the
definition of R2
taken together with the nitrogen to which they are attached form indolinyl,
pyrrolidinyl,
piperidinyl, piperazinyl, or morpholinyl;

[0229] n = 1-3;
[0230] R4 = H;

[0231] R5 is H, C(O)NR6R7 or C(O)OR8, said R6 and R7 in the definition of R5
being each independently H, C1_6 alkyl, C3_7 cycloalkyl, or C4_10
alkylcycloalkyl;
[0232] R8 is C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, all of
which are
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C1_6 alkyl optionally substituted with up to 5 fluoro
groups; or R8 is a
tetrahydrofuran ring linked through the C3 or C4 position of the
tetrahydrofuran ring; or R8
is a tetrapyranyl ring linked through the C4 position of the tetrapyranyl
ring;

-43-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[0233] 'Y is a sulfommide of the formula -C(O)NHS(O)2R 9 , where R9 is C1_6
alkyl, C3_7 cycloalkyl, or 04.10 alkylcycloalkyl, all of which are optionally
substituted from
one to three times with halo, C1_6 alkoxy, or phenyl;
[0234] Rio, R11, R12 and R13 are H;
[0235] p = 0 or 1;

[0236] V = O; and

[0237] W is selected from 0, NH, or CH2.

[0238] In preferred embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV, in which p may be 0. In preferred
embodiments, Section B embodiments provide compounds having the general
Formulas II,
III, and IV, in which p maybe 1.

[0239] In preferred embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV, in which either or both of R1 and
R2 are H. In
some embodiments, p is 0. In other embodiments p is 1.

[0240] In preferred embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV, in which neither R1 nor R2 is H.
In some
embodiments, p is 0. In other embodiments, p is 1.

[0241] In preferred embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV, in which R2 is OCHnNR6R7 or
OCH0R16.

[0242] In preferred embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV in which R9 is C1_6 alkyl, C3_7
cycloalkyl, or C4-
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl.

[0243] In preferred embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV in which R9 is C6 or 10 aryl which
is optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7
cycloalkyl, C4-10
alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl
optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro.

[0244] In preferred embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV in which R9 is a heteroaromatic
ring optionally
substituted up to two times with halo, cyano, nitro, hydroxyl, or C1_6 alkoxy.

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
WA' " In pre er`r`e embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV in which R9 is a C1_6 alkyl
optionally substituted
with up to 5 fluoro groups, NR6R7, or (CO)OH.

[0246] In preferred embodiments, Section B embodiments provide compounds
having the general Formulas II, III, and IV in which the dashed line in
Formula (II), (III), or
(IV) represents a single bond.

[0247] Section B embodiments provide compounds having the general Formula
II:

R1
R11

R10
R20 P R2
N R13
V-\ R12
O N
:7r NH i
R4R5N s O
9 14
12
13
11
II
[0248] wherein:

[0249] R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7 cycloalkyl, 04.10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl,
C1_6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally
substituted with
up to 5 fluoro, C6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy,
thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7, NHC(S)NR6R7, C(O)NR6R7, NR6R7, C(O)R8,
C(O)OR8, NHC(O)R8, NHC(O)OR8, SO11R8, NHS(O)2R8, OCHnNR6R7, or OCH1,R16
where R16 is imidazolyl or pyrazolyl; said thienyl, pyrimidal, furanyl,
thiazolyl and oxazolyl
in the definition of R1 and R2 are optionally substituted by up to two halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro; said C6 or 10 aryl, pyridal,
phenoxy, and
thiophenoxy in the definition of R1 and R2 are optionally substituted by up to
three halo,
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
cyano, nitro, hydroxy, C'1_6 akyi, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2_6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1.6 alkyl optionally substituted with up to 5
fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro;

[0250] in = 0, 1, or 2;
[0251] R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, phenyl, or
benzyl, said phenyl or benzyl optionally substituted by up to three halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2.6 alkenyl,
C1.6 alkoxy,
hydroxy-C1_6 alkyl, CI-6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0252] R5 is H, C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8,
S(O)2R8, or (CO)CHR21NH(CO)R22;

[0253] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4.1o
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-1o alkylcycloalkyl, C2.6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy
optionally substituted
with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to
which they are
attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or
morpholinyl;

[0254] R8 is C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1.6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring;
[0255] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_6
alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, which are all optionally
substituted from one to
three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl, or R9 is
C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro, or R9 is a C1_6 alkyl optionally substituted with up to 5 fluoro
groups, NR6R7, or
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
tt.., tf - thrt+ = m% 7t- ~rr, ff" :f f:. if It
(C'O)OH, or is a l eteroaromatic ring optionally substituted up to two times
with halo,
cyano, nitro, hydroxyl, or C1_6 alkoxy; or Y is a carboxylic acid or
pharmaceutically
acceptable salt, solvate, or prodrug thereof;

[0256] R10 and R11 are each independently H, C1.6 alkyl, C3_7 cycloalkyl,
C4.10
alkylcycloalkyl, C6 or 1o aryl, hydroxy-C1.6 alkyl, C1_6 alkyl optionally
substituted with up to
fluoro, (CH2)11NR6R7, or (CH2)11C(O)OR14 where R14 is H, C1.6 alkyl, C3_7
cycloalkyl, C4-
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which
is optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7
cycloalkyl, C4.10
alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl
optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;
said C6 or 10 aryl, in the definition of R10 and R11 is optionally substituted
by up to three
halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to
5 fluoro, or C1.6
alkoxy optionally substituted with up to 5 fluoro; or R10 and R11 are taken
together with the
carbon to which they are attached to form cyclopropyl, cyclobutyl,
cyclopentyl, or
cyclohexyl; or R10 and R11 are combined as 0;

[0257] p= 0 or 1;

[0258] R12 and R13 are each independently H, C1.6 alkyl, C3_7 cycloalkyl,
C4.10
alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally
substituted with up to
5 fluoro, (CH2)11NR6R7, or (CH2)11C(O)OR14 where R14 is H, C1.6 alkyl, C3_7
cycloalkyl, C4-
10 alkylcycloalkyl, which are all optionally substituted from one to three
times with halo,
cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which
is optionally
substituted by up to three halo, cyano, nitro, hydroxy, C1.6 alkyl, C3_7
cycloalkyl, C4.10
alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl
optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;
said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted
by up to three
halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to
5 fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro; or R12 and R13 are taken
together with the
carbon to which they are attached to form cyclopropyl, cyclobutyl,
cyclopentyl, or
cyclohexyl, or R12 and R13 are each independently C1_6 alkyl optionally
substituted with
(CH2),OR8;

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[025'x]" ".."C1-6" alky1 , C3-7 cycloalky1, C4_10 alkylcycloalkyl, C6 or 10
aryl,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
(CH2),1NR6R7, or
(CH2)11C(O)OR14 where R14 is H, C1.6 alkyl, C3-7 cycloalkyl, C4_10
alkylcycloalkyl, which
are all optionally substituted from one to three times with halo, cyano,
nitro, hydroxy, C1-6
alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by
up to three halo,
cyan, nitro, hydroxy, C1_6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6
alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the
definition of R12
and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4-io alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1-6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;

[0260] n = 0-4;

[0261] V is selected from O. S, or NH;

[0262] when V is 0 or S, W is selected from 0, NR15, or CR15; when V is NH,
W is selected from NR15 or CR15, where R15 is H, C1.6 alkyl, C3-7 cycloalkyl,
C4-10
alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;

[0263] the dashed line represents an optional double bond;

[0264] R21 is C1-6 alkyl, C3_7 cycloalkyl, or C4-10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
C1_6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6
or 10 aryl which
is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7
cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl,
oxazolyl, phenoxy,
or thiophenoxy; and

[0265] R22 is C1.6 alkyl, C3-7 cycloalkyl, or C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkyl
optionally substituted with up to 5 fluoro, or phenyl.
[0266] Section B embodiments provide compounds having the general Formula
IIa:

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R1
R11
R10 -~~

R2
N
O=~
W
O N
NH 1 \\Y 'T7 R
5, N O

H 9 14
12
13
11
IIa
[0267] wherein:

[0268] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl,
or
C1_3 alkoxy;

[0269] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0270] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;

[0271] R8 is C1.6 alkyl, C3_7 cycloalkyl, C4_i0 alkylcycloalkyl, or 3-
tetrahydofuryl.

[0272] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_3
alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two
halo, cyano,
nitro, hydroxy, Ci_3 alkyl, C3.7 cycloalkyl, or C1_3 alkoxy, or Y is a
carboxylic acid or
pharmaceutically acceptable salt, solvate, or prodrug thereof;
[0273] R10 and R1' are each independently H or C1.3 alkyl, or R10 and R11 are
taken together with the carbon to which they are attached to form cyclopropyl,
cyclobutyl,
cyclopentyl, or cyclohexyl;

[0274] W is selected from 0 or NH; and
[0275] the dashed line represents an optional double bond.

[0276] Section B embodiments provide compounds having the general Formula
IIIa:

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R1
t R2

N
O=
W
O N
NH 1 ~~Y
:7r R
N 3 O

H 9 14
12
3
11
Ma
[0277] wherein:

[0278] Ri and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl,
or
C1_3 alkoxy;

[0279] R4 is H;

[0280] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0281] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-
tetrahydrofuryl.

[0282] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_3
alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two
halo, cyano,
nitro, hydroxy, C1_3 alkyl, C3_7 cycloalkyl, or C1.3 alkoxy, or Y is a
carboxylic acid or
pharmaceutically acceptable salt, solvate, or prodrug thereof;

[0283] W is selected from 0 or NH; and

[0284] the dashed line represents an optional double bond.

[0285] Section B embodiments provide compounds having the general Formula
IIb:

-50-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R1
R11
R10 d=~

R2
N
O=~
W
O N J~ O /O
NH 1 N=S=R
R5, H R9
N =, a O

H 9 14
12
13
11
IIb
[0286] wherein:

[0287] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl,
or
C1_3 alkoxy;

[0288] R5 is H, C(O)OR8 or C(O)NHR8;

[0289] R8 is C1_6 alkyl, C5_6 cycloalkyl, or 3-tetrahydrofuryl;

[0290] R9 is C1_3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally
substituted
by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0291] R10 and R11 are each independently H or C1_3 alkyl, or R10 and R11 are
taken together with the carbon to which they are attached to form cyclopropyl,
cyclobutyl,
cyclopentyl, or cyclohexyl;

[0292] W is selected from 0 or NH; and

[0293] the dashed line represents an optional double bond.

[0294] Section B embodiments provide compounds having the general Formula
IIIb:

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R1
&---R2
N
O=~
W
O N 1~ Qv/O
R 7 NH 1'`\N N~S'R9
H
N O d,BB
H
g 14
12
13
11
IIlb
[0295] wherein:

[0296] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl,
or
C1_3 alkoxy;

[0297] R5 is H, C(O)OR8 or C(O)NHR8;

[0298] R8 is C1_6 alkyl, C5_6 cycloalkyl, or 3-tetrahydrofuryl;

[0299] R9 is C1_3 alkyl, C3_5 cycloalkyl, or phenyl which is optionally
substituted
by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0300] R10 and R11 are each independently H, C1.3 alkyl, or C4_5 cycloalkyl;
[0301] W is selected from 0 or NH; and

[0302] the dashed line represents an optional double bond.

[0303] Section B embodiments provide compounds having the general Formula
Ilc:

R1
R11
R10 4I

R2
N
O=<
O
0 N iJ 0/O
NH NR
R O H 9
N s
H 9 14
12
13
10 11
He
-52-


CA 02560897 2006-09-20
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[X04] ` wherein:

[0305] R1 and R2 are each independently H, chloro, fluoro, cyan, hydroxy, C1_3
alkyl, or C1_3 alkoxy;

[0306] R5 is H, C(O)OR8 or C(O)NHR8;
[0307] R8 is C1_6 alkyl or C5_6 cycloalkyl;

[0308] R9 is C1_3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally
substituted
by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;
(e) R10 and R11 are each independently H or C1.3 alkyl, or R10 and R11 are
taken
together with the carbon to which they are attached to form cyclopropyl or
cyclobutyl; and
(f) the dashed line represents an optional double bond.

[0309] Section B embodiments provide compounds having the general Formula
IIIc:
R1
1R2
N
o=~
O
0 0 0
O N \\i/
AS...
NH ,~
R H Rs
N ',8 0
H
9 ~ 14
12
13
11
IIIc
[0310] wherein:

[0311] R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy,
C1.3
alkyl, or C1_3 alkoxy;

[0312] R5 is H, C(O)OR8 or C(O)NHR8;
[0313] R8 is C1_6 alkyl or C5_6 cycloalkyl;

[0314] R9 is C1_3 alkyl, C34 cycloalkyl, or phenyl which is optionally
substituted
by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy; and
[0315] the dashed line represents an optional double bond.

[0316] Section B embodiments provide compounds having the general Formula
IIId:

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R11
R10 R1

R20
N
O==< R2
W

O1 N
NXY
4R5N $ O
R
9 i 14
12 i
13
11
IIId
[0317] wherein:

[0318] R1 and R2 are each independently H, halo, cyano, hydroxy, C1.3 alkyl,
or
C1_3 alkoxy;

[0319] R4 is H;

[0320] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0321] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-
tetrahydrofuryl;

[0322] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_3
alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two
halo, cyan,
nitro, hydroxy, C1_3 alkyl, C3_7 cycloalkyl, or C1_3 alkoxy, or Y is a
carboxylic acid or
pharmaceutically acceptable salt, solvate, or prodrug thereof;
[0323] R10 and R11 are each independently H or C1.3 alkyl, or R10 and R11 are
taken together with the carbon to which they are attached to form cyclopropyl,
cyclobutyl,
cyclopentyl, or cyclohexyl;
[0324] R20 is H, C1_6 alkyl, C3_7 cycloalkyl, C4.1o alkylcycloalkyl, C6 or 10
aryl,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
(CH2)õNR6R7, or
(CH2)õ C(O)OR14 where R14 is H, C1.6 alkyl, C3_7 cycloalkyl, or C4-lo
alkylcycloalkyl, which
are all optionally substituted from one to three times with halo, cyano,
nitro, hydroxy, C1_6
alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by
up to three halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2_6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the
definition of R12
-54-


CA 02560897 2006-09-20
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rr =:ror ~i 1~ 7o-isopd' =:G,r 7iori% m~~6 :=' r:rEbr %~:e: _....
and R tionally substituted by up to three halo, cyan, nitro, hydroxy, C1_6
alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;
[0325] W is selected from 0 or NH; and

[0326] the dashed line represents an optional double bond.

[0327] Section B embodiments provide compounds having the general Formula
IVa:

R11 R1
R10 Z-R2
R20
P
N R13
O=< R12
W

O\/N
J7 NH1Y
~ Cx,
R4R5N O
9 If 14
12
13
11
IVa
[0328] wherein:

[0329] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl,
or
C1_3 alkoxy;

[0330] R4 is H;

[0331] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0332] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-
tetrahydrofuryl;
[0333] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1_3
alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two
halo, cyano,
nitro, hydroxy, C1_3 alkyl, C3_7 cycloalkyl, or C1_3 alkoxy, or Y is a
carboxylic acid or
pharmaceutically acceptable salt, solvate, or prodrug thereof;
[0334] R10 and Rii are each independently H or C1.3 alkyl, or R10 and Rii are
taken together with the carbon to which they are attached to form cyclopropyl,
cyclobutyl,
cyclopentyl, or cyclohexyl;

-55-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[0335] R is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C6 ,. 10
aryl,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
(CH2)õNR6R7, and
(CH2)õC(O)OR14 where R14 is H, C1.6 alkyl, C3_7 cycloalkyl, or C4_10
alkylcycloalkyl, which
are all optionally substituted from one to three times with halo, cyano,
nitro, hydroxy, C1_6
alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by
up to three halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-lo alkylcycloalkyl,
C2_6 alkenyl, C1-6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro; said C6 o, 10 aryl, in the
definition of R12
and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4-1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1.6
alkyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro;

[0336] W is selected from 0 or NH;

[0337] the dashed line represents an optional double bond; and
[0338] where Z is a fused or appended aryl heteroaryl ring system.
Section C

[0339] Section C embodiments provide compounds having the general Formula
XI.

R2
V==<
W
18
17 19
16 1
O 0
S
N NH O O
13 N' \NR1aR1b
R4R5N O H
13
12 7
9
11 10
XI
[0340] wherein:
[0341] Rla and Rib are each independently H, C1_6 alkyl, C3_7 cycloalkyl, or
C4-1o
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1.6 alkoxy, amido, or phenyl;

-56-


CA 02560897 2006-09-20
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104111111.:P :111W 6r -bra ahd"` R'1 b are each independently H or C6 ,. io
aryl which is
optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl,
C3-7 cycloalkyl,
C4-lo alkylcycloalkyl, C2-6 alkenyl, C1_6 alkoxy, hydroxy-C1-6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;

[0343] or Ria and Rlb are each independently H or heterocycle, which is a five-
,
six-, or seven-membered, saturated or unsaturated heterocyclic molecule,
containing from
one to four heteroatoms selected from the group consisting of nitrogen, oxygen
and sulfur;

[0344] or NRIaRIb is a three- to six- membered alkyl cyclic secondary amine,
which optionally has one to three hetero atoms incorporated in the ring, and
which is
optionally substituted from one to three times with halo, cyano, nitro, C1.6
alkoxy, amido, or
phenyl;

[0345] or NR1aRIb is a heteroaiyl selected from the group consisting of:
-`NON -'*--N/N~ ANN
R1c V=~R1c , and Ric

[0346] wherein Rl is H, halo, C1_6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6
cycloalkoxy, NO2, N(Rld)2, NH(CO)RId, or NH(CO)NHRId, wherein each RId is
independently H, C1_6 alkyl, or C3-6 cycloalkyl;

[0347] or R1c is NH(CO)ORIe wherein Rle is C1.6 alkyl or C3-6 cycloalkyl;
[0348] W is 0 or NH;

[0349] V is selected from 0, S, or NH;

[0350] when V is 0 or S, W is selected from 0, NR15, or CR15; when V is NH,
W is selected from NR15 or CR15, where R15 is H, Cl-6 alkyl, C3-7 cycloalkyl,
C4-10
alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;

[0351] R2 is a bicyclic secondary amine with the structure of.
R21
R11
R10

R20 P R22
/ I R13
R12

[0352] wherein R21 and R22 are each independently H, halo, cyano, nitro,
hydroxy, C1_6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl,
C1.6 alkoxy,
hydroxy-C1-6 alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro,
C1-6 alkoxy
optionally substituted with up to 5 fluoro, C6 or to aryl, pyridal, pyrimidal,
thienyl, furanyl,
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CA 02560897 2006-09-20
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thiazolyl, oxazolyl; p' epoxy,"thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7,
NHC(S)NR6R7,
C(O)NR6R7, NR6R7, C(O)R8, C(O)OR8, NHC(O)R8, NHC(O)OR8, SO11R8 (in = 0, 1 or
2),
or NHS(O)2R8; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the
definition of
R21 and R22 are optionally substituted by up to two halo, cyano, nitro,
hydroxy, C1_6 alkyl,
C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-
C1_6 alkyl, C1_6
alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with
up to 5 fluoro; said C6 or 10 aryl, pyridal, phenoxy, and thiophenoxy in the
definition of R21
and R22 are optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;

[0353] wherein R10 and R'1 are each independently H, C1_6 alkyl, C3_7
cycloalkyl, C4-1o alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, or C1_6
alkyl optionally
substituted with up to 5 fluoro, (CH2)nNR6R7, or (CH2)õC(O)OR14 where R14 is
H, C1.6
alkyl, C3_7 cycloalkyl, or C4-lo alkylcycloalkyl, which are all optionally
substituted from one
to three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; or
R14 is C6 or 10 aryl
which is optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1_6 alkyl, C3_7
cycloalkyl, C4-1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, or C1_6 alkyl
optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted
with up to 5
fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is optionally
substituted by up to
three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted
with up to 5
fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro; or R10 and
R'1 are taken
together with the carbon to which they are attached to form cyclopropyl,
cyclobutyl,
cyclopentyl, or cyclohexyl; or R10 and R11 are combined as 0;

[0354] wherein p = 0 or 1;

[0355] wherein R12 and R13 are each independently H, C1.6 alkyl, C3_7
cycloalkyl, 04.10 alkylcycloalkyl, C6 or 1o aryl, hydroxy-C1.6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, (CH2)0NR6R7, (CH2)nC(O)OR14 where R14 is H,
C1.6 alkyl,
C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are all optionally substituted
from one to three
times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; or R14 is C6
or 10 aryl which is
optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl,
C3_7 cycloalkyl,
C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6
alkyl optionally
-58-


CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
" substituted witli'up to5"fluoro, C1_6 alkoxy optionally substituted with up
to 5 fluoro; said
C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted by
up to three halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2.6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro; or R12 and R13 are taken
together with the
carbon to which they are attached to form cyclopropyl, cyclobutyl,
cyclopentyl, or
cyclohexyl;

[0356] wherein R20 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C6 or 10
aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5
fluoro, (CH2)õNR6R7,
(CH2)õC(O)OR14 where R14 is H, CI-6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, which
are all optionally substituted from one to three times with halo, cyan, nitro,
hydroxy, C1_6
alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by
up to three halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2_6 alkenyl, C1_6
alkoxy, hydroxy-C1_6 alkyl, C1.6 alkyl optionally substituted with up to 5
fluoro, C1_6 alkoxy
optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the
definition of R12 and R13
is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;

[0357] wherein n = 0-4;

[0358] wherein R6 and R7 are each independently H, C1.6 alkyl, C3_7
cycloalkyl,
C4_10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to
three halo,
cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl,
C2.6 alkenyl,
hydroxy-C1_6 alkyl, C1.6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R6 and R7 are taken together
with the nitrogen
to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl,
piperazinyl, or
morpholinyl;
[0359] or R2 is R2aR2b when W = NH and V = O, wherein
[0360] R2a is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, phenyl,
pyridine,
pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole,
oxazole, imidazole,
isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline,
quinoxaline,
benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each
optionally
substituted with up to three NR2 R2d, halo, cyano, nitro, hydroxy, C1.6 alkyl,
C3_7 cycloalkyl,
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CA 02560897 2006-09-20
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" C4'lo' alky'1cycoaYy1,"''fC2-`6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl,
C1_6 alkyl optionally
substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted with up to
5 fluoro;

[0361] R2b is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,
furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole,
isothiazole, napthyl,
quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,
benzofuran, indole, or
benzimidazole, each optionally substituted with up to three NR2CR2d, halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0362] said R2o and Red are each independently H, C1_6 alkyl, C3_7 cycloalkyl,
C4_
1o alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R2o and Red are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0363] R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, or phenyl,
said
phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7
cycloalkyl, C4-1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;

[0364] R5 is H, C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, or
S(O)2R8;

[0365] R8 is C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6,,r 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro; and

[0366] the dashed line represents an optional double bond.

[0367] Section C embodiments provide compounds having the general Formula
XII.

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R21
R11
R1o

R22
N R13
O~ R12
O
18'

O N 2 NH iL 'S'
4 1 a 1 b
R5 14 O N' 'NR R
N '' 13 s e H
H 1 7
11 10
XII
[0368] wherein:

[0369] Rla and Rib are each independently H, C1_6 alkyl, C3-7 cycloalkyl, or
C4_1o
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1_6 alkoxy, amido, or phenyl;
[0370] or Ria and Rib are each independently H or heteroaryl selected from a
group consisting of:

S'N O N HN O N O' N RN N
~1) _ N--' , `I , and N=N
R1c R1c R1c R1c R1c

[0371] wherein Ric is H, halo, C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3-6
cycloalkoxy, NO2, N(Rid)2, NH(CO)R1d, or NH(CO)NHRid, wherein each Rid is
independently H, C1_6 alkyl, or C3.6 cycloalkyl;

[0372] or NRlaRib is a three- to six- membered alkyl cyclic secondary amine,
which optionally has one to three hetero atoms incorporated in the ring, and
which is
optionally substituted from one to three times with halo, cyano, nitro, C1_6
alkoxy, amido, or
phenyl;
[0373] R21 and R22 are each independently H, halo, cyano, hydroxy, C1_3 alkyl,
or C1-3 alkoxy;

[0374] R5 is H, C(O)NR6R7, C(O)R$, or C(O)ORB;
[0375] R6 and R7 are each independently H, C1_6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
is O1_6 alkyl, C3_7 cycloalkyl, C4_1 alkylcycloalkyl, or 3-
tetrahydrofuryl;

[0377] R10 and R11 are each independently H, halo, or C1.3 alkyl, or R10 and
Rii
are taken together with the carbon to which they are attached to fonn
cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl;

[0378] R12 and R13 are each independently H, halo, C1.6 alkyl, C3_7
cycloalkyl,
C4_10 alkylcycloalkyl, C6 0110 aryl, hydroxy-C1_6 alkyl, or C1_6 alkyl
optionally substituted
with up to 5 halo atoms; and

[0379] the dashed line represents an optional double bond.

[03801 Section C embodiments provide compounds having the general Formula
XIII.

R21

~ 22
\ R
N
O~
O
18

1
ON 2 NH a,,,~ O~ O
R
~NJ=;a N'SNR1aR1b
/ 13 5 ~I g H
H 1 i 7
9 8
11 10
XIII
[0381] wherein:

[0382] R 1 a and Rib are each independently H, C1_6 alkyl, C3_7 cycloalkyl,
C4.10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1_6 alkoxy, amido, or phenyl;

[0383] or Ria and Rlb are each independently H or heteroaryl selected from a
group consisting of:

/~ ' ' N O" N O' N /~
S N O N HN \`~ RN N
N =N , and N=N
R1C R1c R1c R1c Ric

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[03g4]'t "" wHer`eiii k' I'S' H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6
alkoxy, C3-6
cycloalkoxy, NO2, N(Rid)2, NH(CO)RId, or NH(CO)NHRId, wherein each RId is
independently H, C1_6 alkyl, or C3-6 cycloalkyl;

[0385] or NRlaRlb is a three- to six- membered alkyl cyclic secondary amine,
which optionally has one to three hetero atoms incorporated in the ring, and
which is
optionally substituted from one to three times with halo, cyano, nitro, C1-6
alkoxy, ainido or
phenyl;

[0386] R21 and R22 are each independently H, halo, cyano, hydroxy, C1_3 alkyl,
or C1_3 alkoxy;

[0387] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0388] R6 and R7 are each independently H, C1_6 alkyl, C3-7 cycloalkyl, C4-10
alkylcycloalkyl, or phenyl;

[0389] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-
tetrahydrofuryl; and

[0390] the dashed line represents an optional double bond.

[0391] Section C embodiments provide compounds having the general Formula
XIV.

R 2a
O=~
NH
18

O N 2 NH 4 0 O~ O
, ~1 $
R 1I Ni NR1aR1b
N i 13 5 8 H
H 7
11 10

XIV
[0392] wherein:

[0393] Rla and Rib are each independently H, C1-6 alkyl, C3_7 cycloalkyl, C4-
10
alkylcycloalkyl, which are all optionally substituted from one to three times
with halo,
cyano, nitro, C1-6 alkoxy, amido, or phenyl;

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[039" ] or . "and' - are each independently H or heteroaryl selected from a
group consisting of:

S"N O N HNC N > OWN ON RN"N
N `t N and N=N
R1c R1c R1c R1c R1c

[0395] wherein R10 is H, halo, C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3_6
cycloalkoxy, NO2, N(Rld)2, NH(CO)RId, or NH(CO)NHRId, wherein each RId is
independently H, C1_6 alkyl, or C3_6 cycloalkyl;

[0396] or NR1aR11' is a three- to six- membered alkyl cyclic secondary amine,
which optionally has one to three hetero atoms incorporated in the ring, and
which is
optionally substituted from one to three times with halo, cyano, nitro, C1_6
alkoxy, amido, or
phenyl;

[0397] R2' is C6 or Clo aryl optionally substituted with up to three NR2 R2d,
halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, C2_6 alkenyl,
C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to
5 fluoro, or C1_6
alkoxy optionally substituted with up to 5 fluoro;

[0398] said R2c and Red are each independently H, C1_6 alkyl, C3_7 cycloalkyl,
C4_
to alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R2 and Red are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0399] or Rea is an unsaturated five- or six-membered heteroaryl, or such
defined heteroaryl fused to another cycle be it heterocycle or any other
cycle;

[0400] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0401] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4.10
alkylcycloalkyl, or phenyl;
[0402] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-
tetrahydrofuryl; and
[0403] the dashed line represents an optional double bond.

[0404] Section C embodiments provide compounds having the general Formula
Xv.

-64-


CA 02560897 2007-08-08
R1

I R2
N
O==~
W
O N ~~ 0 O
NH N'R s
R~ 7H
N '"e O
H s 14
12
3
11

xv
[0405] wherein:
[0406] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl,
or C1.3 alkoxy;
[0407] R5 is H, C(O)OR8 or C(O)NHR8;
[0408] R8 is CI-6 alkyl, C5_6 cycloalkyl, or 3-tetrahydrofuryl;
[0409] R9 is C1.3 alkyl, C3_5 cycloalkyl, or phenyl which is optionally
substituted by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1.3 alkoxy;
[0411] W is selected from 0 or NH; and
[0412] the dashed line represents an optional double bond.
[0413] Section C embodiments provide compounds having the general
Formula XVI.

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R1
R11
R10
R2
N
OQ
O
O 010
O N II \\i/
Rs, NH \ 'IS\R9
:7~N ", s O H

H 9 14
12
3
11

XVI
[0414] wherein:

[0415] R' and R2 are each independently H, chloro, fluoro, cyano, hydroxy,
C1_3
alkyl, or C1_3 alkoxy;

[0416] R5 is H, C(O)OR8 or C(O)NHR8;
[0417] R8 is C1_6 alkyl or C5_6 cycloalkyl;

[0418] R9 is C1_3 alkyl, C3.4 cycloalkyl, or phenyl which is optionally
substituted
by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0419] R10 and R11 are each independently H or C1_3 alkyl, or R10 and R11 are
taken together with the carbon to which they are attached to form cyclopropyl
or cyclobutyl;
and

[0420] the dashed line represents an optional double bond.

[0421] Section C embodiments provide compounds having the general Formula
XVII.

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
R1
- R2

N
O=~
O
O N k /
s NH 1' , NHS"R9
R T7 H
N O
H
9 14
12
13
11
XVII
[0422] wherein:

[0423] R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy,
C1_3
alkyl, or C1_3 alkoxy;

[0424] R5 is H, C(O)OR8 or C(O)NHR8;
[0425] R8 is C1_6 alkyl or C5.6 cycloalkyl;

[0426] R9 is C1_3 alkyl, C34 cycloalkyl, or phenyl which is optionally
substituted
by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy; and

[0427] the dashed line represents an optional double bond.
Section D

[0428] Section D embodiments provide compounds having the general Formula
XVIII:

R2
R1
O=<
NH
O N O
NH N.S.RB
8 O H
3 R,N ~
R4
9 14
12 ~
13
10 11
XVIII
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[0429] wherein:

[0430] R1 is C1.6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, phenyl,
pyridine,
pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole,
oxazole, imidazole,
isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline,
quinoxaline,
benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each
optionally
substituted with up to three NR5R6, halo, cyano, nitro, hydroxy, C1.6 alkyl,
C3.7 cycloalkyl,
C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, C1_6
alkyl optionally
substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up
to 5 fluoro;

[0431] R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,
furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole,
isothiazole, napthyl,
quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene,
benzofuran, indole, or
benzimidazole, each optionally substituted with up to three NR5R6, halo,
cyano, nitro,
hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-lo alkylcycloalkyl, C2.6 alkenyl,
C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0432] R3 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or phenyl,
said
phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6
alkyl, C3_7
cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6
alkyl, C1_6 alkyl
optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally
substituted with up to 5
fluoro;

[0433] R4 is C1_6 alkyl, C(O)NRSR6, C(S)NR5R6, C(O)R7, C(O)OR7, or
S(O)2R7;

[0434] R5 and R6 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4.10
alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy
optionally
substituted with up to 5 fluoro; or R5 and R6 are taken together with the
nitrogen to which
they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl,
or morpholinyl;

[0435] R7 is C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, which are
all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R7 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
liydroxy= 16 alky; C` `6`'alkyl optionally substituted with up to 5 fluoro, or
C1_6 alkoxy
optionally substituted with up to 5 fluoro;

[0436] R8 is C1_3 alkyl, C34 cycloalkyl, or phenyl which is optionally
substituted
by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy; and

[0437] the dashed line represents an optional double bond.
Section E

[0438] Section E embodiments provide compounds having the general Formula
XIX:

P2
L

O N O
NH zP11
R5N 8 O
H 14
12
13
11

XIX
[0439] wherein:

[0440] Z is a group configured to hydrogen bond to an NS3 protease His57
imidazole moiety and to hydrogen bond to a NS3 protease Gly137 nitrogen atom;

[0441] P1' is a group configured to form a non-polar interaction with at least
one NS3 protease Si' pocket moiety selected from the group consisting of
Lys136, G1y137,
Ser139, His57, G1y58, G1n41, Ser42, and Phe43;

[0442] L is a linker group consisting of from 1 to 5 atoms selected from the
group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;

[0443] P2 is selected from the group consisting of unsubstituted aryl,
substituted aryl, unsubstituted heteroaryl, substituted heteroaryl,
unsubstituted heterocyclic
and substituted heterocyclic; P2 being positioned by L to form a non-polar
interaction with
at least one NS3 protease S2 pocket moiety selected from the group consisting
of His57,
Arg155, Va178, Asp79, G1n80 and Asp81;
[0444] the dashed line represents an optional double bond;
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[0445] R 'is selected from the group consisting of C(O)NR6R7 and C(O)OR8;
[0446] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4.10
alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three
halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, C2_6
alkenyl, hydroxy-C1_6
alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, C1.6 alkoxy
optionally substituted
with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to
which they are
attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or
morpholinyl; and

[0447] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4-1o alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, C2.6
alkenyl, C1_6 alkoxy,
hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring.
[0448] As used herein, "hydrogen bond" refers to an attractive force between
an
electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a
hydrogen atom
which is linked covalently to another electronegative atom (such as oxygen,
nitrogen, sulfur
or halogen). See, e.g., Stryer et. al. "Biochemistry", Fith Edition 2002,
Freeman & Co.
N.Y. Typically, the hydrogen bond is between a hydrogen atom and two unshared
electrons of another atom. A hydrogen bond between hydrogen and an
electronegative
atom not covalently bound to the hydrogen may be present when the hydrogen
atom is at a
distance of about 2.5 angstroms to about 3.8 angstroms from the not-covalently
bound
electronegative atom, and the angle formed by the three atoms (electronegative
atom
covalently bound to hydrogen, hydrogen, and electronegative atom not-
covalently bound
electronegative atom) deviates from 180 degrees by about 45 degrees or less.
The distance
between the hydrogen atom and the not-covalently bound electronegative atom
may be
referred to herein as the "hydrogen bond length," and the the angle formed by
the three
atoms (electronegative atom covalently bound to hydrogen, hydrogen, and
electronegative
atom not-covalently bound electronegative atom) may be referred to herein as
the
"hydrogen bond angle." In some instances, stronger hydrogen bonds are formed
when the
hydrogen bond length is shorter; thus, in some instances, hydrogen bond
lengths may range
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
fr'om' about2:'7 a'igsffoms 'to' about 3.6 angstroms, or about 2.9 angstroms
to about 3.4
angstroms. In some instances, stronger hydrogen bonds are formed when the
hydrogenbond
angle is closer to linear; thus, in some instances, hydrogen bond angles may
deviate from
180 degrees by about 25 degrees or less, or by about 10 degrees or less.

[0449] As used herein, non-polar interaction refers to proximity of non-polar
molecules or moieties, or proximity of molecules or moieties with low
polarity, sufficient
for van der Waals interaction between the moieties and/or sufficient to
exclude polar
solvent molecules such as water molecules. See, e.g., Stryer et. al.
"Biochemistry", Fith
Edition 2002, Freeman & Co. N.Y. Typically, the distance between atoms
(excluding
hydrogen atoms) of non-polar interacting moieties may range from about 2.9
angstroms to
about 6 angstroms. In some instances, the space separating non-polar
interacting moieties
is less than the space that would accommodate a water molecule. As used herein
a non-
polar moiety or moiety with low polarity refers to moieties with low dipolar
moments
(typically dipolar moments less than the dipolar moment of O-H bonds of H2O
and N-H
bonds of NH3) and/or moieties that are not typically present in hydrogen
bonding or
electrostatic interactions. Exemplary moieties with low polarity are alkyl,
alkenyl, and
unsubstituted aryl moieties.

[0450] As used herein, an NS3 protease S 1' pocket moiety refers to a moiety
of
the NS3 protease that interacts with the amino acid positioned one residue C-
terminal to the
cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the
NS3 protease
moieties that interact with amino acid S in the polypeptide substrate DLEVVT-
STWVLV).
Exemplary moieties include, but are not limited to, atoms of the peptide
backbone or side
chains of amino acids Lys136, Gly137, Ser139, His57, Gly58, G1n41, Ser42, and
Phe43,
see Yao. et. al., Structure 1999, 7, 1353.

[0451] As used herein, an NS3 protease S2 pocket moiety refers to a moiety of
the NS3 protease that interacts with the amino acid positioned two residues N-
terminal to
the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g.,
the NS3
protease moieties that interact with amino acid V in the polypeptide substrate
DLEVVT-
STWVLV). Exemplary moieties include, but are not limited to, atoms of the
peptide
backbone or side chains of amino acids His57, Arg155, Va178, Asp79, G1n80 and
Asp8l,
see Yao. et. al., Structure 1999, 7, 1353.
[0452] As used herein, a first moiety "positioned by" a second moiety refers
to
the spatial orientation of a first moiety as determined by the properties of a
second moiety
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
H P A: ~ d, ,; ndLr ri,"rfr it .n' tr
o' w ich is first atom or moiety is covalently bound. For example, a phenyl
carbon may

position an oxygen atom bonded to the phenyl carbon in a spatial position such
that the
oxygen atom hydrogen bonds with a hydroxyl moiety in an NS3 active site.

[0453] Also provided herein are compounds containing moieties configured to
interact with particular regions, particular amino acid residues, or
particular atoms of NS3
protease. Some compounds provided herein contain one or more moieties
configured to
form a hydrogen bond with NS3 protease at a particular region, amino acid
residue, or
atom. Some compounds provided herein contain one or more moieties configured
to form
a non-polar interaction with NS3 protease at a particular region, amino acid
residue, or
atom. For example, the compound having the general Formula XIX may contain one
or
more moieties that form a hydrogen bond with a peptide backbone atom or side
chain
moiety located in the substrate binding pocket of NS3 protease. In another
example, the
compound having the general Formula XIX may contain one or more moieties that
form
non-polar interactions with peptide backbone or side chain atom or atoms
located in the
substrate binding pocket of NS3 protease. In the compound of formula XIX, the
dashed
line between carbons 13 and 14 may be a single bond or a double bond.

[0454] As provided in the compound having the general formula XIX, Z may be
configured to form a hydrogen bond with a peptide backbone atom or side chain
moiety
located in the substrate binding pocket of NS3 protease, including, but not
limited to, NS3
protease His57 imidazole moiety and NS3 protease G1y137 nitrogen atom. In some
instances, Z may be configured to form a hydrogen bond with both the NS3
protease His57
imidazole moiety and the NS3 protease Glyl37 nitrogen atom.

[0455] The P 1' group of the compound having the general formula XIX may be
configured to form a non-polar interaction with peptide backbone or side chain
atom or
atoms located in the substrate binding pocket of NS3 protease, including, but
not limited to
amino acid residues that form the NS3 protease Si' pocket. For example the P1'
group may
form a non-polar interaction with at least one amino acid selected from
Lys136, Gly137,
Ser139, His57, G1y58, G1n41, Ser42, and Phe43.

[0456] The P2 group of the compound having the general formula XIX may be
configured to form a non-polar interaction with peptide backbone or side chain
atom or
atoms located in the substrate binding pocket of NS3 protease, including, but
not limited to
amino acid residues that form the NS3 protease S2 pocket. For example the P2
group may
form a non-polar interaction with at least one amino acid selected from His57,
Arg155,
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
V a1'/ 8, Asp 7p, Ciln6U and Asp81-: The P2 group also maybe configured to
form a hydrogen
bond with peptide backbone or side chain atom or atoms located in the
substrate binding
pocket of NS3 protease, including, but not limited to amino acid residues that
form the NS3
protease S2 pocket. For example the P2 group may form a hydrogen bond with at
least one
amino acid selected from His57, Arg155, Va178, Asp79, G1n80 and Asp8l. In some
instances, P2 may form both a non-polar interaction and a hydrogen bond with
peptide
backbone or side chain moieties or atoms located in the substrate binding
pocket of NS3
protease, such amino acids selected from His57, Argl55, Va178, Asp79, G1n80
and Asp8 1.
Such hydrogen bond and non-polar interactions may occur with the same amino
acid
residue or with different amino acid residues in the NS3 protease S2 pocket.
In some
embodiments, P2 may be selected from the group consisting of unsubstituted
aryl,
substituted aryl, unsubstituted heteroaryl, substituted heteroaryl,
unsubstituted heterocyclic
and substituted heterocyclic.

[0457] In some embodiments, the position of the P2 group is determined by the
linker L. For example, P2 may be positioned by linker L to form a non-polar
interaction
with peptide backbone or side chain atom or atoms located in the substrate
binding pocket
of NS3 protease, including, but not limited to amino acid residues that form
the NS3
protease S2 pocket. For example the P2 group may be positioned by L to form a
non-polar
interaction with at least one amino acid selected from His57, Arg155, Va178,
Asp79, Gln80
and Asp8 1. In another example, P2 may be positioned by linker L to form a
hydrogen bond
with peptide backbone or side chain atom or atoms located in the substrate
binding pocket
of NS3 protease, including, but not limited to amino acid residues that form
the NS3
protease S2 pocket. For example the P2 group may be positioned by L to form a
hydrogen
bond with at least one amino acid selected from His57, Argl55, Va178, Asp79,
G1n80 and
Asp8 1. In some instances, P2 may be positioned to form both a non-polar
interaction and a
hydrogen bond peptide backbone or side chain atom or atoms located in the
substrate
binding pocket of NS3 protease, such as an amino acid selected from His57,
Arg155,
Va178, Asp79, G1n80 and Asp81. Such hydrogen bond and non-polar interactions
may
occur with the same amino acid residue or with different amino acid residues
in the NS3
protease S2 pocket.
[0458] As provided in the compound having the general formula XIX, L may be
a linker group that links P2 to the heterocyclic backbone of the compound of
formula XIX.
Linker L may contain any of a variety of atoms and moieties suitable for
positioning P2 in
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the NS3 proteasesubstrate binding pocket. In one embodiment, L may contain 1
to 5 atoms
selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and
sulfur. In
another embodiment, L may contain 2 to 5 atoms selected from the group
consisting of
carbon, oxygen, nitrogen, hydrogen, and sulfur. For example, L may contain a
group
having the formula -W-C(=V)-, where V and W are each individually selected
from 0, S or
NH. Specific exemplary groups for L include, but are not limited to, ester,
amide,
carbamate, thioester, and thioamide.

[0459] The compound of formula XIX also may contain an R5 group, where the
R5 group may contain a carboxyl moiety. Exemplary carboxyl moieties of R5
include
C(O)NR6R7 and C(O)OR8 where R6 and R7 are each independently H, C1_6 alkyl,
C3_7
cycloalkyl, C4_10 alkylcycloalkyl or phenyl, said phenyl optionally
substituted by up to three
halo, cyano, nitro, hydroxy, C1_6 alkyl, C3.7 cycloalkyl, C4-1o
alkylcycloalkyl, C2_6 alkenyl,
hydroxy-C1.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R6 and R7 are taken together
with the nitrogen
to which they are attached to form indolinyl, pyrTolidinyl, piperidinyl,
piperazinyl, or
morpholinyl; and where R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10
alkylcycloalkyl, which are all
optionally substituted from one to three times with halo, cyano, nitro,
hydroxy, C1_6 alkoxy,
or phenyl; or R8 is C6 or 1o aryl which is optionally substituted by up to
three halo, cyano,
nitro, hydroxy, C1_6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6
alkenyl, C1_6 alkoxy,
hydroxy-C1.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro,
C1_6 alkoxy
optionally substituted with up to 5 fluoro; or R8 is C1_6 alkyl optionally
substituted with up
to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or
C4 position of
the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4
position of the
tetrapyranyl ring
[0460] In some embodiments, several bonds of the compound of formula XIX
may have a particular chirality.

