U.S. patent application number 11/969195 was filed with the patent office on 2009-01-29 for novel heterocyclic compounds having anti-hbv activity.
This patent application is currently assigned to Valeant Research & Development. Invention is credited to Huanming Chen, Anneke K. Raney, Robert Tam.
Application Number | 20090029983 11/969195 |
Document ID | / |
Family ID | 36913585 |
Filed Date | 2009-01-29 |
United States Patent
Application |
20090029983 |
Kind Code |
A1 |
Chen; Huanming ; et
al. |
January 29, 2009 |
NOVEL HETEROCYCLIC COMPOUNDS HAVING ANTI-HBV ACTIVITY
Abstract
This application relates to novel fused tricyclic
thienopyridines of Formulas I and II, which useful for treating
Hepatitis B infection and other diseases. This application also
relates to pharmaceutical compositions comprising thienopyridines
and to the use of such compositions to treat Hepatitis B and other
diseases.
Inventors: |
Chen; Huanming; (Irvine,
CA) ; Tam; Robert; (Irvine, CA) ; Raney;
Anneke K.; (Oceanside, CA) |
Correspondence
Address: |
MCDERMOTT, WILL & EMERY
4370 LA JOLLA VILLAGE DRIVE, SUITE 700
SAN DIEGO
CA
92122
US
|
Assignee: |
Valeant Research &
Development
Costa Mesa
CA
|
Family ID: |
36913585 |
Appl. No.: |
11/969195 |
Filed: |
January 3, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11347145 |
Feb 3, 2006 |
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11969195 |
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60652308 |
Feb 11, 2005 |
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Current U.S.
Class: |
514/232.8 ;
514/253.03; 514/285; 514/291; 514/293; 544/126; 544/361; 546/61;
546/80; 546/82 |
Current CPC
Class: |
A61P 31/12 20180101;
C07D 495/14 20130101; C07D 495/04 20130101 |
Class at
Publication: |
514/232.8 ;
514/293; 546/80; 546/82; 544/126; 544/361; 514/253.03; 514/291;
514/285; 546/61 |
International
Class: |
C07D 495/04 20060101
C07D495/04; A61K 31/437 20060101 A61K031/437; A61K 31/4365 20060101
A61K031/4365; C07D 495/12 20060101 C07D495/12; A61P 31/12 20060101
A61P031/12; A61K 31/496 20060101 A61K031/496; A61K 31/5377 20060101
A61K031/5377 |
Claims
1. A compound of Formula I ##STR00125## wherein A is S, O, or
N(CH.sub.3); R.sub.1 and R.sub.2 are, independently, H, CH.sub.3,
CF.sub.3, or CH.sub.3O; R.sub.3 is H; or R.sub.3 is a 5- or
6-membered ring, said ring optionally containing one or more double
bonds, optionally containing 1-3 ring heteroatoms independently
selected from O, N, and S, and optionally substituted with one or
two groups independently selected from CH.sub.3, OCH.sub.3,
CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo, wherein all methyl
groups are optionally substituted with 1, 2, or 3 halogen atoms; or
R.sub.3 is C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6 alkenyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkenoxy, wherein said alkyl groups,
the alkyl moieties of said alkanoyl and said alkoxy groups, said
alkenyl groups, and the alkenyl moieties of said alkenoxy groups
may be straight-chain, branched, or cyclic, and can all optionally
be substituted as follows: a) with one, two, or three halogen
atoms; b) with one or two substituents independently selected from
hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy; c) with
one saturated, unsaturated, or aromatic 5- or 6-membered ring
containing 0-3 heteroatoms selected from N, O, and S, said ring
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, C(O)CH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms; and d) with
one group selected from C.sub.1-6 alkanoyl, C.sub.1-6
alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl, ethylcarbamoylmethyl,
methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or
N-phthalimido; or R.sub.3 is R.sub.4NHC(O), R.sub.4NHC(S), or
R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is C.sub.1-6 alkyl, wherein
said alkyl group may be straight-chain, branched, or cyclic, and is
optionally substituted as described for R.sub.3 alkyl groups, or
R.sub.4 is a five- or 6-membered aromatic ring containing 0-3
heteroatoms independently selected from O, N, and S, all R.sub.4
optionally substituted with one or two substituents independently
selected from halo, methyl, and benzyl, wherein all rings are
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3,
CN, and halo, wherein all methyl groups are optionally substituted
with 1, 2, or 3 halogen atoms; and m and n are, independently, 1 or
2, provided that m and n are not both 2; and further provided that
when n=1, m=2, and R.sub.1 and R.sub.2 are both H, then R.sub.3 is
not methyl.
2. The compound of claim 1, wherein A is S, n is 1, m is 1, R.sub.1
is H, and R.sub.2 is H or CH.sub.3.
3. The compound of claim 2, wherein R.sub.3 is H or C.sub.1-6
alkyl, optionally substituted with one or two substituents
independently selected from halo, hydroxy, cyano, phenyl, pyridyl,
benzoyl, benzoyl methyl, benzoyloxy, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkylcarbamoyl, N-phthalimido, or R.sub.3 is a 5- or
6-membered aromatic ring containing 1-3 heteroatoms independently
selected from O, N, and S, wherein all rings are optionally
substituted with one or two substituents independently selected
from halo, CH.sub.3, CH.sub.3O, CN, CF.sub.3, and CH.sub.3C(O),
wherein all methyl groups are optionally substituted 1-3 chlorine
atoms.
4. The compound of claim 3, wherein R.sub.3 is C.sub.1-4 alkyl,
optionally monosubstituted with halogen, hydroxy, phenyl, benzyl,
pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl rings
are optionally further monosubstituted with methyl or halogen.
5. The compound of claim 2, wherein R.sub.3 is R.sub.4NHC(O),
R.sub.4NHC(S), or R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is
C.sub.1-6 alkyl, wherein said alkyl group may be straight-chain,
branched, or cyclic, and is optionally substituted as described for
R.sub.3 alkyl groups, or R.sub.4 is a five- or 6-membered aromatic
ring containing 0-3 heteroatoms independently selected from O, N,
and S, all R.sub.4 optionally substituted with one or two
substituents independently selected from halo, methyl, and benzyl,
wherein all rings are optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms.
6. The compound of claim 1, wherein A is S, n is 2, m is 1, R.sub.1
is H, and R.sub.2 is H or CH.sub.3.
7. The compound of claim 6, wherein R.sub.3 is H or C.sub.1-4
alkyl.
8. The compound of claim 1, wherein A is 0, n is 1, m is 1, R.sub.1
is H, and R.sub.2 is H or CH.sub.3.
9. The compound of claim 8, wherein R.sub.3 is H or C.sub.1-6
alkyl, optionally substituted with one or two substituents
independently selected from halo, hydroxy, cyano, phenyl, pyridyl,
benzoyl, benzoyl methyl, benzoyloxy, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkylcarbamoyl, N-phthalimido, or R.sub.3 is a 5- or
6-membered aromatic ring containing 1-3 heteroatoms independently
selected from O, N, and S, wherein all rings are optionally
substituted with one or two substituents independently selected
from halo, CH.sub.3, CH.sub.3O, CN, CF.sub.3, and CH.sub.3C(O),
wherein all methyl groups are optionally substituted 1-3 chlorine
atoms.
10. The compound of claim 9, wherein R.sub.3 is C.sub.1-4 alkyl,
optionally monosubstituted with halogen, hydroxy, phenyl, benzyl,
pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl rings
are optionally further monosubstituted with methyl or halogen.
11. The compound of claim 8, wherein R.sub.3 is R.sub.4NHC(O),
R.sub.4NHC(S), or R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is
C.sub.1-6 alkyl, wherein said alkyl group may be straight-chain,
branched, or cyclic, and is optionally substituted as described for
R.sub.3 alkyl groups, or R.sub.4 is a five- or 6-membered aromatic
ring containing 0-3 heteroatoms independently selected from O, N,
and S, all R.sub.4 optionally substituted with one or two
substituents independently selected from halo, methyl, and benzyl,
wherein all rings are optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms.