[0461] Section E embodiments provide compounds wherein the C13-C14
double bond is cis. Section E embodiments provide compounds wherein the C13-
C14
double bond is trans.

[0462] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIX, in which L consists of from 2 to 5 atoms.

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.. 0463 In ' "referfed embodiments Section E embodiments provide compounds
having the general Formula XIX, in which L comprises a -W-C(=V)- group, where
V and
W are each individually selected from 0, S or NH.

,[0464] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIX, in which L is selected from the group
consisting of ester,
amide, carbamate, thioester, and thioamide.

[0465] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIX, in which P2 is further positioned by L to form
a hydrogen
bonding interaction with at least one NS3 protease S2 pocket moiety selected
from the
group consisting of His57, Arg155, Va178, Asp79, G1n80 and Asp81.

[0466] In preferred embodiments, Section E embodiments provide compounds
having the the formula XIXa:

/ P2
L

O N O
7 NH 1 J z'P1,
RSN 8 O
H 9 14
12
13
11

XIXa.
[0467] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXa, in which L consists of from 2 to 5 atoms.

[0468] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXa, in which L comprises a -W-C(=V)- group, where
V and
W are each individually selected from 0, S, or NH.

[0469] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXa, in which L is selected from the group
consisting of ester,
amide, carbamate, thioester, and thioamide.

[0470] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXa, in which P2 is further positioned by L to
form a
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hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety
selected
from the group consisting of His57, Arg155, Va178, Asp79, G1n80 and Asp81.

[04711 In preferred embodiments, Section E embodiments provide compounds
H
N
c N~
having the general Fonnula XIX, in which P2 is

[0472] In preferred embodiments, Section E embodiments provide compounds
having the the formula XIXb:

S P2
L

o N o
NH 1 . J~Z.P1
R5N 8 0

H g }14
L 12
13
11

XIXb
[0473] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXb, in which L consists of from 2 to 5 atoms.

[0474] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXb, in which L comprises a -W-C(=V)- group, where
V and
W are each individually selected from 0, S, or NH.

[0475] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXb, in which L is selected from the group
consisting of ester,
amide, carbainate, thioester, and thioamide.

[0476] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXb, in which P2 is further positioned by L to
form a
hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety
selected
from the group consisting of His57, Arg155, Va178, Asp79, G1n80 and Asp8l.

[0477] In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXb, wherein the C13-C14 double bond is cis.

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[04781 In preferred embodiments, Section E embodiments provide compounds
having the general Formula XIXb, wherein the C13-C14 double bond is trans.

[0479] Compounds of the Formula XIX may be prepared in the same general
manner as the compounds of the Formulas I - XVII.

[0480] In certain embodiments, the compounds of general Formula XIX do not
include the compounds disclosed in PCT/USO4/33970. For example, in certain
embodiments, the compounds of general Formula I do not include the compounds
of
Formulas II, III, and IV in Section B above.

Pharmaceutical Compositions

[0481] The embodiments further provide compositions, including
pharmaceutical compositions, comprising compounds of the general formulas I-
XIX, and
salts, esters, or other derivatives thereof. A subject pharmaceutical
composition comprises
a subject compound; and a pharmaceutically acceptable excipient. A wide
variety of
pharmaceutically acceptable excipients is known in the art and need not be
discussed in
detail herein. Pharmaceutically acceptable excipients have been amply
described in a
variety of publications, including, for example, A. Gennaro (2000) "Remington:
The
Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, &
Wilkins;
Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et
al., eds.,
7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical
Excipients
(2000) A.H. Kibbe et al., eds., 31d ed. Amer. Pharmaceutical Assoc.

[0482] The pharmaceutically acceptable excipients, such as vehicles,
adjuvants,
carriers or diluents, are readily available to the public. Moreover,
pharmaceutically
acceptable auxiliary substances, such as pH adjusting and buffering agents,
tonicity
adjusting agents, stabilizers, wetting agents and the like, are readily
available to the public.
Examples of suitable pharmaceutical composition embodiments and methods for
making
them are described in greater detail below.

Inhibiting Enzymatic Activity of a Flavivirus

[0483] In many embodiments, a subject compound inhibits the enzymatic
activity of a flavirus. Whether a subject compound inhibits flavivirus may be
readily
determined using any known method. Flaviviral infections include those caused
by
flaviviruses including, but not limited to, hepatitis virus C, West Nile
Virus, GB virus,
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CA 02560897 2007-08-08

Japanese Encephalitis, Dengue virus and Yellow Fever virus. In many
embodiments, a
subject compound inhibits the enzymatic activity of a hepatitis virus C (HCV)
protease
NS3. Whether a subject compound inhibits HCV NS3 may be readily determined
using
any known method. Typical methods involve a determination of whether an HCV
polyprotein or other polypeptide comprising an NS3 recognition site is cleaved
by NS3 in
the presence of the agent. In many embodiments, a subject compound inhibits
NS3
enzymatic activity by at least about 10%, at least about 15%, at least about
20%, at least
about 25%, at least about 30%, at least about 40%, at least about 50%, at
least about 60%,
at least about 70%, at least about 80%, or at least about 90%, or more,
compared to the
enzymatic activity of NS3 in the absence of the compound.
[0484] In many embodiments, a subject compound inhibits enzymatic activity
of an HCV NS3 protease with an IC50 of less than about 50 M, e.g., a subject
compound
inhibits an HCV NS3 protease with an ICSO of less than about 40 M, less than
about 25
M, less than about 10 M, less than about 1 M, less than about 100 nM, less
than about
80 nM, less than about 60 nM, less than about 50 nM, less than about 25 nM,
less than
about 10 nM, or less than about 1 nM, or less.
[0485] In many embodiments, a subject compound inhibits HCV viral
replication. For example, a subject compound inhibits HCV viral replication by
at least
about 10%, at least about 15%, at least about 20%, at least about 25%, at
least about 30%,
at least about 40%, at least about 50%, at least about 60%, at least about
70%, at least about
80%, or at least about 90%, or more, compared to HCV viral replication in the
absence of
the compound. Whether a subject compound inhibits HCV viral replication may be
determined using methods known in the art, including an in vitro viral
replication assay.
Treatine a Flaviviral Infection
[0486] The methods and compositions described herein are generally useful
in treatment of a flaviviral infection.
[0487] Whether a subject method is effective in treating a flaviviral
infection
may be determined by a reduction in viral load, a reduction in time to
seroconversion (virus
undetectable in patient serum), an increase in the rate of sustained viral
response to therapy,
a reduction of morbidity or mortality in clinical outcomes, or other indicator
of disease
response.

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[64,99f,'"" " to general, an effective amount of a compound of formulas I-XIX,
and
optionally one or more additional antiviral agents, is an amount that is
effective to reduce
viral load or achieve a sustained viral response to therapy.

[0489] Whether a subject method is effective in treating a flaviviral
infection
may be determined by measuring viral load, or by measuring a parameter
associated with a
flaviviral infection, including, but not limited to, liver fibrosis,
elevations in serum
transaminase levels, and necroinflammatory activity in the liver. Indicators
of liver fibrosis
are discussed in detail below.

[0490] The method involves administering an effective amount of a compound
of formulas I-XIX, optionally in combination with an effective amount of one
or more
additional antiviral agents. In some embodiments, an effective amount of a
compound of
formulas I-XIX, and optionally one or more additional antiviral agents, is an
amount that is
effective to reduce viral titers to undetectable levels, e.g., to about 1000
to about 5000, to
about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum.
In some
embodiments, an effective amount of a compound of formulas I-XIX, and
optionally one or
more additional antiviral agents, is an amount that is effective to reduce
viral load to lower
than 100 genome copies/mL serum.

[0491] In some embodiments, an effective amount of a compound of formulas I-
XIX, and optionally one or more additional antiviral agents, is an amount that
is effective to
achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log,
or a 5-log
reduction in viral titer in the serum of the individual.

[0492] In many embodiments, an effective amount of a compound of formulas
I-XIX, and optionally one or more additional antiviral agents, is an amount
that is effective
to achieve a sustained viral response, e.g., no detectable HCV RNA (e.g., less
than about
500, less than about 400, less than about 200, or less than about 100 genome
copies per
milliliter serum) is found in the patient's serum for a period of at least
about one month, at
least about two months, at least about three months, at least about four
months, at least
about five months, or at least about six months following cessation of
therapy.
[0493] As noted above, whether a subject method is effective in treating a
flaviviral infection may be determined by measuring a parameter associated
with a
flaviviral infection, such as liver fibrosis. Methods of determining the
extent of liver
fibrosis are discussed in detail below. In some embodiments, the level of a
serum marker
of liver fibrosis indicates the degree of liver fibrosis.

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[0494] As one non-limiting example, levels of serum alanine aminotransferase
(ALT) are measured, using standard assays. In general, an ALT level of less
than about 45
international units is considered normal. In some embodiments, an effective
amount of a
compound of formulas I-XIX, and optionally one or more additional antiviral
agents, is an
amount effective to reduce ALT levels to less than about 45 IU/ml serum.

[0495] A therapeutically effective amount of a compound of formulas I-XIX,
and optionally one or more additional antiviral agents, is an amount that is
effective to
reduce a serum level of a marker of liver fibrosis by at least about 10%, at
least about 20%,
at least about 25%, at least about 30%, at least about 35%, at least about
40%, at least about
45%, at least about 50%, at least about 55%, at least about 60%, at least
about 65%, at least
about 70%, at least about 75%, or at least about 80%, or more, compared to the
level of the
marker in an untreated individual, or to a placebo-treated individual. Methods
of
measuring serum markers include immunological-based methods, e.g., enzyme-
linked
immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody
specific
for a given serum marker.

[0496] In many embodiments, an effective amount of a compound of formulas
I-XIX and an additional antiviral agent is synergistic amount. As used herein,
a
"synergistic combination" or a "synergistic amount" of a compound of formulas
I-XIX and
an additional antiviral agent is a combined dosage that is more effective in
the therapeutic
or prophylactic treatment of an HCV infection than the incremental improvement
in
treatment outcome that could be predicted or expected from a merely additive
combination
of (i) the therapeutic or prophylactic benefit of the compound of formulas I-
XIX when
administered at that same dosage as a monotherapy and (ii) the therapeutic or
prophylactic
benefit of the additional antiviral agent when administered at the same dosage
as a
monotherapy.
[0497] In some embodiments, a selected amount of a compound of formulas I-
XIX and a selected amount of an additional antiviral agent are effective when
used in
combination therapy for a disease, but the selected amount of the compound of
formulas I-
XIX and/or the selected amount of the additional antiviral agent is
ineffective when used in
monotherapy for the disease. Thus, the embodiments encompass (1) regimens in
which a
selected amount of the additional antiviral agent enhances the therapeutic
benefit of a
selected amount of the compound of formulas I-XIX when used in combination
therapy for
a disease, where the selected amount of the additional antiviral agent
provides no
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ff-i lierie t' when" Used in monotherapy for the disease (2) regimens in which
a
selected amount of the compound of formulas I-XIX enhances the therapeutic
benefit of a
selected amount of the additional antiviral agent when used in combination
therapy for a
disease, where the selected amount of the compound of formulas I-XIX provides
no
therapeutic benefit when used in monotherapy for the disease and (3) regimens
in which a
selected amount of the compound of formula I and a selected amount of the
additional
antiviral agent provide a therapeutic benefit when used in combination therapy
for a
disease, where each of the selected amounts of the compound of formulas I-XIX
and the
additional antiviral agent, respectively, provides no therapeutic benefit when
used in
monotherapy for the disease. As used herein, a "synergistically effective
amount" of a
compound of formulas I-XIX and an additional antiviral agent, and its
grammatical
equivalents, shall be understood to include any regimen encompassed by any of
(1)-(3)
above.

Treating a Hepatitis Virus Infection

[0498] The methods and compositions described herein are generally useful in
treatment of an HCV infection.

[0499] Whether a subject method is effective in treating an HCV infection may
be determined by a reduction in viral load, a reduction in time to
seroconversion (virus
undetectable in patient serum), an increase in the rate of sustained viral
response to therapy,
a reduction of morbidity or mortality in clinical outcomes, or other indicator
of disease
response.

[0500] In general, an effective amount of a compound of formulas I-XIX, and
optionally one or more additional antiviral agents, is an amount that is
effective to reduce
viral load or achieve a sustained viral response to therapy.

[0501] Whether a subject method is effective in treating an HCV infection may
be determined by measuring viral load, or by measuring a parameter associated
with HCV
infection, including, but not limited to, liver fibrosis, elevations in serum
transaminase
levels, and necroinflammatory activity in the liver. Indicators of liver
fibrosis are discussed
in detail below.

[0502] The method involves administering an effective amount of a compound
of formulas I-XIX, optionally in combination with an effective amount of one
or more
additional antiviral agents. In some embodiments, an effective amount of a
compound of
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formulas'"t-XlX, aridopti'onally one or more additional antiviral agents, is
an amount that is
effective to reduce viral titers to undetectable levels, e.g., to about 1000
to about 5000, to
about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum.
In some
embodiments, an effective amount of a compound of formulas I-XIX, and
optionally one or
more additional antiviral agents, is an amount that is effective to reduce
viral load to lower
than 100 genome copies/mL serum.

[0503] In some embodiments, an effective amount of a compound of formulas I-
XIX, and optionally one or more additional antiviral agents, is an amount that
is effective to
achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log,
or a 5-log
reduction in viral titer in the serum of the individual.

[0504] In many embodiments, an effective amount of a compound of formulas
I-XIX, and optionally one or more additional antiviral agents, is an amount
that is effective
to achieve a sustained viral response, e.g., no detectable HCV RNA (e.g., less
than about
500, less than about 400, less than about 200, or less than about 100 genome
copies per
milliliter serum) is found in the patient's serum for a period of at least
about one month, at
least about two months, at least about three months, at least about four
months, at least
about five months, or at least about six months following cessation of
therapy.

[0505] As noted above, whether a subject method is effective in treating an
HCV infection may be determined by measuring a parameter associated with HCV
infection, such as liver fibrosis. Methods of determining the extent of liver
fibrosis are
discussed in detail below. In some embodiments, the level of a serum marker of
liver
fibrosis indicates the degree of liver fibrosis.

[0506] As one non-limiting example, levels of serum alanine aminotransferase
(ALT) are measured, using standard assays. In general, an ALT level of less
than about 45
international units is considered normal. In some embodiments, an effective
amount of a
compound of formulas I-XIX, and optionally one or more additional antiviral
agents, is an
amount effective to reduce ALT levels to less than about 45 IU/ml serum.
[0507] A therapeutically effective amount of a compound of formulas I-XIX,
and optionally one or more additional antiviral agents, is an amount that is
effective to
reduce a serum level of a marker of liver fibrosis by at least about 10%, at
least about 20%,
at least about 25%, at least about 30%, at least about 35%, at least about
40%, at least about
45%, at least about 50%, at least about 55%, at least about 60%, at least
about 65%, at least
about 70%, at least about 75%, or at least about 80%, or more, compared to the
level of the
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If }:: fr F! 'i I :~
: r r:( :i i::i:if =: it
mark er in ari untreated individual, or to a placebo-treated individual.
Methods of
measuring serum markers include immunological-based methods, e.g., enzyme-
linked
immunosorbent assays (ELISA), radioiminunoassays, and the like, using antibody
specific
for a given serum marker.

[0508] In many embodiments, an effective amount of a compound of formulas
I-XIX and an additional antiviral agent is synergistic amount. As used herein,
a
"synergistic combination" or a "synergistic amount" of a compound of formulas
I-XIX and
an additional antiviral agent is a combined dosage that is more effective in
the therapeutic
or prophylactic treatment of an HCV infection than the incremental improvement
in
treatment outcome that could be predicted or expected from a merely additive
combination
of (i) the therapeutic or prophylactic benefit of the compound of formulas I-
XIX when
administered at that same dosage as a monotherapy and (ii) the therapeutic or
prophylactic
benefit of the additional antiviral agent when administered at the same dosage
as a
monotherapy.

[0509] In some embodiments, a selected amount of a compound of formulas I-
XIX and a selected amount of an additional antiviral agent are effective when
used in
combination therapy for a disease, but the selected amount of the compound of
formulas I-
XIX and/or the selected amount of the additional antiviral agent is
ineffective when used in
monotherapy for the disease. Thus, the embodiments encompass (1) regimens in
which a
selected amount of the additional antiviral agent enhances the therapeutic
benefit of a
selected amount of the compound of formulas I-XIX when used in combination
therapy for
a disease, where the selected amount of the additional antiviral agent
provides no
therapeutic benefit when used in monotherapy for the disease (2) regimens in
which a
selected amount of the compound of formulas I-XIX enhances the therapeutic
benefit of a
selected amount of the additional antiviral agent when used in combination
therapy for a
disease, where the selected amount of the compound of formulas I-XIX provides
no
therapeutic benefit when used in monotherapy for the disease and (3) regimens
in which a
selected amount of the compound of formula I and a selected amount of the
additional
antiviral agent provide a therapeutic benefit when used in combination therapy
for a
disease, where each of the selected amounts of the compound of formulas I-XIX
and the
additional antiviral agent, respectively, provides no therapeutic benefit when
used in
monotherapy for the disease. As used herein, a "synergistically effective
amount" of a
compound of formulas I-XIX and an additional antiviral agent, and its
grammatical
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t
W" 6:,m -If 4F F' ..... N Wit I "Ho I'd IF
equivalentss "al'l` be stn erstdo to include any regimen encompassed by any of
(1)-(3)
above.

Treating Fibrosis

[0510] The embodiments provide methods for treating liver fibrosis (including
forms of liver fibrosis resulting from, or associated with, HCV infection),
generally
involving administering a therapeutic amount of a compound of formulas I-XIX,
and
optionally one or more additional antiviral agents. Effective amounts of
compounds of
formulas I-XIX, with and without one or more additional antiviral agents, as
well as dosing
regimens, are as discussed below.

[0511] Whether treatment with a compound of formulas I-XIX, and optionally
one or more additional antiviral agents, is effective in reducing liver
fibrosis is determined
by any of a number of well-established techniques for measuring liver fibrosis
and liver
function. Liver fibrosis reduction is determined by analyzing a liver biopsy
sample. An
analysis of a liver biopsy comprises assessments of two major components:
necroinflammation assessed by "grade" as a measure of the severity and ongoing
disease
activity, and the lesions of fibrosis and parenchymal or vascular remodeling
as assessed by
"stage" as being reflective of long-term disease progression. See, e.g., Brunt
(2000)
Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based on analysis
of
the liver biopsy, a score is assigned. A number of standardized scoring
systems exist which
provide a quantitative assessment of the degree and severity of fibrosis.
These include the
METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[0512] The METAVIR scoring system is based on an analysis of various
features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular
fibrosis, and
cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction,
and ballooning
degeneration); inflammation (portal tract inflammation, portal lymphoid
aggregates, and
distribution of portal inflammation); bile duct changes; and the Knodell index
(scores of
periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and
overall disease
activity). The definitions of each stage in the METAVIR system are as follows:
score: 0,
no fibrosis; score: 1, stellate enlargement of portal tract but without septa
formation; score:
2, enlargement of portal tract with rare septa formation; score: 3, numerous
septa without
cirrhosis; and score: 4, cirrhosis.

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[01 1 .. ...... Knode1l's` scoring system, also called the Hepatitis Activity
Index,
classifies specimens based on scores in four categories of histologic
features: I. Periportal
and/or bridging necrosis; II. Intralobular degeneration and focal necrosis;
III. Portal
inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as
follows: score:
0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2,
moderate fibrosis;
score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The
higher the score,
the more severe the liver tissue damage. Knodell (1981) Hepatol. 1:431.

[0514] In the Scheuer scoring system scores are as follows: score: 0, no
fibrosis;
score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-
portal septa, but intact
architecture; score: 3, fibrosis with architectural distortion, but no obvious
cirrhosis; score:
4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13:372.

[0515] The Ishak scoring system is described in Ishak (1995) J. Hepatol.
22:696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal
areas, with or
without short fibrous septa; stage 2, Fibrous expansion of most portal areas,
with or without
short fibrous septa; stage 3, Fibrous expansion of most portal areas with
occasional portal
to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with
marked bridging
(P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-
C) with
occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or
definite.

[0516] The benefit of anti-fibrotic therapy may also be measured and assessed
by using the Child-Pugh scoring system which comprises a multicomponent point
system
based upon abnormalities in serum bilirubin level, serum albumin level,
prothrombin time,
the presence and severity of ascites, and the presence and severity of
encephalopathy.
Based upon the presence and severity of abnormality of these parameters,
patients may be
placed in one of three categories of increasing severity of clinical disease:
A, B, or C.

[0517] In some embodiments, a therapeutically effective amount of a compound
of formula I, and, optionally one or more additional antiviral agents, is an
amount that
effects a change of one unit or more in the fibrosis stage based on pre- and
post-therapy
liver biopsies. In particular embodiments, a therapeutically effective amount
of a
compound of formulas I-XIX, and optionally one or more additional antiviral
agents,
reduces liver fibrosis by at least one unit in the METAVIR, the Knodell, the
Scheuer, the
Ludwig, or the Ishak scoring system.
[0518] Secondary, or indirect, indices of liver function may also be used to
evaluate the efficacy of treatment with a compound of formulas I-XIX.
Morphometric
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WO 2005/095403 PCT/US2005/010494
computerized semi automated"'as'sessment of the quantitative degree of liver
fibrosis based
upon specific staining of collagen and/or serum markers of liver fibrosis may
also be
measured as an indication of the efficacy of a subject treatment method.
Secondary indices
of liver function include, but are not limited to, serum transaminase levels,
prothromnbin
time, bilirubin, platelet count, portal pressure, albumin level, and
assessment of the Child-
Pugh score.

[0519] An effective amount of a compound of formulas I-XIX, and optionally
one or more additional antiviral agents, is an amount that is effective to
increase an index of
liver function by at least about 10%, at least about 20%, at least about 25%,
at least about
30%, at least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least
about 55%, at least about 60%, at least about 65%, at least about 70%, at
least about 75%,
or at least about 80%, or more, compared to the index of liver function in an
untreated
individual, or to a placebo-treated individual. Those skilled in the art may
readily measure
such indices of liver function, using standard assay methods, many of which
are
commercially available, and are used routinely in clinical settings.

[0520] Serum markers of liver fibrosis may also be measured as an indication
of
the efficacy of a subject treatment method. Serum markers of liver fibrosis
include, but are
not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of
type IV
collagen, C-terminal procollagen I peptide, and laminin. Additional
biochemical markers
of liver fibrosis include a-2-macroglobulin, haptoglobin, gamma globulin,
apolipoprotein
A, and gamma glutamyl transpeptidase.

[0521] A therapeutically effective amount of a compound of formulas I-XIX,
and optionally one or more additional antiviral agents, is an amount that is
effective to
reduce a serum level of a marker of liver fibrosis by at least about 10%, at
least about 20%,
at least about 25%, at least about 30%, at least about 35%, at least about
40%, at least about
45%, at least about 50%, at least about 55%, at least about 60%, at least
about 65%, at least
about 70%, at least about 75%, or at least about 80%, or more, compared to the
level of the
marker in an untreated individual, or to a placebo-treated individual. Those
skilled in the
art may readily measure such serum markers of liver fibrosis, using standard
assay methods,
many of which are commercially available, and are used routinely in clinical
settings.
Methods of measuring serum markers include immunological-based methods, e.g.,
enzyme-
linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using
antibody
specific for a given serum marker.

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CA 02560897 2007-08-08

[0522] Quantitative tests of functional liver reserve may also be used to
assess
the efficacy of treatment with an interferon receptor agonist and pirfenidone
(or a
pirfenidone analog). These include: indocyanine green clearance (ICG),
galactose
elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine
clearance,
monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.
[0523] As used herein, a "complication associated with cirrhosis of the liver"
refers to a disorder that is a sequellae of decompensated liver disease, i.e.,
or occurs
subsequently to and as a result of development of liver fibrosis, and
includes, but it not
limited to, development of ascites, variceal bleeding, portal hypertension,
jaundice,
progressive liver insufficiency, encephalopathy, hepatocellular carcinoma,
liver failure
requiring liver transplantation, and liver-related mortality.
[0524] A therapeutically effective amount of a compound of formulas I-XIX,
and optionally one or more additional antiviral agents, is an amount that is
effective in
reducing the incidence (e.g., the likelihood that an individual will develop)
of a disorder
associated with cirrhosis of the liver by at least about 10%, at least about
20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least
about 50%, at least about 55%, at least about 60%, at least about 65%, at
least about 70%, at
least about 75%, or at least about 80%, or more, compared to an untreated
individual, or to a
placebo-treated individual.
[0525] Whether treatment with a compound of formulas I-XIX, and optionally
one or more additional antiviral agents, is effective in reducing the
incidence of a disorder
associated with cirrhosis of the liver may readily be determined by those
skilled in the art.
[0526] Reduction in liver fibrosis increases liver function. Thus, the
embodiments provide methods for increasing liver function, generally involving
administering a therapeutically effective amount of a compound of formulas I-
XIX, and
optionally one or more additional antiviral agents. Liver functions include,
but are not
limited to, synthesis of proteins such as serum proteins (e.g., albumin,
clotting factors,
alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate
transaminase),
5'-nucleosidase, yglutaminyltranspeptidase, etc.), synthesis of bilirubin,
synthesis of
cholesterol, and synthesis of bile acids; a liver metabolic function,
including, but not limited
to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone
metabolism,
and lipid metabolism; detoxification of exogenous drugs; a hemodynamic
function,
including splanchnic and portal hemodynamics; and the like.

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[027] Whe't'her a fiver function is increased is readily ascertainable by
those
skilled in the art, using well-established tests of liver function. Thus,
synthesis of markers
of liver function such as albumin, alkaline phosphatase, alanine transaminase,
aspartate
transaminase, bilirubin, and the like, may be assessed by measuring the level
of these
markers in the serum, using standard immunological and enzymatic assays.
Splanchnic
circulation and portal hemodynamics may be measured by portal wedge pressure
and/or
resistance using standard methods. Metabolic functions may be measured by
measuring the
level of ammonia in the serum.

[0528] Whether serum proteins normally secreted by the liver are in the normal
range may be determined by measuring the levels of such proteins, using
standard
immunological and enzymatic assays. Those skilled in the art know the normal
ranges for
such serum proteins. The following are non-limiting examples. The normal level
of
alanine transaminase is about 45 IU per milliliter of serum. The normal range
of aspartate
transaminase is from about 5 to about 40 units per liter of serum. Bilirubin
is measured
using standard assays. Normal bilirubin levels are usually less than about 1.2
mg/dL.
Serum albumin levels are measured using standard assays. Normal levels of
serum albumin
are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin
time is
measured using standard assays. Normal prothrombin time is less than about 4
seconds
longer than control.

[0529] A therapeutically effective amount of a compound of formulas I-XIX,
and optionally one or more additional antiviral agents, is one that is
effective to increase
liver function by at least about 10%, at least about 20%, at least about 30%,
at least about
40%, at least about 50%, at least about 60%, at least about 70%, at least
about 80%, or
more. For example, a therapeutically effective amount of a compound of
formulas I-XIX,
and optionally one or more additional antiviral agents, is an amount effective
to reduce an
elevated level of a serum marker of liver function by at least about 10%, at
least about 20%,
at least about 30%, at least about 40%, at least about 50%, at least about
60%, at least about
70%, at least about 80%, or more, or to reduce the level of the serum marker
of liver
function to within a normal range. A therapeutically effective amount of a
compound of
formulas I-XIX, and optionally one or more additional antiviral agents, is
also an amount
effective to increase a reduced level of a serum marker of liver function by
at least about
10%, at least about 20%, at least about 30%, at least about 40%, at least
about 50%, at least
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CA 02560897 2007-08-08

about 60%, at least about 70%, at least about 80%, or more, or to increase the
level of the
serum marker of liver function to within a normal range.

Type I interferon receptor monists
[0530] In any of the above-described methods, in some embodiments a Type I
interferon receptor agonist is administered. Type I interferon receptor
agonists include an
IFN-a; an IFN-(3; an IFN-tau; an IFN-w; antibody agonists specific for a Type
I interferon
receptor; and any other agonist of Type I interferon receptor, including non-
polypeptide
agonists.
Interferon-Alpha
[0531] Any known IFN-a may be used in the embodiments. The term
"interferon-alpha" as used herein refers to a family of related polypeptides
that inhibit viral
replication and cellular proliferation and modulate immune response. The term
"IFN-a"
includes naturally occurring IFN-a; synthetic IFN-a; derivatized IFN-a (e.g.,
PEGylated
IFN-a, glycosylated IFN-(x, and the like); and analogs of naturally occurring
or synthetic
IFN-a; essentially any IFN-a that has antiviral properties, as described for
naturally
occurring IFN-a.
[0532] Suitable alpha interferons include, but are not limited to, naturally-
occurring IFN-a (including, but not limited to, naturally occurring IFN-a2a,
IFN-(x2b);
recombinant interferon alpha-2b such as Intron-A interferon available from
Schering
Corporation, Kenilworth, N.J.; recombinant interferon alpha-2a such as Roferon
interferon
available from Hoffmann-La Roche, Nutley, N. J.; recombinant interferon alpha-
2C such as
Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical,
Inc.,
Ridgefield, Conn.; interferon alpha-n1, a purified blend of natural alpha
interferons such as
Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-n1
(INS)
available from the Glaxo-Wellcome Ltd., London, Great Britain; and interferon
alpha-n3 a
mixture of natural alpha interferons made by Interferon Sciences and available
from the
Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.
[0533] The term "IFN-a" also encompasses consensus IFN-a. Consensus
IFN-a (also referred to as "CIFN" and "IFN-con" and "consensus interferon")
encompasses
but is not limited to the amino acid sequences designated IFN-con 1, IFN-con2
and IFN-con3
which are disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471; and consensus
interferon as
defined by determination of a consensus sequence of naturally occurring
interferon alphas
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CA 02560897 2007-08-08

(e.g., Infergen , InterMune, Inc., Brisbane, Calif.). IFN-conl is the
consensus interferon
agent in the Infergen alfacon-1 product. The Infergen consensus interferon
product is
referred to herein by its brand name (Infergen ) or by its generic name
(interferon alfacon-
1). DNA sequences encoding IFN-con may be synthesized as described in the
aforementioned patents or other standard methods. Use of CIFN is of particular
interest.
[0534] Also suitable for use in the embodiments are fusion polypeptides
comprising an IFN-a and a heterologous polypeptide. Suitable IFN-a fusion
polypeptides
include, but are not limited to, Albuferon-alphaTM (a fusion product of human
albumin and
IFN-(x; Human Genome Sciences; see, e.g., Osborn et al. (2002) J. Pharmacol.
Exp.
Therap. 303:540-548). Also suitable for use in the present embodiments are
gene-shuffled
forms of IFN-a. See., e.g., Masci et al. (2003) Curr. Oncol. Rep. 5:108-113.
PEGylated Interferon-Alpha
[0535] The term "IFN-a" also encompasses derivatives of IFN-a that are
derivatized (e.g., are chemically modified) to alter certain properties such
as serum half-life.
As such, the term "IFN-a" includes glycosylated IFN-a; IFN-a derivatized with
polyethylene glycol ("PEGylated 1FN-(x"); and the like. PEGylated IFN-a, and
methods
for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709;
and
5,951,974. PEGylated IFN-a encompasses conjugates of PEG and any of the above-
described IFN-a molecules, including, but not limited to, PEG conjugated to
interferon
alpha-2a (Roferon, Hoffman La-Roche, Nutley, N.J.), interferon alpha 2b
(Intron, Schering-
Plough, Madison, N.J.), interferon alpha-2c (Berofor Alpha, Boehringer
Ingelheim,
Ingelheim, Germany); and consensus interferon as defined by determination of a
consensus
sequence of naturally occurring interferon alphas (Infergen , InterMune, Inc.,
Brisbane,
Calif.).
[0536] Any of the above-mentioned IFN-a polypeptides may be modified
with one or more polyethylene glycol moieties, i.e., PEGylated. The PEG
molecule of a
PEGylated IFN-a polypeptide is conjugated to one or more amino acid side
chains of the
IFN-a polypeptide. In some embodiments, the PEGylated IFN-a contains a PEG
moiety
on only one amino acid. In other embodiments, the PEGylated IFN-a contains a
PEG
moiety on two or more amino acids, e.g., the IFN-a contains a PEG moiety
attached to two,
three, four, five, six, seven, eight, nine, or ten different amino acid
residues.
[0537] IFN-a may be coupled directly to PEG (i.e., without a linking group)
through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl
group.
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CA 02560897 2007-08-08

[0538] In some embodiments, the PEGylated IFN-a is PEGylated at or near
the amino terminus (N-terminus) of the IFN-a polypeptide, e.g., the PEG moiety
is
conjugated to the IFN-a polypeptide at one or more amino acid residues from
amino acid 1
through amino acid 4, or from amino acid 5 through about 10.
[0539] In other embodiments, the PEGylated IFN-a is PEGylated at one or
more amino acid residues from about 10 to about 28.
[0540] In other embodiments, the PEGylated IFN-a is PEGylated at or near
the carboxyl terminus (C-terminus) of the IFN-a polypeptide, e.g., at one or
more residues
from amino acids 156-166, or from amino acids 150 to 155.
[0541] In other embodiments, the PEGylated IFN-a is PEGylated at one or
more amino acid residues at one or more residues from amino acids 100-114.
[0542] The polyethylene glycol derivatization of amino acid residues at or
near the receptor-binding and/or active site domains of the IFN-a protein may
disrupt the
functioning of these domains. In certain embodiments , amino acids at which
PEGylation
is to be avoided include amino acid residues from amino acid 30 to amino acid
40; and
amino acid residues from amino acid 113 to amino acid 149.
[0543] In some embodiments, PEG is attached to IFN-a via a linking group.
The linking group is any biocompatible linking group, where "biocompatible"
indicates that
the compound or group is non-toxic and may be utilized in vitro or in vivo
without causing
injury, sickness, disease, or death. PEG may be bonded to the linking group,
for example,
via an ether bond, an ester bond, a thiol bond or an amide bond. Suitable
biocompatible
linking groups include, but are not limited to, an ester group, an amide
group, an imide
group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate,
a
succinimide group (including, for example, succinimidyl succinate (SS),
succinimidyl
propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate
(SCM),
succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide
group, an
oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)),
a nitro
phenyl group (including, for example, nitrophenyl carbonate (NPC) or
trichlorophenyl
carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a
vinylsulfone
group, a tyrosine group, a cysteine group, a histidine group or a primary
amine.

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CA 02560897 2007-08-08

[0544] Methods for making succinimidyl propionate (SPA) and succinimidyl
butanoate (SBA) ester-activated PEGs are described in U.S. Pat. No. 5,672,662
(Harris, et
al.) and WO 97/03106.
[0545] Methods for attaching a PEG to an IFN-a polypeptide are known in
the art, and any known method may be used. See, for example, by Park et al,
Antimaycer
Res., 1:373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry:
Biotechnical
and Biomedical Applications, J. M. Harris, ed., Plenum Press, NY, Chapter 21
(1992); U.S.
Patent No. 5,985,265; U.S. Pat. No. 5,672,662 (Harris, et al.) and WO
97/03106.
[0546] Pegylated IFN-a, and methods for making same, is discussed in, e.g.,
U.S. Patent Nos. 5,382,657; 5,981,709; 5,985,265; and 5,951,974. Pegylated IFN-
a
encompasses conjugates of PEG and any of the above-described IFN-a molecules,
including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon,
Hoffman
LaRoche, Nutley, N.J.), where PEGylated Roferon is known as Pegasys (Hoffman
LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, N.J.), where
PEGylated
Intron is known as PEG-Intron (Schering-Plough); interferon alpha-2c (Berofor
Alpha,
Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as
defined
by determination of a consensus sequence of naturally occurring interferon
alphas
(Infergen , InterMune, Inc., Brisbane, Calif.), where PEGylated Infergen is
referred to as
PEG-Infergen.
[0547] In many embodiments, the PEG is a monomethoxyPEG molecule that
reacts with primary amine groups on the IFN-a polypeptide. Methods of
modifying
polypeptides with monomethoxy PEG via reductive alkylation are known in the
art. See,
e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.
[0548] In one non-limiting example, PEG is linked to IFN-a via an SPA
linking group. SPA esters of PEG, and methods for making same, are described
in U.S.
Patent No. 5,672,662. SPA linkages provide for linkage to free amine groups on
the IFN-a
polypeptide.
[0549] For example, a PEG molecule is covalently attached via a linkage that
comprises an amide bond between a propionyl group of the PEG moiety and the
epsilon
amino group of a surface-exposed lysine residue in the IFN-a polypeptide. Such
a bond
may be formed, e.g., by condensation of an a-methoxy, omega propanoic acid
activated
ester of PEG (mPEGspa).

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CA 02560897 2007-08-08

[0550] As one non-limiting example, one monopegylated CIFN conjugate
preferred for use herein has a linear PEG moiety of about 30 kD attached via a
covalent
linkage to the CIFN polypeptide, where the covalent linkage is an amide bond
between a
propionyl group of the PEG moiety and the epsilon amino group of a surface-
exposed
lysine residue in the CIFN polypeptide, where the surface-exposed lysine
residue is chosen
from 1ys31, 1ys50, 1ys71, 1ys84, lys121 lys'22, lys134 lyS135 and lys165, and
the amide bond is

formed by condensation of an a-methoxy, omega propanoic acid activated ester
of PEG.
Polyethylene glycol
[0551] Polyethylene glycol suitable for conjugation to an IFN-a polypeptide
is soluble in water at room temperature, and has the general formula R(O-CH2-
CH2)õ O-R,
where R is hydrogen or a protective group such as an alkyl or an alkanol
group, and where
n is an integer from 1 to 1000. Where R is a protective group, it generally
has from 1 to 8
carbons.
[0552] In many embodiments, PEG has at least one hydroxyl group, e.g., a
terminal hydroxyl group, which hydroxyl group is modified to generate a
functional group
that is reactive with an amino group, e.g., an epsilon amino group of a lysine
residue, a free
amino group at the N-terminus of a polypeptide, or any other amino group such
as an
amino group of asparagine, glutamine, arginine, or histidine.
[0553] In other embodiments, PEG is derivatized so that it is reactive with
free carboxyl groups in the IFN-a polypeptide, e.g., the free carboxyl group
at the carboxyl
terminus of the IFN-a polypeptide. Suitable derivatives of PEG that are
reactive with the
free carboxyl group at the carboxyl-terminus of IFN-a include, but are not
limited to PEG-
amine, and hydrazine derivatives of PEG (e.g., PEG-NH-NH2).
[0554] In other embodiments, PEG is derivatized such that it comprises a
terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino
groups to
generate amide derivatives. Because of the reactive nature of the thio acid,
selectivity of
certain amino groups over others is achieved. For example, -SH exhibits
sufficient leaving
group ability in reaction with N-terminal amino group at appropriate pH
conditions such
that the s-amino groups in lysine residues are protonated and remain non-
nucleophilic. On
the other hand, reactions under suitable pH conditions may make some of the
accessible
lysine residues to react with selectivity.
[0555] In other embodiments, the PEG comprises a reactive ester such as an
N-hydroxy succinimidate at the end of the PEG chain. Such an N-
hydroxysuccinimidate-
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CA 02560897 2007-08-08

containing PEG molecule reacts with select amino groups at particular pH
conditions such
as neutral 6.5-7.5. For example, the N-terminal amino groups may be
selectively modified
under neutral pH conditions. However, if the reactivity of the reagent were
extreme,
accessible-NH2 groups of lysine may also react.
[0556] The PEG may be conjugated directly to the IFN-a polypeptide, or
through a linker. In some embodiments, a linker is added to the IFN-a
polypeptide,
forming a linker-modified IFN-a polypeptide. Such linkers provide various
functionalities,
e.g., reactive groups such sulfhydryl, amino, or carboxyl groups to couple a
PEG reagent to
the linker-modified IFN-a polypeptide.
[0557] In some embodiments, the PEG conjugated to the IFN-a polypeptide
is linear. In other embodiments, the PEG conjugated to the IFN-a polypeptide
is branched.
Branched PEG derivatives such as those described in U.S. Pat. No. 5,643,575,
"star-PEG's"
and multi-armed PEG's such as those described in Shearwater Polymers, Inc.
catalog
"Polyethylene Glycol Derivatives 1997-1998." Star PEGs are described in the
art
including, e.g., in U.S. Patent No. 6,046,305.
[0558] PEG having a molecular weight in a range of from about 2 kDa to
about 100 kDa, is generally used, where the term "about," in the context of
PEG, indicates
that in preparations of polyethylene glycol, some molecules will weigh more,
some less,
than the stated molecular weight. For example, PEG suitable for conjugation to
IFN-a has
a molecular weight of from about 2 kDa to about 5 kDa, from about 5 kDa to
about 10
kDa, from about 10 kDa to about 15 kDa, from about 15 kDa to about 20 kDa,
from about
20 kDa to about 25 kDa, from about 25 kDa to about 30 kDa, from about 30 kDa
to about
40 kDa, from about 40 kDa to about 50 kDa, from about 50 kDa to about 60 kDa,
from
about 60 kDa to about 70 kDa, from about 70 kDa to about 80 kDa, from about 80
kDa to
about 90 kDa, or from about 90 kDa to about 100 kDa.
Preparing PEG-IFN-a conjugates
[0559] As discussed above, the PEG moiety may be attached, directly or via a
linker, to an amino acid residue at or near the N-terminus, internally, or at
or near the C-
terminus of the IFN-a polypeptide. Conjugation may be carried out in solution
or in the
solid phase.
N-terminal linkage

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CA 02560897 2007-08-08

[0560] Methods for attaching a PEG moiety to an amino acid residue at or
near the N-terminus of an IFN-a polypeptide are known in the art. See, e.g.,
U.S. Patent
No. 5,985,265.
[0561] In some embodiments, known methods for selectively obtaining an N-
terminally chemically modified IFN-a are used. For example, a method of
protein
modification by reductive alkylation which exploits differential reactivity of
different types
of primary amino groups (lysine versus the N-terminus) available for
derivatization in a
particular protein may be used. Under the appropriate reaction conditions,
substantially
selective derivatization of the protein at the N-terminus with a carbonyl
group containing
polymer is achieved. The reaction is performed at pH which allows one to take
advantage
of the pKa differences between the c-amino groups of the lysine residues and
that of the a-
amino group of the N-terminal residue of the protein. By such selective
derivatization
attachment of a PEG moiety to the IFN-a is controlled: the conjugation with
the polymer
takes place predominantly at the N-terminus of the IFN-a and no significant
modification of
other reactive groups, such as the lysine side chain amino groups, occurs.
C-terminal linkage

[0562] N-terminal-specific coupling procedures such as described in U.S.
Patent No. 5,985,265 provide predominantly monoPEGylated products. However,
the
purification procedures aimed at removing the excess reagents and minor
multiply
PEGylated products remove the N-terminal blocked polypeptides. In terms of
therapy, such
processes lead to significant increases in manufacturing costs. For example,
examination of
the structure of the well-characterized Infergen Alfacon-1 CIFN polypeptide
amino acid
sequence reveals that the clipping is approximate 5% at the carboxyl terminus
and thus there
is only one major C-terminal sequence. Thus, in some embodiments, N-terminally
PEGylated IFN-a is not used; instead, the IFN-a polypeptide is C-terminally
PEGylated.
[0563] An effective synthetic as well as therapeutic approach to obtain mono
PEGylated Infergen product is therefore envisioned as follows:
[0564] A PEG reagent that is selective for the C-terminal may be prepared
with or without spacers. For example, polyethylene glycol modified as methyl
ether at one
end and having an amino function at the other end may be used as the starting
material.
[0565] Preparing or obtaining a water-soluble carbodiimide as the condensing
agent may be carried out. Coupling IFN-a (e.g., Infergen Alfacon-1 CIFN or
consensus
interferon) with a water-soluble carbodiimide as the condensing reagent is
generally carried
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CA 02560897 2007-08-08

out in aqueous medium with a suitable buffer system at an optimal pH to effect
the amide
linkage. A high molecular weight PEG may be added to the protein covalently to
increase
the molecular weight.
[0566] The reagents selected will depend on process optimization studies. A
non-limiting example of a suitable reagent is EDAC or 1-ethyl-3- (3-
dimethylaminopropyl)
carbodiimide. The water solubility of EDAC allows for direct addition to a
reaction without
the need for prior organic solvent dissolution. Excess reagent and the isourea
formed as the
by-product of the cross-linking reaction are both water-soluble and may easily
be removed
by dialysis or gel filtration. A concentrated solution of EDAC in water is
prepared to
facilitate the addition of a small molar amount to the reaction. The stock
solution is
prepared and used immediately in view of the water labile nature of the
reagent. Most of
the synthetic protocols in literature suggest the optimal reaction medium to
be in pH range
between 4.7 and 6Ø However the condensation reactions do proceed without
significant
losses in yields up to pH 7.5. Water may be used as solvent. In view of the
contemplated
use of Infergen, preferably the medium will be 2-(N-morpholino)ethane sulfonic
acid buffer
pre-titrated to pH between 4.7 and 6Ø However, 0.1M phosphate in the pH 7-
7.5 may also
be used in view of the fact that the product is in the same buffer. The ratios
of PEG amine
to the IFN-a molecule is optimized such that the C-terminal carboxyl
residue(s) are
selectively PEGylated to yield monoPEGylated derivative(s).
[0567] Even though the use of PEG amine has been mentioned above by
name or structure, such derivatives are meant to be exemplary only, and other
groups such
as hydrazine derivatives as in PEG-NH-NH2 which will also condense with the
carboxyl
group of the IFN-a protein, may also be used. In addition to aqueous phase,
the reactions
may also be conducted on solid phase. Polyethylene glycol may be selected from
list of
compounds of molecular weight ranging from 300-40000. The choice of the
various
polyethylene glycols will also be dictated by the coupling efficiency and the
biological
performance of the purified derivative in vitro and in vivo i.e., circulation
times, anti viral
activities etc.
[0568] Additionally, suitable spacers may be added to the C-terminal of the
protein. The spacers may have reactive groups such as SH, NH2 or COOH to
couple with
appropriate PEG reagent to provide the high molecular weight IFN-a
derivatives. A
combined solid/solution phase methodology may be devised for the preparation
of C-
terminal pegylated interferons. For example, the C-terminus of FN-(x is
extended on a
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CA 02560897 2007-08-08

solid phase using a Gly-Gly-Cys-NH2 spacer and then monopegylated in solution
using
activated dithiopyridyl-PEG reagent of appropriate molecular weights. Since
the coupling
at the C-terminus is independent of the blocking at the N-terminus, the
envisioned
processes and products will be beneficial with respect to cost (a third of the
protein is not
wasted as in N-terminal PEGylation methods) and contribute to the economy of
the therapy
to treat virus infection.
[0569] There may be a more reactive carboxyl group of amino acid residues
elsewhere in the molecule to react with the PEG reagent and lead to
monoPEGylation at
that site or lead to multiple PEGylations in addition to the -COOH group at
the C-terminus
of the IFN-a. It is envisioned that these reactions will be minimal at best
owing to the
steric freedom at the C-terminal end of the molecule and the steric hindrance
imposed by
the carbodiimides and the PEG reagents such as in branched chain molecules. It
is
therefore the preferred mode of PEG modification for Infergen and similar such
proteins,
native or expressed in a host system, which may have blocked N-termini to
varying degrees
to improve efficiencies and maintain higher in vivo biological activity.
[0570] Another method of achieving C-terminal PEGylation is as follows.
Selectivity of C-terminal PEGylation is achieved with a sterically hindered
reagent which
excludes reactions at carboxyl residues either buried in the helices or
internally in IFN-a.
For example, one such reagent could be a branched chain PEG -40kd in molecular
weight
and this agent could be synthesized as follows:
[0571] OH3C-(CH2CH2O)n-CH2CH2NH2 + Glutamic Acid i.e., HOCO-
CH2CH2CH(NH2)-COOH is condensed with a suitable agent e.g., dicyclohexyl
carbodiimide or water-soluble EDC to provide the branched chain PEG agent OH3C-

(CH2CH2O)õCH2CH2NH000H(NH2)CH2OCH3-(CH2CH2O).-CH2CH2NHC0CH2.

-97-


CA 02560897 2007-08-08
0

Ii3C-O-(Clf'CH20)n-CI12Ci12NI12 110 C-CIi2C1i2Ci1-COO11
I
C11NH,
EUAC

I1.3C-O-(CI{1_CI120)õ-CI12C112N H-Co
CHNH2
I
(CI12)2
I
H3C-O-(CH>CH20)11-C H wCH2N H-C)

[0572] This reagent may be used in excess to couple the amino group with the
free and flexible carboxyl group of IFN-a to form the peptide bond.
[0573] If desired, PEGylated IFN-a is separated from unPEGylated IFN-a
using any known method, including, but not limited to, ion exchange
chromatography, size
exclusion chromatography, and combinations thereof. For example, where the PEG-
IFN-a
conjugate is a monoPEGylated IFN-a, the products are first separated by ion
exchange
chromatography to obtain material having a charge characteristic of
monoPEGylated material
(other multi-PEGylated material having the same apparent charge may be
present), and then
the monoPEGylated materials are separated using size exclusion chromatography.
MonoPEG (30 kD, linear)-ylated IFN-a
[0574] PEGylated IFN-a that is suitable for use in the embodiments includes a
monopegylated consensus interferon (CIFN) molecule comprised of a single CIFN
polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG
moiety is linear
and about 30 kD in molecular weight and is directly or indirectly linked
through a stable
covalent linkage to either the N-terminal residue in the CIFN polypeptide or a
lysine residue
in the CIFN polypeptide. In some embodiments, the monoPEG (30 kD, linear)-
ylated IFN-a
is monoPEG (30 kD, linear)-ylated consensus IFN-a.
[0575] In some embodiments, the PEG moiety is linked to either the alpha-
amino group of the N-terminal residue in the CIFN polypeptide or the epsilon-
amino group
of a lysine residue in the CIFN polypeptide. In further embodiments, the
linkage comprises
an amide bond between the PEG moiety and either the alpha-amino group of the N-
terminal
residue or the epsilon-amino group of the lysine residue in the CIFN
polypeptide. In still
further embodiments, the linkage comprises an amide bond between a propionyl
group of
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
the PEG noiety`and ei iffier the alpha-amino group of the N-terminal residue
or the epsilon-
amino group of the lysine residue in the CIFN polypeptide. In additional
embodiments, the
amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid
activated ester of the PEG moiety and either the alpha-amino group of the N-
terminal
residue or the epsilon-amino group of the lysine residue in the CIFN
polypeptide, thereby
forming a hydrolytically stable linkage between the PEG moiety and the CIFN
polypeptide.

[0576] In some embodiments, the PEG moiety is linked to the N-terminal
residue in the CIFN polypeptide. In other embodiments, the PEG moiety is
linked to the
alpha-amino group of the N-terminal residue in the CIFN polypeptide. In
further
embodiments, the linkage comprises an amide bond between the PEG moiety and
the
alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still
further
embodiments, the linkage comprises an amide bond between a propionyl group of
the PEG
moiety and the alpha-amino group of the N-terminal residue in the CIFN
polypeptide. In
additional embodiments, the amide bond is formed by condensation of an alpha-
methoxy,
omega-propanoic acid activated ester of the PEG moiety and the alpha-amino
group of the
N-terminal residue of the CIFN polypeptide.

[0577] In some embodiments, the PEG moiety is linked to a lysine residue in
the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the
epsilon-
amino group of a lysine residue in the CIFN polypeptide. In further
embodiments, the
linkage comprises an amide bond between the PEG moiety and the epsilon-amino
group of
the lysine group in the CIFN polypeptide. In still further embodiments, the
linkage
comprises an amide bond between a propionyl group of the PEG moiety and the
epsilon-
amino group of the lysine group in the CIFN polypeptide. In additional
embodiments, the
amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid
activated ester of the PEG moiety and the epsilon-amino group of the lysine
residue in the
CIFN polypeptide.

[0578] In some embodiments, the PEG moiety is linked to a surface-exposed
lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety
is linked to
the epsilon-amino group of a surface-exposed lysine residue in the CIFN
polypeptide. In
further embodiments, the linkage comprises an amide bond between the PEG
moiety and
the epsilon-amino group of the surface-exposed lysine residue in the CIFN
polypeptide. In
still further embodiments, the linkage comprises an amide bond between a
propionyl group
of the PEG moiety and the epsilon-amino group of the surface-exposed lysine
residue in the
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CA 02560897 2007-08-08

CIFN polypeptide. In additional embodiments, the amide bond is formed by
condensation
of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety
and the
epsilon-amino group of the surface-exposed lysine residue in the C1FN
polypeptide.
[0579] In some embodiments, the PEG moiety is linked to a lysine chosen
from 1ys31, 1ys50, 1ys71, lys84, 1ys121, 1ys122, lys134, lys'35, and lys'65 of
the CIFN polypeptide.
In other embodiments, the PEG moiety is linked to the epsilon-amino group of a
lysine
chosen from 1ys31, lys50, 1ys71, 1ys84, lys121, lys'22, 1ys134lys'35, and
lys165 of the CIFN
polypeptide. In further embodiments, the linkage comprises an amide bond
between the
PEG moiety and the epsilon-amino group of the chosen lysine residue in the
CIFN
polypeptide. In still further embodiments, the linkage comprises an amide bond
between a
propionyl group of the PEG moiety and the epsilon-amino group of the chosen
lysine
residue in the CIFN polypeptide. In additional embodiments, the amide bond is
formed by
condensation of an alpha-methoxy, omega-propanoic acid activated ester of the
PEG
moiety and the epsilon-amino group of the chosen lysine residue in the CIFN
polypeptide.
[0580] me embodiments, the PEG moiety is linked to a lysine chosen from
1ys1 , lys , lys , and lys'65 of the CIFN polypeptide. In other embodiments,
the PEG
21'34'35
moiety is linked to the epsilon-amino group of a lysine chosen from 1ys121,
1ys134, lys135, and
1ys165 of the CIFN polypeptide. In further embodiments, the linkage comprises
an amide
bond between the PEG moiety and the epsilon-amino group of the chosen lysine
residue in
the CIFN polypeptide. In still further embodiments, the linkage comprises an
amide bond
between a propionyl group of the PEG moiety and the epsilon-amino group of the
chosen
lysine residue in the CIFN polypeptide. In additional embodiments, the amide
bond is
formed by condensation of an alpha-methoxy, omega-propanoic acid activated
ester of the
PEG moiety and the epsilon-amino group of the chosen lysine residue in the
CIFN
polypeptide.
[0581] In connection with the above-described monopegylated CIFN
molecules, the invention contemplates embodiments of each such molecule where
the CIFN
polypeptide is chosen from interferon alpha-cons, interferon alpha-cone, and
interferon
alpha-con3, the amino acid sequences of which CIFN polypeptides are disclosed
in U.S.
Pat. No. 4,695,623.
Populations of IFN-a
[0582] In addition, any of the methods of the embodiments may employ a
PEGylated IFN-a composition that comprises a population of monopegylated IFN-a
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CA 02560897 2007-08-08

molecules, where the population consists of one or more species of
monopegylated IFN-a
molecules as described above. The subject composition comprises a population
of
modified IFN-a polypeptides, each with a single PEG molecule linked to a
single amino
acid residue of the polypeptide.
[0583] In some of these embodiments, the population comprises a mixture of
a first IFN-a polypeptide linked to a PEG molecule at a first amino acid
residue; and at
least a second IFN-a polypeptide linked to a PEG molecule at a second amino
acid residue,
wherein the first and second IFN-a polypeptides are the same or different, and
wherein the
location of the first amino acid residue in the amino acid sequence of the
first IFN-a
polypeptide is not the same as the location of the second amino acid residue
in the second
IFN-a polypeptide. As one non-limiting example, a subject composition
comprises a
population of PEG-modified IFN-a polypeptides, the population comprising an
IFN-a
polypeptide linked at its amino terminus to a linear PEG molecule; and an IFN-
a
polypeptide linked to a linear PEG molecule at a lysine residue.
[0584] Generally, a given modified IFN-a species represents from about
0.5% to about 99.5% of the total population of monopegylated IFN-a polypeptide
molecules in a population, e.g, a given modified IFN-a species represents
about 0.5%,
about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about
20%,
about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,
about
60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about
95%,
about 99%, or about 99.5% of the total population of monopegylated IFN-a
polypeptide
molecules in a population. In some embodiments, a subject composition
comprises a
population of monopegylated IFN-a polypeptides, which population comprises at
least
about 70%, at least about 80%, at least about 90%, at least about 95%, or at
least about
99%, IFN-a polypeptides linked to PEG at the same site, e.g., at the N-
terminal amino acid.
[0585] In particular embodiments of interest, a subject composition
comprises a population of monopegylated CIFN molecules, the population
consisting of
one or more species of molecules, where each species of molecules is
characterized by a
single CIFN polypeptide linked, directly or indirectly in a covalent linkage,
to a single
linear PEG moiety of about 30 kD in molecular weight, and where the linkage is
to either a
lysine residue in the CIFN polypeptide, or the N-terminal amino acid residue
of the CIFN
polypeptide.

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WO 2005/095403 PCT/US2005/010494
The" ammo acid residue to which the PEG is attached is in many
embodiments the N-terminal amino acid residue. In other embodiments, the PEG
moiety is
attached (directly or via a linker) to a surface-exposed lysine residue. In
additional
embodiments, the PEG moiety is attached (directly or via a linker) to a lysine
residue
chosen from 1ys31, 1ys50, 1ys71, lys84, lys121, 1ys122, lys134, 1ys135, and
1ys165 of the CIFN
polypeptide. In further embodiments, the PEG moiety is attached (directly or
via a linker)
to a lysine residue chosen from 1Ys121, 1Y5134' lYs13s' and 1Ys165 of the CIFN
polypeptide.

[0587] As an example, a subject composition comprises a population of
monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide
species of molecules characterized by a PEG moiety linked at the N-terminal
amino acid
residue of a first CIFN polypeptide, and a second monopegylated CIFN
polypeptide species
of molecules characterized by a PEG moiety linked to a first lysine residue of
a second
CIFN polypeptide, where the first and second CIFN polypeptides are the same or
different.
A subject composition may further comprise at least one additional
monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a
lysine residue
in the CIFN polypeptide, where the location of the linkage site in each
additional
monopegylated CIFN polypeptide species is not the same as the location of the
linkage site
in any other species. In all species in this example, the PEG moiety is a
linear PEG moiety
having an average molecular weight of about 30 kD.

[0588] In connection with each of the above-described populations of
monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide
species of molecules characterized by a PEG moiety linked at the N-terminal
amino acid
residue of a first CIFN polypeptide, and a second monopegylated CIFN
polypeptide species
of molecules characterized by a PEG moiety linked to a first surface-exposed
lysine residue
of a second CIFN polypeptide, where the first and second CIFN polypeptides are
the same
or different. A subject composition may further comprise at least one
additional
monopegylated CIFN polypeptide species of molecules characterized by a PEG
moiety
linked to a surface-exposed lysine residue in the CIFN polypeptide, where the
location of
the linkage site in each additional monopegylated CIFN polypeptide species is
not the same
as the location of the linkage site in any other species. In all species in
this example, the
PEG moiety is a linear PEG moiety having an average molecular weight of about
30 kD.
[0589] As another example, a subject composition comprises a population of
monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
species ofinolecules `characteized by a PEG moiety linked at the N-terminal
amino acid
residue of a first CIFN polypeptide, and a second monopegylated CIFN
polypeptide species
of molecules characterized by a PEG moiety linked to a first lysine residue
selected from
one of 1Ys31, 1Ys50' 1Y571' 1Ys84, 1Y6121' 1Y6122' 1Y6134' 1Y ~ 5135 and
lY5165 in a second CIFN
polypeptide, where the first and second CIFN polypeptides are the same or
different. A
subject composition may further comprise a third monopegylated CIFN
polypeptide species
of molecules characterized by a PEG moiety linked to a second lysine residue
selected from
one of 1Ys31, lYs50, 1Y571, 1Ys84, 1Y5121, 1Y5122, 1Y6134, 1Y5135, and 1Y6165
in a third CIFN
polypeptide, where the third CIFN polypeptide is the same or different from
either of the
first and second CIFN polypeptides, where the second lysine residue is located
in a position
in the amino acid sequence of the third CIFN polypeptide that is not the same
as the
position of the first lysine residue in the amino acid sequence of the second
CIFN
polypeptide. A subject composition may further comprise at least one
additional
monopegylated CIFN polypeptide species of molecules characterized by a PEG
moiety
linked to one of 1ys31, 1ys50, 1ys71, lys84, 1ys121, 1ys122, 1ys134, 1ys135,
and 1ys165, where the
location of the linkage site in each additional monopegylated CIFN polypeptide
species is
not the same as the location of the linkage site in any other species. In all
species in this
example, the PEG moiety is a linear PEG moiety having an average molecular
weight of
about 30 kD.

[0590] As another example, a subject composition comprises a population of
monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide
species of molecules characterized by a PEG moiety linked at the N-terminal
amino acid
residue of a first CIFN polypeptide, and a second monopegylated CIFN
polypeptide species
of molecules characterized by a PEG moiety linked to a first lysine residue
selected from
one of lys 121, 1Y5134, 1Ys135 , and 1Ys165 in a second CIFN polypeptide,
where the first and
second CIFN polypeptides are the same or different. A subject composition may
further
comprise a third monopegylated CIFN polypeptide species of molecules
characterized by a
PEG moiety linked to a second lysine residue selected from one of
lys121,1y5134, 1y5135, and
1ys165 in a third CIFN polypeptide, where the third CIFN polypeptide is the
same or
different from either of the first and second CIFN polypeptides, where the
second lysine
residue is located in a position in the amino acid sequence of the third CIFN
polypeptide
that is not the same as the position of the first lysine residue in the amino
acid sequence of
the second CIFN polypeptide. A subject composition may further comprise at
least one
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
" ad'di Tonal' moiopegyl'ate ,CIPN"'polypeptide species of molecules
characterized by a PEG
moiety linked to one of 1ys121,1yS134, lys135, and 1ys165, where the location
of the linkage site
in each additional monopegylated CIFN polypeptide species is not the same as
the location
of the linkage site in any other species. In all species in this example, the
PEG moiety is a
linear PEG moiety having an average molecular weight of about 30 kD.

[0591] As another non-limiting example, a subject composition comprises a
population of monopegylated CIFN molecules, consisting of a first
monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a
first lysine
residue in a first CIFN polypeptide; and a second monopegylated CIFN
polypeptide species
of molecules characterized by a PEG moiety linked at a second lysine residue
in a second
CIFN polypeptide, where the first and second CIFN polypeptides are the same or
different,
and where the first lysine is located in a position in the amino acid sequence
of the first
CIFN polypeptide that is not the same as the position of the second lysine
residue in the
amino acid sequence of the second CIFN polypeptide. A subject composition may
further
comprise at least one additional monopegylated CIFN species of molecules
characterized
by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the
location of
the linkage site in each additional monopegylated CIFN polypeptide species is
not the same
as the location of the linkage site in any other species. In all species in
this example, the
PEG moiety is a linear PEG moiety having an average molecular weight of about
30 kD.

[0592] As another non-limiting example, a subject composition comprises a
population of monopegylated CIFN molecules, consisting of a first
monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a
first lysine
residue chosen from lys 31, 1Ys50, 1YS71, 1YS84, 1Ys121, 1Y5122, 1Ys134,
lYS135, and 1Y5165 in a first
CIFN polypeptide; and a second monopegylated CIFN polypeptide species of
molecules
characterized by a PEG moiety linked at a second lysine residue chosen from
1ys31, lys50,
1ys71, 1ys84, 1ys121, 1ys122, lys134, 1yS135, and 1ys165 in a second CIFN
polypeptide, where the
first and second CIFN polypeptides are the same or different, and where the
second lysine
residue is located in a position in the amino acid sequence of the second CIFN
polypeptide
that is not the same as the position of the first lysine residue in the first
CIFN polypeptide.
The composition may further comprise at least one additional monopegylated
CIFN
polypeptide species of molecules characterized by a PEG moiety linked to one
of 1ys31,
1Ys50,1Y571, 1YS84, 1Y5121, 1Y5122, 1Y5134, 1Ys13s, and 1Ys16s' where the
location of the linkage site
in each additional monopegylated CIFN polypeptide species is not the same as
the location
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
of the"linkagesite in any of er secies. In all species in this example, the
PEG moiety is a
linear PEG moiety having an average molecular weight of about 30 kD.

[0593] As another non-limiting example, a subject composition comprises a
population of monopegylated CIFN molecules, consisting of a first
monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a
first lysine
residue chosen from 1Ys121, 1Ys134, 1Ys13s, and lys 165 in a first CIFN
polypeptide; and a
second monopegylated CIFN polypeptide species of molecules characterized by a
PEG
moiety linked at a second lysine residue chosen from lys121, 1ys134, lys135,
and lysl65 in a
second CIFN polypeptide, where the first and second CIFN polypeptides are the
same or
different, and where the second lysine residue is located in a position in the
amino acid
sequence of the second CIFN polypeptide that is not the same as the position
of the first
lysine residue in the first CIFN polypeptide. The composition may further
comprise at least
one additional monopegylated CIFN polypeptide species of molecules
characterized by a
PEG moiety linked to one of 1 sl2t 1 s134 1 s13s and 1 s16s
y y y y y ,where the location of the
linkage site in each additional monopegylated CIFN polypeptide species is not
the same as
the location of the linkage site in any other species. In all species in this
example, the PEG
moiety is a linear PEG moiety having an average molecular weight of about 30
kD.

[0594] As another non-limiting example, a subject composition comprises a
monopegylated population of CIFN molecules, consisting of a first
monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a
first surface-
exposed lysine residue in a first CIFN polypeptide; and a second monopegylated
CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a
second surface-
exposed lysine residue in a second CIFN polypeptide, where the first and
second CIFN
polypeptides are the same or different, and where the first surface-exposed
lysine is located
in a position in the amino acid sequence of the first CIFN polypeptide that is
not the same
as the position of the second surface-exposed lysine residue in the amino acid
sequence of
the second CIFN polypeptide. A subject composition may further comprise at
least one
additional monopegylated CIFN species of molecules characterized by a PEG
moiety linked
to a surface-exposed lysine residue in the CIFN polypeptide, where the
location of the
linkage site in each additional monopegylated CIFN polypeptide species is not
the same as
the location of the linkage site in any other species. In all species in this
example, the PEG
moiety is a linear PEG moiety having an average molecular weight of about 30
kD.

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
in "coi nectori with each of the above-described populations of
monopegylated CIFN roolecules, the invention contemplates embodiments where
the
molecules in each such population comprise a CIFN polypeptide chosen from
interferon
alpha-cons, interferon alpha-cone, and interferon alpha-con3.

[0596] Certain embodiments further feature a product that is produced by the
process of reacting CIFN polypeptide with a succinimidyl ester of alpha-
methoxy, omega-
propionylpoly(ethylene glycol) (mPEGspa) that is linear and about 30 kD in
molecular
weight, where the reactants are initially present at a molar ratio of about
1:1 to about 1:5
CIFN:mPEGspa, and where the reaction is conducted at a pH of about 7 to about
9,
followed by recovery of the monopegylated CIFN product of the reaction. In one
embodiment, the reactants are initially present at a molar ratio of about 1:3
CIFN:mPEGspa
and the reaction is conducted at a pH of about 8. In another embodiment where
the product
is generated by a scaled-up procedure needed for toxicological and clinical
investigations,
the reactants are initially present in a molar ratio of 1:2 CIFN:mPEGspa and
the reaction is
conducted at a pH of about 8Ø

[0597] In connection with the above-described product-by-process, the
invention contemplates embodiments where the CIFN reactant is chosen from
interferon
alpha-cons, interferon alpha-cone, and interferon alpha-con3.
IFN-B

[0598] The term interferon-beta ("IFN-13") includes IFN-B polypeptides that
are
naturally occurring; non-naturally-occurring IFN-B polypeptides; and analogs
of naturally
occurring or non-naturally occurring IFN-B that retain antiviral activity of a
parent
naturally-occurring or non-naturally occurring IFN-B.

[0599] Any of a variety of beta interferons may be delivered by the continuous
delivery method of the present embodiments. Suitable beta interferons include,
but are not
limited to, naturally-occurring IFN-B; IFN-B 1 a, e.g., Avonex (Biogen,
Inc.), and Rebif
(Serono, SA); IFN-B1b (Betaseron ; Berlex); and the like.

[0600] The IFN-B formulation may comprise an N-blocked species, wherein the
N-terminal amino acid is acylated with an acyl group, such as a formyl group,
an acetyl
group, a malonyl group, and the like. Also suitable for use is a consensus IFN-
B.

[0601] IFN-B polypeptides may be produced by any known method. DNA
sequences encoding IFN-B may be synthesized using standard methods. In many
embodiments, IFN-B polypeptides are the products of expression of manufactured
DNA
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WO 2005/095403 PCT/US2005/010494
sequences ' transformed or trarisf6cted into bacterial hosts, e.g., E. cols,
or in eukaryotic host
cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In
these
embodiments, the IFN-13 is "recombinant IFN-B." Where the host cell is a
bacterial host
cell, the IFN-B is modified to comprise an N-terminal inethionine.

[0602] It is to be understood that IFN-B as described herein may comprise one
or more modified amino acid residues, e.g., glycosylations, chemical
modifications, and the
like.

IFN-tau
[0603] The term interferon-tau includes IFN-tau polypeptides that are
naturally
occurring; non-naturally-occurring IFN-tau polypeptides; and analogs of
naturally occurring
or non-naturally occurring IFN-tau that retain antiviral activity of a parent
naturally-
occurring or non-naturally occurring IFN-tau.

[0604] Suitable tau interferons include, but are not limited to, naturally-
occurring IFN-tau; Tauferon (Pepgen Corp.); and the like.

[0605] IFN-tau may comprise an amino acid sequence as set forth in any one of
GenBank Accession Nos. P15696; P56828; P56832; P56829; P56831; Q29429; Q28595;
Q28594; S08072; Q08071; Q08070; Q08053; P56830; P28169; P28172; and P28171.
The
sequence of any known IFN-tau polypeptide may be altered in various ways known
in the
art to generate targeted changes in sequence. A variant polypeptide will
usually be
substantially similar to the sequences provided herein, i.e. will differ by at
least one amino
acid, and may differ by at least two but not more than about ten amino acids.
The sequence
changes may be substitutions, insertions or deletions. Conservative amino acid
substitutions typically include substitutions within the following groups:
(glycine, alanine);
(valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine,
glutamine); (serine,
threonine); (lysine, arginine); or (phenylalanine, tyrosine).
[0606] Modifications of interest that may or may not alter the primary amino
acid sequence include chemical derivatization of polypeptides, e.g.,
acetylation, or
carboxylation; changes in amino acid sequence that introduce or remove a
glycosylation
site; changes in amino acid sequence that make the protein susceptible to
PEGylation; and
the like. Also included are modifications of glycosylation, e.g. those made by
modifying
the glycosylation patterns of a polypeptide during its synthesis and
processing or in further
processing steps; e.g. by exposing the polypeptide to enzymes that affect
glycosylation,
such as mammalian glycosylating or deglycosylating enzymes. Also embraced are
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CA 02560897 2007-08-08

sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine,
phosphoserine, or phosphothreonine.
[0607] The IFN-tau formulation may comprise an N-blocked species,
wherein the N-terminal amino acid is acylated with an acyl group, such as a
formyl group,
an acetyl group, a malonyl group, and the like. Also suitable for use is a
consensus IFN-
tau.
[0608] IFN-tau polypeptides may be produced by any known method. DNA
sequences encoding IFN-tau may be synthesized using standard methods. In many
embodiments, IFN-tau polypeptides are the products of expression of
manufactured DNA
sequences transformed or transfected into bacterial hosts, e.g., E. coli, or
in eukaryotic host
cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In
these
embodiments, the IFN-tau is "recombinant IFN-tau." Where the host cell is a
bacterial host
cell, the IFN-tau is modified to comprise an N-terminal methionine.
[0609] It is to be understood that IFN-tau as described herein may comprise
one or more modified amino acid residues, e.g., glycosylations, chemical
modifications,
and the like.
IFN-co
[0610] The term interferon-omega ("IFN-o)") includes IFN-w polypeptides
that are naturally occurring; non-naturally-occurring IFN-w polypeptides; and
analogs of
naturally occurring or non-naturally occurring IFN-w that retain antiviral
activity of a
parent naturally-occurring or non-naturally occurring IFN-co.
[0611] Any known omega interferon may be delivered by the continuous
delivery method of the present embodiments. Suitable IFN-w include, but are
not limited
to, naturally-occurring IFN-co; recombinant IFN-co, e.g., Biomed 510
(BioMedicines); and
the like.
[0612] IFN-w may comprise an amino acid sequence as set forth in GenBank
Accession No. NP_002168; or AAA70091. The sequence of any known IFN-w
polypeptide may be altered in various ways known in the art to generate
targeted changes in
sequence. A variant polypeptide will usually be substantially similar to the
sequences
provided herein, i.e. will differ by at least one amino acid, and may differ
by at least two
but not more than about ten amino acids. The sequence changes may be
substitutions,
insertions or deletions. Conservative amino acid substitutions typically
include
substitutions within the following groups: (glycine, alanine); (valine,
isoleucine, leucine);
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CA 02560897 2007-08-08

(aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine);
(lysine,
arginine); or (phenylalanine, tyrosine).
[0613] Modifications of interest that may or may not alter the primary amino
acid sequence include chemical derivatization of polypeptides, e.g.,
acetylation, or
carboxylation; changes in amino acid sequence that introduce or remove a
glycosylation
site; changes in amino acid sequence that make the protein susceptible to
PEGylation; and
the like. Also included are modifications of glycosylation, e.g. those made by
modifying
the glycosylation patterns of a polypeptide during its synthesis and
processing or in further
processing steps; e.g. by exposing the polypeptide to enzymes that affect
glycosylation,
such as mammalian glycosylating or deglycosylating enzymes. Also embraced are
sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine,
phosphoserine, or phosphothreonine.
[0614] The IFN-co formulation may comprise an N-blocked species, wherein
the N-terminal amino acid is acylated with an acyl group, such as a formyl
group, an acetyl
group, a malonyl group, and the like. Also suitable for use is a consensus IFN-
w.
[0615] IFN-co polypeptides may be produced by any known method. DNA
sequences encoding IFN-co may be synthesized using standard methods. In many
embodiments, IFN-co polypeptides are the products of expression of
manufactured DNA
sequences transformed or transfected into bacterial hosts, e.g., E. coli, or
in eukaryotic host
cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In
these
embodiments, the IFN-co is "recombinant IFN-co." Where the'host cell is a
bacterial host
cell, the IFN-co is modified to comprise an N-terminal methionine.
[0616] It is to be understood that IFN-co as described herein may comprise
one or more modified amino acid residues, e.g., glycosylations, chemical
modifications,
and the like.

Type III interferon receptor agonists
[0617] In any of the above-described methods, the interferon receptor agonist
is in some embodiments an agonist of a Type III interferon receptor (e.g., "a
Type III
interferon agonist"). Type III interferon agonists include an IL-28b
polypeptide; and IL-
28a polypeptide; and IL-29 polypeptide; antibody specific for a Type III
interferon
receptor; and any other agonist of Type III interferon receptor, including non-
polypeptide
agonists.
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WO 2005/095403 PCT/US2005/010494
IU- '8A, L-"29B, and IL-29 (referred to herein collectively as "Type III
interferons" or "Type III IFNs") are described in Sheppard et al. (2003)
Nature 4:63-68.
Each polypeptide binds a heterodiineric receptor consisting of IL- 10 receptor
13 chain and an
IL-28 receptor a. Sheppard et al. (2003), supra. The amino acid sequences of
IL-28A, IL-
28B, and IL-29 are found under GenBank Accession Nos. NP_742150, NP_742151,
and
NP742152, respectively.

[0619] The amino acid sequence of a Type III IFN polypeptide may be altered in
various ways known in the art to generate targeted changes in sequence. A
variant
polypeptide will usually be substantially similar to the sequences provided
herein, i.e. will
differ by at least one amino acid, and may differ by at least two but not more
than about ten
amino acids. The sequence changes may be substitutions, insertions or
deletions. Scanning
mutations that systematically introduce alanine, or other residues, may be
used to determine
key amino acids. Specific amino acid substitutions of interest include
conservative and
non-conservative changes. Conservative amino acid substitutions typically
include
substitutions within the following groups: (glycine, alanine); (valine,
isoleucine, leucine);
(aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine);
(lysine,
arginine); or (phenylalanine, tyrosine).

[0620] Modifications of interest that may or may not alter the primary amino
acid sequence include chemical derivatization of polypeptides, e.g.,
acetylation, or
carboxylation; changes in amino acid sequence that introduce or remove a
glycosylation
site; changes in amino acid sequence that make the protein susceptible to
PEGylation; and
the like. Also included are modifications of glycosylation, e.g. those made by
modifying
the glycosylation patterns of a polypeptide during its synthesis and
processing or in further
processing steps; e.g. by exposing the polypeptide to enzymes that affect
glycosylation,
such as mammalian glycosylating or deglycosylating enzymes. Also embraced are
sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine,
phosphoserine, or phosphothreonine.

[0621] Included in the embodiments are polypeptides that have been modified
using ordinary chemical techniques so as to improve their resistance to
proteolytic
degradation, to optimize solubility properties, or to render them more
suitable as a
therapeutic agent. For examples, the backbone of the peptide may be cyclized
to enhance
stability (see Friedler et al. (2000) J. Biol. Chem. 275:23783-23789). Analogs
may be used
that include residues other than naturally occurring L-amino acids, e.g. D-
amino acids or
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CA 02560897 2007-08-08

non-naturally occurring synthetic amino acids. The protein may be pegylated to
enhance
stability. The polypeptides may be fused to albumin.
[0622] The polypeptides may be prepared by in vitro synthesis, using
conventional methods as known in the art, by recombinant methods, or may be
isolated
from cells induced or naturally producing the protein. The particular sequence
and the
manner of preparation will be determined by convenience, economics, purity
required, and
the like. If desired, various groups may be introduced into the polypeptide
during synthesis
or during expression, which allow for linking to other molecules or to a
surface. Thus
cysteines may be used to make thioethers, histidines for linking to a metal
ion complex,
carboxyl groups for forming amides or esters, amino groups for forming amides,
and the
like.

Type II Interferon receptor agonists
[0623] Type II interferon receptor agonists include any naturally-occurring or
non-naturally-occurring ligand of a human Type II interferon receptor which
binds to and
causes signal transduction via the receptor. Type II interferon receptor
agonists include
interferons, including naturally-occurring interferons, modified interferons,
synthetic
interferons, pegylated interferons, fusion proteins comprising an interferon
and a
heterologous protein, shuffled interferons; antibody specific for an
interferon receptor; non-
peptide chemical agonists; and the like.
[0624] A specific example of a Type II interferon receptor agonist is IFN-y
and variants thereof. While the present embodiments exemplify use of an IFN-y
polypeptide, it will be readily apparent that any Type II interferon receptor
agonist may be
used in a subject method.
Interferon-Gamma
[0625] The nucleic acid sequences encoding IFN-y polypeptides may be
accessed from public databases, e.g., Genbank, journal publications, etc.
While various
mammalian IFN-y polypeptides are of interest, for the treatment of human
disease,
generally the human protein will be used. Human IFN-y coding sequence may be
found in
Genbank, accession numbers X13274; V00543; and NM_000619. The corresponding
genomic sequence may be found in Genbank, accession numbers J00219; M37265;
and

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CA 02560897 2007-08-08

V00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274);
and
Rinderknecht et al. (1984) J.B. C. 259:6790.
[0626] IFN-yl b (Actimmune ; human interferon) is a single-chain
polypeptide of 140 amino acids. It is made recombinantly in Ecoli and is
unglycosylated.
Rinderknecht et at. (1984) J. Biol. Chem. 259:6790-6797. Recombinant IFN-y as
discussed
in U.S. Patent No. 6,497,871 is also suitable for use herein.
[0627] The IFN-y to be used in the methods of the present embodiments may
be any of natural IFN-ys, recombinant IFN-ys and the derivatives thereof so
far as they have
an IFN-y activity, particularly human IFN-y activity. Human IFN-y exhibits the
antiviral
and anti-proliferative properties characteristic of the interferons, as well
as a number of
other immunomodulatory activities, as is known in the art. Although IFN-y is
based on the
sequences as provided above, the production of the protein and proteolytic
processing may
result in processing variants thereof. The unprocessed sequence provided by
Gray et al.,
supra, consists of 166 amino acids (aa). Although the recombinant IFN-y
produced in E.
coli was originally believed to be 146 amino acids, (commencing at amino acid
20) it was
subsequently found that native human IFN-y is cleaved after residue 23, to
produce a 143
as protein, or 144 as if the terminal methionine is present, as required for
expression in
bacteria. During purification, the mature protein may additionally be cleaved
at the C
terminus after reside 162 (referring to the Gray et al. sequence), resulting
in a protein of
139 amino acids, or 140 amino acids if the initial methionine is present, e.g.
if required for
bacterial expression. The N-terminal methionine is an artifact encoded by the
mRNA
translational "start" signal AUG that, in the particular case of E. coli
expression is not
processed away. In other microbial systems or eukaryotic expression systems,
methionine
may be removed.
[0628] For use in the subject methods, any of the native IFN-y peptides,
modifications and variants thereof, or a combination of one or more peptides
may be used.
IFN-y peptides of interest include fragments, and may be variously truncated
at the carboxyl
terminus relative to the full sequence. Such fragments continue to exhibit the
characteristic
properties of human gamma interferon, so long as amino acids 24 to about 149
(numbering
from the residues of the unprocessed polypeptide) are present. Extraneous
sequences may
be substituted for the amino acid sequence following amino acid 155 without
loss of
activity. See, for example, U.S. Patent No. 5,690,925. Native IFN-y moieties
include
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CA 02560897 2007-08-08

molecules variously extending from amino acid residues 24-150; 24-151, 24-152;
24- 153,
24-155; and 24-157. Any of these variants, and other variants known in the art
and having
IFN-y activity, may be used in the present methods.
[0629] The sequence of the IFN-y polypeptide may be altered in various ways
known in the art to generate targeted changes in sequence. A variant
polypeptide will
usually be substantially similar to the sequences provided herein, i.e., will
differ by at least
one amino acid, and may differ by at least two but not more than about ten
amino acids.
The sequence changes may be substitutions, insertions or deletions. Scanning
mutations
that systematically introduce alanine, or other residues, may be used to
determine key
amino acids. Specific amino acid substitutions of interest include
conservative and non-
conservative changes. Conservative amino acid substitutions typically include
substitutions
within the following groups: (glycine, alanine); (valine, isoleucine,
leucine); (aspartic acid,
glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine,
arginine); or
(phenylalanine, tyrosine).
[0630] Modifications of interest that may or may not alter the primary amino
acid sequence include chemical derivatization of polypeptides, e.g.,
acetylation, or
carboxylation; changes in amino acid sequence that introduce or remove a
glycosylation
site; changes in amino acid sequence that make the protein susceptible to
PEGylation; and
the like. One embodiment contemplates the use of IFN-y variants with one or
more non-
naturally occurring glycosylation and/or pegylation sites that are engineered
to provide
glycosyl- and/or PEG-derivatized polypeptides with reduced serum clearance,
such as the
IFN-y polypeptide variants described in International Patent Publication No.
WO 01/36001.
Also included are modifications of glycosylation, e.g., those made by
modifying the
glycosylation patterns of a polypeptide during its synthesis and processing or
in further
processing steps; e.g., by exposing the polypeptide to enzymes that affect
glycosylation,
such as mammalian glycosylating or deglycosylating enzymes. Also embraced are
sequences that have phosphorylated amino acid residues, e.g., phosphotyrosine,
phosphoserine, or phosphothreonine.
[0631] Included in the embodiments are polypeptides that have been
modified using ordinary chemical techniques so as to improve their resistance
to proteolytic
degradation, to optimize solubility properties, or to render them more
suitable as a
therapeutic agent. For examples, the backbone of the peptide may be cyclized
to enhance
stability (see Friedler et at. (2000) J. Biol. Chem. 275:23783-23789). Analogs
may be used
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
that `include"'residues other `than `naturally occurring L-amino acids, e.g.,
D-amino acids or
non-naturally occurring synthetic amino acids. The protein may be pegylated to
enhance
stability.

[0632] The polypeptides may be prepared by in vitro synthesis, using
conventional methods as known in the art, by recombinant methods, or may be
isolated
from cells induced or naturally producing the protein. The particular sequence
and the
manner of preparation will be determined by convenience, economics, purity
required, and
the like. If desired, various groups may be introduced into the polypeptide
during synthesis
or during expression, which allow for linking to other molecules or to a
surface. Thus
cysteines may be used to make thioethers, histidines for linking to a metal
ion complex,
carboxyl groups for forming amides or esters, amino groups for forming amides,
and the
like.

[0633] The polypeptides may also be isolated and purified in accordance with
conventional methods of recombinant synthesis. A lysate may be prepared of the
expression host and the lysate purified using HPLC, exclusion chromatography,
gel
electrophoresis, affinity chromatography, or other purification technique. For
the most part,
the compositions which are used will comprise at least 20% by weight of the
desired
product, more usually at least about 75% by weight, preferably at least about
95% by
weight, and for therapeutic purposes, usually at least about 99.5% by weight,
in relation to
contaminants related to the method of preparation of the product and its
purification.
Usually, the percentages will be based upon total protein.

Pirfenidone and Analogs Thereof
[0634] Pirfenidone (5-methyl- 1 -phenyl-2-(l H)-pyridone) and specific
pirfenidone analogs are disclosed for the treatment of fibrotic conditions. A
"fibrotic
condition" is one that is amenable to treatment by administration of a
compound having
anti-fibrotic activity.

Pirfenidone
Me / N,Ph
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WO 2005/095403 PCT/US2005/010494
Pirfenidone analogs

I
R2rN.RI
O
X

IIA JIB
R2 R2
RI X,' O RI X, LO

Descriptions for Substituents R1, R2, X

[0635] R1: carbocyclic (saturated and unsaturated), heterocyclic (saturated or
unsaturated), alkyls (saturated and unsaturated). Examples include phenyl,
benzyl,
pyrrmidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl,
cyclohexyl, piperidyl,
pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.

[0636] Rl may further include substitutions on the carbocyclic or heterocyclic
moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy,
carboxyl, cyano,
thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for
example, 4-
nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-
pyrrolyl, 2, 5-
dichlorocyclohexyl, guanidinyl-cyclohexenyl and the like.

[0637] R2: alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl,
ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.