12. A compound of Formula II ##STR00126## wherein n is zero, 1, 2,
or 3; A is S, O, or N(CH.sub.3); B and B' are either both H or
jointly oxo; R.sub.1 and R.sub.2 are, independently, H, CH.sub.3,
CF.sub.3, or CH.sub.3O; R.sub.3 is H; or R.sub.3 is a 5- or
6-membered ring, said ring optionally containing one or more double
bonds, optionally containing 1-3 ring heteroatoms independently
selected from O, N, and S, and optionally substituted with one or
two groups independently selected from CH.sub.3, OCH.sub.3,
CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo, wherein all methyl
groups are optionally substituted with 1, 2, or 3 halogen atoms; or
R.sub.3 is C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6 alkenyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkenoxy, wherein said alkyl groups,
the alkyl moieties of said alkanoyl and said alkoxy groups, said
alkenyl groups, and the alkenyl moieties of said alkenoxy groups
may be straight-chain, branched, or cyclic, and may optionally be
substituted as follows: a) with one, two, or three halogen atoms;
b) with one or two substituents independently selected from
hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy; c) with
one saturated, unsaturated, or aromatic 5- or 6-membered ring
containing 0-3 heteroatoms selected from N, O, and S, said ring
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, C(O)CH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms; and d) with
one group selected from C.sub.1-6 alkanoyl, C.sub.1-6
alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl, ethylcarbamoylmethyl
methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or
N-phthalimido; or R.sub.3 is R.sub.4NHC(O), R.sub.4NHC(S), or
R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is C.sub.1-6 alkyl, wherein
said alkyl group may be straight-chain, branched, or cyclic, and is
optionally substituted as described for R.sub.3 alkyl groups, or
R.sub.4 is a five- or 6-membered aromatic ring containing 0-3
heteroatoms independently selected from O, N, and S, all R.sub.4
optionally substituted with one or two substituents independently
selected from halo, methyl, and benzyl, wherein all rings are
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3,
CN, and halo, wherein all methyl groups are optionally substituted
with 1, 2, or 3 halogen atoms; and R.sub.5 is H or C.sub.3 alkyl;
or R.sub.3 and R.sub.5, together with the ring carbon atoms to
which they are attached, form an additional fused 5- or 6-membered
cycloalkyl group; provided that when A is O or S, then R.sub.1,
R.sub.2, R.sub.3, B, and B' are not all H, and further provided
that when A is S and R.sub.1 is methyl, then R.sub.2, R.sub.3, B,
and B' are not all H.
13. A compound according to claim 12, wherein A is S, R.sub.5 is H;
and wherein R.sub.3 is selected from H, C.sub.1-4 alkyl, C.sub.1-4
alkenyl, or C.sub.1-6 alkoxy, wherein said alkyl groups, the alkyl
moieties of said alkoxy groups, and said alkenyl groups may be
straight-chain, branched, or cyclic, and are optionally substituted
with one or two substituents independently selected from halo,
hydroxy, ethylcarbamoylmethyl methylcarbamoylmethyl,
2-hydroxy-2-phenyl-ethylcarbamoylmethyl, benzoyl, benzoyloxy, and a
5- or 6-membered ring, said ring optionally containing one or more
double bonds, optionally containing 1-3 ring heteroatoms
independently selected from O, N, and S, and optionally substituted
with, independently, one or two groups independently selected from
CH.sub.3, OCH.sub.3, CF.sub.3, and halo; and n=0, 1, or 2.
14. The compound of claim 13, wherein n=1 or 2, and R.sub.3 is
hydrogen, methyl, methoxy, ethoxy, or allyl.
15. A method of treating an HBV infection, comprising providing in
a person in need of treatment thereof a therapeutically effective
concentration of a compound of Formula I or a compound of formula
II, where formula I is ##STR00127## wherein A is S, O, or
N(CH.sub.3); R.sub.1 and R.sub.2 are, independently, H, CH.sub.3,
CF.sub.3, or CH.sub.3O; R.sub.3 is H; or R.sub.3 is a 5- or
6-membered ring, said ring optionally containing one or more double
bonds, optionally containing 1-3 ring heteroatoms independently
selected from O, N, and S, and optionally substituted with one or
two groups independently selected from CH.sub.3, OCH.sub.3,
CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo, wherein all methyl
groups are optionally substituted with 1, 2, or 3 halogen atoms; or
R.sub.3 is C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6 alkenyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkenoxy, wherein said alkyl groups,
the alkyl moieties of said alkanoyl and said alkoxy groups, said
alkenyl groups, and the alkenyl moieties of said alkenoxy groups
may be straight-chain, branched, or cyclic, and can all optionally
be substituted as follows: a) with one, two, or three halogen
atoms; b) with one or two substituents independently selected from
hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy; c) with
one saturated, unsaturated, or aromatic 5- or 6-membered ring
containing 0-3 heteroatoms selected from N, O, and S, said ring
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, C(O)CH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms; and d) with
one group selected from C.sub.1-6 alkanoyl, C.sub.1-6
alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl, ethylcarbamoylmethyl
methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or
N-phthalimido; or R.sub.3 is R.sub.4NHC(O), R.sub.4NHC(S), or
R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is C.sub.1-6 alkyl, wherein
said alkyl group may be straight-chain, branched, or cyclic, and is
optionally substituted as described for R.sub.3 alkyl groups, or
R.sub.4 is a five- or 6-membered aromatic ring containing 0-3
heteroatoms independently selected from O, N, and S, all R.sub.4
optionally substituted with one or two substituents independently
selected from halo, methyl, and benzyl, wherein all rings are
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3,
CN, and halo, wherein all methyl groups are optionally substituted
with 1, 2, or 3 halogen atoms; and m and n are, independently, 1 or
2, provided that m and n are not both 2. and where formula II is
##STR00128## wherein n is zero, 1, 2, or 3; A is S, O, or
N(CH.sub.3); B and B' are either both H or jointly oxo; R.sub.1 and
R.sub.2 are, independently, H, CH.sub.3, CF.sub.3, or CH.sub.3O;
R.sub.3 is H; or R.sub.3 is a 5- or 6-membered ring, said ring
optionally containing one or more double bonds, optionally
containing 1-3 ring heteroatoms independently selected from O, N,
and S, and optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms; or R.sub.3 is
C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6 alkenyl, C.sub.1-6
alkoxy, C.sub.1-6 alkenoxy, wherein said alkyl groups, the alkyl
moieties of said alkanoyl and said alkoxy groups, said alkenyl
groups, and the alkenyl moieties of said alkenoxy groups may be
straight-chain, branched, or cyclic, and may optionally be
substituted as follows: a) with one, two, or three halogen atoms;
b) with one or two substituents independently selected from
hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy; c) with
one saturated, unsaturated, or aromatic 5- or 6-membered ring
containing 0-3 heteroatoms selected from N, O, and S, said ring
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, C(O)CH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms; and d) with
one group selected from C.sub.1-6 alkanoyl, C.sub.1-6
alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl, ethylcarbamoylmethyl
methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or
N-phthalimido; or R.sub.3 is R.sub.4NHC(O), R.sub.4NHC(S), or
R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is C.sub.1-6 alkyl, wherein
said alkyl group may be straight-chain, branched, or cyclic, and is
optionally substituted as described for R.sub.3 alkyl groups, or
R.sub.4 is a five- or 6-membered aromatic ring containing 0-3
heteroatoms independently selected from O, N, and S, all R.sub.4
optionally substituted with one or two substituents independently
selected from halo, methyl, and benzyl, wherein all rings are
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3,
CN, and halo, wherein all methyl groups are optionally substituted
with 1, 2, or 3 halogen atoms; and R.sub.5 is H or C.sub.3 alkyl;
or R.sub.3 and R.sub.5, together with the ring carbon atoms to
which they are attached, form an additional fused 5- or 6-membered
cycloalkyl group.
16. The method of claim 15, wherein a compound of formula I is
provided, where A is S, n is 1, m is 1, R.sub.1 is H, and R.sub.2
is H or CH.sub.3.
17. The method of claim 16, wherein R.sub.3 is H or C.sub.1-6
alkyl, optionally substituted with one or two substituents
independently selected from halo, hydroxy, cyano, phenyl, pyridyl,
benzoyl, benzoyl methyl, benzoyloxy, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkylcarbamoyl, N-phthalimido, or R.sub.3 is a 5- or
6-membered aromatic ring containing 1-3 heteroatoms independently
selected from O, N, and S, wherein all rings are optionally
substituted with one or two substituents independently selected
from halo, CH.sub.3, CH.sub.3O, CN, CF.sub.3, and CH.sub.3C(O),
wherein all methyl groups are optionally substituted 1-3 chlorine
atoms.
18. The method of claim 17, wherein R.sub.3 is C.sub.1-4 alkyl,
optionally monosubstituted with halogen, hydroxy, phenyl, benzyl,
pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl rings
are optionally further monosubstituted with methyl or halogen.
19. The method of claim 16, wherein R.sub.3 is R.sub.4NHC(O),
R.sub.4NHC(S), or R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is
C.sub.1-6 alkyl, wherein said alkyl group may be straight-chain,
branched, or cyclic, and is optionally substituted as described for
R.sub.3 alkyl groups, or R.sub.4 is a five- or 6-membered aromatic
ring containing 0-3 heteroatoms independently selected from O, N,
and S, all R.sub.4 optionally substituted with one or two
substituents independently selected from halo, methyl, and benzyl,
wherein all rings are optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms.