[0638] X: may be any number (from 1 to 3) of substituents on the carbocyclic
or heterocyclic ring. The substituents may be the same or different.
Substituents may
include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl,
hydroxyl, cyano,
amino, thio, alkylamino, haloaryl and the like.
[0639] The substituents may be optionally further substituted with 1-3
substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl
and halo
groups. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-
chlorophenyl, 4-
nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.
[0640] Specific Examples include the compounds listed in Table 1:
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
Table 1
IIA IIB
5-Methyl-l-(2'-pyridyl)-2-(1H) pyridine, 6-Methyl-I-phenyl-3-(1H) pyridone,
6-Methyl-l-phenyl-2-(IH) pyridone, 5-Methyl-l-p-tolyl-3-(1H) pyridone,
5-Methyl-3-phenyl-l-(2'-thienyl)-2-(1H) 5-Methyl-l-(2'-naphthyl)-3-(iH)
pyridone,
pyridone,
5-Methyl-l-(2'-naphthyl)-2-(1H) pyridone, 5-Methyl-l-phenyl-3-(lH) pyridone,
5-Methyl-l-p-tolyl-2-(iH) pyridone, 5-Methyl-l-(5'-quinolyl)-3-(1H) pyridone,
5-Methyl-l-(1'naphthyl)-2-(II) pyridone, 5-Ethyl-I-phenyl-3-(iH) pyridone,
5-Ethyl-l-phenyl-2-(iH) pyridone, 5-Methyl-l-(4'-methoxyphenyl)-3-(iH)
pyridone,
5-Methyl-l-(5'-quinolyl)-2-(iH) pyridone, 4-Methyl-I-phenyl-3-(1H) pyridone,
5-Methyl-l-(4'-quinolyl)-2-(1H) pyridone, 5-Methyl-l-(3'-pyridyl)-3-(iH)
pyridone,
5-Methyl-l-(4'-pyridyl)-2-(iH) pyridone, 5-Methyl-l-(2'-Thienyl)-3-(iH)
pyridone,
3-Methyl-1 -phenyl-2-(1 H) pyridone, 5 -Methyl- I -(2'-pyridyl)-3 -(I H)
pyridone,
5-Methyl-l-(4'-methoxyphenyl)-2-(1H) pyridone, 5-Methyl-l-(2'-quinolyl)-3-(lH)
pyridone,
I -Phenyl-2-(l H) pyridone, I-Phenyl-3-(1H) pyridine,
1,3-Diphenyl-2-(lH) pyridone, 1-(2'-Furyl)-5-methyl-3-(iH) pyridone,
1,3 -Diphenyl-5 -methyl-2-(l H) pyridone, 1-(4'-Chlorophenyl)-5-inethyl-3-(1H)
pyridine.
5-Methyl-I -(3'-trifluoroinethylphenyl)-2-(1H)-
pyridone,
3 -Ethyl- l -phenyl-2-(1 H) pyridone,
5-Methyl-l-(3'-pyridyl)-2-(1H) pyridone,
5-Methyl-l-(3-nitrophenyl)-2-(lH) pyridone,
3-(4'-Chlorophenyl)-5-Methyl-l -phenyl-2-(l H)
pyridone,
5-Methyl-l-(2'-Thienyl)-2-(1H) pyridone,
5-Methyl-l-(2'-thiazolyl)-2-(lH) pyridone,
3,6-Dimethyl-l-phenyl-2-(lH) pyridone,
1-(4'Chlorophenyl)-5-Methyl-2-(1H) pyridone,
1-(2'-Imidazolyl)-5-Methyl-2-(1H) pyridone,
1-(4' Nirrophenyl)-2-(1H) pyridone,
1-(2'-Furyl)-5-Methyl-2-(1 H) pyridone,

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CA 02560897 2007-08-08
1-Phenyl-3-(4'-chlorophenyl)-2-(1 H) pyridine.

[0641] U.S. Pat. Nos. 3,974,281; 3,839,346; 4,042,699; 4,052,509; 5,310,562;
5,518,729; 5,716,632; and 6,090,822 describe methods for the synthesis and
formulation of
pirfenidone and specific pirfenidone analogs in pharmaceutical compositions
suitable for
use in the methods of the present embodiments.

Thymosin-a
[0642] Thymosin-a (ZadaxinTM; available from SciClone Pharmaceuticals,
Inc., San Mateo, CA) is a synthetic form of thymosin alpha 1, a hormone found
naturally in
the circulation and produced by the thymus gland. Thymosin-a increases
activity of T cells
and NK cells. ZadaxinTM formulated for subcutaneous injection is a purified
sterile
lyophilized preparation of chemically synthesized thymosin alpha 1 identical
to human
thymosin alpha 1. Thymosin alpha 1 is an acetylated polypeptide with the
following
sequence: Ac - Ser - Asp - Ala - Ala - Val - Asp - Thr - Ser - Ser - Glu - Ile
- Thr - Thr - Lys
- Asp - Leu - Lys - Glu - Lys - Lys - Glu - Val - Val - Glu - Glu - Ala - Glu -
Asn - OH,and
having a molecular weight of 3,108 daltons. The lyophilized preparation
contains 1.6 mg
synthetic thymosin-a, 50 mg mannitol, and sodium phosphate buffer to adjust
the pH to 6.8.
Ribavirin
[0643] Ribavirin, 1-(3-D-ribofuranosyl-LH-1,2,4-triazole-3-carboxamide, is a
nucleoside analog available from ICN Pharmaceuticals, Inc., Costa Mesa,
Calif., and is
described in the Merck Index, compound No. 8199, Eleventh Edition. Its
manufacture and
formulation is described in U.S. Pat. No. 4,211,771. The embodiments also
contemplate use
of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830). The
ribavirin may be
administered orally in capsule or tablet form. Of course, other types of
administration of
ribavirin, as they become available are contemplated, such as by nasal spray,
transdermally,
by suppository, by sustained release dosage form, etc. Any form of
administration will work
so long as the proper dosages are delivered without destroying the active
ingredient.
[0644] Ribavirin is generally administered in an amount ranging from about
400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700
to about
900 mg per day. In some embodiments, ribavirin is administered throughout the
entire
course of NS3 inhibitor therapy.

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CA 02560897 2007-08-08
Levovirin
[0645] Levovirin is the L-enantiomer of ribavirin, and exhibits the property
of enhancing a Thl immune response over a Th2 immune response. Levovirin is
manufactured by ICN Pharmaceuticals.
[0646] Levovirin has the following structure:
0
II N \~

OH
HO OH

Viramidine
[06471 Viramidine is a 3-carboxamidine derivative of ribavirin, and acts as a
prodrug of ribavirin. It is efficiently converted to ribavirin by adenosine
deaminases.
[0648] Viramidine has the following structure:

NH
N
H2N )
N--
N
HO

HO OH
Nucleoside Analogs
[0649] Nucleoside analogs that are suitable for use in a subject combination
therapy include, but are not limited to, ribavirin, levovirin, viramidine,
isatoribine, an L-
ribofuranosyl nucleoside as disclosed in U.S. Patent No. 5,559,101 and
encompassed by
Formula I of U.S. Patent No. 5,559,101 (e.g., 1-0-L-ribofuranosyluracil, 1-0-L-

ribofuranosyl-5-fluorouracil, 1-P-L-ribofuranosylcytosine, 9-5-L-
ribofuranosyladenine, 9-
(3-L-ribofuranosylhypoxanthine, 9-0-L-ribofuranosylguanine, 9-0-L-
ribofuranosyl-6-
thioguanine, 2-amino-a-L-ribofuranl[1',2':4,5]oxazoline, 02,02-anhydro-l-a-L-
ribofuranosyluracil, 1-a-L-ribofuranosyluracil, 1-(2,3,5-tri-O-benzoyl-a-
ribofuranosyl)-4-
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CA 02560897 2007-08-08

thiouracil, I-a-L-ribofuranosylcytosine, 1-a-L-ribofuranosyl-4-thiouracil, 1-a-
L-
ribofuranosyl-5-fluorouracil, 2-amino-(3-L-arabinofurano[ 1',2'
:4,5]oxazoline, 02,02-
anhydro-(3-L-arabinofuranosyluracil, 2'-deoxy-(3-L-uridine, 3'5'-Di-O-benzoyl-
2'deoxy-4-
thio (3-L-uridine, 2'-deoxy-(3-L-cytidine, 2'-deoxy-(3-L-4-thiouridine, 2'-
deoxy-(3-L-
thymidine, 2'-deoxy-p-L-5-fluorouridine, 2',3'-dideoxy-f -L-uridine, 2'-deoxy-
(3-L-5-
fluorouridine, and 2'-deoxy-(3-L-inosine); a compound as disclosed in U.S.
Patent No.
6,423,695 and encompassed by Formula I of U.S. Patent No. 6,423,695; a
compound as
disclosed in U.S. Patent Publication No. 2002/0058635, and encompassed by
Formula I of
U.S. Patent Publication No. 2002/0058635; a nucleoside analog as disclosed in
WO
01/90121 A2 (Idenix); a nucleoside analog as disclosed in WO 02/069903 A2
(Biocryst
Pharmaceuticals Inc.); a nucleoside analog as disclosed in WO 02/057287 A2 or
WO
02/057425 A2 (both Merck/Isis); and the like.

TNF Antagonists
[0650] In some embodiments, a subject method comprises administering an
effective amount of a NS3 inhibitor and an effective amount of a tumor
necrosis factor-a
(TNF-(x) antagonist. Suitable TNF-a antagonists for use herein include agents
that
decrease the level of TNF-a synthesis, agents that block or inhibit the
binding of TNF-a to
a TNF-a receptor (TNFR), and agents that block or inhibit TNFR-mediated signal
transduction. Unless otherwise expressly stated, every reference to a "TNF-a
antagonist"
or "TNF antagonist" herein will be understood to mean a TNF-a antagonist other
than
pirfenidone or a pirfenidone analog.
[0651] As used herein, the terms "TNF receptor polypeptide" and "TNFR
polypeptide" refer to polypeptides derived from TNFR (from any species) which
are
capable of binding TNF. Two distinct cell-surface TNFRs have described: Type
II TNFR
(or p75 TNFR or TNFRII) and Type I TNFR (or p55 TNFR or TNFRI). The mature
full-
length human p75 TNFR is a glycoprotein having a molecular weight of about 75-
80
kilodaltons (kD). The mature full-length human p55 TNFR is a glycoprotein
having a
molecular weight of about 55-60 kD. Exemplary TNFR polypeptides are derived
from
TNFR Type I and/or TNFR type II. Soluble TNFR includes p75 TNFR polypeptide;
fusions of p75 TNFR with heterologous fusion partners, e.g., the Fc portion of
an
immunoglobulin.

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CA 02560897 2007-08-08

[0652] TNFR polypeptide may be an intact TNFR or a suitable fragment of
TNFR. U.S. Pat. No. 5,605,690 provides examples of TNFR polypeptides,
including
soluble TNFR polypeptides, appropriate for use in the present embodiments. In
many
embodiments, the TNFR polypeptide comprises an extracellular domain of TNFR.
In some
embodiments, the TNFR polypeptide is a fusion polypeptide comprising an
extracellular
domain of TNFR linked to a constant domain of an immunoglobulin molecule. In
other
embodiments, the TNFR polypeptide is a fusion polypeptide comprising an
extracellular
domain of the p75 TNFR linked to a constant domain of an IgGI molecule. In
some
embodiments, when administration to humans is contemplated, an Ig used for
fusion
proteins is human, e.g., human IgGi.
[0653] Monovalent and multivalent forms of TNFR polypeptides may be
used in the present embodiments. Multivalent forms of TNFR polypeptides
possess more
than one TNF binding site. In some embodiments, the TNFR is a bivalent, or
dimeric, form
of TNFR. For example, as described in U.S. Pat. No. 5,605,690 and in Mohler et
al., 1993,
J. Immunol., 151:1548-1561, a chimeric antibody polypeptide with TNFR
extracellular
domains substituted for the variable domains of either or both of the
immunoglobulin heavy
or light chains would provide a TNFR polypeptide for the present embodiments.
Generally,
when such a chimeric TNFR:antibody polypeptide is produced by cells, it forms
a bivalent
molecule through disulfide linkages between the immunoglobulin domains. Such a
chimeric TNFR:antibody polypeptide is referred to as TNFR:Fc.
[0654] In one embodiment, a subject method involves administration of an
effective amount of the soluble TNFR ENBREL . ENBREL is a dimeric fusion
protein
consisting of the extracellular ligand-binding portion of the human 75
kilodalton (p75)
TNFR linked to the Fc portion of human IgG1. The Fc component of ENBREL
contains
the CH2 domain, the CH3 domain and hinge region, but not the CH 1 domain of
IgG 1.
ENBREL is produced in a Chinese hamster ovary (CHO) mammalian cell expression
system. It consists of 934 amino acids and has an apparent molecular weight of
approximately 150 kilodaltons. Smith et al. (1990) Science 248:1019-1023;
Mohler et al.
(1993) J. Immunol. 151:1548-1561; U.S. Pat. No. 5,395,760; and U.S. Pat. No.
5,605,690.
[0655] Also suitable for use are monoclonal antibodies that bind TNF-a.
Monoclonal antibodies include "humanized" mouse monoclonal antibodies;
chimeric
antibodies; monoclonal antibodies that are at least about 80%, at least about
90%, at least
about 95%, or 100% human in amino acid sequence; and the like. See, e.g., WO
90/10077;
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CA 02560897 2007-08-08

WO 90/04036; and WO 92/02190. Suitable monoclonal antibodies include antibody
fragments, such as Fv, F(ab')2 and Fab; synthetic antibodies; artificial
antibodies; phage
display antibodies; and the like.
[0656] Examples of suitable monoclonal antibodies include Infliximab
(REMICADE , Centocor); and Adalimumab (HUMIRATM, Abbott). REMICADE is a
chimeric monoclonal anti-TNF-cs antibody that includes about 25% mouse amino
acid
sequence and about 75% human amino acid sequence. REMICADE comprises a
variable
region of a mouse monoclonal anti-TNF-a antibody fused to the constant region
of a
human IgG 1. Elliott et al. (1993) Arthritis Rheum. 36:1681-1690; Elliott et
at. (1994)
Lancet 344:1105-1110; Baert et al. (1999) Gastroenterology 116:22-28. HUMIRATM
is a
human, full-length IgGI monoclonal antibody that was identified using phage
display
technology. Piascik (2003) J. Am. Pharm. Assoc. 43:327-328.
[0657] Also included in the term "TNF antagonist," and therefore suitable for
use in a subject method, are stress-activated protein kinase (SAPK)
inhibitors. SAPK
inhibitors are known in the art, and include, but are not limited to 2-alkyl
imidazoles
disclosed in U.S. Patent No. 6,548,520; 1,4,5-substituted imidazole compounds
disclosed in
U.S. Patent No. 6,489,325; 1,4,5-substituted imidazole compounds disclosed in
U.S. Patent
No. 6,569,871; heteroaryl aminophenyl ketone compounds disclosed in Published
U.S.
Patent Application No. 2003/0073832; pyridyl imidazole compounds disclosed in
U.S.
Patent No. 6,288,089; and heteroaryl aminobenzophenones disclosed in U.S.
Patent No.
6,432,962. Also of interest are compounds disclosed in U.S. Patent Application
Publication No. 2003/0149041; and U.S. Patent No. 6,214,854. A stress-
activated protein
kinase is a member of a family of mitogen-activated protein kinases which are
activated in
response to stress stimuli. SAPK include, but are not limited to, p38 (Lee et
al. (1994)
Nature 372:739) and c-jun N-terminal kinase (JNK).
[0658] Methods to assess TNF antagonist activity are known in the art and
exemplified herein. For example, TNF antagonist activity may be assessed with
a cell-based
competitive binding assay. In such an assay, radiolabeled TNF is mixed with
serially
diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions
of the
suspension are centrifuged to separate free and bound TNF and the amount of
radioactivity
in the free and bound fractions determined. TNF antagonist activity is
assessed by
inhibition of TNF binding to the cells in the presence of the TNF antagonist.

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WO 2005/095403 PCT/US2005/010494
[
s"`another"examp
le TNF antagonists may be analyzed for the ability to
neutralize TNF activity in vitro in a bioassay using cells susceptible to the
cytotoxic activity
of TNF as target cells. In such an assay, target cells, cultured with TNF, are
treated with
varying amounts of TNF antagonist and subsequently are examined for cytolysis.
TNF
antagonist activity is assessed by a decrease in TNF-induced target cell
cytolysis in the
presence of the TNF antagonist.

NS5B Inhibitors

[0660] Some embodiments provides a method comprising administering an
effective amount of a subject NS3 inhibitor and an effective amount of an HCV
non-
structural protein-5 (NS5; RNA-dependent RNA polymerase) inhibitor to an HCV
patient
in need thereof. Suitable NS5B inhibitors include, but are not limited to, a
compound as
disclosed in U.S. Patent No. 6,479,508 (Boehringer-Ingelheim); a compound as
disclosed in
any of International Patent Application Nos. PCT/CA02/01127, PCT/CA02/01128,
and
PCT/CA02/01129, all filed on July 18, 2002 by Boehringer Ingelheim; a compound
as
disclosed in U.S. Patent No. 6,440,985 (ViroPharma); a compound as disclosed
in WO
01/47883, e.g., JTK-003 (Japan Tobacco); a dinucleotide analog as disclosed in
Zhong et
al. (2003) Anthnicrob. Agents Chernother. 47:2674-2681; a benzothiadiazine
compound as
disclosed in Dhanak et al. (2002) J. Biol Chein. 277(41):38322-7; an NS5B
inhibitor as
disclosed in WO 02/100846 Al or WO 02/100851 A2 (both Shire); an NS5B
inhibitor as
disclosed in WO 01/85172 Al or WO 02/098424 Al (both Glaxo SmithKline); an
NS5B
inhibitor as disclosed in WO 00/06529 or WO 02/06246 Al (both Merck); an NS5B
inhibitor as disclosed in WO 03/000254 (Japan Tobacco); an NS5B inhibitor as
disclosed
in EP 1 256,628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan
Tobacco); and
the like.
[0661] Of particular interest in many embodiments are NS5 inhibitors that are
specific NS5 inhibitors, e.g., NS5 inhibitors that inhibit NS5 RNA-dependent
RNA
polymerase and that lack significant inhibitory effects toward other RNA
dependent RNA
polymerases and toward DNA dependent RNA polymerases.

Additional antiviral agents
[0662] Additional antiviral therapeutic agents that may be administered in
combination with a subject NS3 inhibitor compound include, but are not limited
to,
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WO 2005/095403 PCT/US2005/010494
iiTibitorg" of iriosirie" 'inohdphosphate dehydrogenase (IMPDH); ribozymes
that are
complementary to viral nucleotide sequences; antisense RNA inhibitors; and the
like.
IMPDH Inhibitors

[0663] IMPDH inhibitors that are suitable for use in a subject combination
therapy include, but are not limited to, VX-497 ((S)-N-3-[3-(3-methoxy-4-
oxazol-5-yl-
phenyl)-ureido]-benzyl-carbainic acid tetrahydrofuran-3-yl-ester); Vertex
Pharmaceuticals;
see, e.g., Markland et al. (2000) Antimicrob. Agents Chemother. 44:859-866);
ribavirin;
levovirin (Ribapharm; see, e.g., Watson (2002) Curr Opin Investig Drugs
3(5):680-3);
viramidine (Ribapharm); and the like.

Ribozyme and Antisense

[0664] Ribozyme and antisense antiviral agents that are suitable for use in a
subject combination therapy include, but are not limited to, ISIS 14803 (ISIS
Pharmaceuticals/Elan Corporation; see, e.g., Witherell (2001) Curr Opin
Investig Drugs.
2(11):1523-9); HeptazymeTM; and the like.

[0665] In some embodiments, an additional antiviral agent is administered
during the entire course of NS3 inhibitor compound treatment. In other
embodiments, an
additional antiviral agent is administered for a period of time that is
overlapping with that
of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent
treatment may
begin before the NS3 inhibitor compound treatment begins and end before the
NS3
inhibitor compound treatment ends; the additional antiviral agent treatment
may begin after
the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor
compound
treatment ends; the additional antiviral agent treatment may begin after the
NS3 inhibitor
compound treatment begins and end before the NS3 inhibitor compound treatment
ends; or
the additional antiviral agent treatment may begin before the NS3 inhibitor
compound
treatment begins and end after the NS3 inhibitor compound treatment ends.

Dosages, Formulations, and Routes of Administration

[0666] In the subject methods, the active agent(s) (e.g., compound of formula
I,
and optionally one or more additional antiviral agents) may be administered to
the host
using any convenient means capable of resulting in the desired therapeutic
effect. Thus, the
agent may be incorporated into a variety of formulations for therapeutic
administration.
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WO 2005/095403 PCT/US2005/010494
More parricular`fy'; tle`" `agerifs "of the present embodiments may be
formulated into
pharmaceutical compositions by combination with appropriate, pharmaceutically
acceptable
carriers or diluents, and maybe formulated into preparations in solid, semi-
solid, liquid or
gaseous forms, such as tablets, capsules, powders, granules, ointments,
solutions,
suppositories, injections, inhalants and aerosols.

Formulations
[0667] The above-discussed active agent(s) may be formulated using well-
known reagents and methods. Compositions are provided in formulation with a
pharmaceutically acceptable excipient(s). A wide variety of pharmaceutically
acceptable
excipients are known in the art and need not be discussed in detail herein.
Pharmaceutically acceptable excipients have been amply described in a variety
of
publications, including, for example, A. Gennaro (2000) "Remington: The
Science and
Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins;
Pharmaceutical
Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7th
ed.,
Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients
(2000) A.H.
Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.

[0668] The pharmaceutically acceptable excipients, such as vehicles,
adjuvants,
carriers or diluents, are readily available to the public. Moreover,
pharmaceutically
acceptable auxiliary substances, such as pH adjusting and buffering agents,
tonicity
adjusting agents, stabilizers, wetting agents and the like, are readily
available to the public.

[0669] In some embodiments, an agent is formulated in an aqueous buffer.
Suitable aqueous buffers include, but are not limited to, acetate, succinate,
citrate, and
phosphate buffers varying in strengths from 5mM to 100mM. In some embodiments,
the
aqueous buffer includes reagents that provide for an isotonic solution. Such
reagents
include, but are not limited to, sodium chloride; and sugars e.g., mannitol,
dextrose,
sucrose, and the like. In some embodiments, the aqueous buffer further
includes a non-
ionic surfactant such as polysorbate 20 or 80. Optionally the formulations may
further
include a preservative. Suitable preservatives include, but are not limited
to, a benzyl
alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many
cases, the
formulation is stored at about 4 C. Formulations may also be lyophilized, in
which case
they generally include cryoprotectants such as sucrose, trehalose, lactose,
maltose,
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
`f"mannito;an``"ll~e`lllk' ' Iftyopl it zed formulations may be stored over
extended periods of
time, even at ambient temperatures.

[0670] As such, administration of the agents may be achieved in various ways,
including oral, buccal, rectal, parenteral, intraperitoneal, intradermal,
subcutaneous,
intramuscular, transdennal, intratracheal,etc., administration. In many
embodiments,
administration is by bolus injection, e.g., subcutaneous bolus injection,
intramuscular bolus
injection, and the like.

[0671] The pharmaceutical compositions of the present embodiments may be
administered orally, parenterally or via an implanted reservoir. Oral
administration or
administration by injection are preferred.

[0672] Subcutaneous administration of a pharmaceutical composition of the
present embodiments is accomplished using standard methods and devices, e.g.,
needle and
syringe, a subcutaneous injection port delivery system, and the like. See,
e.g., U.S. Patent
Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328. A combination
of a
subcutaneous injection port and a device for administration of a
pharmaceutical
composition of the embodiments to a patient through the port is referred to
herein as "a
subcutaneous injection port delivery system." In many embodiments,
subcutaneous
administration is achieved by bolus delivery by needle and syringe.

[0673] In pharmaceutical dosage forms, the agents may be administered in the
form of their pharmaceutically acceptable salts, or they may also be used
alone or in
appropriate association, as well as in combination, with other
pharmaceutically active
compounds. The following methods and excipients are merely exemplary and are
in no way
limiting.

[0674] For oral preparations, the agents may be used alone or in combination
with appropriate additives to make tablets, powders, granules or capsules, for
example, with
conventional additives, such as lactose, mannitol, corn starch or potato
starch; with binders,
such as crystalline cellulose, cellulose derivatives, acacia, corn starch or
gelatins; with
disintegrators, such as corn starch, potato starch or sodium
carboxymethylcellulose; with
lubricants, such as talc or magnesium stearate; and if desired, with diluents,
buffering
agents, moistening agents, preservatives and flavoring agents.

[0675] The agents may be formulated into preparations for injection by
dissolving, suspending or emulsifying them in an aqueous or nonaqueous
solvent, such as
vegetable or other similar oils, synthetic aliphatic acid glycerides, esters
of higher aliphatic
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WO 2005/095403 PCT/US2005/010494
.` acids or propylene"glycol'; and if desired, with conventional additives
such as solubilizers,
isotonic agents, suspending agents, emulsifying agents, stabilizers and
preservatives.

[0676] Furthermore, the agents may be made into suppositories by mixing with
a variety of bases such as emulsifying bases or water-soluble bases. The
compounds of the
present embodiments may be administered rectally via a suppository. The
suppository may
include vehicles such as cocoa butter, carbowaxes and polyethylene glycols,
which melt at
body temperature, yet are solidified at room temperature.

[0677] Unit dosage forms for oral or rectal administration such as syrups,
elixirs, and suspensions may be provided wherein each dosage unit, for
example,
teaspoonful, tablespoonful, tablet or suppository, contains a predetermined
amount of the
composition containing one or more inhibitors. Similarly, unit dosage forms
for injection
or intravenous administration may comprise the inhibitor(s) in a composition
as a solution
in sterile water, normal saline or another pharmaceutically acceptable
carrier.

[0678] The term "unit dosage form," as used herein, refers to physically
discrete
units suitable as unitary dosages for human and animal subjects, each unit
containing a
predetermined quantity of compounds of the embodiments calculated in an amount
sufficient to produce the desired effect in association with a
pharmaceutically acceptable
diluent, carrier or vehicle. The specifications for the novel unit dosage
forms of the present
embodiments depend on the particular compound employed and the effect to be
achieved,
and the pharmacodynamics associated with each compound in the host.

[0679] The pharmaceutically acceptable excipients, such as vehicles,
adjuvants,
carriers or diluents, are readily available to the public. Moreover,
pharmaceutically
acceptable auxiliary substances, such as pH adjusting and buffering agents,
tonicity
adjusting agents, stabilizers, wetting agents and the like, are readily
available to the public.
Other antiviral agents

[0680] As discussed above, a subject method will in some embodiments be
carried out by administering an NS3 inhibitor that is a compound of formulas I-
XIX, and
optionally one or more additional antiviral agent(s).
[0681] In some embodiments, the method further includes administration of one
or more interferon receptor agonist(s). Interferon receptor agonists are
described above.
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[x`6$2] 1 'Bt ter embodiments, the method further includes administration of
pirfenidone or a pirfenidone analog. Pirfenidone and pirfenidone analogs are
described
above.

[0683] Additional antiviral agents that are suitable for use in combination
therapy include, but are not limited to, nucleotide and nucleoside analogs.
Non-limiting
examples include azidothyinidine (AZT) (zidovudine), and analogs and
derivatives thereof,
2',3'-dideoxyinosine (DDI) (didanosine), and analogs and derivatives thereof;
2',3'-
dideoxycytidine (DDC) (dideoxycytidine), and analogs and derivatives thereof;
2'3,'-
didehydro-2',3'-dideoxythymidine (D4T) (stavudine), and analogs and
derivatives thereof;
combivir; abacavir; adefovir dipoxil; cidofovir; ribavirin; ribavirin analogs;
and the like.

[0684] In some embodiments, the method further includes administration of
ribavirin. Ribavirin, 1-13-D-ribofiuanosyl-1H-1,2,4-triazole-3-carboxamide,
available from
ICN Pharmaceuticals, Inc., Costa Mesa, Calif., is described in the Merck
Index, compound
No. 8199, Eleventh Edition. Its manufacture and formulation is described in
U.S. Pat. No.
4,211,771. The embodiments also contemplate use of derivatives of ribavirin
(see, e.g.,
U.S. Pat. No. 6,277,830). The ribavirin may be administered orally in capsule
or tablet
form, or in the same or different administration form and in the same or
different route as
the interferon receptor agonist. Of course, other types of administration of
both
medicaments, as they become available are contemplated, such as by nasal
spray,
transdermally, intravenously, by suppository, by sustained release dosage
form, etc. Any
form of administration will work so long as the proper dosages are delivered
without
destroying the active ingredient.

[0685] In some embodiments, an additional antiviral agent is administered
during the entire course of NS3 inhibitor compound treatment. In other
embodiments, an
additional antiviral agent is administered for a period of time that is
overlapping with that
of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent
treatment may
begin before the NS3 inhibitor compound treatment begins and end before the
NS3
inhibitor compound treatment ends; the additional antiviral agent treatment
may begin after
the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor
compound
treatment ends; the additional antiviral agent treatment may begin after the
NS3 inhibitor
compound treatment begins and end before the NS3 inhibitor compound treatment
ends; or
the additional antiviral agent treatment may begin before the NS3 inhibitor
compound
treatment begins and end after the NS3 inhibitor compound treatment ends.

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CA 02560897 2007-09-18

[0686] The NS3 inhibitor compounds of the embodiments are suitable for use in
formulations that require good solubility in water. For example, the compounds
of the embodiments may
be used in formulations that are free of sugar alcohols and polyols, such as
trihydric or higher sugar
alcohols, e.g., glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol,
and mannitol, and free of other
alcohols, such as propylene glycol and poly (ethylene glycol) (PEG), or other
agent used to compensate
for inadequate solubility in water. In one aspect, the embodiments provide the
subject NS3 inhibitor
compound in a capsule, tablet or caplet formulation, where the capsule, tablet
or caplet formulation
provides an adequate bioavailability because of the superior water solubility
of the compound. In some
embodiments, the solubility of the subject compound permits the administration
of dosages equal to or
greater than I mg of drug compound/kg of patient body weight.

Methods of Treatment
[0686a] The compounds described herein or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition containing either entity may be used
for the treatment of an
individual in need thereof as described herein.
Monotheranies
[0687] The NS3 inhibitor compound of the embodiments may be used in acute or
chronic
therapy for HCV disease. In many embodiments, the NS3 inhibitor compound is
administered for a
period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or
about 2 weeks to about 3
weeks, or about 3 weeks to about 4 weeks, or about I month to about 2 months,
or about 3 months to
about 4 months, or about 4 months to about 6 months, or about 6 months to
about 8 months, or about 8
months to about 12 months, or at least one year, and may be administered over
longer periods of time.
The NS3 inhibitor compound may be administered 5 times per day, 4 times per
day, tid, bid, qd, qod,
biw, tiw, qw, qow, three times per month, or once monthly. In other
embodiments, the NS3 inhibitor
compound is administered as a continuous infusion.
[0688] In many embodiments, an NS3 inhibitor compound of the embodiments is
administered orally.
[0689] In connection with the above-described methods for the treatment of HCV
disease
in a patient, an NS3 inhibitor compound of the embodiments may be administered
to the patient at a
dosage from about 0.01 mg to about 100 mg/kg patient bodyweight per day, in 1
to 5 divided doses per
day. In some embodiments, the NS3 inhibitor compound is administered at a
dosage of about 0.5 mg to
about 75 mg/kg patient bodyweight per day, in I to 5 divided doses per day.

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CA 02560897 2006-09-20
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The amount of active ingredient that may be combined with carrier
materials to produce a dosage form may vary depending on the host to be
treated and the
particular mode of administration. A typical pharmaceutical preparation may
contain from
about 5% to about 95% active ingredient (w/w). In other embodiments, the
phanmaceutical
preparation may contain from about 20% to about 80% active ingredient.

[0691] Those of skill will readily appreciate that dose levels may vary as a
function of the specific NS3 inhibitor compound, the severity of the symptoms
and the
susceptibility of the subject to side effects. Preferred dosages for a given
NS3 inhibitor
compound are readily determinable by those of skill in the art by a variety of
means. A
preferred means is to measure the physiological potency of a given interferon
receptor
agonist.

[0692] In many embodiments, multiple doses of NS3 inhibitor compound are
administered. For example, an NS3 inhibitor compound is administered once per
month,
twice per month, three times per month, every other week (qow), once per week
(qw), twice
per week (biw), three times per week (tiw), four times per week, five times
per week, six
times per week, every other day (qod), daily (qd), twice a day (qid), or three
times a day
(tid), over a period of time ranging from about one day to about one week,
from about two
weeks to about four weeks, from about one month to about two months, from
about two
months to about four months, from about four months to about six months, from
about six
months to about eight months, from about eight months to about 1 year, from
about 1 year
to about 2 years, or from about 2 years to about 4 years, or more.

Combination therapies with ribavirin

[0693] In some embodiments, the methods provide for combination therapy
comprising administering an NS3 inhibitor compound as described above, and an
effective
amount of ribavirin. Ribavirin may be administered in dosages of about 400 mg,
about 800
mg, about 1000 mg, or about 1200 mg per day.
[0694] One embodiment provides any of the above-described methods modified
to include co-administering to the patient a therapeutically effective amount
of ribavirin for
the duration of the desired course of NS3 inhibitor compound treatment.
[0695] Another embodiment provides any of the above-described methods
modified to include co-administering to the patient about 800 mg to about 1200
mg
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ribavirin orally per day for the duration of the desired course of NS3
inhibitor compound
treatment.
[0696] Another embodiment provides any of the above-described methods
modified to include co-administering to the patient (a) 1000 mg ribavirin
orally per day if
the patient has a body weight less than 75 kg or (b) 1200 mg ribavirin orally
per day if the
patient has a body weight greater than or equal to 75 kg, where the daily
dosage of ribavirin
is optionally divided into to 2 doses for the duration of the desired course
of NS3 inhibitor
compound treatment.

Combination therapies with levovirin
[0697] In some embodiments, the methods provide for combination therapy
comprising administering an NS3 inhibitor compound as described above, and an
effective
amount of levovirin. Levovirin is generally administered in an amount ranging
from about
30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to
about 200
mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from
about
400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700
to about
900 mg per day, or about 10 mg/kg body weight per day. In some embodiments,
levovirin is
administered orally in dosages of about 400, about 800, about 1000, or about
1200 mg per
day for the desired course of NS3 inhibitor compound treatment.

Combination therapies with viramidine
[0698] In some embodiments, the methods provide for combination therapy
comprising administering an NS3 inhibitor compound as described above, and an
effective
amount of viramidine. Viramidine is generally administered in an amount
ranging from
about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125
mg to
about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about
400 mg,
from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or
from about
700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some
embodiments, viramidine is administered orally in dosages of about 800, or
about 1600 mg
per day for the desired course of NS3 inhibitor compound treatment.

Combination therapies with thymosin-a

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[0699] In some embodiments, the methods provide for combination therapy
comprising administering an NS3 inhibitor compound as described above, and an
effective
amount of thymosin-a. Thymosin-a (ZadaxinTM) is generally administered by
subcutaneous
injection. Thymosin-a may be administered tid, bid, qd, qod, biw, tiw, qw,
qow, three times
per month, once monthly, substantially continuously, or continuously for the
desired course
of NS3 inhibitor compound treatment. In many embodiments, thymosin-a is
administered
twice per week for the desired course of NS3 inhibitor compound treatment.
[0700] Effective dosages of thymosin-a range from about 0.5 mg to about 5
mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5
mg, from about
1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg
to about 3.0
mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from
about 4.0
mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In particular
embodiments,
thymosin-a is administered in dosages containing an amount of 1.0 mg or 1.6
mg.
[0701] Thymosin-a may be administered over a period of time ranging from
about one day to about one week, from about two weeks to about four weeks,
from about
one month to about two months, from about two months to about four months,
from about
four months to about six months, from about six months to about eight months,
from about
eight months to about 1 year, from about 1 year to about 2 years, or from
about 2 years to
about 4 years, or more. In one emobidment, thymosin-a is administered for the
desired
course of NS3 inhibitor compound treatment.

Combination therapies with interferon(s)
[0702] In many embodiments, the methods provide for combination therapy
comprising administering an NS3 inhibitor compound as described above, and an
effective
amount of an interferon receptor agonist. In some embodiments, a compound of
formula I
and a Type I or III interferon receptor agonist are co-administered in the
treatment methods
of the embodiments. Type I interferon receptor agonists suitable for use
herein include any
interferon-(x (IFN-a). In certain embodiments, the interferon-a is a PEGylated
interferon-a.
In certain other embodiments, the interferon-a is a consensus interferon, such
as
INFERGEN interferon alfacon-1. In still other embodiments, the interferon-a
is a
monoPEG (30 kD, linear)-ylated consensus interferon.
[0703] Effective dosages of an IFN-a range from about 3 g to about 27 g,
from about 3 MU to about 10 MU, from about 90 gg to about 180 g, or from
about 18 g
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to about 90 g. Effective dosages of Infergen consensus IFN-a include about 3
g, about
6 jig, about 9 g, about 12 g, about 15 jig, about 18 g, about 21 g, about
24 g, about
27 g, or about 30 g, of drug per dose. Effective dosages of IFN-a2a and IFN-
a2b range
from 3 million Units (MU) to 10 MU per dose. Effective dosages of
PEGASYS PEGylated IFN-a2a contain an amount of about 90 g to 270 g, or about
180
g, of drug per dose. Effective dosages of PEG-INTRON PEGylated IFN-a2b contain
an
amount of about 0.5 g to 3.0 g of drug per kg of body weight per dose.
Effective
dosages of PEGylated consensus interferon (PEG-CIFN) contain an amount of
about 18 g
to about 90 g, or from about 27 g to about 60 g, or about 45 g, of CIFN
amino acid
weight per dose of PEG-CIFN. Effective dosages of monoPEG (30 kD, linear)-
ylated
CIFN contain an amount of about 45 gg to about 270 g, or about 60 gg to about
180 g,
or about 90 g to about 120 g, of drug per dose. IFN-a may be administered
daily, every
other day, once a week, three times a week, every other week, three times per
month, once
monthly, substantially continuously or continuously.
[0704] In many embodiments, the Type I or Type III interferon receptor
agonist and/or the Type II interferon receptor agonist is administered for a
period of about 1
day to about 7 days, or about I week to about 2 weeks, or about 2 weeks to
about 3 weeks,
or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or
about 3 months
to about 4 months, or about 4 months to about 6 months, or about 6 months to
about 8
months, or about 8 months to about 12 months, or at least one year, and may be
administered over longer periods of time. Dosage regimens may include tid,
bid, qd, qod,
biw, tiw, qw, qow, three times per month, or monthly administrations. Some
embodiments
provide any of the above-described methods in which the desired dosage of IFN-
a is
administered subcutaneously to the patient by bolus delivery qd, qod, tiw,
biw, qw, qow,
three times per month, or monthly, or is administered subcutaneously to the
patient per day
by substantially continuous or continuous delivery, for the desired treatment
duration.
Other embodiments provide any of the above-described methods in which the
desired
dosage of PEGylated IFN-a (PEG-IFN-a) is administered subcutaneously to the
patient by
bolus delivery qw, qow, three times per month, or monthly for the desired
treatment
duration.
[0705] In other embodiments, an NS3 inhibitor compound and a Type II
interferon receptor agonist are co-administered in the treatment methods of
the
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embodiments. Type II interferon receptor agonists suitable for use herein
include any
interferon-y (IFN-y).
[0706] Effective dosages of IFN-y may range from about 0.5 g/m2 to about
500 g/m2, usually from about 1.5 gg/m2 to 200 g/m2, depending on the size of
the patient.
This activity is based on 106 international units (U) per 50 gg of protein.
IFN-y may be
administered daily, every other day, three times a week, or substantially
continuously or
continuously.
[0707] In specific embodiments of interest, IFN-y is administered to an
individual in a unit dosage form of from about 25 gg to about 500 g, from
about 50 gg to
about 400 g, or from about 100 jig to about 300 g. In particular embodiments
of interest,
the dose is about 200 g IFN-y. In many embodiments of interest, IFN-yl b is
administered.
[0708] Where the dosage is 200 g IFN-y per dose, the amount of IFN-y per
body weight (assuming a range of body weights of from about 45 kg to about 135
kg) is in
the range of from about 4.4 jig IFN-y per kg body weight to about 1.48 g IFN-
y per kg body
weight.
[0709] The body surface area of subject individuals generally ranges from
about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage
ranges from
about 150 g/m2 to about 20 gg/m2. For example, an IFN-y dosage ranges from
about 20
g/m2 to about 30 g/m2, from about 30 g/m2 to about 40 g/m2, from about 40
g/m2 to
about 50 gg/m2, from about 50 g/m2 to about 60 gg/m2, from about 60 g/m2 to
about 70
g/m2, from about 70 g/m2 to about 80 g/m2, from about 80 gg/m2 to about 90
g/m2, from
about 90 g/m2 to about 100 g/m2, from about 100 g/m2 to about 110 gg/m2,
from about
110 gg/m2 to about 120 g/m2, from about 120 gg/m2 to about 130 g/m2, from
about 130
g/m2 to about 140 g/m2, or from about 140 g/m2 to about 150 gg/m2. In some
embodiments, the dosage groups range from about 25 g/m2 to about 100 g/m2.
In other
embodiments, the dosage groups range from about 25 g/m2 to about 50 g/m2.
[0710] In some embodiments, a Type I or a Type III interferon receptor agonist
is administered in a first dosing regimen, followed by a second dosing
regimen. The first
dosing regimen of Type I or a Type III interferon receptor agonist (also
referred to as "the
induction regimen") generally involves administration of a higher dosage of
the Type I or
Type III interferon receptor agonist. For example, in the case of Infergen
consensus IFN-ct
(CIFN), the first dosing regimen comprises administering CIFN at about 9 g,
about 15 g,
about 18 g, or about 27 g. The first dosing regimen may encompass a single
dosing
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event, or at least two or more dosing events. The first dosing regimen of the
Type I or Type
III interferon receptor agonist may be administered daily, every other day,
three times a week,
every other week, three times per month, once monthly, substantially
continuously or
continuously.
[0711] The first dosing regimen of the Type I or Type III interferon receptor
agonist is administered for a first period of time, which time period may be
at least about 4
weeks, at least about 8 weeks, or at least about 12 weeks.
[0712] The second dosing regimen of the Type I or Type III interferon receptor
agonist (also referred to as "the maintenance dose") generally involves
administration of a
lower amount of the Type I or Type III interferon receptor agonist. For
example, in the case
of CIFN, the second dosing regimen comprises administering CIFN at a dose of
at least about
3 g, at least about 9 g, at least about 15 g, or at least about 18 g. The
second dosing
regimen may encompass a single dosing event, or at least two or more dosing
events.
[0713] The second dosing regimen of the Type I or Type III interferon receptor
agonist may be administered daily, every other day, three times a week, every
other week,
three times per month, once monthly, substantially continuously or
continuously.
[0714] In some embodiments, where an "induction"P'maintenance" dosing
regimen of a Type I or a Type III interferon receptor agonist is administered,
a "priming"
dose of a Type II interferon receptor agonist (e.g., IFN-y) is included. In
these embodiments,
IFN-y is administered for a period of time from about 1 day to about 14 days,
from about 2
days to about 10 days, or from about 3 days to about 7 days, before the
beginning of
treatment with the Type I or Type III interferon receptor agonist. This period
of time is
referred to as the "priming" phase.
[0715] In some of these embodiments, the Type II interferon receptor agonist
treatment is continued throughout the entire period of treatment with the Type
I or Type III
interferon receptor agonist. In other embodiments, the Type II interferon
receptor agonist
treatment is discontinued before the end of treatment with the Type I or Type
III interferon
receptor agonist. In these embodiments, the total time of treatment with Type
II interferon
receptor agonist (including the "priming" phase) is from about 2 days to about
30 days, from
about 4 days to about 25 days, from about 8 days to about 20 days, from about
10 days to
about 18 days, or from about 12 days to about 16 days. In still other
embodiments, the
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Type II interferon receptor agonist treatment is discontinued once Type I or a
Type III
interferon receptor agonist treatment begins.
[0716] In other embodiments, the Type I or Type III interferon receptor
agonist is administered in single dosing regimen. For example, in the case of
CIFN, the
dose of CIFN is generally in a range of from about 3 g to about 15 g, or from
about 9 g
to about 15 g. The dose of Type I or a Type III interferon receptor agonist
is generally
administered daily, every other day, three times a week, every other week,
three times per
month, once monthly, or substantially continuously. The dose of the Type I or
Type III
interferon receptor agonist is administered for a period of time, which period
may be, for
example, from at least about 24 weeks to at least about 48 weeks, or longer.
[0717] In some embodiments, where a single dosing regimen of a Type I or a
Type III interferon receptor agonist is administered, a "priming" dose of a
Type II
interferon receptor agonist (e.g., IFN-y) is included. In these embodiments,
IFN-y is
administered for a period of time from about I day to about 14 days, from
about 2 days to
about 10 days, or from about 3 days to about 7 days, before the beginning of
treatment with
the Type I or Type III interferon receptor agonist. This period of time is
referred to as the
"priming" phase. In some of these embodiments, the Type II interferon receptor
agonist
treatment is continued throughout the entire period of treatment with the Type
I or Type III
interferon receptor agonist. In other embodiments, the Type II interferon
receptor agonist
treatment is discontinued before the end of treatment with the Type I or Type
III interferon
receptor agonist. In these embodiments, the total time of treatment with the
Type II
interferon receptor agonist (including the "priming" phase) is from about 2
days to about 30
days, from about 4 days to about 25 days, from about 8 days to about 20 days,
from about
days to about 18 days, or from about 12 days to about 16 days. In still other
embodiments, Type II interferon receptor agonist treatment is discontinued
once Type I or a
Type III interferon receptor agonist treatment begins.
[0718] In additional embodiments, an NS3 inhibitor compound, a Type I or
III interferon receptor agonist, and a Type II interferon receptor agonist are
co-administered
for the desired duration of treatment in the methods of the embodiments. In
some
embodiments, an NS3 inhibitor compound, an interferon-a, and an interferon-y
are co-
administered for the desired duration of treatment in the methods of the
embodiments.
[0719] Some embodiments provide methods using an amount of a Type I or
Type III interferon receptor agonist, a Type II interferon receptor agonist,
and an NS3
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inhibitor compound, effective for the treatment of HCV infection in a patient.
In some
embodiments, the embodiments provide methods using an effective amount of an
IFN-a,
IFN-y, and an NS3 inhibitor compound in the treatment of HCV infection in a
patient. One
embodiment provides a method using an effective amount of a consensus IFN-a,
IFN-y and
an NS3 inhibitor compound in the treatment of HCV infection in a patient.
[0720] In general, an effective amount of a consensus interferon (CIFN) and
IFN-y suitable for use in the methods of the embodiments is provided by a
dosage ratio of 1
tg CIFN: 10 g IFN-y, where both CIFN and IFN-y are unPEGylated and
unglycosylated
species.
[0721] One embodiment provides any of the above-described methods
modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in
the
treatment of HCV infection in a patient comprising administering to the
patient a dosage of
INFERGEN containing an amount of about I g to about 30 g, of drug per dose
of
INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month,
once
monthly, or per day substantially continuously or continuously, in combination
with a
dosage of IFN-y containing an amount of about 10 jig to about 300 g of drug
per dose of
IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or
per day substantially continuously or continuously, for the desired duration
of treatment
with an NS3 inhibitor compound.
[0722] Another embodiment provides any of the above-described methods
modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in
the
treatment of virus infection in a patient comprising administering to the
patient a dosage of
INFERGEN containing an amount of about 1 gg to about 9 g, of drug per dose
of
INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month,
once
monthly, or per day substantially continuously or continuously, in combination
with a
dosage of IFN-y containing an amount of about 10 gg to about 100 g of drug
per dose of
IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or
per day substantially continuously or continuously, for the desired duration
of treatment
with an NS3 inhibitor compound.
[0723] Another embodiment provides any of the above-described methods
modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in
the
treatment of virus infection in a patient comprising administering to the
patient a dosage of
INFERGEN containing an amount of about 1 gg of drug per dose of INFERGEN ,
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subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or per
day substantially continuously or continuously, in combination with a dosage
of IFN-y
containing an amount of about 10 .tg to about 50 g of drug per dose of IFN-y,
subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or per
day substantially continuously or continuously, for the desired duration of
treatment with an
NS3 inhibitor compound.
[0724] Another embodiment provides any of the above-described methods
modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in
the
treatment of a virus infection in a patient comprising administering to the
patient a dosage
of INFERGEN containing an amount of about 9 g of drug per dose of INFERGEN ,
subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or per
day substantially continuously or continuously, in combination with a dosage
of IFN-y
containing an amount of about 90 g to about 100 g of drug per dose of IFN-y,
subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or per
day substantially continuously or continuously, for the desired duration of
treatment with an
NS3 inhibitor compound.
[0725] Another embodiment provides any of the above-described methods
modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in
the
treatment of a virus infection in a patient comprising administering to the
patient a dosage
of INFERGEN containing an amount of about 30 gg of drug per dose of INFERGEN
,
subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or per
day substantially continuously or continuously, in combination with a dosage
of IFN-y
containing an amount of about 200 g to about 300 g of drug per dose of IFN-
y,
subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or per
day substantially continuously or continuously, for the desired duration of
treatment with an
NS3 inhibitor compound.
[0726] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEGylated consensus IFN-a and IFN-y in
the
treatment of a virus infection in a patient comprising administering to the
patient a dosage
of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 4 g to
about
60 gg of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow,
three
times per month, or monthly, in combination with a total weekly dosage of IFN-
y
containing an amount of about 30 g to about 1,000 gg of drug per week in
divided doses
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administered subcutaneously qd, qod, tiw, biw, or administered substantially
continuously
or continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0727] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEGylated consensus IFN-a and IFN-y in
the
treatment of a virus infection in a patient comprising administering to the
patient a dosage
of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 18 g to
about
24 g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow,
three
times per month, or monthly, in combination with a total weekly dosage of IFN-
y
containing an amount of about 100 tg to about 300 tg of drug per week in
divided doses
administered subcutaneously qd, qod, tiw, biw, or substantially continuously
or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0728] In general, an effective amount of IFN-a 2a or 2b or 2c and IFN-y
suitable for use in the methods of the embodiments is provided by a dosage
ratio of 1
million Units (MU) IFN-a 2a or 2b or 2c : 30 g ITN-y, where both IFN-a 2a or
2b or 2c
and IFN-y are unPEGylated and unglycosylated species.
[0729] Another embodiment provides any of the above-described methods
modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the
treatment of a
virus infection in a patient comprising administering to the patient a dosage
of IFN-a 2a, 2b
or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of
IFN-a 2a,
2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially
continuously or
continuously, in combination with a dosage of IFN-y containing an amount of
about 30 g
to about 600 gg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw,
or per day
substantially continuously or continuously, for the desired duration of
treatment with an
NS3 inhibitor compound.
[0730] Another embodiment provides any of the above-described methods
modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the
treatment of a
virus infection in a patient comprising administering to the patient a dosage
of IFN-a 2a, 2b
or 2c containing an amount of about 3 MU of drug per dose of FN-(x 2a, 2b or
2c
subcutaneously qd, qod, tiw, biw, or per day substantially continuously or
continuously, in
combination with a dosage of IFN-y containing an amount of about 100 g of
drug per dose
of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.