20. The method of claim 15, wherein a compound of formula I is
provided, and A is S, n is 2, m is 1, R.sub.1 is H, and R.sub.2 is
H or CH.sub.3.
21. The method of claim 20, wherein R.sub.3 is H or C.sub.1-4
alkyl.
22. The method of claim 15, wherein a compound of formula I is
provided, and A is O, n is 1, m is 1, R.sub.1 is H, and R.sub.2 is
H or CH.sub.3.
23. The method of claim 22, wherein R.sub.3 is H or C.sub.1-6
alkyl, optionally substituted with one or two substituents
independently selected from halo, hydroxy, cyano, phenyl, pyridyl,
benzoyl, benzoyl methyl, benzoyloxy, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkylcarbamoyl, N-phthalimido, or R.sub.3 is a 5- or
6-membered aromatic ring containing 1-3 heteroatoms independently
selected from O, N, and S, wherein all rings are optionally
substituted with one or two substituents independently selected
from halo, CH.sub.3, CH.sub.3O, CN, CF.sub.3, and CH.sub.3C(O),
wherein all methyl groups are optionally substituted 1-3 chlorine
atoms.
24. The method of claim 23, wherein R.sub.3 is C.sub.1-4 alkyl,
optionally monosubstituted with halogen, hydroxy, phenyl, benzyl,
pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl rings
are optionally monosubstituted with methyl or halogen.
25. The method of claim 22, wherein R.sub.3 is R.sub.4NHC(O),
R.sub.4NHC(S), or R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is
C.sub.1-6 alkyl, wherein said alkyl group may be straight-chain,
branched, or cyclic, and is optionally substituted as described for
R.sub.3 alkyl groups, or R.sub.4 is a five- or 6-membered aromatic
ring containing 0-3 heteroatoms independently selected from O, N,
and S, all R.sub.4 optionally substituted with one or two
substituents independently selected from halo, methyl, and benzyl,
wherein all rings are optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms.
26. The method claim 15, wherein a compound of formula II is
provided.
27. The method of claim 26, wherein A is S, R.sub.5 is H; and
wherein R.sub.3 is selected from H, C.sub.1-4 alkyl, C.sub.1-4
alkenyl, or C.sub.1-6 alkoxy, wherein said alkyl groups, the alkyl
moieties of said alkoxy groups, and said alkenyl groups may be
straight-chain, branched, or cyclic, and are optionally substituted
with one or two substituents independently selected from halo,
hydroxy, ethylcarbamoylmethyl, methylcarbamoylmethyl,
2-hydroxy-2-phenyl-ethylcarbamoylmethyl, benzoyl, benzoyloxy, and a
5- or 6-membered ring, said ring optionally containing one or more
double bonds, optionally containing 1-3 ring heteroatoms
independently selected from O, N, and S, and optionally substituted
with, independently, one or two groups independently selected from
CH.sub.3, OCH.sub.3, CF.sub.3, and halo; and n=0, 1, or 2.
28. The method of claim 26, wherein n=1 or 2, and R.sub.3 is H,
methyl, methoxy, ethoxy or allyl.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/652,308, filed Feb. 11, 2005, which is hereby
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This application concerns novel fused tricyclic
thienopyridines which are useful for treating hepatitis B infection
and other diseases.
BACKGROUND OF THE INVENTION
[0003] Hepatitis B virus (HBV) causes acute or chronic hepatitis,
which may progress to liver cirrhosis and liver cancer. HBV is a
DNA virus which replicates via an RNA intermediate and utilizes
reverse transcription in its replication strategy [Summers and
Mason, Cell 29; 403-415, 1982]. HBV DNA polymerase is responsible
for the reverse transcription and has been considered the main
target for anti-HBV intervention. Many nucleoside or nucleotides
analogs have been discovered to be effective anti-viral agents.
Examples of nucleoside analogs which have been tested are
penciclovir and its oral form (FCV) [Vere Hodge, Antiviral Chem.
Chemother. 4: 67-84, 1993; Kruger et al., Hepatology 22: 219A,
1994; Main et al., J. Viral Hepatitis 3: 211-215, 1996], and
Lamivudine[(-)-.beta.-2'-deoxy-3'-thiacytidine]; (3TC or LMV)
[Severini et al., Antimicrobial Agents Chemother. 39: 430-435,
1995; Dienstag et al., New England J Med 333: 1657-1661, 1995]. New
nucleoside or nucleotide analogs that have progressed to clinical
trials or are approved for HBV by FDA include Emtricitabine (FTC),
Clevudine (L-FMAU), Entecavir (BMS-200, 475; ETV), diaminopurine
dioxolane (DAPD), adefovir dipivoxil.
(9-(2-((bis((pivaloyloxy)methoxy)phosphinyl)methoxy)-ethyl)adenine).
Additionally, for a number of years interferon alpha also has been
widely used for the treatment of chronic HBV infection.
[0004] Although these agents are highly effective in inhibiting HBV
DNA synthesis, resistant mutants of HBV have emerged during long
term nucleoside or nucleotide antiviral chemotherapy. Sustained
responses to HBV treatment--as evidenced by a decrease of HBV DNA
in serum and by anti-HBe or HBs seroconversion--has been observed
only in a relatively small patient population.
[0005] For example, for several years interferon alpha has been
widely used for the treatment of chronic HBV infection. However,
interferon is effective only in certain subpopulations of chronic
hepatitis B patients, and even in such patients it is poorly
tolerated. Similarly, lamivudine (3'-thia-2',3'-dideoxycytidine), a
particularly strong inhibitor of HBV replication, is used to treat
HBV infection. However, resistance to lamivudine is increasingly
common and has limited its efficacy in a high proportion of
patients. The most recently-approved treatment for HBV is adefovir
dipivoxil
(9-(2-((-bis((pivaloyloxy)methoxy)phosphinyl)methoxy)ethyl)adenine).
Although this nucleoside analog is active against the
lamivudine-resistant viruses, its sustained viral response rate is
poor (below 20%), and its maximum tolerated dose and treatment
duration are often limited by nephrotoxicity.
[0006] More recent developments in HBV research have led to
clinical trials for several compounds with promising antiviral
activity. For example, certain nucleoside analogs have been
reported to exhibit significant anti-HBV activity (e.g.,
2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (Bukwang) and
2'-deoxy-5-fluoro-3'-thiacytidine (Gilead); 2'-deoxy-L-thymidine
and 2'-deoxy-L-cytidine (both Idenix)). Similarly, carbocyclic
nucleoside analogs (6H-purin-6-one,
2-amino-1,9-dihydro-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylene-
cyclopentyl)monohydrate (Bristol-Myers Squibb), as well as acyclic
nucleoside analogs with liver targeting properties (Remofovir;
Ribapharm), were reported as having anti-HBV activity in clinical
trials.).
[0007] However, while most of the recently discovered drugs with
anti-HBV activity exhibited promising in vitro antiviral activity,
low response rates and the emergence of resistance limit the
efficacy of these clinical candidates. Therefore, although various
compositions and methods for HBV treatment are known in the art,
there is still a need to provide new and improved compositions and
methods for treatment of HBV infections in human patients.
[0008] Thus, in light of the limited efficacy, resistance profiles,
and toxicity of current anti-HBV drugs, there is a strong need for
novel anti-HBV drugs that are more effective and less toxic and
that exhibit a different resistance profile.
[0009] Therefore, it is an object of the present invention to
provide a compounds and methods for the treatment of HBV infection.
Such compounds and methods also have potential for the treatment of
other conditions associated with dysregulated protein kinase
activity, such as inflammation and neoplastic disease.
[0010] The NF-.kappa.B pathway plays a complex role in an antiviral
immune response. Nuclear factor-.kappa.B (NF-.kappa.B) is a
ubiquitously expressed transcription factor that is essential to
the regulation of such cellular functions as apoptosis,
proliferation, and differentiation [Ghosh et al., Annu. Rev.
Immunol. 16:225, 1998]. NF-.kappa.B accomplishes this regulation by
coordinating the expression of genes responsible for protecting an
organism after physical, chemical, and/or microbial damage. Thus,
NF-.kappa.B has an inherent role in the induction of an immune
response and concomitant inflammation. [Baeuerle and Baltimore.
Cell 87:13, 1996]. The activity of NF-.kappa.B can be modulated by
viral proteins. (Bose et al., PNAS 100, 2003; Purcell et al., Am.
J. Physiol. Gastrointest. Liver Physiol. 280, 2001). Such effects
can be both interferon-dependent and interferon-independent
(Pfeffer et al., J. Biol. Chem. 279:30, 31304-31311, 2004).
[0011] The NF-.kappa.B family of transcription factors includes a
set of structurally related and evolutionarily conserved DNA
binding proteins (Baldwin, Annu. Rev. Immunol. 14:649, 1996).
NF-.kappa.B contains a nuclear localization sequence (NLS) that
directs the protein to the nucleus to carry out its role in genetic
regulation. However, under normal conditions NF-.kappa.B is
sequestered in the cytoplasm because the NLS is masked by tightly
bound inhibitory proteins; these inhibitors of NF-.kappa.B are
known as I.kappa.B (Beg and Baldwin, Genes Dev. 7:2064, 1993;
Thompson et al., Cell 80:573, 1995; Whiteside et al., EMBO J.
16:1413, 1997). Activators of NF-.kappa.B act by inactivating
I.kappa.B, via the mechanisms of phosphorylation, ubiquitination,
and degradation. Thus, the elimination of I.kappa.B exposes the NLS
allowing NF-.kappa.B to translocate to the nucleus to activate
specific target genes.
[0012] The signal responsible for inactivation of I.kappa.B is
typically a cellular response to an extracellular stimulus (Tumor
Necrosis Factor .alpha. (TNF.alpha.), Interleukin-1.beta.
(IL-1.beta.), lipopolysaccharide (LPS)) or to chemical and physical
stress. The signal originates at a cell surface receptor, such as
the TNF-receptor or IL-1 receptor; the signal is internalized and
transduced through the cell via a cascade of phosphorylation
events. Each receptor binds unique adapter molecules specific to
the receptor and stimulus and in turn activates downstream kinases
including NF-.kappa.B interacting kinase (NIK), MAPK/extracellular
signal-regulated kinase kinase-1 (MEKK-1), and I.kappa.B kinases
.alpha. and .beta. (IKK.alpha./.beta.). IKK.beta. is responsible
for liberating NF-.kappa.B by phosphorylating the inhibitory
subunit I.kappa.Ba. Phosphorylation of I.kappa.Ba by IKK.beta.
triggers ubiquitin ligase (Skp1/Cul 1/F-box protein FWD1) to
ubiquitinate I.kappa.Ba and target it for degradation via the 26S
proteasome [Yaron et al., Nature 396:590, 1998; Winston et al.,
Genes Dev. 13:270, 1999; Spencer et al., Genes Dev. 13:284,
1999].
[0013] The I.kappa.B kinases (IKK.alpha. and IKK.beta.) are
serine-threonine protein kinases. They belong to a large
multi-protein complex, called the "signalsome" [Mercurio et al.,
Science 278:860, 1997; Woronicz et al., Science 278:866, 1997;
Zandi et al., 91:243, 1997]. The signalsome is the machinery
responsible for transducing the stimulus that results in
NF-.kappa.B activation. The genes that encode the signalsome
components have been cloned, expressed, and reconstituted in vitro
to demonstrate activation of NF-.kappa.B via I.kappa.B
phosphorylation [Regnier et al., Cell 90:373, 1997; DiDonato et
al., Nature 388:548, 1997; Zandi et al., Cell 91:243, 1997;
Woronicz et al., Science 278: 866, 1997; Mercurio et al., Science
278:860, 1997; Cohen et al., Nature 395:292, 1998]. IKK family
members share homologous amino-terminal kinase domains that are
activated by NIK. In turn, IKK specifically phosphorylates
I.kappa.Ba and I.kappa.B.beta. on regulatory serine residues.
Genetic studies with IKK knock-out mice point to an essential role
for IKK, in transmission of inflammatory signals, whereas
IKK.alpha. is involved in developmental processes requiring
NF-.kappa.B activation [Takeda et al., Science 284:313, 1999; Hu et
al., Science 284:316, 1999; Li et al., Science 284:321, 1999].
Embryonic fibroblasts isolated from IKK.beta.-deficient mice show
defects in TNF.alpha.- and IL-1-induced degradation of I.kappa.B.
Furthermore, inhibition of pro-inflammatory cytokine-induced
I.kappa.B degradation is not observed in cells derived from
IKK.alpha.-deficient mice, suggesting that IKK.beta. controls the
NF-.kappa.B activation rather than IKK.alpha. [Takeda et al.,
Science 284:313, 1999]. Moreover, a catalytically inactive mutant
of IKK.beta. has been shown to inhibit inflammation via activation
of NF-.kappa.B through TNF.alpha., IL-1.beta., LPS, and
anti-CD3/anti-CD28 stimulation [O'Connell et al., J. Biol. Chem.
273:30410, 1998; Woronicz et al., Science 278:866, 1997; Zandi et
al., Cell 91:243, 1997.]. Thus, IKK.beta. is considered by the
inventors to be a validated target for therapeutic interference in
a variety of pathological situations, including chronic
inflammatory and autoimmune diseases, viral infection, and
cancer.
[0014] Some inhibitors of EKK.beta. have previously been reported.
WO 03/103661, WO 01/58890, and WO 03/037886 describe substituted
thienopyridines and heteroaromatic carboxamide derivatives as
inhibitors of IKK.beta.. WO 01/68648 describes substituted
.beta.-carbolines having IKK.beta. inhibiting activity. Substituted
indoles with IKK.beta. inhibitory activity are reported in WO
01/30774, and substituted benzimidazoles with NK-.kappa.B
inhibitory activity are described in WO 01/00610. Recently, a
number of imidazoloquinoxalines and related compounds have been
reported to have IKK-inhibiting activity and to be useful in
treating arthritis, transplant rejection, inflammatory bowel
disease, and pulmonary inflammation disease in U.S. Pub. No.
2003/0022898. Additionally, aspirin and other salicylates have been
reported to bind to and inhibit IKK.beta. (M. Yin et al., Nature,
1998, 396, 77).
[0015] Substituted thienopyridines that inhibit cell adhesion are
reported in U.S. 2001/0020030 and in A. O, Stewart et al., J. Med.
Chem., 2001, 44, 988. Thienopyridines with activity as antagonists
of gonadotropin releasing hormone are reported in U.S. Pat. No.
6,313,301. Substituted thienopyridines described as telomerase
inhibitors are disclosed in U.S. Pat. No. 5,656,638.
BRIEF DESCRIPTION OF THE INVENTION
[0016] The present invention comprises fused tricyclic
thienopyridine compounds of Formulas I and II below, which are
potentially useful in treating HBV infection, as well as methods of
treatment of HBV infection utilizing compounds of Formulas I and II
and other fused tricyclic thienopyridines.
[0017] The present inventors have discovered that such fused
tricyclic thienopyridines are effective as IKK.beta. inhibitors.
Such compounds may be used for treatment of HBV, as well as other
diseases that are directly or indirectly associated with a
dysregulated kinase.
[0018] In one embodiment the present invention provides a compound
of compound of Formula I below,
##STR00001##
in which A is S, O, or N(CH.sub.3); R.sub.1 and R.sub.2 are,
independently, H, CH.sub.3, CF.sub.3, or CH.sub.3O; R.sub.3 is H;
or R.sub.3 is a 5- or 6-membered ring, said ring optionally
containing one or more double bonds, optionally containing 1-3 ring
heteroatoms independently selected from O, N, and S, and optionally
substituted with one or two groups independently selected from
CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo,
wherein all methyl groups are optionally substituted with 1, 2, or
3 halogen atoms; or R.sub.3 is C.sub.1-6 alkyl, C.sub.1-6 alkanoyl,
C.sub.1-6 alkenyl, C.sub.1-6 alkoxy, C.sub.1-6 alkenoxy, wherein
said alkyl groups, the alkyl moieties of said alkanoyl and said
alkoxy groups, said alkenyl groups, and the alkenyl moieties of
said alkenoxy groups may be straight-chain, branched, or cyclic,
and can all optionally be substituted as follows:
[0019] a) with one, two, or three halogen atoms;
[0020] b) with one or two substituents independently selected from
hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy;
[0021] c) with one saturated, unsaturated, or aromatic 5- or
6-membered ring containing 0-3 heteroatoms selected from N, O, and
S, said ring optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, C(O)CH.sub.3,
CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo, wherein all methyl
groups are optionally substituted with 1, 2, or 3 halogen atoms;
and
[0022] d) with one group selected from C.sub.1-6 alkanoyl,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl,
ethylcarbamoylmethyl methylcarbanoylmethyl,
2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
[0023] or R.sub.3 is R.sub.4NHC(O), R.sub.4NHC(S), or
R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is C.sub.1-6 alkyl, wherein
said alkyl group may be straight-chain, branched, or cyclic, and is
optionally substituted as described for R.sub.3 alkyl groups, or
R.sub.4 is a five- or 6-membered aromatic ring containing 0-3
heteroatoms independently selected from O, N, and S, all R.sub.4
optionally substituted with one or two substituents independently
selected from halo, methyl, and benzyl, wherein all rings are
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3,
CN, and halo, wherein all methyl groups are optionally substituted
with 1, 2, or 3 halogen atoms; and m and n are, independently, 1 or
2, provided that m and n are not both 2; and further provided that
when n=l, m=2, and R.sub.1 and R.sub.2 are both H, then R.sub.3 is
not methyl.