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[0731] Another embodiment provides any of the above-described methods
modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the
treatment of a
virus infection in a patient comprising administering to the patient a dosage
of IFN-a 2a, 2b
or 2c containing an amount of about 10 MU of drug per dose of IFN-a 2a, 2b or
2c
subcutaneously qd, qod, tiw, biw, or per day substantially continuously or
continuously, in
combination with a dosage of IFN-y containing an amount of about 300 g of
drug per dose
of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0732] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEGASYS PEGylated IFN-a2a and IFN-y in
the
treatment of a virus infection in a patient comprising administering to the
patient a dosage
of PEGASYS containing an amount of about 90 g to about 360 g, of drug per
dose of
PEGASYS , subcutaneously qw, qow, three times per month, or monthly, in
combination
with a total weekly dosage of IFN-y containing an amount of about 30 gg to
about 1,000
g, of drug per week administered in divided doses subcutaneously qd, qod, tiw,
or biw, or
administered substantially continuously or continuously, for the desired
duration of
treatment with an NS3 inhibitor compound.
[0733] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEGASYS PEGylated IFN-a2a and IFN-y in
the
treatment of a virus infection in a patient comprising administering to the
patient a dosage
of PEGASYS containing an amount of about 180 g of drug per dose of PEGASYS ,
subcutaneously qw, qow, three times per month, or monthly, in combination with
a total
weekly dosage of IFN-y containing an amount of about 100 g to about 300 g,
of drug per
week administered in divided doses subcutaneously qd, qod, tiw, or biw, or
administered
substantially continuously or continuously, for the desired duration of
treatment with an
NS3 inhibitor compound.
[0734] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and IFN-y
in
the treatment of a virus infection in a patient comprising administering to
the patient a
dosage of PEG-INTRON containing an amount of about 0.75 gg to about 3.0 g of
drug
per kilogram of body weight per dose of PEG-INTRON , subcutaneously qw, qow,
three
times per month, or monthly, in combination with a total weekly dosage of IFN-
y
containing an amount of about 30 g to about 1,000 gg of drug per week
administered in
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divided doses subcutaneously qd, qod, tiw, or biw, or administered
substantially
continuously or continuously, for the desired duration of treatment with an
NS3 inhibitor
compound.
[0735] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and IFN-y
in
the treatment of a virus infection in a patient comprising administering to
the patient a
dosage of PEG-INTRON containing an amount of about 1.5 g of drug per
kilogram of
body weight per dose of PEG-INTRON , subcutaneously qw, qow, three times per
month,
or monthly, in combination with a total weekly dosage of IFN-y containing an
amount of
about 100 tg to about 300 gg of drug per week administered in divided doses
subcutaneously qd, qod, tiw, or biw, or administered substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0736] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 g INFERGEN consensus IFN-a
administered subcutaneously qd or tiw, and ribavirin administered orally qd,
where the
duration of therapy is 48 weeks. In this embodiment, ribavirin is administered
in an amount
of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for
individuals weighing
75 kg or more.
[0737] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 g INFERGEN consensus IFN-a
administered subcutaneously qd or tiw; 50 gg Actimmune human IFN-71b
administered
subcutaneously tiw; and ribavirin administered orally qd, where the duration
of therapy is
48 weeks. In this embodiment, ribavirin is administered in an amount of 1000
mg for
individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75
kg or more.
[0738] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 tg INFERGEN consensus IFN-a
administered subcutaneously qd or tiw; 100 g Actimmune human IFN-71b
administered
subcutaneously tiw; and ribavirin administered orally qd, where the duration
of therapy is
48 weeks. In this embodiment, ribavirin is administered in an amount of 1000
mg for
individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75
kg or more.
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[0739] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a
administered subcutaneously qd or tiw; and 50 g Actimmune human IFN-ylb
administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0740] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a
administered subcutaneously qd or tiw; and 100 gg Actimmune human IFN-ylb
administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0741] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a
administered subcutaneously qd or tiw; 25 g Actimmune human IFN-ylb
administered
subcutaneously tiw; and ribavirin administered orally qd, where the duration
of therapy is 48
weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg
for
individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75
kg or more.
[0742] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a
administered subcutaneously qd or tiw; 200 gg Actimmune human IFN-ylb
administered
subcutaneously tiw; and ribavirin administered orally qd, where the duration
of therapy is 48
weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg
for
individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75
kg or more.
[0743] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a
administered subcutaneously qd or tiw; and 25 g Actimmune human IFN-ylb
administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0744] One embodiment provides any of the above-described methods
modified to comprise administering to an individual having an HCV infection an
effective
amount of an NS3 inhibitor; and a regimen of 9 g INFERGEN consensus IFN-a
administered
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subcutaneously qd or tiw; and 200 g Actimmune human IFN-71b administered
subcutaneously tiw, where the duration of therapy is 48 weeks.
[0745] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw, and ribavirin administered
orally qd, where
the duration of therapy is 48 weeks. In this embodiment, ribavirin is
administered in an
amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for
individuals
weighing 75 kg or more.
[0746] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; 50 g Actimmune human IFN-
71b
administered subcutaneously tiw; and ribavirin administered orally qd, where
the duration of
therapy is 48 weeks. In this embodiment, ribavirin is administered in an
amount of 1000 mg
for individuals weighing less than 75 kg, and 1200 mg for individuals weighing
75 kg or more.
[0747] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; 100 g Actimmune human IFN-
ylb
administered subcutaneously tiw; and ribavirin administered orally qd, where
the duration of
therapy is 48 weeks. In this embodiment, ribavirin is administered in an
amount of 1000 mg
for individuals weighing less than 75 kg, and 1200 mg for individuals weighing
75 kg or more.
[0748] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; and 50 g Actimmune human
IFN-ylb
administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0749] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus
IFN-
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a administered subcutaneously every 10 days or qw; and 100 g Actimmune human
IFN-ylb
administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0750] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 150 .tg monoPEG(30 kD, linear)-ylated
consensus IFN-a
administered subcutaneously every 10 days or qw, and ribavirin administered
orally qd, where
the duration of therapy is 48 weeks. In this embodiment, ribavirin is
administered in an
amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for
individuals
weighing 75 kg or more.
[0751] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; 50 g Actimmune human IFN-
ylb
administered subcutaneously tiw; and ribavirin administered orally qd, where
the duration of
therapy is 48 weeks. In this embodiment, ribavirin is administered in an
amount of 1000 mg
for individuals weighing less than 75 kg, and 1200 mg for individuals weighing
75 kg or more.
[0752] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; 100 g Actimmune human IFN-
ylb
administered subcutaneously tiw; and ribavirin administered orally qd, where
the duration of
therapy is 48 weeks. In this embodiment, ribavirin is administered in an
amount of 1000 mg
for individuals weighing less than 75 kg, and 1200 mg for individuals weighing
75 kg or more.
[0753] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; and 50 g Actimmune human
IFN-ylb
administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0754] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus
IFN-
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a administered subcutaneously every 10 days or qw; and 100 g Actimmune human
IFN-ylb
administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0755] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw, and ribavirin administered
orally qd, where
the duration of therapy is 48 weeks. In this embodiment, ribavirin is
administered in an
amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for
individuals
weighing 75 kg or more.
[0756] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; 50 gg Actimmune human IFN-
ylb
administered subcutaneously tiw; and ribavirin administered orally qd, where
the duration of
therapy is 48 weeks. In this embodiment, ribavirin is administered in an
amount of 1000 mg
for individuals weighing less than 75 kg, and 1200 mg for individuals weighing
75 kg or more.
[0757] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; 100 gg Actimmune human IFN-
ylb
administered subcutaneously tiw; and ribavirin administered orally qd, where
the duration of
therapy is 48 weeks. In this embodiment, ribavirin is administered in an
amount of 1000 mg
for individuals weighing less than 75 kg, and 1200 mg for individuals weighing
75 kg or more.
[0758] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus
IFN-a
administered subcutaneously every 10 days or qw; and 50 g Actimmune human
IFN-ylb
administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0759] One embodiment provides any of the above-described methods modified
to comprise administering to an individual having an HCV infection an
effective amount of an
NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus
IFN-
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a administered subcutaneously every 10 days or qw; and 100 .tg Actimmune
human IFN-
ylb administered subcutaneously tiw, where the duration of therapy is 48
weeks.
[0760] Any of the above-described methods involving administering an NS3
inhibitor, a Type I interferon receptor agonist (e.g., an IFN-(x), and a Type
II interferon
receptor agonist (e.g., an IFN-y), may be augmented by administration of an
effective
amount of a TNF-a antagonist (e.g., a TNF-a antagonist other than pirfenidone
or a
pirfenidone analog). Exemplary, non-limiting TNF-a antagonists that are
suitable for use
in such combination therapies include ENBREL , REMICADE , and HUMIRATM.
[0761] One embodiment provides a method using an effective amount of
ENBREL ; an effective amount of IFN-a; an effective amount of IFN-y, and an
effective
amount of an NS3 inhibitor in the treatment of an HCV infection in a patient,
comprising
administering to the patient a dosage ENBREL containing an amount of from
about 0.1
g to about 23 mg per dose, from about 0.1 g to about I g, from about 1 tg to
about 10
g, from about 10 gg to about 100 g, from about 100 gg to about 1 mg, from
about I mg
to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15
mg, from
about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL ,
subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or once
every other month, or per day substantially continuously or continuously, for
the desired
duration of treatment.
[0762] One embodiment provides a method using an effective amount of
REMICADE , an effective amount of IFN-a with or without an effective amount of
IFN-y; and an effective amount of an NS3 inhibitor in the treatment of an HCV
infection in
a patient, comprising administering to the patient a dosage of REMICADE
containing an
amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to
about 0.5
mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about
1.5
mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about
2.5
mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about
3.5
mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to
about 4.5
mg/kg per dose of REMICADE , intravenously qd, qod, tiw, biw, qw, qow, three
times
per month, once monthly, or once every other month, or per day substantially
continuously
or continuously, for the desired duration of treatment.
[0763] One embodiment provides a method using an effective amount of
HUMIRATM, an effective amount of IFN-a; an effective amount of IFN-y; and an
effective
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amount of an NS3 inhibitor in the treatment of an HCV infection in a patient,
comprising
administering to the patient a dosage of HUMIRATM containing an amount of from
about
0.1 gg to about 35 mg, from about 0.1 g to about 1 g, from about I g to
about 10 g,
from about 10 gg to about 100 g, from about 100 g to about 1 mg, from about
1 mg to
about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg,
from
about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg
to about
30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRATM,
subcutaneously qd,
qod, tiw, biw, qw, qow, three times per month, once monthly, or once every
other month, or
per day substantially continuously or continuously, for the desired duration
of treatment.
Combination therapies with pirfenidone
[0764] In many embodiments, the methods provide for combination therapy
comprising administering an NS3 inhibitor compound as described above, and an
effective
amount of pirfenidone or a pirfenidone analog. In some embodiments, an NS3
inhibitor
compound, one or more interferon receptor agonist(s), and pirfenidone or
pirfenidone
analog are co-administered in the treatment methods of the embodiments. In
certain
embodiments, an NS3 inhibitor compound, a Type I interferon receptor agonist,
and
pirfenidone (or a pirfenidone analog) are co-administered. In other
embodiments, an NS3
inhibitor compound, a Type I interferon receptor agonist, a Type II interferon
receptor
agonist, and pirfenidone (or a pirfenidone analog) are co-administered. Type I
interferon
receptor agonists suitable for use herein include any IFN-a, such as
interferon alfa-2a,
interferon alfa-2b, interferon alfacon- 1, and PEGylated IFN-a's, such as
peginterferon alfa-
2a, peginterferon alfa-2b, and PEGylated consensus interferons, such as
monoPEG (30 kD,
linear)-ylated consensus interferon. Type II interferon receptor agonists
suitable for use
herein include any interferon-y.
[0765] Pirfenidone or a pirfenidone analog may be administered once per
month, twice per month, three times per month, once per week, twice per week,
three times
per week, four times per week, five times per week, six times per week, daily,
or in divided
daily doses ranging from once daily to 5 times daily over a period of time
ranging from
about one day to about one week, from about two weeks to about four weeks,
from about
one month to about two months, from about two months to about four months,
from about
four months to about six months, from about six months to about eight months,
from about
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eight months to about 1 year, from about 1 year to about 2 years, or from
about 2 years to
about 4 years, or more.
[0766] Effective dosages of pirfenidone or a specific pirfenidone analog
include a weight-based dosage in the range from about 5 mg/kg/day to about 125
mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or
about 800 mg to
about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about
1200 mg to
about 1600 mg per day, administered orally in one to five divided doses per
day. Other
doses and formulations of pirfenidone and specific pirfenidone analogs
suitable for use in
the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562;
5,518,729;
5,716,632; and 6,090,822.
[0767] One embodiment provides any of the above-described methods
modified to include co-administering to the patient a therapeutically
effective amount of
pirfenidone or a pirfenidone analog for the duration of the desired course of
NS3 inhibitor
compound treatment.

Combination therapies with TN-F-(x antagonists
[0768] In many embodiments, the methods provide for combination therapy
comprising administering an effective amount of an NS3 inhibitor compound as
described
above, and an effective amount of TNF-a antagonist, in combination therapy for
treatment
of an HCV infection.
[0769] Effective dosages of a TNF-a antagonist range from 0.1 gg to 40 mg
per dose, e.g., from about 0.1 g to about 0.5 g per dose, from about 0.5 gg
to about 1.0 g
per dose, from about 1.0 g per dose to about 5.0 gg per dose, from about 5.0
g to about 10
gg per dose, from about 10 gg to about 20 g per dose, from about 20 g per
dose to about
30 gg per dose, from about 30 g per dose to about 40 g per dose, from about
40 gg per
dose to about 50 g per dose, from about 50 g per dose to about 60 gg per
dose, from
about 60 g per dose to about 70 gg per dose, from about 70 g to about 80 g
per dose,
from about 80 gg per dose to about 100 gg per dose, from about 100 gg to about
150 gg per
dose, from about 150 g to about 200 g per dose, from about 200 gg per dose
to about 250
pg per dose, from about 250 gg to about 300 gg per dose, from about 300 gg to
about 400
gg per dose, from about 400 g to about 500 g per dose, from about 500 g to
about 600
g per dose, from about 600 g to about 700 gg per dose, from about 700 gg to
about 800
g per dose, from about 800 g to about 900 gg per dose, from about 900 gg to
about 1000
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gg per dose, from about I mg to about 10 mg per dose, from about 10 mg to
about 15 mg
per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about
25 mg per
dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35
mg per
dose, or from about 35 mg to about 40 mg per dose.
[0770] In some embodiments, effective dosages of a TNF-a antagonist are
expressed as mg/kg body weight. In these embodiments, effective dosages of a
TNF-a
antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight,
e.g.,
from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about
0.5 mg/kg
body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight
to about
2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg
body
weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or
from about
7.5 mg/kg body weight to about 10 mg/kg body weight.
[0771] In many embodiments, a TNF-a antagonist is administered for a
period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or
about 2 weeks
to about 3 weeks, or about 3 weeks to about 4 weeks, or about I month to about
2 months,
or about 3 months to about 4 months, or about 4 months to about 6 months, or
about 6
months to about 8 months, or about 8 months to about 12 months, or at least
one year, and
may be administered over longer periods of time. The TNF-a antagonist may be
administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once
monthly,
substantially continuously, or continuously.
[0772] In many embodiments, multiple doses of a TNF-a antagonist are
administered. For example, a TNF-a antagonist is administered once per month,
twice per
month, three times per month, every other week (qow), once per week (qw),
twice per week
(biw), three times per week (tiw), four times per week, five times per week,
six times per
week, every other day (qod), daily (qd), twice a day (bid), or three times a
day (tid),
substantially continuously, or continuously, over a period of time ranging
from about one
day to about one week, from about two weeks to about four weeks, from about
one month
to about two months, from about two months to about four months, from about
four months
to about six months, from about six months to about eight months, from about
eight months
to about 1 year, from about 1 year to about 2 years, or from about 2 years to
about 4 years,
or more.
[0773] A TNF-a antagonist and an NS3 inhibitor are generally administered
in separate formulations. A TNF-a antagonist and an NS3 inhibitor may be
administered
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substantially simultaneously, or within about 30 minutes, about 1 hour, about
2 hours,
about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours,
about 72
hours, about 4 days, about 7 days, or about 2 weeks of one another.
[0774] One embodiment provides a method using an effective amount of a
TNF-a antagonist and an effective amount of an NS3 inhibitor in the treatment
of an HCV
infection in a patient, comprising administering to the patient a dosage of a
TNF-a
antagonist containing an amount of from about 0.1 gg to about 40 mg per dose
of a TNF-a
antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0775] One embodiment provides a method using an effective amount of
ENBREL and an effective amount of an NS3 inhibitor in the treatment of an HCV
infection in a patient, comprising administering to the patient a dosage
ENBREL
containing an amount of from about 0.1 gg to about 23 mg per dose, from about
0.1 g to
about 1 g, from about 1 g to about 10 g, from about 10 g to about 100 g,
from about
100 tg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about
10 mg,
from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from
about 20 mg
to about 23 mg of ENBREL , subcutaneously qd, qod, tiw, biw, qw, qow, three
times per
month, once monthly, or once every other month, or per day substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0776] One embodiment provides a method using an effective amount of
REMICADE and an effective amount of an NS3 inhibitor in the treatment of an
HCV
infection in a patient, comprising administering to the patient a dosage of
REMICADE
containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about
0.1 mg/kg to
about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg
to about
1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to
about 2.5
mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about
3.5
mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to
about 4.5
mg/kg per dose of REMICADE , intravenously qd, qod, tiw, biw, qw, qow, three
times
per month, once monthly, or once every other month, or per day substantially
continuously
or continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0777] One embodiment provides a method using an effective amount of
HUMIRATM and an effective amount of an NS3 inhibitor in the treatment of an
HCV
infection in a patient, comprising administering to the patient a dosage of
HUMIRATM
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containing an amount of from about 0.1 g to about 35 mg, from about 0.1 .tg
to about 1
g, from about I g to about 10 g, from about 10 g to about 100 g, from
about 100 g
to about I mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg,
from
about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg
to about
25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per
dose of
a HUMIRATM, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month,
once
monthly, or once every other month, or per day substantially continuously or
continuously,
for the desired duration of treatment with an NS3 inhibitor compound.

Combination therapies with thymosin-a
[0778] In many embodiments, the methods provide for combination therapy
comprising administering an effective amount of an NS3 inhibitor compound as
described
above, and an effective amount of thymosin-a, in combination therapy for
treatment of an
HCV infection.
[0779] Effective dosages of thymosin-a range from about 0.5 mg to about 5
mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5
mg, from
about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about
2.5 mg to
about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about
4.0 mg, from
about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In
particular
embodiments, thymosin-a is administered in dosages containing an amount of 1.0
mg or
1.6 mg.
[0780] One embodiment provides a method using an effective amount of
ZADAXINTM thymosin-a and an effective amount of an NS3 inhibitor in the
treatment of
an HCV infection in a patient, comprising administering to the patient a
dosage of
ZADAXINTM containing an amount of from about 1.0 mg to about 1.6 mg per dose,
subcutaneously twice per week for the desired duration of treatment with the
NS3 inhibitor
compound.

Combination therapies with a TNF-a antagonist and an interferon
[0781] Some embodiments provide a method of treating an HCV infection in
an individual having an HCV infection, the method comprising administering an
effective
amount of an NS3 inhibitor, and effective amount of a TNF-a antagonist, and an
effective
amount of one or more interferons.

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[0782] One embodiment provides any of the above-described methods
modified to use an effective amount of IFN-y and an effective amount of a TNF-
a antagonist
in the treatment of HCV infection in a patient comprising administering to the
patient a
dosage of IFN-y containing an amount of about 10 g to about 300 g of drug
per dose of
IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or
per day substantially continuously or continuously, in combination with a
dosage of a TNF-a
antagonist containing an amount of from about 0.1 gg to about 40 mg per dose
of a TNF-a
antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0783] One embodiment provides any of the above-described methods
modified to use an effective amount of IFN-y and an effective amount of a TNF-
a antagonist
in the treatment of HCV infection in a patient comprising administering to the
patient a
dosage of IFN-y containing an amount of about 10 g to about 100 gg of drug
per dose of
IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once
monthly, or
per day substantially continuously or continuously, in combination with a
dosage of a TNF-a
antagonist containing an amount of from about 0.1 g to about 40 mg per dose
of a TNF-a
antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0784] Another embodiment provides any of the above-described methods
modified to use an effective amount of IFN-y and an effective amount of a TNF-
a antagonist
in the treatment of a virus infection in a patient comprising administering to
the patient a total
weekly dosage of IFN-y containing an amount of about 30 g to about 1,000 g
of drug per
week in divided doses administered subcutaneously qd, qod, tiw, biw, or
administered
substantially continuously or continuously, in combination with a dosage of a
TNF-a
antagonist containing an amount of from about 0.1 g to about 40 mg per dose
of a TNF-a
antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0785] Another embodiment provides any of the above-described methods
modified to use an effective amount of IFN-y and an effective amount of a TNF-
a antagonist
in the treatment of a virus infection in a patient comprising administering to
the patient a total
weekly dosage of IFN-y containing an amount of about 100 g to about 300 g of
drug per
week in divided doses administered subcutaneously qd, qod, tiw, biw, or
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administered substantially continuously or continuously, in combination with a
dosage of a
TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per
dose of a
TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day
substantially
continuously or continuously, for the desired duration of treatment with an
NS3 inhibitor
compound.
[0786] One embodiment provides any of the above-described methods
modified to use an effective amount of INFERGEN consensus IFN-a and a TNF-a
antagonist in the treatment of HCV infection in a patient comprising
administering to the
patient a dosage of INFERGEN containing an amount of about I g to about 30
g, of
drug per dose of INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three
times per
month, once monthly, or per day substantially continuously or continuously, in
combination
with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g
to about
40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or
per day
substantially continuously or continuously, for the desired duration of
treatment with an
NS3 inhibitor compound.
[0787] One embodiment provides any of the above-described methods
modified to use an effective amount of INFERGEN consensus IFN-a and a TNF-a
antagonist in the treatment of HCV infection in a patient comprising
administering to the
patient a dosage of INFERGEN containing an amount of about I g to about 9
g, of
drug per dose of INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three
times per
month, once monthly, or per day substantially continuously or continuously, in
combination
with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g
to about
40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or
per day
substantially continuously or continuously, for the desired duration of
treatment with an
NS3 inhibitor compound.
[0788] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEGylated consensus IFN-a and an
effective
amount of a TNF-a antagonist in the treatment of a virus infection in a
patient comprising
administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN)
containing an amount of about 4 g to about 60 g of CIFN amino acid weight
per dose of
PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in
combination
with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g
to about
40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or
per day
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substantially continuously or continuously, for the desired duration of
treatment with an NS3
inhibitor compound.
[0789] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEGylated consensus IFN-a and an
effective amount
of a TNF-a antagonist in the treatment of a virus infection in a patient
comprising
administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN)
containing
an amount of about 18 g to about 24 g of CIFN amino acid weight per dose of
PEG-CIFN,
subcutaneously qw, qow, three times per month, or monthly, in combination with
a dosage of
a TNF-a antagonist containing an amount of from about 0.1 .ig to about 40 mg
per dose of a
TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day
substantially continuously
or continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0790] Another embodiment provides any of the above-described methods
modified to use an effective amount of IFN-a 2a or 2b or 2c and an effective
amount of a
TNF-a antagonist in the treatment of a virus infection in a patient comprising
administering
to the patient a dosage of 1FN-a 2a, 2b or 2c containing an amount of about 1
MU to about
20 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw,
or per day
substantially continuously or continuously, in combination with a dosage of a
TNF-a
antagonist containing an amount of from about 0.1 g to about 40 mg per dose
of a TNF-a
antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially
continuously or
continuously, for the desired duration of treatment with an NS3 inhibitor
compound.
[0791] Another embodiment provides any of the above-described methods
modified to use an effective amount of IFN-a 2a or 2b or 2c and an effective
amount of a
TNF-a antagonist in the treatment of a virus infection in a patient comprising
administering
to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 3
MU of drug
per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day
substantially
continuously or continuously, in combination with a dosage of a TNF-a
antagonist
containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a
antagonist,
subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or
continuously,
for the desired duration of treatment with an NS3 inhibitor compound.
[0792] Another embodiment provides any of the above-described methods
modified to use an effective amount of IFN-a 2a or 2b or 2c and an effective
amount of a
TNF-a antagonist in the treatment of a virus infection in a patient comprising
administering
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to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 10
MU of drug
per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day
substantially
continuously or continuously, in combination with a dosage of a TNF-a
antagonist
containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a
antagonist,
subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or
continuously,
for the desired duration of treatment with an NS3 inhibitor compound.
[0793] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEGASYS PEGylated IFN-a2a and an
effective
amount of a TNF-a antagonist in the treatment of a virus infection in a
patient comprising
administering to the patient a dosage of PEGASYS containing an amount of
about 90 g
to about 360 g, of drug per dose of PEGASYS , subcutaneously qw, qow, three
times per
month, or monthly, in combination with a dosage of a TNF-a antagonist
containing an
amount of from about 0.1 gg to about 40 mg per dose of a TNF-a antagonist,
subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or
continuously,
for the desired duration of treatment with an NS3 inhibitor compound.
[0794] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEGASYS PEGylated IFN-a2a and an
effective
amount of a TNF-a antagonist in the treatment of a virus infection in a
patient comprising
administering to the patient a dosage of PEGASYS containing an amount of
about 180
g, of drug per dose of PEGASYS , subcutaneously qw, qow, three times per
month, or
monthly, in combination with a dosage of a TNF-a antagonist containing an
amount of
from about 0.1 g to about 40 mg per dose of a TNF-a antagonist,
subcutaneously qd, qod,
tiw, or biw, or per day substantially continuously or continuously, for the
desired duration
of treatment with an NS3 inhibitor compound.
[0795] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and an
effective amount of a TNF-a antagonist in the treatment of a virus infection
in a patient
comprising administering to the patient a dosage of PEG-INTRON containing an
amount
of about 0.75 g to about 3.0 gg of drug per kilogram of body weight per dose
of PEG-
INTRON , subcutaneously qw, qow, three times per month, or monthly, in
combination
with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g
to about
40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or
per day
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substantially continuously or continuously, for the desired duration of
treatment with an
NS3 inhibitor compound.
[0796] Another embodiment provides any of the above-described methods
modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and an
effective amount of a TNF-a antagonist in the treatment of a virus infection
in a patient
comprising administering to the patient a dosage of PEG-INTRON containing an
amount
of about 1.5 .tg of drug per kilogram of body weight per dose of PEG-INTRON ,
subcutaneously qw, qow, three times per month, or monthly, in combination with
a dosage
of a TNF-a antagonist containing an amount of from about 0.1 .tg to about 40
mg per dose
of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day
substantially
continuously or continuously, for the desired duration of treatment with an
NS3 inhibitor
compound.

Combination therapies with other antiviral agents
[0797] Other agents such as inhibitors of HCV NS3 helicase are also
attractive drugs for combinational therapy, and are contemplated for use in
combination
therapies described herein. Ribozymes such as HeptazymeTM and phosphorothioate
oligonucleotides which are complementary to HCV protein sequences and which
inhibit the
expression of viral core proteins are also suitable for use in combination
therapies described
herein.
[0798] In some embodiments, the additional antiviral agent(s) is administered
during the entire course of treatment with the NS3 inhibitor compound of the
embodiments,
and the beginning and end of the treatment periods coincide. In other
embodiments, the
additional antiviral agent(s) is administered for a period of time that is
overlapping with
that of the NS3 inhibitor compound treatment, e.g., treatment with the
additional antiviral
agent(s) begins before the NS3 inhibitor compound treatment begins and ends
before the
NS3 inhibitor compound treatment ends; treatment with the additional antiviral
agent(s)
begins after the NS3 inhibitor compound treatment begins and ends after the
NS3 inhibitor
compound treatment ends; treatment with the additional antiviral agent(s)
begins after the
NS3 inhibitor compound treatment begins and ends before the NS3 inhibitor
compound
treatment ends; or treatment with the additional antiviral agent(s) begins
before the NS3
inhibitor compound treatment begins and ends after the NS3 inhibitor compound
treatment
ends.

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[0799] The NS3 inhibitor compound may be administered together with (i.e.,
simultaneously in separate formulations; simultaneously in the same
formulation;
administered in separate formulations and within about 48 hours, within about
36 hours,
within about 24 hours, within about 16 hours, within about 12 hours, within
about 8 hours,
within about 4 hours, within about 2 hours, within about 1 hour, within about
30 minutes, or
within about 15 minutes or less) one or more additional antiviral agents.
[0800] As non-limiting examples, any of the above-described methods featuring
an IFN-a regimen may be modified to replace the subject IFN-a regimen with a
regimen of
monoPEG (30 kD, linear)-ylated consensus IFN-a comprising administering a
dosage of
monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 .tg
of drug
per dose, subcutaneously once weekly, once every 8 days, or once every 10 days
for the
desired treatment duration with an NS3 inhibitor compound.
[0801] As non-limiting examples, any of the above-described methods featuring
an IFN-a regimen may be modified to replace the subject IFN-a regimen with a
regimen of
monoPEG (30 kD, linear)-ylated consensus IFN-a comprising administering a
dosage of
monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g
of drug
per dose, subcutaneously once weekly, once every 8 days, or once every 10 days
for the
desired treatment duration with an NS3 inhibitor compound.
[0802] As non-limiting examples, any of the above-described methods featuring
an IFN-a regimen may be modified to replace the subject IFN-a regimen with a
regimen of
monoPEG (30 kD, linear)-ylated consensus IFN-a comprising administering a
dosage of
monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g
of drug
per dose, subcutaneously once weekly, once every 8 days, or once every 10 days
for the
desired treatment duration with an NS3 inhibitor compound.
[0803] As non-limiting examples, any of the above-described methods featuring
an IFN-a regimen may be modified to replace the subject IFN-a regimen with a
regimen of
INFERGEN interferon alfacon-1 comprising administering a dosage of INFERGEN
interferon alfacon-1 containing an amount of 9 g of drug per dose,
subcutaneously once
daily or three times per week for the desired treatment duration with an NS3
inhibitor
compound.
[0804] As non-limiting examples, any of the above-described methods featuring
an IFN-a regimen may be modified to replace the subject ]FN-a regimen with a
regimen of
INFERGEN interferon alfacon-1 comprising administering a dosage of INFERGEN
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interferon alfacon-1 containing an amount of 15 g of drug per dose,
subcutaneously once
daily or three times per week for the desired treatment duration with an NS3
inhibitor
compound.
[0805] As non-limiting examples, any of the above-described methods
featuring an IFN-y regimen may be modified to replace the subject IFN-y
regimen with a
regimen of IFN-y comprising administering a dosage of IFN-y containing an
amount of 25
g of drug per dose, subcutaneously three times per week for the desired
treatment duration
with an NS3 inhibitor compound.
[0806] As non-limiting examples, any of the above-described methods
featuring an IFN-y regimen may be modified to replace the subject IFN-y
regimen with a
regimen of IFN-y comprising administering a dosage of IFN-y containing an
amount of 50
g of drug per dose, subcutaneously three times per week for the desired
treatment duration
with an NS3 inhibitor compound.
[0807] As non-limiting examples, any of the above-described methods
featuring an IFN-y regimen may be modified to replace the subject IFN-y
regimen with a
regimen of IFN-y comprising administering a dosage of IFN-y containing an
amount of 100
g of drug per dose, subcutaneously three times per week for the desired
treatment duration
with an NS3 inhibitor compound.
[0808] As non-limiting examples, any of the above-described methods
featuring an IFN-a and IFN-y combination regimen may be modified to replace
the subject
IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination
regimen
comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated
consensus IFN-a
containing an amount of 100 .tg of drug per dose, subcutaneously once weekly,
once every 8
days, or once every 10 days; and (b) administering a dosage of IFN-y
containing an amount
of 50 g of drug per dose, subcutaneously three times per week; for the
desired treatment
duration with an NS3 inhibitor compound.
[0809] As non-limiting examples, any of the above-described methods
featuring a TNF antagonist regimen may be modified to replace the subject TNF
antagonist
regimen with a TNF antagonist regimen comprising administering a dosage of a
TNF
antagonist selected from the group of. (a) etanercept in an amount of 25 mg of
drug per dose
subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drug per
kilogram of
body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter, or
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(c) adalimumab in an amount of 40 mg of drug per dose subcutaneously once
weekly or once
every 2 weeks; for the desired treatment duration with an NS3 inhibitor
compound.
[0810] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen can be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a
containing an
amount of 100 g of drug per dose, subcutaneously once weekly, once every 8
days, or once
every 10 days; and (b) administering a dosage of IFN-y containing an amount of
100 g of
drug per dose, subcutaneously three times per week; for the desired treatment
duration with an
NS3 inhibitor compound.
[0811] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a
containing an
amount of 150 g of drug per dose, subcutaneously once weekly, once every 8
days, or once
every 10 days; and (b) administering a dosage of IFN-y containing an amount of
50 g of drug
per dose, subcutaneously three times per week; for the desired treatment
duration with an NS3
inhibitor compound.
[0812] As non-limiting examples, any of the above-described methods featuring
an IFN-a and 1FN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a
containing an
amount of 150 g of drug per dose, subcutaneously once weekly, once every 8
days, or once
every 10 days; and (b) administering a dosage of IFN-y containing an amount of
100 gg of
drug per dose, subcutaneously three times per week; for the desired treatment
duration with an
NS3 inhibitor compound.
[0813] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-7 combination regimen
comprising: (a)
administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a
containing an
amount of 200 gg of drug per dose, subcutaneously once weekly, once every 8
days, or once
every 10 days; and (b) administering a dosage of IFN-y containing an amount of
50 jig
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of drug per dose, subcutaneously three times per week; for the desired
treatment duration with
an NS3 inhibitor compound.
[0814] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a
containing an
amount of 200 gg of drug per dose, subcutaneously once weekly, once every 8
days, or once
every 10 days; and (b) administering a dosage of IFN-y containing an amount of
100 g of
drug per dose, subcutaneously three times per week; for the desired treatment
duration with an
NS3 inhibitor compound.
[0815] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon- I containing an amount
of 9 g of
drug per dose, subcutaneously three times per week; and (b) administering a
dosage of IFN-y
containing an amount of 25 g of drug per dose, subcutaneously three times per
week; for the
desired treatment duration with an NS3 inhibitor compound.
[0816] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon- I containing an amount
of 9.tg of
drug per dose, subcutaneously three times per week; and (b) administering a
dosage of IFN-y
containing an amount of 50 .tg of drug per dose, subcutaneously three times
per week; for the
desired treatment duration with an NS3 inhibitor compound.
[0817] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon-1 containing an amount
of 9 g of
drug per dose, subcutaneously three times per week; and (b) administering a
dosage of IFN-7
containing an amount of 100 tg of drug per dose, subcutaneously three times
per week; for
the desired treatment duration with an NS3 inhibitor compound.
[0818] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
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IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon-1 containing an amount
of 9 .tg of
drug per dose, subcutaneously once daily; and (b) administering a dosage of
IFN-y containing
an amount of 25 tg of drug per dose, subcutaneously three times per week; for
the desired
treatment duration with an NS3 inhibitor compound.
[0819] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon-1 containing an amount
of 9 gg of
drug per dose, subcutaneously once daily; and (b) administering a dosage of
IFN-y containing
an amount of 50 g of drug per dose, subcutaneously three times per week; for
the desired
treatment duration with an NS3 inhibitor compound.
[0820] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an 1FN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon-1 containing an amount
of 9 .tg of
drug per dose, subcutaneously once daily; and (b) administering a dosage of
IFN-y containing
an amount of 100 g of drug per dose, subcutaneously three times per week; for
the desired
treatment duration with an NS3 inhibitor compound.
[0821] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon-1 containing an amount
of 15 gg
of drug per dose, subcutaneously three times per week; and (b) administering a
dosage of
IFN-y containing an amount of 25 g of drug per dose, subcutaneously three
times per week;
for the desired treatment duration with an NS3 inhibitor compound.
[0822] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon-1 containing an amount
of 15 g
of drug per dose, subcutaneously three times per week; and (b) administering a
dosage of
IFN-y containing an amount of 50 .tg of drug per dose, subcutaneously three
times per week;
for the desired treatment duration with an NS3 inhibitor compound.

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[0823] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon-1 containing an amount
of 15 gg
of drug per dose, subcutaneously three times per week; and (b) administering a
dosage of
IFN-y containing an amount of 100 g of drug per dose, subcutaneously three
times per week;
for the desired treatment duration with an NS3 inhibitor compound.
[0824] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon-1 containing an amount
of 15 g
of drug per dose, subcutaneously once daily; and (b) administering a dosage of
IFN-y
containing an amount of 25 .tg of drug per dose, subcutaneously three times
per week; for the
desired treatment duration with an NS3 inhibitor compound.
[0825] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon- I containing an amount
of 15 g
of drug per dose, subcutaneously once daily; and (b) administering a dosage of
IFN-y
containing an amount of 50 g of drug per dose, subcutaneously three times per
week; for the
desired treatment duration with an NS3 inhibitor compound.
[0826] As non-limiting examples, any of the above-described methods featuring
an IFN-a and IFN-y combination regimen may be modified to replace the subject
IFN-a and
IFN-y combination regimen with an IFN-a and IFN-y combination regimen
comprising: (a)
administering a dosage of INFERGEN interferon alfacon- I containing an amount
of 15 gg
of drug per dose, subcutaneously once daily; and (b) administering a dosage of
IFN-'y
containing an amount of 100 g of drug per dose, subcutaneously three times
per week; for
the desired treatment duration with an NS3 inhibitor compound.
[0827] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-
y and
TNF antagonist combination regimen comprising: (a) administering a dosage of
monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug
per dose,
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CA 02560897 2007-08-08

subcutaneously once weekly, once every 8 days, or once every 10 days; (b)
administering a
dosage of IFN-y containing an amount of 100 g of drug per dose,
subcutaneously three times
per week; and (c) administering a dosage of a TNF antagonist selected from (i)
etanercept in
an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount
of 3 mg of
drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every
8 weeks
thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
weekly or once
every other week; for the desired treatment duration with an NS3 inhibitor
compound.
[0828] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-
y and
TNF antagonist combination regimen comprising: (a) administering a dosage of
monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug
per dose,
subcutaneously once weekly, once every 8 days, or once every 10 days; (b)
administering a
dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously
three times
per week; and (c) administering a dosage of a TNF antagonist selected from (i)
etanercept in
an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount
of 3 mg of
drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every
8 weeks
thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
weekly or once
every other week; for the desired treatment duration with an NS3 inhibitor
compound.
[0829] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-
y and
TNF antagonist combination regimen comprising: (a) administering a dosage of
monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug
per dose,
subcutaneously once weekly, once every 8 days, or once every 10 days; (b)
administering a
dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously
three times
per week; and (c) administering a dosage of a TNF antagonist selected from (i)
etanercept in
an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount
of 3 mg of
drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every
8 weeks
thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
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CA 02560897 2007-08-08

weekly or once every other week; for the desired treatment duration with an
NS3 inhibitor
compound.
[0830] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-
y and
TNF antagonist combination regimen comprising: (a) administering a dosage of
monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 150 gg of drug
per dose,
subcutaneously once weekly, once every 8 days, or once every 10 days; (b)
administering a
dosage of IFN-y containing an amount of 100 g of drug per dose,
subcutaneously three times
per week; and (c) administering a dosage of a TNF antagonist selected from (i)
etanercept in
an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount
of 3 mg of
drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every
8 weeks
thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
weekly or once
every other week; for the desired treatment duration with an NS3 inhibitor
compound.
[0831] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-
y and
TNF antagonist combination regimen comprising: (a) administering a dosage of
monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 200 gg of drug
per dose,
subcutaneously once weekly, once every 8 days, or once every 10 days; (b)
administering a
dosage of IFN-y containing an amount of 50 gg of drug per dose, subcutaneously
three times
per week; and (c) administering a dosage of a TNF antagonist selected from (i)
etanercept in
an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount
of 3 mg of
drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every
8 weeks
thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
weekly or once
every other week; for the desired treatment duration with an NS3 inhibitor
compound.
[0832] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-
y and
TNF antagonist combination regimen comprising: (a) administering a dosage of
monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug
per dose,
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CA 02560897 2007-08-08

subcutaneously once weekly, once every 8 days, or once every 10 days; (b)
administering a
dosage of IFN-y containing an amount of 100 g of drug per dose,
subcutaneously three
times per week; and (c) administering a dosage of a TNF antagonist selected
from (i)
etanercept in an amount of 25 mg subcutaneously twice per week, (ii)
infliximab in an
amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2
and 6, and
every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg
subcutaneously once
weekly or once every other week; for the desired treatment duration with an
NS3 inhibitor
compound.
[0833] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-y and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon-1 containing an amount of 9 g of drug per dose,
subcutaneously three times per week; (b) administering a dosage of IFN-y
containing an
amount of 25 gg of drug per dose, subcutaneously three times per week; and (c)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per
kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter or
(iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once
every other
week; for the desired treatment duration with an NS3 inhibitor compound.
[0834] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-y and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon-1 containing an amount of 9 g of drug per dose,
subcutaneously three times per week; (b) administering a dosage of IFN-y
containing an
amount of 50 p.g of drug per dose, subcutaneously three times per week; and
(c)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per
kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter or
(iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once
every other
week; for the desired treatment duration with an NS3 inhibitor compound.

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CA 02560897 2007-08-08

[0835] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-y and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon- I containing an amount of 9 gg of drug per dose,
subcutaneously three times per week; (b) administering a dosage of IFN-y
containing an
amount of 100 gg of drug per dose, subcutaneously three times per week; and
(c)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per
kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter or
(iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once
every other
week; for the desired treatment duration with an NS3 inhibitor compound.
[0836] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-7 and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon-1 containing an amount of 9 gg of drug per dose,
subcutaneously once daily; (b) administering a dosage of IFN-y containing an
amount of 25
gg of drug per dose, subcutaneously three times per week; and (c)
administering a dosage
of a TNF antagonist selected from (i) etanercept in an amount of 25 mg
subcutaneously
twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of
body weight
intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii)
adalimumab in an
amount of 40 mg subcutaneously once weekly or once every other week; for the
desired
treatment duration with an NS3 inhibitor compound.
[0837] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-y and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon-1 containing an amount of 9 gg of drug per dose,
subcutaneously once daily; (b) administering a dosage of IFN-y containing an
amount of 50
gg of drug per dose, subcutaneously three times per week; and (c)
administering a dosage
of a TNF antagonist selected from (i) etanercept in an amount of 25 mg
subcutaneously
twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of
body weight
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CA 02560897 2007-08-08

intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii)
adalimumab in an
amount of 40 mg subcutaneously once weekly or once every other week; for the
desired
treatment duration with an NS3 inhibitor compound.
[0838] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-y and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon-1 containing an amount of 9 g of drug per dose,
subcutaneously once daily; (b) administering a dosage of IFN-y containing an
amount of
100 g of drug per dose, subcutaneously three times per week; and (c)
administering a
dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg
subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per kilogram
of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter
or (iii)
adalimumab in an amount of 40 mg subcutaneously once weekly or once every
other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0839] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-y and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose,
subcutaneously three times per week; (b) administering a dosage of IFN-y
containing an
amount of 25 g of drug per dose, subcutaneously three times per week; and (c)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per
kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter or
(iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once
every other
week; for the desired treatment duration with an NS3 inhibitor compound.
[0840] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-y and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon- I containing an amount of 15 .tg of drug per
dose,
subcutaneously three times per week; (b) administering a dosage of IFN-y
containing an
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CA 02560897 2007-08-08

amount of 50 g of drug per dose, subcutaneously three times per week; and (c)
administering
a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25
mg
subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per kilogram of
body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or
(iii)
adalimumab in an amount of 40 mg subcutaneously once weekly or once every
other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0841] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-
y and
TNF antagonist combination regimen comprising: (a) administering a dosage of
INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose,
subcutaneously three times per week; (b) administering a dosage of IFN-y
containing an
amount of 100 g of drug per dose, subcutaneously three times per week; and
(c)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per kilogram
of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter
or (iii)
adalimumab in an amount of 40 mg subcutaneously once weekly or once every
other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0842] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an 1FN-a, IFN-
y and
TNF antagonist combination regimen comprising: (a) administering a dosage of
INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose,
subcutaneously once daily; (b) administering a dosage of IFN-y containing an
amount of 25
g of drug per dose, subcutaneously three times per week; and (c) administering
a dosage of a
TNF antagonist selected from (i) etanercept in an amount of 25 mg
subcutaneously twice per
week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight
intravenously
at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an
amount of 40 mg
subcutaneously once weekly or once every other week; for the desired treatment
duration with
an NS3 inhibitor compound.
[0843] As non-limiting examples, any of the above-described methods featuring
an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to
replace the
subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-
y and
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CA 02560897 2007-08-08

TNF antagonist combination regimen comprising: (a) administering a dosage of
INFERGEN interferon alfacon-I containing an amount of 15 g of drug per dose,
subcutaneously once daily; (b) administering a dosage of IFN-y containing an
amount of 50
g of drug per dose, subcutaneously three times per week; and (c) administering
a dosage
of a TNF antagonist selected from (i) etanercept in an amount of 25 mg
subcutaneously
twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of
body weight
intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii)
adalimumab in an
amount of 40 mg subcutaneously once weekly or once every other week; for the
desired
treatment duration with an NS3 inhibitor compound.
[0844] As non-limiting examples, any of the above-described methods
featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be
modified to
replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with
an IFN-a,
IFN-y and TNF antagonist combination regimen comprising: (a) administering a
dosage of
INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose,
subcutaneously once daily; (b) administering a dosage of IFN-y containing an
amount of
100 g of drug per dose, subcutaneously three times per week; and (c)
administering a
dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg
subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per kilogram
of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter
or (iii)
adalimumab in an amount of 40 mg subcutaneously once weekly or once every
other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0845] As non-limiting examples, any of the above-described methods
featuring an IFN-a and TNF antagonist combination regimen may be modified to
replace
the subject IFN-a and TNF antagonist combination regimen with an IFN-a and TNF
antagonist combination regimen comprising: (a) administering a dosage of
monoPEG (30
kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per
dose,
subcutaneously once weekly, once every 8 days, or once every 10 days; and (b)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per
kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter or
(iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once
every other
week; for the desired treatment duration with an NS3 inhibitor compound.

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CA 02560897 2007-08-08

[0846] As non-limiting examples, any of the above-described methods
featuring an IFN-a and TNF antagonist combination regimen may be modified to
replace
the subject IFN-a and TNF antagonist combination regimen with an IFN-(x and
TNF
antagonist combination regimen comprising: (a) administering a dosage of
monoPEG (30
kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per
dose,
subcutaneously once weekly, once every 8 days, or once every 10 days; and (b)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per
kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter or
(iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once
every other
week; for the desired treatment duration with an NS3 inhibitor compound.
[0847] As non-limiting examples, any of the above-described methods
featuring an IFN-(x and TNF antagonist combination regimen may be modified to
replace
the subject IFN-a and TNF antagonist combination regimen with an IFN-(x and
TNF
antagonist combination regimen comprising: (a) administering a dosage of
monoPEG (30
kD, linear)-ylated consensus IFN-(x containing an amount of 200 g of drug per
dose,
subcutaneously once weekly, once every 8 days, or once every 10 days; and (b)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per
kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter or
(iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once
every other
week; for the desired treatment duration with an NS3 inhibitor compound.
[0848] As non-limiting examples, any of the above-described methods
featuring an IFN-a and TNF antagonist combination regimen may be modified to
replace
the subject IFN-(x and TNF antagonist combination regimen with an IFN-a and
TNF
antagonist combination regimen comprising: (a) administering a dosage of
INFERGEN
interferon alfacon-1 containing an amount of 9 g of drug per dose,
subcutaneously once
daily or three times per week; and (b) administering a dosage of a TNF
antagonist selected
from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii)
infliximab in
an amount of 3 mg of drug per kilogram of body weight intravenously at weeks
0, 2 and 6,
and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg
subcutaneously
once weekly or once every other week; for the desired treatment duration with
an NS3
inhibitor compound.
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CA 02560897 2007-08-08

[0849] As non-limiting examples, any of the above-described methods featuring
an IFN-a and TNF antagonist combination regimen may be modified to replace the
subject
IFN-a and TNF antagonist combination regimen with an IFN-a and TNF antagonist
combination regimen comprising: (a) administering a dosage of INFERGEN
interferon
alfacon-1 containing an amount of 15 gg of drug per dose, subcutaneously once
daily or three
times per week; and (b) administering a dosage of a TNF antagonist selected
from (i)
etanercept in an amount of 25 mg subcutaneously twice per week, (ii)
infliximab in an amount
of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6,
and every 8
weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once
weekly or
once every other week; for the desired treatment duration with an NS3
inhibitor compound.
[0850] As non-limiting examples, any of the above-described methods featuring
an IFN-y and TNF antagonist combination regimen may be modified to replace the
subject
IFN-y and TNF antagonist combination regimen with an IFN-y and TNF antagonist
combination regimen comprising: (a) administering a dosage of IFN-y containing
an amount
of 25 gg of drug per dose, subcutaneously three times per week; and (b)
administering a
dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg
subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per kilogram of
body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or
(iii)
adalimumab in an amount of 40 mg subcutaneously once weekly or once every
other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0851] As non-limiting examples, any of the above-described methods featuring
an IFN-y and TNF antagonist combination regimen may be modified to replace the
subject
IFN-y and TNF antagonist combination regimen with an IFN-y and TNF antagonist
combination regimen comprising: (a) administering a dosage of IFN-y containing
an amount
of 50 pg of drug per dose, subcutaneously three times per week; and (b)
administering a
dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg
subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per kilogram of
body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or
(iii)
adalimumab in an amount of 40 mg subcutaneously once weekly or once every
other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0852] As non-limiting examples, any of the above-described methods featuring
an IFN-y and TNF antagonist combination regimen may be modified to replace the
subject
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CA 02560897 2007-08-08

IFN-y and TNF antagonist combination regimen with an IFN-y and TNF antagonist
combination regimen comprising: (a) administering a dosage of IFN-y containing
an
amount of 100 g of drug per dose, subcutaneously three times per week; and
(b)
administering a dosage of a TNF antagonist selected from (i) etanercept in an
amount of 25
mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug
per
kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks
thereafter or
(iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once
every other
week; for the desired treatment duration with an NS3 inhibitor compound.
[0853] As non-limiting examples, any of the above-described methods that
includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a may be
modified
to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with
a regimen
of peginterferon alfa-2a comprising administering a dosage of peginterferon
alfa-2a
containing an amount of 180 g of drug per dose, subcutaneously once weekly
for the
desired treatment duration with an NS3 inhibitor compound.
[0854] As non-limiting examples, any of the above-described methods that
includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a may be
modified
to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with
a regimen
of peginterferon alfa-2b comprising administering a dosage of peginterferon
alfa-2b
containing an amount of 1.0 .tg to 1.5 g of drug per kilogram of body weight
per dose,
subcutaneously once or twice weekly for the desired treatment duration with an
NS3
inhibitor compound.
[0855] As non-limiting examples, any of the above-described methods may
be modified to include administering a dosage of ribavirin containing an
amount of 400 mg,
800 mg, 1000 mg or 1200 mg of drug orally per day, optionally in two or more
divided
doses per day, for the desired treatment duration with an NS3 inhibitor
compound.
[0856] As non-limiting examples, any of the above-described methods may
be modified to include administering a dosage of ribavirin containing (i) an
amount of 1000
mg of drug orally per day for patients having a body weight of less than 75 kg
or (ii) an
amount of 1200 mg of drug orally per day for patients having a body weight of
greater than
or equal to 75 kg, optionally in two or more divided doses per day, for the
desired treatment
duration with an NS3 inhibitor compound.
[0857] As non-limiting examples, any of the above-described methods may
be modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor
regimen
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of
body
weight orally daily, optionally in two or more divided doses per day, for the
desired
treatment duration with the NS3 inhibitor compound.

[0858] As non-limiting examples, any of the above-described methods may be
modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor
regimen
comprising administering a dosage of 0.1 mg to I ing of drug per kilogram of
body weight
orally daily, optionally in two or more divided doses per day, for the desired
treatment
duration with the NS3 inhibitor compound.

[0859] As non-limiting examples, any of the above-described methods may be
modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor
regimen
comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of
body weight
orally daily, optionally in two or more divided doses per day, for the desired
treatment
duration with the NS3 inhibitor compound.

[0860] As non-limiting examples, any of the above-described methods may be
modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor
regimen
comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of
body
weight orally daily, optionally in two or more divided doses per day, for the
desired
treatment duration with the NS3 inhibitor compound.

[0861] As non-limiting examples, any of the above-described methods featuring
an NS5B inhibitor regimen may be modified to replace the subject NSSB
inhibitor regimen
with an NS5B inhibitor regimen comprising administering a dosage of 0.01 mg to
0.1 mg of
drug per kilogram of body weight orally daily, optionally in two or more
divided doses per
day, for the desired treatment duration with an NS3 inhibitor compound.
[0862] As non-limiting examples, any of the above-described methods featuring
an NS5B inhibitor regimen may be modified to replace the subject NS5B
inhibitor regimen
with an NS5B inhibitor regimen comprising administering a dosage of 0.1 mg to
1 mg of
drug per kilogram of body weight orally daily, optionally in two or more
divided doses per
day, for the desired treatment duration with an NS3 inhibitor compound.
[0863] As non-limiting examples, any of the above-described methods featuring
an NS5B inhibitor regimen may be modified to replace the subject NS5B
inhibitor regimen
with an NS5B inhibitor regimen comprising administering a dosage of 1 mg to 10
mg of
drug per kilogram of body weight orally daily, optionally in two or more
divided doses per
day, for the desired treatment duration with an NS3 inhibitor compound.

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[0864] As non-limiting examples, any of the above-described methods featuring
.an NS5B inhibitor regimen may be modified to replace the subject NS5B
inhibitor regimen
with an NS5B inhibitor regimen comprising administering a dosage of 10 ing to
100 mg of
drug per kilogram of body weight orally daily, optionally in two or more
divided doses per
day, for the desired treatment duration with an NS3 inhibitor compound.

Patient Identification

[0865] In certain embodiments, the specific regimen of drug therapy used in
treatment of the HCV patient is selected according to certain disease
parameters exhibited
by the patient, such as the initial viral load, genotype of the HCV infection
in the patient,
liver histology and/or stage of liver fibrosis in the patient.

[0866] Thus, some embodiments provide any of the above-described methods
for the treatment of HCV infection in which the subject method is modified to
treat a
treatment failure patient for a duration of 48 weeks.

[0867] Other embodiments provide any of the above-described methods for
HCV in which the subject method is modified to treat a non-responder patient,
where the
patient receives a 48 week course of therapy.

[0868] Other embodiments provide any of the above-described methods for the
treatment of HCV infection in which the subject method is modified to treat a
relapser
patient, where the patient receives a 48 week course of therapy.

[0869] Other embodiments provide any of the above-described methods for the
treatment of HCV infection in which the subject method is modified to treat a
naive patient
infected with HCV genotype 1, where the patient receives a 48 week course of
therapy.
[0870] Other embodiments provide any of the above-described methods for the
treatment of HCV infection in which the subject method is modified to treat a
naive patient
infected with HCV genotype 4, where the patient receives a 48 week course of
therapy.
[0871] Other embodiments provide any of the above-described methods for the
treatment of HCV infection in which the subject method is modified to treat a
naive patient
infected with HCV genotype 1, where the patient has a high viral load (HVL),
where
"HVL" refers to an HCV viral load of greater than 2 x 106 HCV genome copies
per mL
serum, and where the patient receives a 48 week course of therapy.
[0872] One embodiment provide any of the above-described methods for the
treatment of an HCV infection, where the subject method is modified to include
the steps of
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(l~ identifying a patient Iaving advanced or severe stage liver fibrosis as
measured by a
Knodell score of 3 or 4 and then (2) administering to the patient the drug
therapy of the
subject method for a time period of about 24 weeks to about 60 weeks, or about
30 weeks
to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to
about 48
weeks, or at least about 24 weeks, or at least about 30 weeks, or at least
about 36 weeks, or
at least about 40 weeks, or at least about 48 weeks, or at least about 60
weeks.

[0873] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having advanced or severe stage liver
fibrosis as measured
by a Knodell score of 3 or 4 and then (2) administering to the patient the
drug therapy of the
subject method for a time period of about 40 weeks to about 50 weeks, or about
48 weeks.

[0874] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 1 infection and an
initial viral
load of greater than 2 million viral genome copies per ml of patient serum and
then (2)
administering to the patient the drug therapy of the subject method for a time
period of
about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or
about 36 weeks
to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24
weeks, or at
least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks,
or at least
about 48 weeks, or at least about 60 weeks.
[0875] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 1 infection and an
initial viral
load of greater than 2 million viral genome copies per ml of patient serum and
then (2)
administering to the patient the drug therapy of the subject method for a time
period of
about 40 weeks to about 50 weeks, or about 48 weeks.
[0876] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 1 infection and an
initial viral
load of greater than 2 million viral genome copies per ml of patient serum and
no or early
stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2)
administering
to the patient the drug therapy of the subject method for a time period of
about 24 weeks to
about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to
about 50 weeks,
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or about 40'week to about 48 weeks, or at least about 24 weeks, or at least
about 30 weeks,
or at least about 36 weeks, or at least about 40 weeks, or at least about 48
weeks, or at least
about 60 weeks.

[0877] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 1 infection and an
initial viral
load of greater than 2 million viral genie copies per ml of patient serum and
no or early
stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2)
administering
to the patient the drug therapy of the subject method for a time period of
about 40 weeks to
about 50 weeks, or about 48 weeks.

[0878] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 1 infection and an
initial viral
load of less than or equal to 2 million viral genome copies per ml of patient
serum and then
(2) administering to the patient the drug therapy of the subject method for a
time period of
about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or
about 30 weeks
to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to
about 30
weeks, or up to about 36 weeks, or up to about 48 weeks.

[0879] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 1 infection and an
initial viral
load of less than or equal to 2 million viral genome copies per ml of patient
serum and then
(2) administering to the patient the drug therapy of the subject method for a
time period of
about 20 weeks to about 24 weeks.
[0880] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 1 infection and an
initial viral
load of less than or equal to 2 million viral genome copies per ml of patient
serum and then
(2) administering to the patient the drug therapy of the subject method for a
time period of
about 24 weeks to about 48 weeks.
[0881] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and
then (2)
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a:,m if r' 'Fop ,1utl: ndf,= tlv,k:.._.:f..' X:t ::lradministering to the
patient the drug therapy of the subject method for a time period of
about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or
about 36 weeks
to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24
weeks, or at
least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks,
or at least
about 48 weeks, or at least about 60 weeks.

[0882] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and
then (2)
administering to the patient the drug therapy of the subject method for a time
period of
about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or
about 30 weeks
to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to
about 30
weeks, or up to about 36 weeks, or up to about 48 weeks.

[0883] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and
then (2)
administering to the patient the drug therapy of the subject method for a time
period of
about 20 weeks to about 24 weeks.

[0884] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and
then (2)
administering to the patient the drug therapy of the subject method for a time
period of at
least about 24 weeks.

[0885] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV genotype 1 or 4 infection and
then (2)
administering to the patient the drug therapy of the subject method for a time
period of
about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or
about 36 weeks
to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24
weeks, or at
least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks,
or at least
about 48 weeks, or at least about 60 weeks.
[0886] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the
steps of (1) identifying a patient having an HCV infection characterized by
any of HCV
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CA 02560897 2007-08-08

genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug
therapy of the
subject method for a time period of about 20 weeks to about 50 weeks.
[0887] Another embodiment provides any of the above-described methods for
the treatment of an HCV infection, where the subject method is modified to
include the steps
of (1) identifying a patient having an HCV infection characterized by any of
HCV genotypes
5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of
the subject
method for a time period of at least about 24 weeks and up to about 48 weeks.
Subjects Suitable for Treatment
[0888] Any of the above treatment regimens may be administered to
individuals who have been diagnosed with an HCV infection. Individuals who are
infected
with HCV are identified as having HCV RNA in their blood, and/or having anti-
HCV
antibody in their serum. Any of the above treatment regimens may be
administered to
individuals who have failed previous treatment for HCV infection ("treatment
failure
patients," including non-responders and relapsers).
[0889] Individuals who have been clinically diagnosed as infected with HCV
are of particular interest in many embodiments. Individuals who are infected
with HCV are
identified as having HCV RNA in their blood, and/or having anti-HCV antibody
in their
serum. Such individuals include anti-HCV ELISA-positive individuals, and
individuals with
a positive recombinant immunoblot assay (RIBA). Such individuals may also, but
need not,
have elevated serum ALT levels.
[0890] Individuals who are clinically diagnosed as infected with HCV include
naive individuals (e.g., individuals not previously treated for HCV,
particularly those who
have not previously received IFN-(x-based and/or ribavirin-based therapy) and
individuals
who have failed prior treatment for HCV ("treatment failure" patients).
Treatment failure
patients include non-responders (i.e., individuals in whom the HCV titer was
not
significantly or sufficiently reduced by a previous treatment for HCV, e.g., a
previous IFN-a
monotherapy, a previous IFN-a and ribavirin combination therapy, or a previous
pegylated
IFN-a and ribavirin combination therapy); and relapsers (i.e., individuals who
were
previously treated for HCV, e.g., who received a previous IFN-(X monotherapy,
a previous
IFN-a and ribavirin combination therapy, or a previous pegylated IFN-a and
ribavirin
combination therapy, whose HCV titer decreased, and subsequently increased).
[0891] In particular embodiments of interest, individuals have an HCV titer of
at least about 105, at least about 5 x 105, or at least about 106, or at least
about 2 x 106,
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CA 02560897 2007-08-08

genome copies of HCV per milliliter of serum. The patient may be infected with
any HCV
genotype (genotype 1, including la and lb, 2, 3, 4, 6, etc. and subtypes
(e.g., 2a, 2b, 3a,
etc.)), particularly a difficult to treat genotype such as HCV genotype 1 and
particular HCV
subtypes and quasispecies.
[0892] Also of interest are HCV-positive individuals (as described above)
who exhibit severe fibrosis or early cirrhosis (non-decompensated, Child's-
Pugh class A or
less), or more advanced cirrhosis (decompensated, Child's-Pugh class B or C)
due to
chronic HCV infection and who are viremic despite prior anti-viral treatment
with IFN-a-
based therapies or who cannot tolerate IFN-a-based therapies, or who have a
contraindication to such therapies. In particular embodiments of interest, HCV-
positive
individuals with stage 3 or 4 liver fibrosis according to the METAVIR scoring
system are
suitable for treatment with the methods of the present embodiments. In other
embodiments,
individuals suitable for treatment with the methods of the embodiments are
patients with
decompensated cirrhosis with clinical manifestations, including patients with
far-advanced
liver cirrhosis, including those awaiting liver transplantation. In still
other embodiments,
individuals suitable for treatment with the methods of the embodiments include
patients
with milder degrees of fibrosis including those with early fibrosis (stages I
and 2 in the
METAVIR, Ludwig, and Scheuer scoring systems; or stages 1, 2, or 3 in the
Ishak scoring
system.).

Preparation of Section A Viral Inhibitors
[0893] Compounds of the general Formula I may be synthesized in the same
general manner as described below for compounds of the general Formulas lI-
XIX. The
syntheses of various specific compounds of the general Formula I are described
in the
Examples below. Those skilled in the art will appreciate variations in the
sequence and,
further, will recognize variations in the appropriate reaction conditions from
the analogous
reactions shown or otherwise known which may be appropriately used in the
processes
described below to make the compounds of formula I.
[0894] The products of the reactions described herein are isolated by
conventional means such as extraction, distillation, chromatography, and the
like.
[0895] The salts of the compounds of formula described above are prepared
by reacting the appropriate base or acid with a stoichiometric equivalent of
the compounds
of formula I.

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Preparation o 'Section B Viral inhibitors

[0896] The meanings of the terms and structural names used within this section
are the same as those in Section B above. Any references within this section
to a particular
number or label should be understood in the context of the corresponding
numbering or
labeling scheme used within this section or Section B above, rather than in
the context of a
possibly similar or identical numbering or labeling scheme used elsewhere
herein, unless
otherwise indicated.

[0897] The compounds of formulas II-X may be synthesized according to the
methods described below.

Methodology
Preparation of Compounds

[0898] Two methods were used in preparing compounds with formulas II-X. In
both methods, intermediates 1 and 4 were prepared according to the procedures
disclosed in
International Application PCT/CAOO/00353 (Publication No. WO 00/59929).
Intermediate
4 was also purchased from RSP Amino Acids.

Example 1-1: Synthesis of Compound # 101 (Compound AR00220042) by Method A:
OyN I i
O
HO,
O N O
0 H
H

A

Compound #101 (Compound AR00220042)
Method A:

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OH
NR1R2
OH BocN 2 I 1) CDI, DCM 0-- NRIR
HCI HZN
_~O + HATU, DIEA p O I p
BocN +
p DMF p H 1 O I 2) RjR2NH BocN BocN II
O O 0 "'0
H 3 p H p O
1 2 1:1 (1R, 2S)/(1S, 2R) 1 ,';\I
(1R, 2S) (1S, 2R)
O), NRi R2
O~NR1R2
NR1 Rz O
-0 Nolan's catalyst
p 1) 4N HCl (dioxane) 0 N (30 mol%) O O
BocN 2) HATU, DIEA, DMF BocHW. O DCE, 50 C BocHN,. N O
N
p H O BocHN,, O 0 H 0 p H
p OH 1 _
-
(1R, 2S) 4

OO NR1 R2
P
LiOH-H20 O N HOB
THF:MeOH:H20 BocHN,,. ' O
(2:1:1) O H~

Step 1: Synthesis of 2S-(1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-
hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3)
OH
OH
HCI'H2N + BocN 2,.
0 BocN HATU, DIEA
DMF p H O
HO O
2 3
1:1 (1R, 2S)/(1S, 2R)

[0899] To a flask charged with ethyl-(1R, 2S)/(1S, 2R)-1-amino-2-
vinylcyclopropyl carboxylate (1, 1.0 g, 5.2 mmol), trans-N-(tert-
Butoxycarbonyl)-4-
hydroxy-L-proline (2, 1.3 g, 1.1 equiv), and HATU (2.7 g, 1.1 equiv) were
added 30 mL
DMF to make a solution. It was cooled to 0 oC in an ice-water bath, followed
by slow
addition of a solution of DIEA (4.4 mL, 4 equiv) in DMF (15 mL) while
stirring. The
reaction was allowed to warm up to rt and stirred overnight

[0900] After 16 h, the reaction was complete as monitored by HPLC. It was
diluted with EtOAc (100 mL), washed with water (3 x 40 mL), sat. NaHCO3 (2 x
40 mL),
and brine (2 x 40 mL), then dried over Na2SO4 and concentrated down to give a
dark
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copper colored" oil. Tli'e 'crude was purified on silica gel (eluent:
acetone/hexanes 3:7),
giving pure 3 as tan foamy powder (770 mg, 32

Step 2: Syntheses of 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1-tert-
butoxycarbonyl-5-(1R-ethoxycarbonyl-2S-vinyl-cyclopropylcarbamoyl)-pyrrolidin-
3R-yl ester (5), and 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1-tert-
butoxycarbonyl-5-(1S-ethoxycarbonyl-2R-vinyl-cyclopropylcarbamoyl)-pyrrolidin-
3R-yl ester (6)

OH
BocN I 1) N_j L_/N O_(N O \\
0 NI ,,r0 2 O
H O 2) I c H BocN BocN ~2 ,,,
v 0 N~~ 1 O 0 14 'r0
3 DCM, rt H O H O

(1 R, 2S) 6 (IS, 2R)

[0901] The dipeptide 3 (300 mg, 0.81 mmol) was dissolved in DCM (8 mL),
followed by addition of CDI (163 mg, 1.2 equiv) in one portion. The reaction
was stirred at
rt overnight. After 15 h, the reaction was complete as monitored by TLC
(DCM/MeOH
9:1). 1,2,3,4-tetrahydroisoquinoline (0.32 mL, 3 equiv) was added to the
reaction portion-
wise, and the reaction was stirred at rt for overnight.

[0902] After 22h, TLC showed reaction complete. The reaction was diluted
with DCM (15 mL) and washed with IN aq. HCl (15 mL), brine (15 mL), dried
(Na2SO4),
and concentrated down. The crude was purified on silica gel (eluent:
DCM/Et2O/acetone
30:10:1). The top spot isolated (5) was white foamy powder (169 mg, 40 %), and
the
bottom spot (6) was white solid (156 mg, 38 %). MS m/e 550 (M++Na).

Step 3: Synthesis of 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1-(2S-tert-
butoxycarbonylamino-non-8-enoyl)-5-(1R-ethoxycarbonyl-2S-vinyl-
cyclopropylcarbamoyl)-pyrrolidin-3R-yl ester (7)

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O
O
O
N O HN,,
0 OH 1) 4N HCI (dioxane) O O
BocN O I + 2) HATU, DIEA, DMF o `H,'' N
O
O N'
N' O H
O Ol
H

4 7

[0903] The top isomer 5 (118 mg, 0.22 mmol) was dissolved in 4N HCl
(dioxane, 8 mL) and left at rt for 90 min to remove the BOC protective group.
It was then
concentrated down, taken up in acetonitrile and concentrated down again twice.
To this
light brownish residue was added 4 (66.8 mg, 1.1 equiv) and HATU (93.5 mg, 1.1
equiv),
followed by 2 mL DMF under nitrogen. The reaction was cooled on ice-water bath
for 15
min, after which a 0.5 mL DMF solution of DIEA (0.13 mL, 4 equiv) was added to
the
reaction drop-wise while stirring. The ice bath was left to slowly rise to rt
and the reaction
stirred for overnight.

[0904] After 24h, the reaction has turned dark brownish. Its aliquot TLC shows
reaction complete. The reaction was diluted with EtOAc (30 mL) and washed with
water
(3 x 15 mL), sat. NaHCO3 (2 x 15 mL), brine (15 mL), dried (Na2SO4), and
concentrated to
give 7 as an orange oily residue (156 mg). It was directly used in the next
step without
further purification. MS 1n/e 703 (M++Na).

Step 4: Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-
(3,4-
dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo
[14.3Ø0
4'6]nonadec-7-ene-4-carboxylic acid ethyl ester (8)

\ N N
N I/ 1
O
Y J

O )Lb O OYNO N O
O Cy3P
H/ O (30 mol%) N Isf,
H O DCE, 50 C OO
O H
7 8

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109.05i The crude 7 (135 mg, 0.2 mmol) was dissolved in 20 mL DriSolve DCE
to make a solution, followed by addition of the Nolan's catalyst (5 mg, 0.3
equiv) at rt under
nitrogen. The solution turned purplish. The reaction was put on a pre-heated
oil bath (50
C) and stirred for overnight.

[0906] After 10 h, the reaction had turned dark brownish. TLC (DCM/EtOAc
1:1) showed clean conversion to a new spot with slightly lower Rf. The
reaction was
concentrated down and purified on silica gel (eluent: DCM/EtOAc gradient from
5:1 to
2:1), giving product 8 as a tan foamy powder (75 ing, 58 %). MS m/e 653.1
(M++1).

Step 5: Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tent-Butoxycarbonylamino-18-
(3,4-
dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo
[14.3Ø0
4'6]nonadec-7-ene-4-carboxylic acid (Compound# 101)

O N I/ 0y N
~~
O l i
O O N HOB
O O
\\ N O=0 UGH-H20 W.
N 2 THF:MeOH:H2O O H
O H
(2:1:1)
8 Compound# 101

[0907] The macrocyclic ester 8 (60 mg, 0.092 mmol) was dissolved in 0.9 mL
of a mixed solvent (THF/MeOH/H20 2:1:1), followed by addition of LiOH-H20 (23
mg, 6
equiv). The mixture was stirred at rt for overnight. After 18h, TLC (DCM/MeOH
9:1)
showed a clean new spot with a lower Rf. The reaction was concentrated down to
almost
dryness and partitioned between 1N aq. HCl (15 mL) and DCM (20 mL). The
aqueous
layer was extracted with DCM (2 x 10 mL). The organic layers were combined,
dried over
Na2SO4 and concentrated down, giving compound # 101 as a light brownish foamy
powder
(50 mg, 87 %). 1H NMR (CD3OD, 400 MHz) 51.20-1.67 (m, 21H), 1.70-1.83 (m, 1H),
1.88-2.10 (m, 1H), 2.12-2.58 (m, 4H), 2.82 (m, 2H), 3.60-3.80 (m, 2H), 3.86
(m, 1H), 4.20
(m, 1H), 4.35 (m, 1H), 4.54 (s, 7H), 4.58 (m, 3H), 5.29-5.41 (m, 2H), 5.57 (m,
1H), 7.0-
7.24 (m, 4H). MS m/e 625.1 (M++1).

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Example 1-la:

OyN
O
H O N HO
N,,, O
O
;
O H,

Compound AR00220122

[0908] (1S, 4S, 6R, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4-
dihydro-1 H-is oquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo [
14.3Ø0
4,6]nonadec-7-ene-4-carboxylic acid (Compound AR00220122) was prepared
similarly
according to procedures described in Example 1-1, substituting compound 5 with
6 in Step
3. MS m/e 625 (M++l).

Example 1-2: Synthesis of Compound# 101 (Compound AR00220042) by Method B:
Method B:

OH OH pH
HCI=H2N + HATU, DIEA BocN 2 1) 4N HCI (dioxane) 0
N
BocN DMF O 2) HATU, DIEA, DMF BocHN,.
O O
/Pv) N1
O N O
HO 0 H 0 BocHN, 0
(1R, 2S) 11 OH
1 2 3
9
4

NR1R2
OH OY
Nolan's catalyst
or Hoveyda's Catalyst (8 %) 0 0
N \O 1) CDI, DCM O
BocHNi,. = N 0`=0
DCE, 50 C 0 Hmv 2) R1R2NH BocHN ,.
0 N>
H
OYNR1R2
O
LiOH-H20 0 N HOBO
BocHN,,. a
THF:MeOH:H20
(2:1:1) 0 H
II

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Compound' 1`01 was also prepared according to the above procedure.
The synthesis of the macrocyclic intennediate 10 described here is similar to
that described
in International Application PCT/CAOO/00353 (Publication No. WO 00/59929).

Step 1: Synthesis of 2S-(1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-
hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (3)
OH
OH II
31 HCI=HZN + BocN
O O BocN HATU, DIEA 7, o
0\ DMF O
H O
H 1
1 2 3
1:1 (1R, 2S)/(1S, 2R)
[0910] To a flask charged with ethyl-(1R, 2S)/(1S, 2R)-l-amino-2-
vinylcyclopropyl carboxylate (1, 1.0 g, 5.2 mmol), trans-N-(test-
Butoxycarbonyl)-4-
hydroxy-L-proline (2, 1.3 g, 1.1 equiv), and HATU (2.7 g, 1.1 equiv) were
added 30 mL
DMF to make a solution. It was cooled to 0 C in an ice-water bath, followed
by slow
addition of a solution of DIEA (4.4 mL, 4 equiv) in DMF (15 mL) while
stirring. The
reaction was allowed to warm up to rt and stirred overnight.

[0911] After 16 h, the reaction was complete as monitored by HPLC. It was
diluted with EtOAc (100 mL), washed with water (3 x 40 mL), sat. NaHCO3 (2 x
40 mL),
and brine (2 x 40 mL), then dried over Na2SO4 and concentrated down to give a
dark
copper colored oil. The crude was purified on silica gel (eluent:
acetone/hexanes 3:7),
giving pure 3 as tan foamy powder (770 mg, 32 %).

Step 2: Synthesis of 1R-{[1-(2S-tert-Butoxycarbonylamino-non-8-enoyl)-4R-
hydroxy-
pyrrolidine-2S-carbonyl]-amino}-2S-vinyl-cyclopropanecarboxylic acid ethyl
ester (9)
OH OH
I 1) 4N HCI (dioxane) O
BocN BocHN':. N
O 2) HATU, DIEA, DMF N O
O H O O H
O BOCHN, O
OH

3 9
4

[0912] Compound 3 (2.85 g, 7.7 mmol) was dissolved in 10 mL 4N HCl
(dioxane) and left at rt for 90 min to remove the Boc protective group. It was
then
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WO 2005/095403 PCT/US2005/010494
concentrated down, taken up in acetonitrile and concentrated down again twice.
To this
light brownish residue was added 4 (2.2 g, 8.1 mmol) and HATU (3.2 g, 8.5
minol),
followed by 80 mL DMF under nitrogen. The reaction was cooled on ice-water
bath for 15
min, after which a 5 mL DMF solution of DIEA (5.4 mL, 30.9 mmol) was added to
the
reaction drop-wise while stirring. The ice bath was left to slowly rise to rt
and the reaction
stirred for overnight.

[0913] After 18h, TLC showed reaction complete. The reaction was diluted
with EtOAc (300 mL) and washed with water (3 x 150 mL), sat. NaHCO3 (2 x 150
mL),
brine (150 mL), dried (Na2SO4), and solvent removed. The crude was purified by
silica gel
flash chromatography on Biotage 40M (eluent = 3 % to 5 % MeOH in DCM) to give
9 as a
brownish foamy solid (3.5 g, 87 %).

Step 3: Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-
hydroxy-
2,15-dioxo-3,16-diaza-tricyclo[14.3Ø0 4'6]nonadec-7-ene-4-carboxylic acid
ethyl ester
(10)
OH
O I OH
N Nolan's catalyst N
BocHN .. or Hoveyda's Catalyst (5 to 30 %) BocHN .. O
O
O H 0 O H
DCE, 50 C

9 10

[0914] Compound 9 (2.6 g, 5.0 mmol) was dissolved in 500 mL DriSolve DCE
in a 1 L round-bottomed flask to make a solution. It was degassed by bubbling
nitrogen
through for 1 h. Then the Hoveyda catalyst (0.25 equiv) was added at rt under
nitrogen.
The reaction was put on a pre-heated oil bath (50 C) and stirred for
overnight. After 16 h,
the reaction had turned dark brownish. TLC (DCM/EtOAc 1:1) showed clean
conversion
to a new spot with slightly lower Rf. The reaction was concentrated down and
purified on
silica gel (Biotage 40 M, eluent = DCM/EtOAc gradient from 1:1 to 1:2), giving
product 10
as a tan foamy powder (0.64 g, 52 %). 1H NMR (CDC13, 400 MHz) 8 1.21 (t, J =
7.0 Hz,
3H), 1.43 (s, 9H), 1.20-1.50 (m, 6H), 1.53-1.68 (m, 2H), 1.83-1.96 (m, 2H),
1.98-2.28 (m,
4H), 2.60 (m, 1H), 3.13 (brs, I H), 3.68 (m, I H), 3.94 (m, I H), 4.01-4.19
(m, 2H), 4.48 (m,
1H), 4.56 (brs, 1H), 4.79 (m, 1H), 5.26 (t, J= 9.4 Hz, 1H), 5.36 (d, J= 7.8
Hz, 1H), 5.53
(m, 1H), 7.19 (brs, I H). MS m/e 494.0 (M++1).

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WO 2005/095403 PCT/US2005/010494

Step 4: Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-
(3,4-
dihydro-IH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo
[14.3Ø0
4,6]nonadec-7-ene-4-carboxylic acid ethyl ester (11)

OH O
N O)\__O 1) CDI, DCM O
BocHN,,. = N OHO
O IN ~ 2) BocHN?~.
i NH O H
ZZ
11

[0915] The macrocyclic intermediate 10 (110 mg, 0.22 mmol) was dissolved in
DCM (2.2 mL), followed by addition of CDI (45 mg, 0.27 minol) in one portion.
The
reaction was stirred at rt overnight. After 15 h, the reaction was complete as
monitored by
TLC (DCM/MeOH 9:1). 1,2,3,4-tetrahydroisoquinoline (0.14 mL, 1.1 mmol) was
added to
the reaction drop-wise, and the reaction was stirred at rt for overnight.
After 22h, TLC
showed reaction complete. The reaction was diluted with DCM (6 mL) and washed
with
1N aq. HCl (2 x 2 mL), sat. sodium bicarbonate (2 mL), brine (2 mL), dried
(Na2SO4), and
concentrated down. The crude was purified on silica gel (Biotage 40S, eluent:
2 to 4 %
MeOH in DCM), giving 11 as a pale yellowish foamy powder (131 mg, 90 %).

Step 5: Compound 11 was hydrolyzed in the same fashion as described in the
Step 5
of Example 1-1 to give compound# 101.