[0024] In a more particular embodiment, the present invention
provides a compound of Formula I above, wherein A is S, n is 1, m
is 1, R.sub.1 is H, and R.sub.2 is H or CH.sub.3.
[0025] In another particular embodiment, this invention provides a
compound of Formula I above, in which A is S, n is 1, m is 1,
R.sub.1 is H, R.sub.2 is H or CH.sub.3, and R.sub.3 is H or
C.sub.1-6 alkyl, optionally substituted with one or two
substituents independently selected from halo, hydroxy, cyano,
phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C.sub.1-6
alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl, N-phthalimido, or R.sub.3
is a 5- or 6-membered aromatic ring containing 1-3 heteroatoms
independently selected from O, N, and S, wherein all rings are
optionally substituted with one or two substituents independently
selected from halo, CH.sub.3, CH.sub.3O, CN, CF.sub.3, and
CH.sub.3C(O), wherein all methyl groups are optionally substituted
1-3 chlorine atoms.
[0026] In another particular embodiment, this invention provides a
compound of Formula I above, in which A is S, n is 1, m is 1,
R.sub.1 is H, R.sub.2 is H or CH.sub.3, and R.sub.3 is C.sub.1-4
alkyl, optionally monosubstituted with halogen, hydroxy, phenyl,
benzyl, pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl
rings are optionally further monosubstituted with methyl or
halogen.
[0027] In another particular embodiment, this invention provides a
compound of Formula I above, in which A is S, n is 1, m is 1, R is
H, R.sub.2 is H or CH.sub.3, and R.sub.3 is R.sub.4NHC(O),
R.sub.4NHC(S), or R.sub.4NHCH.sub.2C(O), where R.sub.4 is C.sub.1-6
alkyl, which alkyl group may be straight-chain, branched, or
cyclic, and which is optionally substituted as described in
previous paragraphs for R.sub.3 alkyl groups, or R.sub.4 is a five-
or 6-membered aromatic ring containing 0-3 heteroatoms
independently selected from O, N, and S, all R.sub.4 optionally
substituted with one or two substituents independently selected
from halo, methyl, and benzyl, in which all rings are optionally
substituted with one or two groups independently selected from
CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo,
wherein all methyl groups are optionally substituted with 1, 2, or
3 halogen atoms.
[0028] In another embodiment, this invention provides a compound of
Formula I in which A is S, n is 2, m is 1, R.sub.1 is H, and
R.sub.2 is H or CH.sub.3.
[0029] In another embodiment, this invention provides a compound of
Formula I in which A is S, n is 2, m is 1, R.sub.1 is H, R.sub.2 is
H or CH.sub.3 and in which R.sub.3 is H or C.sub.1-4 alkyl.
[0030] In another embodiment, this invention provides a compound of
Formula I in which A is 0, n is 1, m is 1, R.sub.1 is H, and
R.sub.2 is H or CH.sub.3.
[0031] In another embodiment, this invention provides a compound of
Formula I in which A is O, n is 1, m is 1, R.sub.1 is H, R.sub.2 is
H or CH.sub.3, and R.sub.3 is H or C.sub.1-6 alkyl, optionally
substituted with one or two substituents independently selected
from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl
methyl, benzoyloxy, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbamoyl, N-phthalimido, or R.sub.3 is a 5- or 6-membered
aromatic ring containing 1-3 heteroatoms independently selected
from O, N, and S, in which all rings are optionally substituted
with one or two substituents independently selected from halo,
CH.sub.3, CH.sub.3O, CN, CF.sub.3, and CH.sub.3C(O), where all
methyl groups are optionally substituted 1-3 chlorine atoms.
[0032] In another embodiment, this invention provides a compound of
Formula I in which A is 0, n is 1, m is 1, R.sub.1 is H, R.sub.2 is
H or CH.sub.3, and R.sub.3 is C.sub.1-4 alkyl, optionally
monosubstituted with halogen, hydroxy, phenyl, benzyl, pyridyl, and
pyridyl methyl, wherein the phenyl and pyridyl rings are optionally
further monosubstituted with methyl or halogen.
[0033] In another embodiment, this invention provides a compound of
Formula I in which A is 0, n is 1, m is 1, R.sub.1 is H, R.sub.2 is
H or CH.sub.3, and R.sub.3 is R.sub.4NHC(O), R.sub.4NHC(S), or
R.sub.4NHCH.sub.2C(O), where R.sub.4 is C.sub.1-6 alkyl, which
alkyl group may be straight-chain, branched, or cyclic, and is
optionally substituted as described for R.sub.3 alkyl groups, or
R.sub.4 is a five- or 6-membered aromatic ring containing 0-3
heteroatoms independently selected from O, N, and S, all R.sub.4
optionally substituted with one or two substituents independently
selected from halo, methyl, and benzyl, wherein all rings are
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3,
CN, and halo, wherein all methyl groups are optionally substituted
with 1, 2, or 3 halogen atoms.
[0034] In another embodiment, this invention provides a compound of
Formula II below
##STR00002##
where n is zero, 1, 2, or 3; A is S, O, or N(CH.sub.3); B and B'
are either both H or jointly oxo; R.sub.1 and R.sub.2 are,
independently, H, CH.sub.3, CF.sub.3, or CH.sub.3O; R.sub.3 is H;
or R.sub.3 is a 5- or 6-membered ring, which optionally contains
one or more double bonds and also optionally contains 1-3 ring
heteroatoms independently selected from O, N, and S, which may be
substituted with one or two groups independently selected from
CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo,
where all methyl groups are optionally substituted with 1, 2, or 3
halogen atoms; or R.sub.3 is C.sub.1-6 alkyl, C.sub.1-6 alkanoyl,
C.sub.1-6 alkenyl, C.sub.1-6 alkoxy, C.sub.1-6 alkenoxy, wherein
said alkyl groups, the alkyl moieties of said alkanoyl and said
alkoxy groups, said alkenyl groups, and the alkenyl moieties of
said alkenoxy groups may be straight-chain, branched, or cyclic,
and may optionally be substituted as follows:
[0035] a) with one, two, or three halogen atoms;
[0036] b) with one or two substituents independently selected from
hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy;
[0037] c) with one saturated, unsaturated, or aromatic 5- or
6-membered ring containing 0-3 heteroatoms selected from N, O, and
S, said ring optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, C(O)CH.sub.3,
CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo, wherein all methyl
groups are optionally substituted with 1, 2, or 3 halogen atoms;
and
[0038] d) with one group selected from C.sub.1-6 alkanoyl,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl,
ethylcarbamoylmethyl methylcarbamoylmethyl,
2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
[0039] or R.sub.3 is R.sub.4NHC(O), R.sub.4NHC(S), or
R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is C.sub.1-6 alkyl, wherein
said alkyl group may be straight-chain, branched, or cyclic, and is
optionally substituted as described for R.sub.3 alkyl groups, or
R.sub.4 is a five- or 6-membered aromatic ring containing 0-3
heteroatoms independently selected from O, N, and S, all R.sub.4
optionally substituted with one or two substituents independently
selected from halo, methyl, and benzyl, wherein all rings are
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3,
CN, and halo, wherein all methyl groups are optionally substituted
with 1, 2, or 3 halogen atoms; and R.sub.5 is H or C.sub.3
alkyl;
or R.sub.3 and R.sub.5, together with the ring carbon atoms to
which they are attached, form an additional fused 5- or 6-membered
cycloalkyl group, provided that when A is O or S, then R.sub.1,
R.sub.2, R.sub.3, B, and B' are not all H, and further provided
that when A is S and R.sub.1 is CH.sub.3, then R.sub.2, R.sub.3, B,
and B' are not all H.
[0040] In another embodiment, this invention provides a compound of
Formula I, as described in the previous paragraph, in which A is S,
R.sub.5 is H; and in which R.sub.3 is selected from H, C.sub.1-4
alkyl, C.sub.1-4 alkenyl, or C.sub.1-6 alkoxy, wherein said alkyl
groups, the alkyl moieties of said alkoxy groups, and said alkenyl
groups may be straight-chain, branched, or cyclic, and are
optionally substituted with one or two substituents independently
selected from halo, hydroxy, ethylcarbamoylmethyl,
methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl,
benzoyl, benzoyloxy, and a 5- or 6-membered ring, said ring
optionally containing one or more double bonds, optionally
containing 1-3 ring heteroatoms independently selected from O, N,
and S, and optionally substituted with, independently, one or two
groups independently selected from CH.sub.3, OCH.sub.3, CF.sub.3,
and halo; and n=0, 1, or 2.
[0041] In another embodiment, the present invention provides a
compound of Formula II as described above, further characterized in
that n=1 or 2, and R.sub.3 is hydrogen, methyl, methoxy, ethoxy or
allyl.
[0042] In another embodiment, the present invention provides a
method of treating an HBV infection, comprising providing in a
person in need of treatment thereof a therapeutically effective
concentration of a compound of Formula I,
##STR00003##
where A is S, O, or N(CH.sub.3); R.sub.1 and R.sub.2 are,
independently, H, CH.sub.3, CF.sub.3, or CH.sub.3O; R.sub.3 is H;
or R.sub.3 is a 5- or 6-membered ring, said ring optionally
containing one or more double bonds, optionally containing 1-3 ring
heteroatoms independently selected from O, N, and S, and optionally
substituted with one or two groups independently selected from
CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo,
wherein all methyl groups are optionally substituted with 1, 2, or
3 halogen atoms;
[0043] or R.sub.3 is C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6
alkenyl, C.sub.1-6 alkoxy, C.sub.1-6 alkenoxy, wherein said alkyl
groups, the alkyl moieties of said alkanoyl and said alkoxy groups,
said alkenyl groups, and the alkenyl moieties of said alkenoxy
groups may be straight-chain, branched, or cyclic, and can all
optionally be substituted as follows:
[0044] a) with one, two, or three halogen atoms;
[0045] b) with one or two substituents independently selected from
hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy;
[0046] c) with one saturated, unsaturated, or aromatic 5- or
6-membered ring containing 0-3 heteroatoms selected from N, O, and
S, said ring optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, C(O)CH.sub.3,
CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo, wherein all methyl
groups are optionally substituted with 1, 2, or 3 halogen atoms;
and
[0047] d) with one group selected from C.sub.1-6 alkanoyl,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl,
ethylcarbamoylmethyl methylcarbamoylmethyl,
2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R.sub.3 is R.sub.4NHC(O), R.sub.4NHC(S), or
R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is C.sub.1-6 alkyl, wherein
said alkyl group may be straight-chain, branched, or cyclic, and is
optionally substituted as described for R.sub.3 alkyl groups, or
R.sub.4 is a five- or 6-membered aromatic ring containing 0-3
heteroatoms independently selected from O, N, and S, all R.sub.4
optionally substituted with one or two substituents independently
selected from halo, methyl, and benzyl, wherein all rings are
optionally substituted with one or two groups independently
selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3,
CN, and halo, wherein all methyl groups are optionally substituted
with 1, 2, or 3 halogen atoms; and m and n are, independently, 1 or
2, provided that m and n are not both 2.
[0048] Another embodiment of the invention provides a method of
treating an HBV infection, comprising providing in a person in need
of treatment thereof a therapeutically effective concentration of a
compound of Formula I above, where A is S, n is 1, m is 1, R.sub.1
is H, and R.sub.2 is H or CH.sub.3.
[0049] Another embodiment of the invention provides a method of
treating an HBV infection, comprising providing in a person in need
of treatment thereof a therapeutically effective concentration of a
compound of Formula I above, where A is S, n is 1, m is 1, R.sub.1
is H, R.sub.2 is H or CH.sub.3, and where R.sub.3 is H or C.sub.1-6
alkyl, optionally substituted with one or two substituents
independently selected from halo, hydroxy, cyano, phenyl, pyridyl,
benzoyl, benzoyl methyl, benzoyloxy, C.sub.1-6 alkoxycarbonyl,
C.sub.1-6 alkylcarbamoyl, N-phthalimido, or R.sub.3 is a 5- or
6-membered aromatic ring containing 1-3 heteroatoms independently
selected from O, N, and S, wherein all rings are optionally
substituted with one or two substituents independently selected
from halo, CH.sub.3, CH.sub.3O, CN, CF.sub.3, and CH.sub.3C(O),
wherein all methyl groups are optionally substituted 1-3 chlorine
atoms.
[0050] Another embodiment of the invention provides a method of
treating an HBV infection, comprising providing in a person in need
of treatment thereof a therapeutically effective concentration of a
compound of Formula I above, where A is S, n is 1, m is 1, R.sub.1
is H, R.sub.2 is H or CH.sub.3, and where R.sub.3 is C.sub.1-4
alkyl, optionally monosubstituted with halogen, hydroxy, phenyl,
benzyl, pyridyl, and pyridyl methyl, wherein the phenyl and pyridyl
rings are optionally further monosubstituted with methyl or
halogen.
[0051] Another embodiment of the invention provides a method of
treating an HBV infection, comprising providing in a person in need
of treatment thereof a therapeutically effective concentration of a
compound of Formula I above, where A is S, n is 1, m is 1, R.sub.1
is H, R.sub.2 is H or CH.sub.3, and where R.sub.3 is R.sub.4NHC(O),
R.sub.4NHC(S), or R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is
C.sub.1-6 alkyl, wherein said alkyl group may be straight-chain,
branched, or cyclic, and is optionally substituted as described for
R.sub.3 alkyl groups, or R.sub.4 is a five- or 6-membered aromatic
ring containing 0-3 heteroatoms independently selected from O, N,
and S, all R.sub.4 optionally substituted with one or two
substituents independently selected from halo, methyl, and benzyl,
wherein all rings are optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms.
[0052] Another particular embodiment of the present invention is a
method treating an HBV infection, comprising providing in a person
in need of treatment thereof a therapeutically effective
concentration of a compound of Formula I, where A is S, n is 2, m
is 1, R.sub.1 is H, and R.sub.2 is H or CH.sub.3.
[0053] Another particular embodiment of the present invention is a
method treating an HBV infection, comprising providing in a person
in need of treatment thereof a therapeutically effective
concentration of a compound of Formula I, where A is S, n is 2, m
is 1, R.sub.1 is H, and R.sub.2 is H or CH.sub.3, wherein R.sub.3
is H or C.sub.1-4 alkyl.
[0054] Another particular embodiment of the present invention is a
method treating an HBV infection, comprising providing in a person
in need of treatment thereof a therapeutically effective
concentration of a compound of Formula I, where A is 0, n is 1, m
is 1, R.sub.1 is H, and R.sub.2 is H or CH.sub.3.
[0055] Another particular embodiment of the present invention is a
method treating an HBV infection, comprising providing in a person
in need of treatment thereof a therapeutically effective
concentration of a compound of Formula I, where A is 0, n is 1, m
is 1, R.sub.1 is H, R.sub.2 is H or CH.sub.3, and R.sub.3 is H or
C.sub.1-6 alkyl, optionally substituted with one or two
substituents independently selected from halo, hydroxy, cyano,
phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C.sub.1-6
alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl, N-phthalimido, or R.sub.3
is a 5- or 6-membered aromatic ring containing 1-3 heteroatoms
independently selected from O, N, and S, wherein all rings are
optionally substituted with one or two substituents independently
selected from halo, CH.sub.3, CH.sub.3O, CN, CF.sub.3, and
CH.sub.3C(O), wherein all methyl groups are optionally substituted
1-3 chlorine atoms.
[0056] Another particular embodiment of the present invention is a
method treating an HBV infection, comprising providing in a person
in need of treatment thereof a therapeutically effective
concentration of a compound of Formula I, where A is 0, n is 1, m
is 1, R.sub.1 is H, R.sub.2 is H or CH.sub.3, and R.sub.3 is
C.sub.1-4 alkyl, optionally monosubstituted with halogen, hydroxy,
phenyl, benzyl, pyridyl, and pyridyl methyl, wherein the phenyl and
pyridyl rings are optionally monosubstituted with methyl or
halogen.
[0057] Another particular embodiment of the present invention is a
method treating an HBV infection, comprising providing in a person
in need of treatment thereof a therapeutically effective
concentration of a compound of Formula I, where A is 0, n is 1, m
is 1, R.sub.1 is H, R.sub.2 is H or CH.sub.3, and R.sub.3 is
R.sub.4NHC(O), R.sub.4NHC(S), or R.sub.4NHCH.sub.2C(O), wherein
R.sub.4 is C.sub.1-6 alkyl, wherein said alkyl group may be
straight-chain, branched, or cyclic, and is optionally substituted
as described for R.sub.3 alkyl groups, or R.sub.4 is a five- or
6-membered aromatic ring containing 0-3 heteroatoms independently
selected from O, N, and S, all R.sub.4 optionally substituted with
one or two substituents independently selected from halo, methyl,
and benzyl, wherein all rings are optionally substituted with one
or two groups independently selected from CH.sub.3, OCH.sub.3,
CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo, wherein all methyl
groups are optionally substituted with 1, 2, or 3 halogen
atoms.