[0916] The following compounds were also prepared according to Method B
described above, with 1,2,3,4-tetrahydroisoquinoline being substituted by
various other
secondary amines. Most of these amines were either purchased from commercial
sources,
or are known literature compounds, therefore were prepared using the
procedures listed
here (1. Stokker, G E. Tetrahedron Lett. 1996, 37(31), 5453-5456. 2. Chan, N
W.
Bioorganic & Medicinal Chemistry 2000, 8, 2085-2094. 3. Vecchietti, V. et al,
J. Med.
Chem. 1991, 34, 2624-2633.) For those amine inputs that were not directly
prepared
according to literature procedures, or the specific input has not been
reported in literature
before at our best knowledge, their syntheses are given within each example.

Example 1-3:

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CA 02560897 2007-08-08
N
O=~
O
O
H N \--OH
O~N,,.

~(O O H
Compound AR00226824
[0917] (1S, 4R, 6S, 14S, 18R)- 14-tert-Butoxycarbonylamino- 18-(6,7-
dimethoxy-3,4-dihydro- IH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[14.3 Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00226824)
was
synthesized according to Method B, except 6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline
was used in Step 4 instead. MS m/e 585.2 (M++1-100).

Example 1-4:

N N
O=~ H
O
O O
H N ~--OH
N.,
O~(0 O H~
Compound AR00226825
[0918] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-2,15-dioxo-18-
(1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-
ene-4-carboxylic acid (compound AR00226825) was synthesized according to
Method B,
except 2,3,4,9-Tetrahydro-IH-b-carboline was used in Step 4 instead. MS m/e
564.2
(M++ I-100).

Example 1-5:

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CA 02560897 2007-08-08
OY N
O
O~N1
O H~
H N O
..

H
O

Compound AR00291871
[0919] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-l8-(1,3-dihydro-
isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04' 6]nonadec-7-
ene-4-
carboxylic acid (compound AR00291871) was synthesized according to Method B,
except
2,3-Dihydro-lH-isoindole was used in Step 4 instead. 'H NMR (CDC13, 500 MHz) 6
1.21-
1.44 (m, 8H), 1.32 (s, 9H), 1.54-1.62 (m, 2H), 1.78-1.88 (m, 2H), 2.04-2.13
(m, 1H), 2.16-
2.23 (m, 1H), 2.24-2.36 (m, 2H), 2.66-2.74 (m, 1H), 3.87-3.90 (m, 1H), 4.15
(d, J = 11.0
Hz, 1H), 4.37-4.43 (m, 1H), 4.61-4.77 (m, 5H), 5.18 (t, J = 10.3 Hz, 1H), 5.24-
5.31 (m,
1H), 5.40-5.45 (m, 1H), 5.58-5.66 (m, 1H), 7.11-7.30 (m, 4H). MS m/e 611.0
(M++l).
Example 1-6:

OON I /
O
O HO
~No. N O
O
~(O O H~
Compound AR00291875
[0920] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(2,3-dihydro-
indole- l-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04' 6]nonadec-7-
ene-4-
carboxylic acid (compound AR00291875) was synthesized according to Method B,
except
2,3-Dihydro-lH-indole was used in Step 4 instead. MS m/e 610.9 (M++1).

Example 1-7:

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CA 02560897 2007-08-08
OyN I /
O F F
0\` O N O -F
,.OH
Ol_ W.

O H
Compound AR00294382
[0921] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-2,15-dioxo-18-
(8-trifluoromethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00294382) was
synthesized according to Method B, except 8-Trifluoromethyl-1,2,3,4-tetrahydro-

isoquinoline was used in Step 4 instead. MS m/e 693.0 (M+)

Example 1-8:
F F
F
O"~r N
O
O O O
N \\-OH
O N~
H
Compound AR00294383
[0922] (IS, 4R, 6S, 14S, 18R)-14-tert-B utoxycarbonylamino-2,15-dioxo-18-
(6-trifluoromethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00294383)
was
synthesized according to Method B, except 6-Trifluoromethyl-1,2,3,4-tetrahydro-

isoquinoline was used in Step 4 instead. 1H NMR (500 MHz, CDC13): S 7.46-7.38
(m, 2H),
7.26-7.18 (m, 1H), 6.98 (s, 1H), 5.62 (q, 1H), 5.42 (s, 1H), 5.21-5.15 (m,
2H), 4.78-4.60
(m, 3H), 4.40 (s, 1H), 4.16-4.00 (m, 1H), 3.92-3.81 (m, 1H), 3.80-3.60 (m,
2H), 3.00-2.85
(m, 2H), 2.72-2.64 (br s, 1H), 2.40-1.18 (m, 20H). MS: We 693.0 (M+).

Example 1-9:

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CA 02560897 2007-08-08

F
O"~' N
O
O
N 0%l--OH
N4>
H

Compound AR00294384
[0923] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5-fluoro-
3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00294384)
was
synthesized according to Method B, except 5-fluoromethyl-1,2,3,4-tetrahydro-
isoquinoline
was used in Step 4 instead. 1H NMR (500 MHz, CDC13): 8 7.19-7.11 (m, 1H), 7.05
(m,
1H), 6.91 (t, 2H), 5.62 (q, iH), 5.40 (s, 1H), 5.24 (d, 1H), 5.20 (t, 1H),
4.78 (s, 1H), 4.64-
4.56 (m, 2H), 4.42 (s, 1H), 4.12-4.02 (m, 1H), 3.92-3.81 (m, 1H), 3.78-3.61
(m, 2H), 2.84-
2.80 (m, 2H), 2.74-2.64 (m, 1H), 2.36-2.18 (m, 2H), 1.91-1.81 (m, 2H), 1.64-
1.54 (m, 2H),
1.48-1.10 (m, 15H). MS: m/e 643.0 (M+)

Example 1-10:
NH2
OyN I /
O
O
O O
N -OH
O)HS,.
O N4>
H

Compound AR00301745
[0924] (1S, 4R, 6S, 14S, 18R)-18-(5-Amino-3,4-dihydro-IH-isoquinoline-2-
carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00301745)
was
synthesized according to Method B, except 5-amino-1,2,3,4-tetrahydro-
isoquinoline was
used in Step 4 instead. MS: m/e 640.1 (M+)

Example 1-11:
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CA 02560897 2007-08-08
OyN I NH2
1O
\`H O N ~-OH
O Not~-
H
[0925] Compound AR00301749
[0926] (1S, 4R, 6S, 14S, 18R)-18-(7-Amino-3,4-dihydro-1H-isoquinoline-2-
carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00301749) was
synthesized according to Method B, except 7-amino-1,2,3,4-tetrahydro-
isoquinoline was
used in Step 4 instead. MS: We 640.1 (M+), 641.1 (M++1)

Example 1-12:

O
O"k N S
-NH
N

~ AOyN N~ O
OH
N
H
Compound AR00304000
[0927] (1 S, 4R, 6S, 14S, 18R)- 14-tert-Butoxycarbonylamino-2,15-dioxo- 18-(2-
phenylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304000)
was
synthesized according to Method B, except Phenyl-(4,5,6,7-tetrahydro-
thiazolo[5,4-
c]pyridin-2-yl)-amine was used in Step 4 instead. MS m/e 721.2 (M-1).

Example 1-13:

O.
N I a CI
O

O O O
N \\--OH
H

Compound AR00304062
-192-


CA 02560897 2007-08-08

[0928] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(7-chloro-3,4-
dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-
7-ene-4-carboxylic acid (compound AR00304062) was synthesized according to
Method B,
except 7-Chloro-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. MS
mle 659.0
(M+), 661.0 (M++2)

Example 1-14:
F
OYN I
O
O\\\\ O N O`\-OH
Ol'H,,. Y
N
H
Compound AR00304063
[0929] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-fluoro-3.4-
dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-
7-ene-4-carboxylic acid (compound AR00304063) was synthesized according to
Method B,
except 6-fluoro-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. MS
m/e 643.0
(M+), 644.0 (M++1)

Example 1-15:

N
O=(
O
O
O
HN'" N -OH
O 0 0 H~

Compound AR00304065
[0930] (1 S, 4R, 6S, 14S, 18R)- 14-tert-Butoxycarbonylamino-18-(4,4-
spirocyclobutyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-
diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304065)
was
synthesized according to Method B, except 4,4-siprocyclobutyl-1,2,3,4-
tetrahydro-
isoquinoline was used in Step 4 instead. 1H NMR (400 MHz, d6-acetone) S 7.99
(d, 1H),
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WO 2005/095403 PCT/US2005/010494
7:5'7.7:66(, Y'I ,' 7.2'7'(t, 'lH), 7.09-7.22 (m, 2H), 5.99 (bs, 1H), 5.56
(dd, 1H), 5.42 (bs,
1H), 5.19-5.30 (m, 1H), 4.52-4.70 (in, 1H), 4.27-4.42 (m, I H), 4.17-4.27 (in,
1H), 3.91 (dd,
1H), 3.63-3.82 (m, 2H), 2.22-2.51 (m, 6H), 1.93-2.20 (m, 3H), 1.79-1.91 (m,
1H), 1.52-
1.66 (m, 1H), 1.16-1.50 (in, 19H). MS in/z 665.1 (M++1)

Example 1-15a:

Preparation of 4,4-siprocyclobutyl-1,2,3,4-tetrahydro-isoquinoline:
LiAIH4 McOCOCI H
NC THE H,N,_~ TEA, THF McOUN
A B O
PPA LiAIH4
150 C HN THE HN

C O D

[0931] A: To a solution of 1-phenyl-l-cyclopropane carbonitrile (2.00 g, 12.7
mmol) in 100 ml THE was added a 1.0 M solution of LiAlH (19.1 ml, 19.1 mmol)
dropwise
at r.t. The reaction was stirred at r.t. for 15 hours, then quenched slowly at
OC with 10 ml
H2O and then 10 ml l.ON NaOH and stirred at r.t. for 1.5 hours. The solution
was filtered,
and the THE was removed by rotary evaporation. The aqueous was extracted with
EtOAc,
and the organic extract was washed with H2O and brine, dried over Na2SO4, and
concentrated to give 0.70 g (34%) of a clear oil which was used in the next
step without
further purification.

[0932] B: To a solution of C-(1-Phenyl-cyclobutyl)-inethylamine (0.70 g, 4.34
mmol) and TEA (0.67 ml, 4.78 mmol) in 40 ml THE at 0 C was added methyl
chloroformate dropwise. The reaction was stirred at r.t. for 15 hours. The
next day water
and EtOAc were added and the organic layer was separated and washed with 1N
HCl and
brine, dried over Na2SO4, concentrated to an oil, and used directly in the
next step without
further purification.

[0933] C: A mixture of (1-Phenyl-cyclobutylmethyl)-carbamic acid methyl
ester (0.95 g, 4.34 mmol) and PPA (20ml) were added to a sand bath preheated
to 150 C.
After 30 minutes the reaction was cooled to room temperature (r.t.). After
cooling, water
was added dropwise and the solution was extracted twice with DCM. The organic
extracts
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CA 02560897 2007-08-08

were washed with brine, dried over Na2SO4, and concentrated to a clear oil
which was used
directly in the in the next step without further purification.
[0934] D: To a solution of the 3,4-dihydro-2H-isoquinolin-l-one (0.406 g, 2.17
mmol) in 20 ml THE at 0 C was added a 1.0 M solution of LiA1H (3.26 ml, 3.26
mmol)
dropwise. The reaction was allowed to warm to r.t. and was stirred for 15
hours, then
quenched slowly at 0 C with 5 ml H2O and then 5 ml 1.ON NaOH and stirred at
r.t. for 1.5
hours. The solution was filtered, and the THE was removed by rotary
evaporation. The
aqueous was extracted with EtOAc, and the organic extract was washed with H2O
and brine,
dried over Na2SO4, and concentrated to give 0.21 g (56%) of a clear oil which
was used in the
next step without further purification.

Example 1-16:

N
O=(
O
O
O
HNC,. N ~-OH
00 O H'

Compound AR00304066
[0935] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4,4-dimethyl-
3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304066)
was
synthesized according to Method B, except 4,4-Dimethyl-1,2,3,4-tetrahydro-
isoquinoline was
used in Step 4 instead. 'H NMR (400 MHz, d6-acetone) b 7.98 (d, 1H), 7.39 (bs,
1H), 7.09-
7.24 (m, 3H), 5.99 (bs, 1H), 5.57 (dd, 1H), 5.37-5.46 (bs, 1H), 5.24 (dd, IH),
4.55-4.69 (m,
1H), 4.26-4.36 (m, 1H), 4.16-4.26 (m, 1H), 3.90 (dd, IH), 3.40-3.49 (m, 1H),
2.28-2.50 (m,
4H), 1.98-2.09 ( 2H), 1.79-1.92 (m, 1H), 1.52-1.65 (m, 3H), 1.16-1.51 (m,
22H). MS m/z
653.0 (M++1)

Example 1-16a:

HN

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CA 02560897 2007-08-08

[0936] 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline was prepared following the
experimental of steps A through D in Example 1-15a, 2-Methyl-2-phenyl-
propionitrile
(prepared according to Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc.
2000, 122,
712-713) was converted to the title compound.

Example 1-17:

N
O~

O
O
HNt,. N -OH
TN
00 O H
Compound AR00304067
[0937] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4-methyl-3,4-
dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-
7-ene-4-carboxylic acid (compound AR00304067) was synthesized according to
Method B,
except 4-methyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. 1H
NMR (400
MHz, d6-acetone) 6 7.93-8.03 (m, 1H), 7.04-7.28 (m, 4H), 6.02 (bs, 1H), 5.56
(dd, 1H), 5.40
(m, 1H), 5.23 (dd, 1H), 4.66-4.85 (m, 1H), 4.54-4.64 (m, 1H), 4.34-4.54 (m,
1H), 4.17-4.34
(m, 1H), 3.91 (dd, 1H), 3.57-3.78 (m, 1H), 3.42-3.57 (m, 1H), 2.26-2.52 (m,
4H), 1.96-2.09
(m, 2.0), 1.77-1.92 (m, 1.0), 1.50-1.64 (m, 3.0), 1.13-1.50 (m, 17h). MS m/z
639.0 (M++1)
Example 1-17a:

HN
[0938] 4-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 2-phenyl-
propylamine according to Grunewald, G. L.; Sall, D. J.; Monn, J. A. J. Med.
Chem. 1988, 31,
433-444.

Example 1-18:

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CA 02560897 2007-08-08
0
oAN s
>--NH
N

~OO~N N, 0
OH
H

Compound AR00304103
[0939] (1 S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino- I 8-(2-tert-
butylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-2,15-dioxo-
3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304103)
was
synthesized according to Method B, except tert-Butyl-(4,5,6,7-tetrahydro-
thiazolo[5,4-
c]pyridin-2-yl)-amine was used in Step 4 instead. MS We 731.2 (M++ 1).

Example 1-19:
0
ON S -NH
OH
AO'N N, 0
H

Compound AR00304154
[0940] (IS, 4R, 6S, 145, 18R)-18-(2-Amino-6,7-dihydro-4H-thiazolo[5,4-
c]pyridine-5-carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304154)
was
synthesized according to Method B, except 4,5,6,7-Tetrahydro-thiazolo[5,4-
c]pyridin-2-
ylamine was used in Step 4 instead. MS m/e 675.1 (M++1).

Example 1-20:
0
O-'- N 3
v '
N
~OOTN O N" 0
OH
N
H

Compound AR00304158
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CA 02560897 2007-08-08

[0941] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(2-methyl-6,7-
dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304158)
was
synthesized according to Method B, except 2-Methyl-4,5,6,7-tetrahydro-
thiazolo[5,4-
c]pyridine was used in Step 4 instead. MS m/e 546.2 (M++1-100).

Example 1-21:
O
ON N
ON N O
O
OH
H

Compound AR00304183
[0942] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-l8-(7,8-dihydro-
5H-pyrido[4,3-d]pyrimidine-6-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304183) was
synthesized according to Method B, except 5,6,7,8-Tetrahydro-pyrido[4,3-
d]pyrimidine was
used in Step 4 instead. MS m/e 625.2 (M-1).

Example 1-22:

O~N
O
~H O N HO
/ N,,O
O
H
O

Compound AR00312023
[0943] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4-dihydro-
l H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadecane-4-
carboxylic acid (Compound AR00312023) was synthesized according to Method B,
except
that the ring-closing metathesis product 10 from step 3 was further reduced
with H2 / Rh-
A1203 before the next coupling step (WO 0059929, p.p. 76-77). MS m/e 625.3 (M-
1).

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CA 02560897 2007-08-08
Example 1-23:
O
0-1-N I \
M NH2
0 N H O
_0OH
O
H

Compound AR00314578
[0944] (1S, 4R, 6S, 14S, 18R)-18-(6-Amino-3,4-dihydro-lH-isoquinoline-2-
carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00314578)
was
synthesized according to Method B, except 1,2,3,4-Tetrahydro-isoquinolin-6-
ylamine was
used in Step 4 instead. MS (POS ESI) m/z 540.2 [parent, (M++1)-100 (Boc
group)].

Example 1-24:
O 0
,>-NH
O)~N S
N
0'N N O
OH
N
H

Compound AR00314685
[0945] (1S, 4R, 6S, 14S, 18R)-18-(2-Acetylamino-6,7-dihydro-4H-thiazolo[5,4-
c]pyridine-5-carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00314685) was
synthesized according to Method B, except N-(4,5,6,7-Tetrahydro-thiazolo[5,4-
c]pyridin-2-
yl)-acetamide was used in Step 4 instead. MS We 589.2 (M++1-100).

Example 1-25:

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CA 02560897 2007-08-08

1~ N
0Y N I /
O
O
H N \\-OH
O

H
O

Compound AR00315997
[0946] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5-
dimethylamino-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-
diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00315997) was
synthesized according to Method B, except Dimethyl-(1,2,3,4-tetrahydro-
isoquinolin-5-yl)-
amine (Example 1-25a) was used in Step 4 instead. MS We 668.0 (M+).

Example 1-25a
NMe2
bOH
[0947] The synthesis of dimethyl-(1,2,3,4-tetrahydro-isoquinolin-5-yl)-amine
is
described in the following scheme:
1) Boc2O, NaOH
NH2 2) NaH, Mel NMe2
3) TFA, DCM
\ \
/ NH I / NH
[0948] To a solution of 5-aminotetrahydroisoquinoline (3.68 g, 24.8 mmol) in
1,4-dioxane (100 mL) was added 3 N NaOH (8.27 mL, 24.8 mmol). After cooling to
0 C,
(Boc)20 (5.42 g, 24.8 mmol) in 1,4-dioxane (10 mL) was added drop-wise and
stirred for
overnight at room temperature. The reaction mixture was poured into water and
extracted
with EtOAc (2x). The combined organic layers was washed with sat. aq. NaHCO3
solution,
water, and brine, then dried and concentrated. The residue was purified by
silica gel column
chromatography to give 5.44 g (88%) of the desired Boc-protected product as a
white solid.
[0949] To a solution of the product from the previous step described above
(0.2
g, 0.81 mmol) in THE (5 mL) was added NaH at 0 T. After 15 minutes, CH3I was
added and
the stirring continued for overnight at room temperature. After completion the
reaction
mixture was quenched with ice water, extracted with EtOAc (25 mL), dried
(Na2SO4) and
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CA 02560897 2007-08-08

concentrated. The Boc group was removed with 60% TFA-DCM (2 mL) at 0 C to
give 110
mg (77.5%) of the final product as a light greenish solid. MS: 177.1 (MH+).

Example 1-26:

ci
O. N
O
O
O
!~H N ~--OH
O N,,.

H
O

Compound AR00315998
[0950] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5-chloro-1,3-
dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-
4-carboxylic acid (Compound AR00315998) was synthesized according to Method B,
except
5-Chloro-2,3-dihydro-lH-isoindole was used in Step 4 instead. 1H NMR (400 MHz,
CDC13):
S 7.24-7.02 (m, 3H), 6.82 (s, 1H), 5.68-5.51 (m, 1H), 5.36 (s, 1H), 5.11-4.96
(m, 2H), 4.67-
4.44 (m, 5H), 4:29-4.20 (m, 1H),4.20-4.11(m, 1H), 3.82-3.74 (m, 1H), 2.69-2.55
(m, 1H),
2.31-2.15 (m, 1H), 2.14-2.06 (m, 1H), 2.03 (s, 1H), 2.01-1.86 (m, 1H), 1.86-
1.24 (m, 11H),
1.22 (s, 9H). MS: m/e 644.9 (M+), 646.9 (M++2)

Example 1-27:
C1
OY N
O
O
H N \\-OH
O
O No.
N
H
Compound AR00315999
[0951] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5,6-dichloro-
1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-
ene-4-carboxylic acid (Compound AR00315999) was synthesized according to
Method B,
except 5,6-Dichloro-2,3-dihydro-lH-isoindole was used in Step 4 instead. 'H
NMR
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CA 02560897 2007-08-08

(400 MHz, CDC13): S 7.29 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 5.57-5.50 (m,
1H), 5.33 (s, 1H),
5.23-5.09 (m, 2H), 4.73-4.65 (m, 1H), 4.64-4.48 (m, 5H), 4.33-4.29 (m, 1H),
4.11-4.02 (m,
1H), 3.82-3.74 (m, 1H), 2.73-2.61 (m, 1H), 2.29-2.08 (m, 3H), 2.01 (s, 1H),
1.83-1.65 (m,
2H), 1.63-1.46 (m, 2H), 1.40-1.12 (m, 15H). MS: m/e 678.9 (M+), 681 (M++2)

Example 1-28:

bN'
O=<
0
O
H N O
NI.- -OH
O H
Compound AR00320122
[0952] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4R-methyl-3,4-
dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-
7-ene-4-carboxylic acid (Compound AR00320122) was synthesized according to
Method B,
except 4R-Methyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead.
1H NMR (400
MHz, CD3OD) 8 7.02-7.24 (m, 3H), 5.59 (dd, 1H), 5.30-5.44 (m, 2H), 4.66-4.81
(m, 1H),
4.14-4.64 (m, 3H), 3.83-3.92 (m, 1H), 3.58-3.81 (m, 1H), 3.44-3.56 (m, 1H),
2.86-3.86 (m,
1H), 2.23-2.58 (m, 4H), 1.87-2.13 (m, 2H), 1.70-1.87 (m, 1H), 1.50-1.70 (m,
3H), 1.07-1.51
(m, 19H), 0.80-0.96 (m, 2H). MS m/z 639.0 (M++1)

Example 1-29:

0\-llj
N
O=<
0
O
N O
OyN,,.-OH
O H
Compound AR00320123
[0953] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4S-methyl-3,4-
dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø046]
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CA 02560897 2007-08-08

nonadec-7-ene-4-carboxylic acid (Compound AR00320123) was synthesized
according to
Method B, except 4S-Methyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4
instead. 1H
NMR (400 MHz, CD3OD) 8 7.01-7.23 (m, 3H), 5.58 (dd, 1H), 5.32-5.45 (m, 2H),
4.66-4.82
(m, 1H), 4.12-4.64 (m, 3H), 3.86-3.94 (m, 1H), 3.52-3.74 (m, 1H), 3.43-3.56
(m, 1H), 2.88-
3.85 (m, 1H), 2.24-2.60 (m, 4H), 1.87-2.15 (m, 2H), 1.71-1.87 (m, 1H), 1.52-
1.70 (m, 3H),
1.07-1.52 (m, 19H), 0.80-0.96 (m, 2H). MS m/z 639.0 (M++1)

Example 1-30:

T NO-

O=<
O
O
N,. N OOH
O t~
Compound AR00320576
[0954] (IS, 4R, 6S, 14S, 18R)-14-tert-B utoxycarbonylamino- l 8-[4-(2-methoxy-
phenyl)-piperidine-1-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'
6]nonadec-7-ene-
4-carboxylic acid (Compound AR00320576) was synthesized according to Method B,
except
4-(2-Methoxy-phenyl)-piperidine was used in Step 4 instead. MS m/e 583.3 (M++1-
100).
Example 1-31:
O O\
N

H
H N O
O '10 (:~
OYN,,. OH
O H

Compound AR00320577
[0955] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-methoxy-
1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320577)
was

-203-


CA 02560897 2007-08-08

synthesized according to Method B, except 6-Methoxy-2,3,4,9-tetrahydro-IH-b-
carboline
was used in Step 4 instead. MS We 594.2 (M++1-100).

Example 1-32:

O No
OAN I \
~OAO~N N" O
OH
N
H
Compound AR00301383

[0956] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-2,15-dioxo-18-(1-
piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00301383)
was
synthesized according to Method B, except 1-Piperidin-1-ylmethyl-1,2,3,4-
tetrahydro-
isoquinoline was used in Step 4 instead. lH NMR (500 MHz, CD3OD) S 7.33 - 7.24
(m,
4H), 7.20 (br s, IH), 6.61 (br s, IH), 5.75 - 5.52 (m, 2H), 5.50 - 5.33 (m,
2H), 4.63 - 4.43
(m, 2H), 4.42 - 4.07 (m, 4H), 3.96 (br s, I H), 3.67 - 3.11 (m, 5H), 3.06 -
2.88 (m, 2 H),
2.86 - 2.74 (m, 2 H), 2.56 - 2.35 (m, 3H), 2.23 (q, 1H), 2.04 - 1.90 (m, 2H),
1.89 - 1.52 (m,
IOH), 1.51 - 1.32 (m, 12H); MS (POS APCI) m/z 722.3 (M++1).

Example 1-33:

oo
OAN I \
~O OTN O H O
N N,' OH
H

Compound AR00333842
[0957] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-methoxy- l -
methoxymethyl-3,4-dihydro-IH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-

tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333842)
was
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CA 02560897 2007-08-08

synthesized according to the procedures described in Example 1-2, except that
6-methoxy-l-
methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used to replace
1,2,3,4-
Tetrahydro-isoquinoline in Step 4 instead. MS (APCI-): m/z 697.2 (M-1).

Example 1-34:
F
N
0-0-1-0
Of NO
OH
OA N=, O
H
Compound AR00365349
[0958] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-l8-(5-fluoro-l-
methoxymethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-
diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00365349) was
synthesized according to the procedures described in Example 1-2, except that
5-fluoro-l-
methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used to replace
1,2,3,4-
Tetrahydro-isoquinoline in Step 4 instead. MS (APCI-): m/z 685.3 (M-1).

Example 1-35:

O
O~N I ~
~OAO~N O H O
OH
N
H
Compound AR00333224
[0959] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(1-
dimethylaminomethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-
3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333224)
was
synthesized according to the procedures described in Example 1-2, except that
dimethyl-
(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-amine (synthesized according to
Example 1-35a)
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CA 02560897 2007-08-08

was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS
(APCI+): mlz
582.3 (MH+-Boc).

Example 1-35a:

~
HN I \

[0960] Dimethyl-(1,2,3,4-tetrahydro-isoquinolin-l-ylmethyl)-amine was
synthesized by a similar fashion as shown in Example 3-76a, except that in
Step 1,
phenethylamine was used to replace 2-(3-methoxy-phenyl)-ethylamine, and that
in the first
part of Step 3, dimethyl-amine was used to replace sodium methoxide as the
nucleophile.
The crude product was used directly in the next coupling step without further
purification.
Example 1-36:
ro
O NJ
O-kN

O
O
` ON O N%
JJJ OH
H

Compound AR00333225

[0961] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(1-morpholin-
4-ylmethyl-3,4-dihydro- I H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333225)
was
synthesized according to the procedures described in Example 1-2, except that
1-morpholin-
4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to Example 1-
36a) was
used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS (APCI-):
m/z 722.3
(M-1).

Example 1-36a:

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CA 02560897 2007-08-08
O

HN I

[0962] 1 -Morpholin-4-ylmethyl- 1,2,3,4-tetrahydro-isoquinoline was
synthesized by a similar fashion as shown in Example 3-76a, except that in
Step 1,
phenethylamine was used to replace 2-(3-methoxy-phenyl)-ethylamine, and that
in the first
part of Step 3, morpholin was used to replace sodium methoxide as the
nucleophile. The
crude product was used directly in the next coupling step without further
purification.

Example 1-37:

O
O' N

OO N H O
N,' OH
XO'`N O
H
Compound AR00333248
[0963] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-methoxy-l-
piperidin-1-ylmethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-
3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333248)
was
synthesized according to the procedures described in Example 1-2, except that
6-methoxy-l-
piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to
Example 1-
37a) was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS
(APCI-):
m/z 750.4 (M- 1).

Example 1-37a:

ND
HN

[0964] 6-Methoxy-l-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was
synthesized by a similar fashion as shown in Example 3-76a, except that in the
first part of
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CA 02560897 2007-08-08

Step 3, piperidine was used to replace sodium methoxide as the nucleophile.
The crude
product was used directly in the next coupling step without further
purification.

Example 1-38:

0 NJ
Or N

O
OAO:N NH , OH
N
H
Compound AR00333276
[0965] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-methoxy- t -
morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-
3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333276)
was
synthesized according to the procedures described in Example 1-2, except that
6-methoxy-l-
morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to
Example 1-
38a) was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS
(APCI-):
m/z 750.3 (M-1).

Example I -38a:
r o
N.J
HN
O"
[0966] 6-Methoxy- l -morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was
synthesized by a similar fashion as shown in Example 3-76a, except that in the
first part of
Step 3, morpholin was used to replace sodium methoxide as the nucleophile. The
crude
product was used directly in the next coupling step without further
purification.

Example 1-39:

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CA 02560897 2007-08-08

O & O'er
OO N H O
OA N N OH
- = ~ O
H
Compound AR00333277
[0967] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(1-
dimethylaminomethyl-6-methoxy-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-
dioxo-
3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound
AR00333277)
was synthesized according to the procedures described in Example 1-2, except
that (6-
methoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-dimethyl-amine (synthesized
according
to Example 1-39a) was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step
4 instead.
MS (APCI+): m/z 712.3 (MH+).

Example 1-39a:

N~
HN I \

[0968] 6-Methoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-dimethyl-amine
was synthesized by a similar fashion as shown in Example 3-76a, except that in
the first part
of Step 3, dimethylamine was used to replace sodium methoxide as the
nucleophile. The
crude product was used directly in the next coupling step without further
purification.

Example 1-40:

F
N
O:--,-O
_~'O/X 0. N H O
~'J( N'' OH
N O
H

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CA 02560897 2007-08-08
Compound AR00365369

[0969] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4-fluoro-1,3-
dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-
4-carboxylic acid (Compound AR00365369) was synthesized according to the
procedures
described in Example 1-2, except that 4-fluoro-2,3-dihydro-1H-isoindole
(synthesized
according to Example 3-55a) was used to replace 1,2,3,4-tetrahydro-
isoquinoline in Step 4
instead. 'H NMR (500 MHz, DMSO) 8 12.21 (br s, 1 H), 8.66 (br s, 1 H), 7.35
(q, 1 H),
7.19 (d, 1 H), 7.11 (q, 2 H), 7.03 (br s, I H), 5.51 (q, I H), 5.33 - 5.21 (m,
2 H), 4.66 (s, 4
H), 4.22 (q, I H), 4.24 (t, I H), 3.99 - 3.89 (m, 1 H), 3.73 - 3.64 (m, I H),
2.65 - 2.55 (m, 1
H), 2.28 - 2.08 (m, 3 H), 1.77 - 1.61 (m, 2 H), 1.54 - 1.42 (m, l H), 1.42 -
1.03 (m, 16 H);
MS (APCI-): m/z 627.3 (M-1).

Example 1-41

oNS

N
O01-O
'o O~ N H O
N
A OH
N o
H
Compound AR00371946
[0970] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-[5-(2-
morpholin-4-yl-ethoxy)-1,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-
diaza-
tricyclo[ I4.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00371946)
was
synthesized according to the procedures described in Example 1-2, except that
5-(2-
Morpholin-4-yl-ethoxy)-2,3-dihydro-1 H-isoindole (prepared according to the
procedures
described in J. Med. Chem. 2002, Vol. 45, No. 26, 5771, preparation method D,
and in
Bioorg. Med. Chem. Lett. 11 (2001) 685-688. For the N-Boc protected amine
input: 'H
NMR (500 MHz, CDC13) b 7.13 (dd, 1H), 6.85 - 6.74 (m, 2H), 4.61 (t, 4H), 4.10
(t, 2H),

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CA 02560897 2007-08-08

3.73 (t, 4H), 2.81 (t, 2H), 2.61 - 2.54 (m, 4H), 1.51 (s, 9H); MS (APCI+): mlz
349.1 (M+1))
was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 instead. MS
(APCI+): m/z
640.3 [(M+1)-Boc].

Example 1-42

N-
0

N
o

j ,N N O
OH
N O
H
Compound AR00371947
[0971] (1 S, 4R, 6S, 14S, 18R)- 14-tert-Butoxycarbonylamino- 18-[5-(2-
dimethylamino-ethoxy)- 1,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-
diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00371947)
was
synthesized according to the procedures described in Example 1-2, except that
[2-(2,3-
Dihydro-IH-isoindol-5-yloxy)-ethyl]-dimethyl-amine (prepared according to the
procedures
described in J. Med. Chem. 2002, Vol. 45, No. 26, 5771, preparation method D,
and in
Bioorg. Med. Chem. Lett. 11 (2001) 685-688. For the N-Boc protected amine
input: 'H
NMR (500 MHz, CDC13) S 7.14 (dd, 1H), 6.88 - 6.76 (m, 2H), 4.61 (t, 4H), 4.04
(t, 2H),
2.72 (t, 2H), 2.34 (s, 6H), 1.50 (s, 9H); MS (APCI+): m/z 307.1 (M+1)) was
used to replace
1,2,3,4-tetrahydro-isoquinoline in Step 4 instead. MS (APCI+): m/z 698.2
(M+1).

Example 1-43

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CA 02560897 2007-08-08
HN-~
O

N
O--~-O
O O~- N N, 0
O-kN O OH
H

Compound AR00371948

[0972] (1 S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-[5-(2-
isopropylamino-ethoxy)-1,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-
diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00371948) was
synthesized according to the procedures described in Example 1-2, except that
[2-(2,3-
Dihydro- I H-isoindol-5-yloxy)-ethyll-isopropyl-amine (prepared according to
the procedures
described in J. Med. Chem. 2002, Vol. 45, No. 26, 5771, preparation method D,
and in
Bioorg. Med. Chem. Lett. 11 (2001) 685-688. For the N-Boc protected amine
input: 'H
NMR (500 MHz, CDC13) b 7.13 (dd, IH), 6.86 - 6.75 (m, 2H), 4.62 (t, 4H), 4.06
(t, 2H),
2.99 (t, 2H), 2.88 (septuplet, 1H), 1.62 (br s, 1H), 1.51 (s, 9H), 1.10 (d,
6H); MS (APCI+):
m/z 321.2 (M+ 1)) was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step
4 instead. MS
(APCI-): m/z 710.3 (M-1).

Preparation of Compounds with General Structure III
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
2 OYNR1R2 ONR1R2
O N O~ 4N HCI (dioxane) O N O R3X N O~
BocHN,,. O e HZN,,. O R3HN,,. O
N"> HCl O N
O H _ O H H
X= OC(O)CI, NCO, COCI ]

la
OYNRIR2
O
O
LiOH-H20 N HOBO
R3HN,,.
THE/MeOH/H2O O N
III

[0973] Compounds with general structure II were prepared according to the
general scheme shown above. A compound with structure la was first removed of
its Boc
protective group, followed by nucleophillic attack of the amino group on an
electrophile, to
form a carbamate, amide, or urea.

Example 2-1:

OyN I i
O
O
H N HOBO
O-~ N,,.
O O
H~

Compound AR002473 10

Step 1: Preparation of (1S, 4R, 6S, 14S, 18R)-14-Amino-18-(3,4-dihydro-iH-
isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø0
4'6]nonadec-7-ene-
4-carboxylic acid ethyl ester.

OYN I / I \
OYN
O
O 4N HCI (Dioxane)
~=O _ O O
05-H ,,, N HZN,,. N ~O
O H HCI O H v

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
[0974] The -Boc protected starting material (102 mg, 0.16 mmol) was
dissolved in 6 mL 4N HCl (dioxane), and left at rt for 90 min. HPLC showed
complete
removal of the Boc protective group. The reaction mixture was then
concentrated down,
taken up in acetonitrile and concentrated down again twice. The resulting
light brownish
foamy powder was carried out to the next step.

Step 2: Preparation of (1S, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-
18-
(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid ethyl ester.

OyN I

O O O O
H2N,,. N ~=0 ~J~OyCI THF, TEA ~H,,, N
O m
HCI O H O O H I~

[0975] To a solution of cyclopentanol (42 mg, 0.48 mmol) in THE (16 mL), a
toluene solution of phosgene (0.42 mL, 1.9 M, 0.80 mmol) was added drop-wise.
The
mixture was stirred at rt for 2 h to form the cyclopentyl chloroformate
reagent. The
reaction was then concentrated down to about half the volume. It was then
diluted with
DCM to the original volume, and concentrated down again to half the volume, in
order to
completely remove excess phosgene. This solution of the cyclopentyl
chloroformate was
further diluted with THE (16 mL), cooled to 0 C, and added to the solid
residue (0.16
mmol) from Step 1 above at 0 C. TEA (0.11 mL, 0.81 mmol) was then added to
the
reaction mixture, and the reaction was stirred at 0 C for 2 h. The reaction
was complete by
HPLC. It was concentrated down, taken up in EtOAc (15 mL), and then washed
with
water, sat. sodium bicarbonate, water, and brine (10 mL each), dried over
Na2SO4 and
concentrated down. The crude yellowish thick oil residue was purified by flash
chromatography on Biotage 40S (eluent = hexanes/EtOAc 1:1), giving the desired
product
as a white crispy foamy powder (65.2 mg, 63 %). MS (MH+ 665.2)

Step 3: Preparation of (1S, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-
18-
(3,4-dihydro-iH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00247310).

-214-


CA 02560897 2007-08-08

OI OyN I /
N I /
O
p O O LiOH, THF/MeOH/H2O O\\`` O N HO
N ~p !~N ,,O
p~H,,. p H
0 /-H H~
N
O H

[0976] Followed the same hydrolysis procedures as in Step 5 of Example 1-1.
[0977] The following compounds were also prepared following the same
procedures as aforementioned in Example 2-1, with either the cyclopentyl
chloroformate being
substituted by other electrophiles, and/or the P2-tetrahydroisoquinoline being
substituted by
other amine inputs as illustrated in Step 4 of Method B in Example 1-2.

Example 2-2:

N
O=<
O
O

0 0 H
Compound AR00294376
[0978] (iS, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-lH-isoquinoline-2-carbonyloxy)-
14-methoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04' 6]nonadec-7-
ene-4-
carboxylic acid (Compound AR00294376) was synthesized according to the
procedures
described in Example 2-1, except that methyl chloroformate was used in Step 2
instead.
Example 2-3:

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CA 02560897 2007-08-08

F
(:p
N
O=<
O
O
H N O
O~N,,.-OH
O O H
Compound AR00304074
[0979] (1S, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-18-(5-fluoro-
3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304074)
was
synthesized according to the procedures described in Examples 1-2 and 2-1,
except that 5-
Fluoro-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4 of Example 1-
2. MS m/e
583.2 (M++1).

Example 2-4:

N
O~ F F F
O
O
H O
N ~'-OH
O O H
Compound AR00304075
[0980] (IS, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-2,15-dioxo-18-
(8-trifluoromethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304075)
was
synthesized according to the procedures described in Examples 1-2 and 2-1,
except that 8-
trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4 of
Example 1-2. MS
m/e 705.1 (M++ 1).

Example 2-5:

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CA 02560897 2007-08-08
N
O==<
p
O O`\
N~,. N Y-OH
O O H~
Compound AR00304076
[0981] (IS, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-18-(1,3-
dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-
carboxylic acid (Compound AR00304076) was synthesized according to the
procedures
described in Examples 1-2 and 2-1, except that 2,3-Dihydro-lH-isoindole was
used instead in
Step 4 of Example 1-2. MS m/e 623.2 (M++ 1).

Example 2-6:

N
O O
H N O
OH
O
O H

Compound AR00304125
[0982] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-lH-isoquinoline-2-carbonyloxy)-
14-(2-fluoro-ethoxycarbonylamino)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-
4-carboxylic acid (Compound AR00304125) was synthesized according to the
procedures
described in Example 2-1, except that 2-fluoroethanol was used to form the
chloroformate
reagent in Step 2 instead of cyclopentanol. MS m/e 615.1 (M++ 1).

Example 2-7:

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CA 02560897 2007-08-08
N
O=<
O
O
O
O~H N ~OH
O~ O O TN

Compound AR00304126
[0983] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-1H-isoquinoline-2-carbonyloxy)-
2,15-dioxo-14-(tetrahydro-furan-3S-yloxycarbonylamino)-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304126) was
synthesized according to the procedures described in Example 2-1, except that
tetrahydro-
furan-3S-ol was used to form the chioroformate reagent in Step 2 instead of
cyclopentanol. MS
m/e 639.2 (M++1).

Example 2-8:

N
O=<
O
O
O
OC)O"rW. N OH
O O N
H
Compound AR00304127
[0984] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-IH-isoquinoline-2-carbonyloxy)-
2,15-dioxo-14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304127)
was
synthesized according to the procedures described in Example 2-1, except that
tetrahydro-
furan-3R-ol was used to form the chloroformate reagent in Step 2 instead of
cyclopentanol. MS
m/e 639.2 (M++1).

Example 2-9:

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CA 02560897 2007-08-08
N
O=<
O
O
W. N O\\--OH
~O
O O O H~
Compound AR00320002
[0985] (IS, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-lH-isoquinoline-2-carbonyloxy)-
2,15-dioxo-14-(tetrahydro-pyran-4-yloxycarbonylamino)-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320002) was
synthesized according to the procedures described in Example 2-1, except that
tetrahydro-
pyran-4-ol was used to form the chloroformate reagent in Step 2 instead of
cyclopentanol. MS
m/e 653.2 (M++1).

Example 2-10:
it
N
O=~
O
O O
H N ~--OH
00 O O H~
Compound AR00320074
[0986] (1S, 4R, 6S, 14S, 18R)-18-(1,3-Dihydro-isoindole-2-carbonyloxy)-2,15-
dioxo-14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-
7-ene-4-carboxylic acid (Compound AR00320074) was synthesized according to the
procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-lH-
isoindole was used
instead in Step 4 of Example 1-2, and that tetrahydro-furan-3R-ol was used to
form the
chloroformate reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS
m/e 625.2
(M++ 1).

Example 2-11:

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CA 02560897 2007-08-08
N
o=
O
0 O
H N -OH

O H O O lI

Compound AR00320075
[0987] (IS, 4R, 6S, 14S, 18R)-18-(1,3-Dihydro-isoindole-2-carbonyloxy)-2,15-
dioxo- l4-(tetrahydro-furan-3S-yloxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-
ene-4-carboxylic acid (Compound AR00320075) was synthesized according to the
procedures
described in Examples 1-2 and 2-1, except that 2,3-Dihydro-1H-isoindole was
used instead in
Step 4 of Example 1-2, and that tetrahydro-furan-3S-ol was used to form the
chloroformate
reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS m/e 625.2
(M++1).

Example 2-12:
i
N
o=
O
O O
H N \-OH
F~ W.

O O H
Compound AR00320076
[0988] (1 S,4R,6S, 14S, 18R)- 18-(1,3-Dihydro-isoindole-2-carbonyloxy)-2,15-
dioxo- 14-(2-fluoro-ethoxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-
carboxylic acid (Compound AR00320076) was synthesized according to the
procedures
described in Examples 1-2 and 2-1, except that 2,3-Dihydro-1H-isoindole was
used instead in
Step 4 of Example 1-2, and that 2-fluoroethanol was used to form the
chloroformate reagent in
Step 2 of Example 2-1 instead of cyclopentanol. MS m/e 601.1 (M++1).

Example 2-13:

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CA 02560897 2007-08-08
N
O=
O
0 O
H N \~--OH
O-1~N ,,
O O O H~
Compound AR00320077
[0989] (IS, 4R, 6S, 14S, 18R)-18-(1,3-Dihydro-isoindole-2-carbonyloxy)-2,15-
dioxo-14-(tetrahydro-pyran-4-yloxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-
ene-4-carboxylic acid (Compound AR00320077) was synthesized according to the
procedures
described in Examples 1-2 and 2-1, except that 2,3-Dihydro-]H-isoindole was
used instead in
Step 4 of Example 1-2, and that tetrahydro-pyran-4-ol was used to form the
chloroformate
reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS m/e 601.1 (M++
1).

Example 2-14:
C1
O.-Y N
O
OO O
O N-OH
~H
O H
Compound AR00320445
[0990] (1S, 4R, 6S, 14S, 18R)-18-(5,6-Dichloro-1,3-dihydro-isoindole-2-
carbonyloxy)-2,15-dioxo-14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-diaza-

tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320445)
was
synthesized according to the procedures described in Examples 1-2 and 2-1,
except that 5,6-
dichloro-2,3-dihydro-1H-isoindole was used instead in Step 4 of Example 1-2,
and that
tetrahydro-furan-3R-ol was used to form the chloroformate reagent in Step 2 of
Example 2-1
instead of cyclopentanol. MS: m/e 693.0 (M+), 695.1 (M++2).

Example 2-15:

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CA 02560897 2007-08-08

r (-N CI
OY N
O
O0 0
O N,.. N Z~--OH
N">
H

Compound AR00320448
[0991] (IS, 4R, 6S, 14S, 18R)- 18-(5-Chloro- 1,3-dihydro-isoindole-2-
carbonyloxy)-2,15-dioxo- 14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-
diaza-
tricyclo[14.3 Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320448)
was
synthesized according to the procedures described in Examples 1-2 and 2-1,
except that 5-
dichloro-2,3-dihydro-lH-isoindole was used instead in Step 4 of Example 1-2,
and that
tetrahydro-furan-3R-ol was used to form the chloroformate reagent in Step 2 of
Example 2-1
instead of cyclopentanol. 1H NMR (500 MHz, CD3OD): S 7.38 (s, 1H), 7.32-7.28
(m, 2H),
7.22 (d, 1H), 7.10 (br s, 1H), 5.56-5.50 (q, 1H), 5.42-5.38 (t, 1H), 5.35 (br
s, 1H), 4.80-4.48
(m, 6H), 4.44 (m, 1H), 4.16 (d, 1H), 3.84 (dd, 1H), 3.78-3.69 (m, 1H), 3.68-
3.60 (m, 1H), 3.50
(t, 1H), 2.55-2.36 (m, 3H), 2.21-2.12 (m, 1H), 1.98-1.85 (m, 1H), 1.72-1.62
(m, 2H), 1.61-1.51
(m, 2H), 1.50-1.20 (m, 9H). MS: We 659.1 (M+), 661.1 (M+2)

Example 2-16:

O
0
O N.. N Z~--OH
0 N-

AR00248689
[0992] Synthesis of (1S, 4R, 6S, 14S, 18R)-14-(Cyclopentanecarbonyl-amino)-
18-(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR248689)
[0993] Cyclopentyl carboxylic acid was first loaded on PS-TFP resin (purchased
from Argonaut Technologies) to form an active ester. The activated ester on
resin (26 mg,
1.16 mmol/g, 0.03 mmol) was swelled in 0.5 mL chloroform first, followed by
addition of
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CA 02560897 2007-08-08

MP-carbonate resin (purchased from Argonaut Technologies, 300 mg, 2.5 mmol/g,
0.75
mmol). To this resin mixture was then added 0.5 M chloroform solution of the
macrocyclic
material (15 mg, 0.02 mmol), and the reaction was shaken for overnight at it
The reaction
was complete by HPLC after 16h. It was then filtered and concentrated down,
giving clean
N-acylated product. It was then hydrolyzed following the same hydrolysis
procedures as in
Step 5 of Example 1-1, giving the desired product AR248689 as a white solid
(12.5 mg, 88
%). MS (APCI+): m/z 621.3 (MH+).

Example 2-17:

0
O
O
O H N O~--OH
O N~
H

Compound AR00248687
[0994] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-1H-isoquinoline-2-
carbonyloxy)-14-(2,2-dimethyl-propionylamino)-2,15-dioxo-3,16-diaza-
tricycio[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00248687)
was
synthesized following the same procedures as described in Example 2-16, except
that tert-
butyl carboxylic acid was first loaded on PS-TFP resin instead. MS (APCI+):
m/z 609.3
(MH+).

Example 2-18:

O\/N
O
O O H N O\-OH

0 N~
H
Compound AR00248688
[0995] (1 S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro- I H-isoquinoline-2-
carbonyloxy)-
14-isobutyrylamino-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-
carboxylic
acid (Compound AR00248688) was synthesized following the same procedures as
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
escri e in Example 2-16, except that isopropyl carboxylic acid was first
loaded on PS-
TFP resin instead. MS (APCI+): m/z 595.3 (MH).

Example 2-19:

N
O==(
O
H O N \~-OH
Boc-N-~-I Nmm
H O O H

Compound AR00298989

Synthesis of (1S, 4R, 6S, 14S, 18R)-14-(2-tert-Butoxycarbonylamino-3-methyl-
butyrylamino)-18-(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-
diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR298989)

N O N
C (~P
O O r
1) Boc N O \\ O
O O O O O
N \\-OEt ~~ H N \--OH
HZN,,. N,,.
O H~ DCM, rt Boc-N O H'>
2) LIOH

[0996] 14-Amino-l8-(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-
3,16-diaza-tricyclo[14.3Ø04,6]nonadec-7-ene-4-carboxylic acid ethyl ester
(120 mg, 217
umol) and N-a-t-Boc-L-valine N-hydroxysuccinamide ester (96 mg, 300 umol) were
stirred
together in 1.1 mL dichloromethane for 14 hours. The solvent was removed in
vacuo and 1
mL each of water and ethyl acetate were added. The phases were separated and
the
aqueous layer was washed twice with 500 uL of ethyl acetate. The combined
organics were
dried over MgSO4 and the solvents removed in vacuo to provide the desired
compound as a
white solid (132 mg, 81%). MS na/z 752.2 (MH+).

Example 2-20:

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CA 02560897 2007-08-08

N
O:=<
O
O
O \~ H N 0
N,,. -OH
C i H O O H
N =
Compound AR00301338
[0997] (IS, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-1 H-isoquinoline-2-
carbonyloxy)-14- (3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino }-2,15-
dioxo-
3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound
AR00301338)
was synthesized following the same procedures as described in Example 2-19,
except that 3-
methyl-2-[(pyrazine-2-carbonyl)-amino]-butyric acid 2,5-dioxo-pyrrolidin-l-yl
ester was used
to replace N-a-t-B oc-L-valine N-hydroxysuccinamide ester instead. MS m/e
730.3 (M++1).
Example 2-21:

O=<
O
O N,,. N ~-OH
- H O
&-~
O
N
1 /
Compound AR00304072
[0998] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-1 H-isoquinoline-2-
carbonyloxy)-14-{ 2-[(6-dimethylamino-pyridine-3-carbonyl)-amino]-3-methyl-
butyrylamino }-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-
carboxylic acid
(Compound AR00304072) was synthesized following the same procedures as
described in
Example 2-19, except that 2-[(6-Dimethylamino-pyridine-3-carbonyl)-amino]-3-
methyl-
butyric acid 2,5-dioxo-pyrrolidin-l-yl ester was used to replace N-a-t-Boc-L-
valine N-
hydroxysuccinamide ester instead. 'H NMR (CD3OD, 500 MHz): 6 8.69 (s, 1 H),
8.46 (s, 1
H), 8.37-8.39 (m, 1 H), 8.14-8.21 (m, 2 H), 7.07-7.18 (m, 5 H), 5.63 (q, I H),
5.36-5.42 (m, 2
H), 4.49-4.56 (m, 3 H), 4.42-4.45 (m, 1 H), 4.31-4.32 (m, 1 H), 3.92-3.95 (m,
1 H), 3.65-
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CA 02560897 2007-08-08

3.72 (m, 2 H), 2.85-2.91 (m, 2 H), 2.33-2.55 (m, 4 H), 1.93-2.03 (m, 3 H),
1.61-1.68 (m, 3
H), 1.27-1.52 (m, 12 H), 0.86-0.96 (m, 8 H). MS We 770.4 (M-1).

Example 2-22:

N
O--X
O
O
W. N O)- OH
O H
N 1 H 0
O O
Compound AR00304073
[0999] (IS, 4R, 6S, 14S, 18R)- 18-(3,4-Dihydro- IH-isoquinoline-2-
carbonyloxy)- 14-{ 3-methyl-2-[(pyridine-3-carbonyl)-amino]-butyrylamino }-
2,15-dioxo-3,16-
diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound
AR00304073) was
synthesized following the same procedures as described in Example 2-19, except
that 3-
Methyl-2-[(pyridine-3-carbonyl)-amino]-butyric acid 2,5-dioxo-pyrrolidin-1-yl
ester was used
to replace N-a-t-Boc-L-valine N-hydroxysuccinamide ester instead. MS m/e 729.2
(M++1).
Example 2-23:

N
O=(
O
H N O
N,.. ZLOH
H2N
O O H-1-1
Compound AR00298990
[1000] (IS, 4R, 6S, 14S, 18R)-14-(2-Amino-3-methyl-butyrylamino)-18-(3,4-
dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04,6]nonadec-
7-ene-4-carboxylic acid (Compound AR00298990) was prepared by following the
same
procedures as the Step I of Example 2-1. MS We 624.2 (M++1).

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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
Example-12-2`4:"`

N
O-(
O
O
NON,,. N \LOH

O O H

Compound AR00294378

Synthesis of (1S, 4R, 6S, 14S, 18R)-14-(3-Cyclopentyl-ureido)-18-(3,4-dihydro-
lH-
isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo
[14.3Ø04'6]nonadec-7-ene-
4-carboxylic acid (Compound AR294378)

cp ~/N
O O NCO O-\
O
O DIEA, DCM O O
O
H2Ni,. N \\--OEt H N,., N \\-OH
2) UGH Nom(

[1001] 14-Amino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1 H-
isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[ 14.3Ø04,6]nonadec-7-ene-4-
carboxylic
acid ethyl ester hydrochloride salt (49 mg, 74 umol), diisopropylethylamine
(29 mg, 222
umol), and cyclopentyl isocyanate (25 mg, 222 umol) were taken up in 375 uL
dichloromethane and stirred at 19 C for 1 hour. The reaction was loaded
directly onto a
C18 flash column and eluted with water/acetonitrile (10 to 100 %) containing
0.1% TFA to
provide the title product as a white solid (42 mg, 77%). MS m/z 732.2 (MH+).

Example 2-25:

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CA 02560897 2007-08-08
N
O
O
H H N O
~N-f N,. OH

O O
Compound AR00294377
[1002] (1S, 4R, 6S, 14S, 18R)-14-(3-tert-Butyl-ureido)-18-(3,4-dihydro-lH-
isoquinoline-2-carbonyloxy)-2, l 5-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-
carboxylic acid (Compound AR00294377) was synthesized according to the
procedures
described in Examples 1-2 and 2-24, except that tert-butyl isocyanate was used
to replace
cyclopentyl isocyanate in the Example 2-24 procedures. MS We 624.1 (M++1).

Example 2-26:
F
( :p
N
O=<
O
O
H H N O
N"~ NJ,. -OH
O O H

Compound AR00304077
[1003] (IS, 4R, 6S, 14S, 18R)-14-(3-Cyclopentyl-ureido)-18-(5-fluoro-3,4-
dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-
7-ene-4-carboxylic acid (Compound AR00304077) was synthesized according to the
procedures described in Examples 1-2 and 2-24, except that 5-Fluoro-1,2,3,4-
tetrahydro-
isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of
Example 1-2.
MS m/e 654.2 (M++ 1).

Example 2-27:

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CA 02560897 2007-08-08

F
O= F F
O
O
H O
NN~,. N OH
O O H

Compound AR00304078
[1004] (IS, 4R, 6S, 14S, 18R)-14-(3-Cyclopentyl-ureido)-2,15-dioxo-18-(8-
trifluoromethyl-3,4-dihydro-I H-isoquinoline-2-carbonyloxy)-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304078) was
synthesized according to the procedures described in Examples 1-2 and 2-24,
except that 8-
trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-
isoquinoline in Step 4 of Example 1-2. MS m/e 704.1 (M++1).

Example 2-28:

PN
O=~
O
O
O
H N \\--OH
NON
O O H
Compound AR00304079
[1005] (IS, 4R, 6S, 14S, 18R)-14-(3-Cyclopentyl-ureido)-18-(1,3-dihydro-
isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-
ene-4-
carboxylic acid (Compound AR00304079) was synthesized according to the
procedures
described in Examples 1-2 and 2-24, except that 2,3-dihydro-IH-isoindole was
used to
replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. MS m/e 622.2
(M++1).
Example 2-29:

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CA 02560897 2007-08-08
9N
O=~
O
O O
H N ~-OH
NON,õ
O O N'00>
Compound AR00320078
[1006] (1S, 4R, 6S, 14S, 18R)-14-(3-tert-Butyl-ureido)-18-(1,3-dihydro-
isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-
ene-4-
carboxylic acid (Compound AR00320078) was synthesized according to the
procedures
described in Examples 1-2 and 2-24, except that 2,3-dihydro-1 H-isoindole was
used to
replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that
tert-butyl
isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24
procedures. MS
m/e 610.1 (M++1).

Example 2-30:

O~N I /
O
O O`\
H W. -OH
O O N
H
Compound AR00320221
[1007] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-lH-isoquinoline-2-
carbonyloxy)-2,15-dioxo-l4-[3-(tetrahydro-furan-3-yl)-ureido]-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320221) was
synthesized according to the procedures described in Examples 1-2 and 2-24,
except that 3-
isocyanato-tetrahydro-furan was used to replace cyclopentyl isocyanate in the
Example 2-24
procedures. MS m/e 638.2 (M++ 1).

Example 2-31:

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CA 02560897 2007-08-08

CI
~- a~xl~
OY N
O
0 O O
N `\
H Y-OH
W.

H
Compound AR00320449
[1008] (1S, 4R, 6S, 14S, 18R)-14-(3-tert-Butyl-ureido)-18-(5-chloro-1,3-
dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'
6]nonadec-7-ene-
4-carboxylic acid (Compound AR00320449) was synthesized according to the
procedures
described in Examples 1-2 and 2-24, except that 5-chloro-2,3-dihydro- I H-
isoindole was used
to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that
tert-butyl
isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24
procedures. 'H
NMR (500 MHz, CD3OD): S 7.34 (s, 1H), 7.28-7.25 (m, 2H), 7.24 (s, 1H), 7.20
(s, 1H), 5.51
(m, 2H), 5.40 (s, 1H), 4.73-4.60 (m, 3H), 4.53 (t, 1H), 4.38 (d, 1H), 4.28 (d,
1H), 3.98 (dd,
1H), 2.43 (m, 2H), 2.38-2.30 (m, 1H), 2.12-2.00 (m, 2H), 1.81-1.70 (m, 1H),
1.64-1.56 (m,
3H), 1.48-1.20 (m, 8H), 1.18 (s, 9H). MS: m/e 644.0 (M+), 645.9 (M++2)

Example 2-32:
C1
CI
OYN
O
O O
N `\
JAN,.. Y--OH
H
H O N~
H
Compound AR00320450
[1009] (IS, 4R, 6S, 14S, 18R)-14-(3-tert-Butyl-ureido)-18-(5,6-dichloro-1,3-
dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-
4-carboxylic acid (Compound AR00320450) was synthesized according to the
procedures
described in Examples 1-2 and 2-24, except that 5,6-dichloro-2,3-dihydro-1H-
isoindole was
used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and
that tert-butyl
isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24
-231-


CA 02560897 2007-08-08

procedures. 1H NMR (500 MHz,CD3OD): S 7.50 (s, 1H), 7.38 (s, 1H), 5.56 (q,
1H), 5.42-
5.38 (m, 2H), 4.72-4.61 (m, 4H), 4.55 (t, 1H), 4.34 (dd, 1H), 4.28 (d, 1H),
3.92 (dd, 1H),
2.45-2.32 (m, 2H), 2.32-2.18 (m, 1H), 2.08-2.00 (m, 1H), 1.75-1.68 (m, 1H),
1.63-1.54 (m,
3H), 1.50-1.22 (m, 8H), 1.18 (s, 9H). MS: We 678.0 (M+), 680.0 (M++2).

Example 2-33
F
iO ? N

O 9
aJN 0 N H O
OH
O
H
Compound AR00365381
[1010] (IS, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-18-(5-fluoro-
1-methoxymethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-
diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00365381)
was
synthesized according to the procedures described in Examples 1-2 and 2-1,
except that 5-
fluoro-l-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used to
replace
1,2,3,4-Tetrahydro-isoquinoline in Step 4 of Example 1-2 instead. MS (APCI-):
m/z 697.4
(M-1).

Preparation of Compounds with General Structure IV

OONR1R2 O I NR1R2
P p 0
0 HO 1. CDI, DMF 0 O 0`S-R3
N O N NH
R4HN,,. 2. R3SO2NH2 R4HN~,.
H~ H

III IV
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
1f(11l ,.,Co'm p"oun"ds"' with general structure IV were prepared according to
the
[
scheme shown above (1. Khan et al, Bioorg. & Med. Chem. Lett., 1997, 7 (23),
3017-3022.
2. International Application PCT/US02/39926, WO 03/053349).

Example 3-1:

O~N
O O
O O O
\ NH
O H
N 0
O
H

Compound AR00261408

Synthesis of (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic
acid 14-
tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-
diaza-tricyclo [14.3Ø04'6] nonadec-7-en-18-yl ester (AR00261408)

O N I/ O OC
O O O`Q
O O HO 1. CDI, DMF, 40 C
O -~I
\\\\ N \O 2. DBU, 40 C N NH
~`NO. O N,,.
O H O1, ,O H NII:~-
NH2

[1012] The macrocyclic acid compound# 101 (7 mg, 0.011 mmol) was
dissolved in 0.1 mL DMF, followed by addition of CDI (1.8 mg, 0.011 minol).
The
mixture was stirred in a 40 C oil bath for 1 h. Then cyclopropylsulfonamide
(2.0 mg, 0.017
mmol) was added to the reaction, followed by DBU (1.7 mg, 0.011 mmol). The
reaction
was stirred at 40 C for overnight. After 14h, LCMS showed reaction complete.
The
reaction was cooled to rt, partitioned between 2 mL EA and 2 mL 5 % HC1 (aq).
The
organic layer was washed with water, bicarb (2 mL ea), then dried (Na2SO4).
The crude was
flashed on Biotage 12M (eluent = DCM:MeOH 20:1), giving AR00261408 (4.2 mg, 52
%)
1H NMR (CDC13, 500 MHz): 6 0.80-2.10 (m, 25H), 2.20-2.27 (m, 1H), 2.37-2.59
(m, 3H),
2.84 (m, 1H), 3.60-3.70 (m, 1H), 3.82-3.90 (m, 1H), 4.20-4.30 (m, 2H), 4.45-
4.70 (m, 5H),
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CA 02560897 2006-09-20
WO 2005/095403 PCT/US2005/010494
2H), 5.74 (m, 1H), 6.74 (m, 1H), 7.0-7.23 (m, 4H). MS
m/e 728.0 (M++H).

Example 3-2:

O~N
O
O O
0
N
O\\ \ NH
O HIS.
N">
O H

Compound AR00261407

[1013] 1S, 4R, 6S, 145, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
14-tert-butoxycarb onyl amino-2,15 -dioxo-4-(propane-2-sulfonylamino carbonyl)-
3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00261407) was
synthesized
according to the procedures described in Example 3-1, except that isopropyl
sulfonamide
was used to replace cyclopropyl sulfonamide in the coupling step. MS m/e 728.4
(M-1).
Example 3-3:

OYN
O
O
'
O O
N O \~-NiH
O H1,.
O H
Compound AR00254906

[1014] 1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
14-tert-butoxycarbonylamino-4-methanesulfonylamino carb onyl-2,15 -dioxo-3,16-
diaza-
tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00254906) was
synthesized
according to the procedures described in Example 3-1, except that methyl
sulfonamide was
used to replace cyclopropyl sulfonamide in the coupling step. 1H NMR (CDC13,
500 MHz):
1.20-1.52 (m, 16H), 1.54-1.98 (m, 5H), 2.20-2.30 (m, 1H), 2.38-2.46 (m, 1H),
2.47-2.59
(m, 3H), 2.84 (m, 1H), 3.18 (s, 3H), 3.56-3.70 (m, 1H), 3.82-3.90 (m, 1H),
4.22-4.33 (m,
2H), 4.47-4.69 (m, 4H), 4.90-5.10 (m, 2H), 5.47 (brs, I H), 5.74 (m, 1H), 6.74
(m, I H),
7.03-7.23 (m, 4H). MS m/e 701.9 (M), 602.2 (parent, MH+-Boc group).

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CA 02560897 2007-08-08
Example 3-4:

O'Y N 01

O O
O O O O, i
DH,,. H
qO
Compound AR00261409
[1015] (IS, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
4-(butane- l-sulfonylaminocarbonyl)-14-tert-butoxycarbonylamino-2,15-dioxo-
3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00261409) was
synthesized
according to the procedures described in Example 3-1, except that n-butyl
sulfonamide was
used to replace cyclopropyl sulfonamide in the coupling step. 1H NMR (CDC13,
500 MHz):
80.80-1.03 (m, 7H), 1.20-2.10 (m, 22H), 2.20-2.60 (m, 4H), 2.84 (m, 1H), 3.20
(m, I H),
3.44 (m, 1H), 3.65 (m, IH), 3.80-3.95 (m, 1H), 4.20-4.34 (m, 2H), 4.50-4.65
(m, 4H), 4.95-
5.05 (m, 1H), 5.30-5.39 (m, 1H), 5.44-5.49 (m, 1H), 5.74 (m, 1H), 6.74 (m,
1H), 7.0-7.23 (m,
4H). MS We 743.3 (M+, APCI-).

Example 3-5:

OON I /
O
O O O O`SO
- N ~-NH
O N,,.
0
H
Compound AR00282131
[1016] (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-
3,16-
diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00282131) was
synthesized according to the procedures described in Examples 2-1 and 3-1. MS
We 738.4
(M-1).

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CA 02560897 2007-08-08
Example 3-6:

O.Y N
O
O
O O O`\ O` S
H N Y NH
W.
0
H
Compound AR00294381
[1017] (1S, 4R, 6S, 14S, 18R)-1,3-Dihydro-isoindole-2-carboxylic acid 14-tert-
butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00294381) was
synthesized
according to the procedures described in Examples 1-5 and 3-1. 'H NMR (CDC13,
500
MHz): 8 0.89-2.08 (m, 25H), 2.21-2.28 (m, 1H), 2.41-2.49 (m, 1H), 2.51-2.61
(m, 2H), 2.91
(m, 1H), 3.83 (m, 1H), 4.21 (m, 1H), 4.40 (d, J = 11.7 Hz, 1H), 4.53-4.80 (m,
5H), 4.95-5.04
(m, 2H), 5.47 (brs, 1H), 5.72 (m, 1H), 6.77 (m, 1H), 7.16 (m, 1H), 7.23-7.31
(m, 3H). MS
m/e 712.3 (APCI-, M-H).

Example 3-7:
F
Oy
O
O O O S
N O=-<
OHi,. H
N
H
Compound AR00298996
[1018] (IS, 4R, 6S, 14S, 18R)-5-Fluoro-3,4-dihydro-IH-isoquinoline-2-
carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-
dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound
AR00298996)
was synthesized according to the procedures described in Examples 1-2 and 3-1,
except that
5-Fluoro-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-isoquinoline
in Step 4 of Example 1-2. 'H NMR (400 MHz, CDCl3): 810.05 (s, 1H), 8.12 (s,
IH), 7.04 (s,
1H), 6.84-6.73 (m, 2H), 6.70 (s, 1H), 5.65 (q, IH), 5.40 (s, IH), 4.59 (m,
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CA 02560897 2007-08-08

2H), 4.54-4.40 (m, 3H), 4.30-4.10 (m, 2H), 3.82-3.74 (m, 1H), 3.72-3.51 (m,
2H), 2.92-2.68
(m, 3H), 2.55-2.30 (m, 3H), 2.21-2.15 (m, 1H), 2.00-1.60 (m, 3H), 1.40-0.75
(m, 18H). MS:
m/e 746.0 (M+).

Example 3-8:

O,~, N I /
F F
O O~NH F
N

~ O O
H

Compound AR00298997
[1019] (1S, 4R, 6S, 14S, 18R)-8-Trifluoromethyl-3,4-dihydro-lH-isoquinoline-
2-carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-
dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound
AR00298997)
was synthesized according to the procedures described in Examples 1-2 and 3-1,
except that
8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-
isoquinoline in Step 4 of Example 1-2. 'H NMR (500 MHz, CD3OD): S 7.55 (dd,
1H), 7.42
(dd, IH), 7.35 (t, 1H), 5.71-5.61 (m, 1H), 5.40 (m, 1H), 4.60 (s, 1H), 4.52
(m, 1H), 4.42 (m,
1H), 4.15 (m, IH), 3.91 (m, IH), 3.78-3.62 (m, 2H), 3.00-2.82 (m, 3H), 2.58-
2.52 (m, 3H),
2.51-2.32 (m, 2H), 1.86-1.56 (m, 3H), 1.41 (m, 2H), 1.32-1.21 (m, 5H), 1.04-
0.98 (m, 14H).
MS: m/e 795.9 (M+).

Example 3-9:

0 N CI
Y O
O
O O N O 0_S-<
W. N

H
O

Compound AR00301746
[1020] (1S, 4R, 6S, 14S, 18R)-7-Chloro-3,4-dihydro-lH-isoquinoline-2-
carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-
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CA 02560897 2007-08-08

dioxo-3,16-diaza-tricyclo[ 14.3Ø04' 6]nonadec-7-en-18-yl ester (Compound
AR00301746)
was synthesized according to the procedures described in Examples 1-2 and 3-1,
except that
7-chloro-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-isoquinoline
in Step 4 of Example 1-2. 'H NMR (400 MHz, CDC13): 6 10.10 (s, 1H), 7.08 (d,
1H), 7.02-
6.96 (m, 2H), 6.60 (d, 1H), 5.64 (q, 1H), 5.40 (s,1H), 4.92-4.41 (m, 2H), 4.55-
4.40 (m, 3H),
4.28-4.12 (m, 2H), 3.82-3.75 (m, 1H), 3.65-3.46 (m, 3H), 2.88-2.80 (m, 1H),
2.78-2.56 (m,
2H), 2.52-2.42 (m, 1H), 2.38-2.30 (m, 1H), 2.21-2.12 (q, 1H), 1.82-1.74 (m,
2H), 1.45-1.12
(m, 16H), 1.10-0.98 (m, 2H), 0.90-0.75 (m, 2H). MS m/e 761.9 (M+)

Example 3-10:
F F
F
OYN I /
O
O O O O,S
~~Nr,. NH
N
H
Compound AR00301747
[10211 (IS, 4R, 6S, 14S, 18R)-6-Trifluoromethyl-3,4-dihydro-lH-isoquinoline-
2-carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-
dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound
AR00301747)
was synthesized according to the procedures described in Examples 1-2 and 3-1,
except that
6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-
isoquinoline in Step 4 of Example 1-2. 1H NMR (500MHz, CD3OD): S 7.44 (m, 2H),
7.38-
7.30 (m, I H), 7.28-7.24 (m, I H), 5.65 (q, 1H), 5.40 (m, 1H), 5.08 (m, I H),
4.56 (brs, 2H),
4.60-4.50 (m, 1H), 4.48 (m, 1H), 4.15 (d, 1H), 3.88 (d, 1H), 3.75-3.67 (m,
2H), 2.93-2.82 (m,
3H), 2.66-2.54 (m, 1H), 2.52-2.44 (m, 1H), 2.42-2.40 (m, 2H), 1.91-1.76 (m,
2H), 1.74-1.70
(dd, I H), 1.64-1.58 (m, I H), 1.54-1.36 (m, 4H), 1.34-1.25 (m, 12H), 1.50-
1.20 (m, 2H),
1.00-0.70 (m, 1H), 0.52-0.34 (m, 1H). MS: m/e 795.9 (M+)

Example 3-11:

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CA 02560897 2007-08-08

0 F
Y N I /
O
\\\\ 0
l_N,,o N ~V -S-<

H N H
0 -
H

Compound AR00301751
[1022] (1S, 4R, 6S, 145, 18R)-6-Fluoro-3,4-dihydro-1H-isoquinoline-2-
carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-
dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound
AR00301751)
was synthesized according to the procedures described in Examples 1-2 and 3-1,
except that
6-fluoro-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-isoquinoline
in Step 4 of Example 1-2. 'H NMR (500 MHz, CD3OD): S 7.21-7.02 (m, 1H), 6.92
(m, 2H),
6.92 (m, 2H), 5.68 (q, 1H), 5.40 (m, 1H), 5.08 (t, 1H), 4.58 (m, 2H), 4.45 (m,
1H), 4.12 (d,
1H), 3.88 (d, 1H), 3.78-3.60 (m, 3H), 2.86-2.72 (m, 3H), 2.71-2.61 (m, 1H),
2.52-2.42 (m,
1H), 2.41-2.34 (m, 1H), 1.88-1.76 (m, 2H), 1.74-1.70 (m, 1H), 1.64-1.58 (m,
1H), 1.56-1.38
(m, 2H), 1.37-1.24 (m, 14H), 1.13-1.04 (m, 2H), 1.02-0.89 (m, 1H), 0.88-0.82
(m, 1H). MS:
m/e 746.0 (M+). MS m/e 757.2 (M++1).

Example 3-12:
F
N
O~
O
0 00
H O
NW. N )---N
H
0 0 H
Compound AR00304080
[1023] (IS, 4R, 6S, 14S, 18R)-5-Fluoro-3,4-dihydro-IH-isoquinoline-2-
carboxylic acid 14-(3-cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-
2,15-dioxo-
3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound
AR00304080) was
synthesized according to the procedures described in Examples 1-2, 2-24 and 3-
1,
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CA 02560897 2007-08-08

except that 5-fluoro- 1,2,3,4-tetrahydro-isoquinoline was used to replace
1,2,3,4-tetrahydro-
isoquinoline in Step 4 of Example 1-2.

Example 3-13:

N F
O=< F F
p

H O $RS
NOH S--'q
O O H-tl~
Compound AR00304081
[1024] (1S, 4R, 6S, 14S, 18R)-8-Trifluoromethyl-3,4-dihydro-lH-isoquinoline-
2-carboxylic acid 14-(3-cyclopentyl-ureido)-4-
cyclopropanesulfonylaminocarbonyl-2,15-
dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound
AR00304081)
was synthesized according to the procedures described in Examples 1-2, 2-24
and 3-1, except
that 8-trifluoromethyl- 1,2,3,4-tetrahydro-isoquinoline was used to replace
1,2,3,4-tetrahydro-
isoquinoline in Step 4 of Example 1-2. MS m/e 807.2 (M++1).

Example 3-14:

PN
O~
O O
O O "'S-<
HN~õ N -NFi
N
O O H
Compound AR00304082
[1025] (1S, 4R, 6S, 14S, 18R)-1,3-Dihydro-isoindole-2-carboxylic acid 14-(3-
cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-
tricyclo[14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound AR00304082) was
synthesized
according to the procedures described in Examples 1-2, 2-24 and 3-1, except
2,3-Dihydro-
1H-isoindole was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of
Example 1-2.
MS We 725.2 (M++1).
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CA 02560897 2007-08-08
Example 3-15:

N
O=<
O
O O 00
H
O W. N N
F H
O O H~
Compound AR00304161
[1026] (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
4-cyclopropanesulfonylaminocarbonyl-14-(2-fluoro-ethoxycarbonylamino)-2,15-
dioxo-3,16-
diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00304161) was
synthesized according to the procedures described in Examples 1-2, 2-1 and 3-
1, except that
2-fluoroethanol was used to form the chloroformate reagent in Step 2 of
Example 2-1,
instead of cyclopentanol. MS m/e 718.1 (M++1).

Example 3-16:

N
O=(
O
O O OO
H
ONt, N '-N'S
H
O O H
Compound AR00304162
[1027] (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydro-furan-3-
yloxycarbonylamino)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester
(Compound
AR00304162) was synthesized according to the procedures described in Examples
1-2, 2-1
and 3-1, except that tetrahydro-furan-3S-ol was used to form the chloroformate
reagent in
Step 2 of Example 2-1, instead of cyclopentanol. MS m/e 742.1 (M++1).

Example 3-17:

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CA 02560897 2007-08-08
N
O=<
H p O OO
NH
p^.., O O H~
Compound AR00304163
[1028] (IS, 4R, 6S, 14S, 18R)-3,4-Dihydro-IH-isoquinoline-2-carboxylic acid
4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydro-furan-3R-
yloxycarbonylamino)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester
(Compound
AR00304163) was synthesized according to the procedures described in Examples
1-2, 2-1
and 3-1, except that tetrahydro-furan-3R-ol was used to form the chloroformate
reagent in
Step 2 of Example 2-1, instead of cyclopentanol. 'H NMR (d6-Benzene, 500 MHz):
S 10.53
(s, I H), 6.78-6.96 (m, 4 H), 5.83-5.90 (m, 1 H), 5.66 (q, 1 H), 5.18-5.21 (m,
I H), 5.13 (brs,
I H), 5.04 (brs, 1 H), 4.41-4.87 (m, 3 H), 3.85-4.05 (m, 4 H), 3.67-3.74 (m, I
H), 3.46-3.53
(m, 3 H), 3.23-3.34 (m, 1 H), 2.80-2.85 (m, 1 H), 2.34-2.59 (m, 4 H), 1.84-
1.99 (m, 4 H),
0.98-1.60 (m, 14 H), 0.42-0.47 (m, 1 H), 0.27-0.32 (m, I H). MS m/e 741.2 (M-
1).

Example 3-18:

p
O--'- N S
/>--NH
N
0 N H O O
N,
pAN H'S
H

Compound AR00311814
[1029] (IS, 4R, 6S, 14S, 18R)-2-Phenylamino-6,7-dihydro-4H-thiazolo[5,4-
c]pyridine-5-carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-
en-18-yI ester (Compound AR00311814) was synthesized according to the
procedures
described in Examples 1-2 and 3-1, except that phenyl-(4,5,6,7-tetrahydro-
thiazolo[5,4-

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CA 02560897 2007-08-08

c]pyridin-2-yl)-amine was used to replace 1,2,3,4-tetrahydro-isoquinoline in
Step 4 of Example
1-2. MS We 826.2 (M+1).

Example 3-19:

O NDI
O-'-N

O O
N,, 0
O N NHS O
H X
Compound AR00311815
[1030] (1 S, 4R, 6S, 14S, 18R)-1-Piperidin-1-ylmethyl-3,4-dihydro-1 H-
isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-en-
18-yI ester (Compound AR00311815) was synthesized according to the procedures
described
in Examples 1-2 and 3-1, except that 1-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-
isoquinoline
was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
'H NMR (500
MHz, CD3OD) 8 8.94 (d, IH), 7.59 (s, 1H), 7.31 - 7.23 (m, 3H), 7.22 - 7.15 (m,
2H), 5.74-
5.64 (m, 2H), 5.47 (br s, 1H), 5.06 (t, 1H), 4.54 (dt, 1H), 4.40 - 4.17 (m,
4H), 4.11 - 4.04 (m,
111), 3.96 - 3.88 (m, 1H), 3.75 - 3.40 (m, 5H), 3.14 - 2.32 (m, 7H), 2.05 (dd,
IH), 1.99 - 1.68
(m, 5H), 1.65 - 0.95 (m, 24H); MS (POS ESI) m/z 825.4 (M+).

Example 3-20:

N
O=<
O
O
N O
HN. \\-NH
O0 O H~
Compound AR00312024
[1031] (1S, 4R, 6S, 14S, 18R)-4,4-Spirocyclobutyl-3,4-dihydro-IH-isoquinoline-
2-carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-
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CA 02560897 2007-08-08

2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound
AR00312024) was synthesized according to the procedures described in Examples
1-2 and 3-
1, except that 4,4-spirocyclobutyl-1,2,3,4-tetrahydro-isoquinoline was used to
replace
1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 'H NMR (400 MHz,
CD3OD)
&7.54-7.60 (m, 1H), 7.26 (dd, 1H), 6.97-7.21 (m, 1H), 5.66 (dd, 1H), 5.37-5.48
(m, 1H),
5.11 (dd, 1H), 4.58 (s, 2H), 4.39 (t, 3H), 4.11-4.26 (m, 1H), 3.77-3.96 (m,
1H), 3.87 (t, 311),
3.60-3.70 (m, 1H), 2.83-2.93 (m, 1H), 2.23-2.68 (m, 6H), 1.70-2.23 (m, 7H),
1.18-1.69 (m,
18H), 0.81-1.12 (m, 3H). MS m/z 767.9 (M++1)

Example 3-21:

O=<
O
O O
O
HNC,. N -NH
Compound AR00312025
[10321 (IS, 4R, 6S, 14S, 18R)-4,4-Dimethyl-3,4-dihydro-1H-isoquinoline-2-
carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-
dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound
AR00312025)
was synthesized according to the procedures described in Examples 1-2 and 3-1,
except that
4,4-dmethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-
isoquinoline in Step 4 of Example 1-2. 'H NMR (400 MHz, CD3OD) S 7.31-7.40 (m,
1H),
6.97-7.23 (m, 3H), 5.67 (dd, 1H), 5.34-5.49 (m, 1H), 5.09 (dd, 1H), 4.64 (s,
1H), 4.50-4.61
(m, 1H), 4.33-4.44 (m, 3H), 4.11-4.24 (m, 1.0), 3.82-3.95 (m, 3H), 3.36-3.55
(m, 2H), 2.84-
2.94 (m, 1H), 2.25-2.69 (m, 4H), 1.68-2.24 (m, 4H), 1.15-1.68 (m, 23H), 0.81-
1.15 (m, 3H).
MS m/z 756.0 (M++1)

Example 3-22:

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CA 02560897 2007-08-08
N
O=<
O O
O
HNC,. N -NH
Compound AR00312026
[1033] (IS, 4R, 6S, 145, 18R)-4-Methyl-3,4-dihydro-IH-isoquinoline-2-
carboxylic acid 14-tert-butoxycarbonylamino-4-
cyclopropanesulfonylaminocarbonyl-2,15-
dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound
AR00312026)
was synthesized according to the procedures described in Examples 1-2 and 3-1,
except that
4-methyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-isoquinoline
in Step 4 of Example 1-2. 'H NMR (400 MHz, CD3OD) S 7.76 (s, 1H), 6.98-7.24
(m, 3H),
5.67 (dd, 1H), 5.2-5.51 (m, 1H), 5.04-5.15 (dd, 1H), 4.28-4.63 (m, 5H), 4.10-
4.24 (m, 1H),
3.81-3.96 (m, 3H), 3.37-3.78 (m, 2H), 2.83-3.06 (m, 2H), 2.54-2.71 (m, 1H),
2.25-2.54 (m,
3H), 1.69-1.94 (m, 3H), 1.16-1.69 (m, 20H), 0.81-1.15 (3H). MS m/z 742.0
(M++1)

Example 3-23:

N
O=<
p O O
H N O
.O-If N,,, '-NH
OD O O H
Compound AR00314635
[1034] (IS, 4R, 6S, 14S, 18R)-4,4-Spirocyclobutyl-3,4-dihydro-1 H-
isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-
14-
(tetrahydro-furan-3-yloxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-en-18-yl
ester (Compound AR00314635) was synthesized according to the procedures
described in
Examples 1-2, 2-1 and 3-1, except that 4,4-spirocyclobutyl-1,2,3,4-tetrahydro-
isoquinoline
was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2,
and
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CA 02560897 2007-08-08

tetrahydro-furan-3R-ol was used to replace cyclopentanol in Step 2 of Example
2-1 to form
the chloroformate reagent. 'H NMR (500 MHz, CD2CI2) S 10.24-10.29 (s, 1H),
7.49-7.55
(m, 1H), 7.24 (dd, 1H), 7.14 (dd, 1H), 7.04 (dd, 1H), 6.81 (d 1H), 5.71 (dd,
1H), 4.95 (dd,
1H), 4.90 (bs, 1H), 4.48-4.59 (m, 3H), 4.17-4.30 (m, 2H), 3.51-3.74 (m, 3H),
3.51-3.72 (6H),
2.80-2.86 (m, 1H), 2.36-2.54 (m, 3H), 2.10-2.33 (m, 411), 1.80-2.10 (m, 6H),
1.24-1.80 (m,
7H), 0.65-1.24 (m, l OH). MS m/z 741.2 (M++ 1)

Example 3-24:

N
O=<
O
H O O OAS
O~N~,. N NH
O~ O O H'
Compound AR00314654
[1035] (1S, 4R, 6S, 14S, 18R)-4,4-Dimethyl-3,4-dihydro-1H-isoquinoline-2-
carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydro-
furan-3S-
yloxycarbonylamino)-3,16-diaza-tricyclo[ 14.3 Ø046]nonadec-7-en-18-yl ester
(Compound
AR00314654) was synthesized according to the procedures described in Examples
1-2, 2-1
and 3-1, except that 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline was used to
replace 1,2,3,4-
tetrahydro-isoquinoline in Step 4 of Example 1-2, and tetrahydro-furan-3S-ol
was used to
replace cyclopentanol in Step 2 of Example 2-1 to form the chloroformate
reagent. 'H NMR
(500 MHz, CD2C12) S 8.51-8.64 (bs, 1H), 7.26-7.36 (m, 1H), 7.09-7.19 (m, 2H),
6.98-7.08
(m, 1H), 5.70 (dd, 1H), 4.95 (dd, 111), 4.83 (d, 1H), 4.44-4.72 (m, 3H), 4.17-
4.30 (m, 2H),
3.25-3.91 (m, 911), 2.80-2.86 (m, 1H), 2.35-2.55 (m, 4H), 2.13-2.34 (m, 4H),
1.91-2.07 (m,
2H), 1.80-1.90 (m, 2H), 1.66-1.80 (m, 2H), 1.51-1.63 (m, 2H), 1.30-1.51 (m,
2H), 0.96-1.15
(m, 3H), 0.65-0.95 (m, 9H). MS m/z 770.1 (M++1)

Example 3-25:

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CA 02560897 2007-08-08
N
O=~
H H O 0 p~,S
NH
O p H

Compound AR00314656
[1036] (1S, 4R, 6S, 14S, 18R)-4-Methyl-3,4-dihydro-1H-isoquinoline-2-
carboxylic acid 14-(3-tert-butyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-
2,15-dioxo-
3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00314656)
was
synthesized according to the procedures described in Examples 1-2, 2-24 and 3-
1, except that
4-methyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-
tetrahydro-isoquinoline
in Step 4 of Example 1-2, and t-butyl isocyanate was used to replace
cyclopentyl isocyanate
in Example 2-24. 1H NMR (500 MHz, CD2CI2) 6 7.60-7.72 (m, 1H), 7.06-7.48 (m,
4H),
5.73 (dd, 111), 5.39-5.48 (m 1H), 5.18-5.27 (bs 1H), 4.98 (dd, 1H), 4.79-4.90
(bs, 1H), 4.30-
4.72 (m, 4H), 3.40-3.77 (m, 5H), 2.97 (d, 1H), 2.83-2.90 (m, 1H), 2.37-2.58
(m, 3H), 2.17-
2.30 (dt, 1H), 2.22-2.35 (dt, 1H), 1.97-2.07 (m, 1H), 1.82-1.95 (m, 2H), 1.68-
1.79 (m, 1H),
1.55-1.66 (m, 2H), 1.05-1.55 (m, 15H), 0.83-0.98 (m, 3H). MS m/z 741.2 (M++1)

Example 3-26:

O-YN I /
O
O0
0 O
) N,,. N Z~-NH
O
H
0 N
H
Compound AR00314719

[1037] (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-
3,16-diaza-
tricyclo[ 14.3Ø04'6]nonadec-18-yl ester (Compound AR00314719) was
synthesized
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CA 02560897 2007-08-08

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COMPREND PLUS D'UN TOME.

CECI EST LE TOME 1 DE 2

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des
Brevets.

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