[0058] Another particular embodiment of the present invention is a
method treating an HBV infection, comprising providing in a person
in need of treatment thereof a therapeutically effective
concentration of a compound of Formula II
##STR00004##
wherein n is zero, 1, 2, or 3; A is S, O, or N(CH.sub.3); B and B'
are either both H or jointly oxo; R.sub.1 and R.sub.2 are,
independently, H, CH.sub.3, CF.sub.3, or CH.sub.3O;
R.sub.3 is H;
[0059] or R.sub.3 is a 5- or 6-membered ring, said ring optionally
containing one or more double bonds, optionally containing 1-3 ring
heteroatoms independently selected from O, N, and S, and optionally
substituted with one or two groups independently selected from
CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo,
wherein all methyl groups are optionally substituted with 1, 2, or
3 halogen atoms;
[0060] or R.sub.3 is C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6
alkenyl, C.sub.1-6 alkoxy, C.sub.1-6 alkenoxy, wherein said alkyl
groups, the alkyl moieties of said alkanoyl and said alkoxy groups,
said alkenyl groups, and the alkenyl moieties of said alkenoxy
groups may be straight-chain, branched, or cyclic, and may
optionally be substituted as follows:
[0061] a) with one, two, or three halogen atoms;
[0062] b) with one or two substituents independently selected from
hydroxy, carboxyl, cyano, benzyl, benzoyl, and benzoyloxy;
[0063] c) with one saturated, unsaturated, or aromatic 5- or
6-membered ring containing 0-3 heteroatoms selected from N, O, and
S, said ring optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, C(O)CH.sub.3,
CO.sub.2CH.sub.3, OC(O)CH.sub.3, CN, and halo, wherein all methyl
groups are optionally substituted with 1, 2, or 3 halogen atoms;
and
[0064] d) with one group selected from C.sub.1-6 alkanoyl,
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkylcarbamoyl,
ethylcarbamoylmethyl methylcarbarnoylmethyl,
2-hydroxy-2-phenyl-ethylcarbamoylmethyl,
[0065] or N-phthalimido; or R.sub.3 is R.sub.4NHC(O),
R.sub.4NHC(S), or R.sub.4NHCH.sub.2C(O), wherein R.sub.4 is
C.sub.1-6 alkyl, wherein said alkyl group may be straight-chain,
branched, or cyclic, and is optionally substituted as described for
R.sub.3 alkyl groups, or R.sub.4 is a five- or 6-membered aromatic
ring containing 0-3 heteroatoms independently selected from O, N,
and S, all R.sub.4 optionally substituted with one or two
substituents independently selected from halo, methyl, and benzyl,
wherein all rings are optionally substituted with one or two groups
independently selected from CH.sub.3, OCH.sub.3, CO.sub.2CH.sub.3,
OC(O)CH.sub.3, CN, and halo, wherein all methyl groups are
optionally substituted with 1, 2, or 3 halogen atoms; and R.sub.5
is H or C.sub.3 alkyl; or R.sub.3 and R.sub.5, together with the
ring carbon atoms to which they are attached, form an additional
fused 5- or 6-membered cycloalkyl group.
[0066] In another embodiment, this invention provides a method as
described in the previous paragraph, where A is S, R.sub.5 is H;
and where R.sub.3 is selected from H, C.sub.1-4 alkyl, C.sub.1-4
alkenyl, or C.sub.1-6 alkoxy, wherein said alkyl groups, the alkyl
moieties of said alkoxy groups, and said alkenyl groups may be
straight-chain, branched, or cyclic, and are optionally substituted
with one or two substituents independently selected from halo,
hydroxy, ethylcarbamoylmethyl, methylcarbamoylmethyl,
2-hydroxy-2-phenyl-ethylcarbamoylmethyl, benzoyl, benzoyloxy, and a
5- or 6-membered ring, said ring optionally containing one or more
double bonds, optionally containing 1-3 ring heteroatoms
independently selected from O, N, and S, and optionally substituted
with, independently, one or two groups independently selected from
CH.sub.3, OCH.sub.3, CF.sub.3, and halo; and n=0, 1, or 2.
[0067] In another embodiment, this invention provides a method
treating an HBV infection, comprising providing in a person in need
of treatment thereof a therapeutically effective concentration of a
compound of Formula II above, wherein n is 1 or 2, A is S, O, or
N(CH.sub.3); B and B' are either both H or jointly oxo; R.sub.1 and
R.sub.2 are, independently, H, CH.sub.3, CF.sub.3, or CH.sub.3O;
and R.sub.3 is H, methyl, methoxy, ethoxy or allyl.
DETAILED DESCRIPTION OF THE INVENTION
[0068] The term "alkyl," as used herein, refers to a straight-chain
or branched saturated group with 1-20 carbon atoms, derived from an
alkane by the removal of one hydrogen atom.
[0069] The term "alkenyl," as used herein, refers to a monovalent
straight-chain or branched group of 2-12 carbon atoms containing at
least one carbon-carbon double bond, derived from an alkene by the
removal of one hydrogen atom.
[0070] The term "alkoxy," as used herein, refers to an alkyl group
attached to the parent molecular group through an oxygen atom.
[0071] The term "amino," as used herein, refers to a
--NR.sub.aR.sub.b group, where R.sub.a and R.sub.b are
independently selected from hydrogen, alkyl, aryl or
heteroaryl.
[0072] The term "aminocarbonyl," as used herein, refers to an amino
group, as defined herein, attached to the parent molecular moiety
through a carbonyl group, as defined herein.
[0073] The term "aminocarbonyloxy," as used herein, refers to an
aminocarbonyl group, as defined herein, attached to the parent
molecular moiety through an oxygen atom.
[0074] The term "aryl," as used herein, refers to a carbocyclic
ring system, mono- or bi-cyclic, having one or two aromatic rings.
The aryl group can also be fused to a cyclohexane, cyclohexene,
cyclopentane or cyclopentene ring. The aryl groups of this
invention are optionally substituted.
[0075] The term "oxo," as used herein, refers to .dbd.O, and the
term "carbonyl," as used herein, refers to a C.dbd.O group.
[0076] The term "cycloalkyl," as used herein, refers to a
monovalent aliphatic cyclic hydrocarbon group of 3-12 carbons
derived from a cycloalkane by the removal of one hydrogen atom.
[0077] The terms "halo" and "halogen," as used herein, refer to F,
Cl, Br, or I.
[0078] The term "heteroaryl" represents an aryl group containing in
which one, two, or three ring atoms are substituted with
heteroatoms independently selected from nitrogen, oxygen, and
sulfur.
[0079] The term "oxy," as used herein, refers to --O--.
[0080] The term "methylene," as used herein, refers to a
--CH.sub.2-- group.
[0081] The term "perfluoroalkyl," as used herein, refers to an
alkyl group in which all of the hydrogen atoms have been replaced
by fluorine atoms.
[0082] The term "phenyl," as used herein, refers to a monocyclic
carbocyclic ring system having one aromatic ring. The phenyl group
can also be fused to another ring. The phenyl groups of this
invention can be optionally substituted.
[0083] The term "prodrug," as used herein, represents compounds
that are transformed in vivo to the parent compound of the above
formula, for example, by hydrolysis in blood. A thorough discussion
is provided in T. Higuchi and V. Stella, Pro-drugs as Novel
Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in
Edward B. Roche, ed., Bioreversible Carriers in Drug Design,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated herein by reference.
[0084] The terms "thioalkoxy," and "thio," as used herein, refer to
an alkyl group attached to the parent molecular group through a
sulfur atom.
[0085] The term "treating," as used herein, refers to reversing,
alleviating, or inhibiting the progress of the disease, disorder or
condition, or one or more symptoms of such disease, disorder or
condition, to which such term applies. Depending on the condition
of the patient, as used herein, this term also refers to preventing
a disease, disorder or condition, and includes preventing the onset
of a disease, disorder or condition, or preventing the symptoms
associated with a disease, disorder or condition. As used herein,
this term also refers to reducing the severity of a disease,
disorder or condition or symptoms associated with such disease,
disorder or condition prior to affliction with the disease,
disorder or condition. Such prevention or reduction of the severity
of a disease, disorder or condition prior to affliction refers to
administration of the composition of the present invention, as
described herein, to a subject that is not at the time of
administration afflicted with the disease, disorder or condition.
"Preventing" also refers to preventing the recurrence of a disease,
disorder or condition or of one or more symptoms associated with
such disease, disorder or condition. The terms "treatment" and
"therapeutically," as used herein, refer to the act of treating, as
"treating" is defined above.
Synthetic Methods
[0086] The compounds of this invention may be prepared by the
general methods and examples presented below, and methods known to
those of ordinary skill in the art. Optimum reaction conditions and
reaction times may vary depending on the particular reactants used.
Unless otherwise specified, solvents, temperatures, pressures, and
other reaction conditions may be readily selected by one of
ordinary skill in the art. Specific procedures are provided in the
Synthetic Examples section. Reaction progress may be monitored by
conventional methods such as thin layer chromatography (TLC) and
mass spectrum (MS). Intermediates and products may be purified by
methods known in the art, including column chromatography, high
pressure liquid chromatography (HPLC), and recrystallization.
[0087] Additional abbreviations which have been used in the
descriptions of the schemes and the examples that follow are: DMF
for N,N-dimethylformamide, DMSO for dimethylsulfoxide, and THF for
tetrahydrofuran.
[0088] As shown in Scheme I, reaction of I with one equivalent of
cyanothioacetamide II in a suitable solvent such as ethanol, in the
presence of a suitable base such as N-methylmorpholine produces
intermediates III. Reaction of III with substituted cyclic,
heterocyclic, and polycyclic ketones IV, e.g., cyclopentanones,
cyclohexanones, cycloheptanones, piperidinones, pyrrolidinones,
azepanones, tetrahydrofuranones, decalones, cyclohexanediones, and
tetrahydropyranones, in a suitable solvent such as ethanol, in the
presence of a suitable base such as N-methylmorpholine or
morpholine, provides the intermediates V. Reaction of V with
chloro- or bromoacetamide in a suitable solvent such as ethanol or
acetone, in the presence of a suitable base such as potassium
carbonate, sodium ethoxide, potassium tert-butoxide, with or
without heating, provides compounds of formula VI. Substituent
R.sub.1 may be further modified by methods known in the art to
produce additional compounds of the invention.
##STR00005##
[0089] For example, as illustrated in Scheme II, beginning with
substituted or unsubstituted piperidinones, pyrrolidinones,
azepanones with protected groups, the procedure above affords VIa.
The protecting group of VIa is removed by methods and conditions
known in the art to produce VII. Substituent R.sub.1 may be
modified by commonly known methods to make other desired
substituents (VIII) by reaction of VII with an additional reagent
such as an alkyl halide, aromatic or aliphatic carboxylic acid,
acid halides, sulfonyl halide, anhydride, isocyanate, and
isothiocyanate, in a solvent such as DMF, dichloromethane, THF, in
the presence of a suitable base such as triethylamine,
diisopropylethylamine, pyridine, and potassium carbonate.
##STR00006##
SYNTHETIC PROCEDURES--EXAMPLES
Example I
Synthesis of
3-amino-6-benzyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indace-
ne-2-carboxylic acid amide (21)
##STR00007##
[0090] 2-Cyano-3-thiophen-2-yl-thioacrylamide
[0091] To a mixture of 2-thiophencarbaldehyde (22.4 g, 0.2 mol) and
2-cyanothioacetamide (22 g, 0.22 mol) in 250 ml of ethanol was
added N-methylmorpholine (30.3 g, 0.3 mol) at room temperature. The
resulting mixture was stirred at room temperature overnight. The
solid was filtered and washed with ethanol to give 28.2 g (72%) of
product as a yellow solid after drying in vacuo. .sup.1H-NMR (300
MHz, DMSO-d6): .delta. 10.0 (brs, 1H), 9.45 (brs, 1H), 8.37 (s,
1H), 8.12 (d, J=4.8 Hz, 1H), 7.88 (d, J=3.3 Hz, 1H), 7.32 (dd,
J=3.3, 4.8 Hz, 1H). ES MS m/z 195 (M+H).sup.+, 193(M-H).sup.-.
3-Amino-2-carbamoyl-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacen-
e-6-carboxylic acid tert-butyl ester (1)
[0092] To a mixture of 2-cyano-3-thiophen-2-yl-thioacrylamide (4.38
g, 22.5 mmol) and 1-boc-3-pyrrolidine synthesized from pyrrolidinol
by reference procedures (Synthetic Commun. 1985, 15(7), 587-598)
(4.16 g, 22.5 mmol) in 200 ml of anhydrous ethanol was added
morpholine (3.94 g, 45 mmol) at room temperature with stirring. The
resulting mixture was heated to reflux overnight. Then,
2-chloroacetamide (4.21 g, 45 mmol) and K.sub.2CO.sub.3 (6.23 g, 45
mmol) were added. The reaction mixture was continued to heat at
80.degree. C. overnight and then cooled to room temperature. The
crystals was filtered and washed with ethanol and water to give the
desired product as yellow crystals. .sup.1H-NMR (300 MHz, DMSO-d6):
.delta. 7.92 (dd, J=1.2, 5.1 Hz, 1H), 7.33 (dd, J=1.2, 3.6 Hz, 1H),
7.30 (dd, J=3.6, 5.1 Hz, 1H), 7.26 (brs, 1H), 5.97 (d, J=10.5 Hz,
2H), 4.70 (d, J=6.0 Hz, 2H), 4.45 (d, J=10.5 Hz, 2H), 1.42 (m, 9H).
ES MS m/z 417 (M+H).sup.+, 415 (M-H)--.
3-Amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carbo-
xylic acid amide hydrochloride (2)
[0093] To a suspension of
3-amino-2-carbamoyl-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indace-
ne-6-carboxylic acid tert-butyl ester (4 g, 9.6 mmol)) in 70 ml of
anhydrous methanol was added dropwise 7 ml of acetyl chloride under
argon. The resulting mixture was stirred for 48 hours at room
temperature. The solid was filtered and washed with methanol to
give 3.14 g (93%) of the yellow product as its hydrochloride salt.
.sup.1H-NMR (300 MHz, DMSO-d6): .delta. 10.20 (brs, 2H), 7.96 (dd,
J=1.2, 5.1 Hz, 1H), 7.36 (dd, J=1.2, 3.6 Hz, 1H), 7.32 (brs, 2H),
7.31 (dd, J=3.6, 5.1 Hz, 1H), 6.02 (brs, 2H), 4.63 (s, 2H), 4.42
(s, 2H). ES MS m/z 317 (M+H).sup.+, 315 (M-H).sup.-.
3-Amino-6-benzyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacen-
e-2-carboxylic acid amide (21)
[0094] A mixture of
3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carb-
oxylic acid amide hydrochloride (70 mg, 0.2 mmol), benzyl bromide
(38 mg, 0.22 mmol), and triethylamine (0.2 ml) in 2 ml of anhydrous
DMF was heated at 60.degree. C. for 24 hours. The solvent was
removed in vacuo, and the residue was purified by preparative HPLC
to give a yellow solid. .sup.1H-NMR (300 MHz, DMSO-d6): .delta.
7.83 (d, J=5.1 Hz, 1H), 7.32 (m, 3H), 7.31 (d, J=3.6 Hz, 1H), 7.26
(dd, J=3.6, 5.1 Hz, 1H), 7.22 (m, 2H), 7.22 (brs, 2H), 5.96 (brs,
2H), 4.02 (s, 2H), 3.86 (s, 2H), 3.72 (s, 2H). ES MS m/z 407
(M+H).sup.+, 405 (M-H).sup.-.
[0095] The following compounds were prepared by using the same
procedure described in Example 1, substituting a suitable aldehyde
for 2-thiophencarbaldehyde as the starting material. In some cases,
if the product was not recrystallized from methanol or ethanol, the
reaction mixture was purified by flash column chromatography or
preparative HPLC. [0096]
3-Amino-6-pyridin-2-ylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-
-6,8-diaza-s-indacene-2-carboxylic acid amide (7) [0097]
3-Amino-6-pyridin-3-ylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-di-
aza-s-indacene-2-carboxylic acid amide (20) [0098]
3-Amino-6-(2-methyl-benzyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-dia-
za-s-indacene-2-carboxylic acid amide (22) [0099]
3-Amino-6-(3-fluoro-benzyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-dia-
za-s-indacene-2-carboxylic acid amide (23) [0100]
3-Amino-6-(3,5-dimethoxy-benzyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,-
8-diaza-s-indacene-2-carboxylic acid amide (24)
Example 2
Synthesis of
3-amino-6-cyclopropylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-dia-
za-s-indacene-2-carboxylic acid amide (8)
##STR00008##
[0102] A mixture of
3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carb-
oxylic acid amide hydrochloride (70 mg, 0.2 mmol), bromomethyl
cyclopropane (54 mg, 0.4 mmol), and triethylamine (0.2 ml) in 2 ml
of anhydrous DMF was heated at 60.degree. C. for 24 hours. The
solvent was removed in vacuo and the residue was purified by
preparative HPLC to give pure products as a yellow solid.
.sup.1H-NMR (500 MHz, DMSO-d6): .delta. 8.00 (d, J=5.1 Hz, 1H),
7.31 (d, J=3.6 Hz, 1H), 7.26 (dd, J=3.6, 5.1 Hz, 1H), 7.22 (brs,
2H), 6.05 (brs, 2H), 4.90 (s, 2H), 4.75 (s, 2H), 3.30 (d, J=7.0 Hz,
2H), 1.15 (m, 1H), 0.65 (m, 2H), 0.40 (m, 2H). ES MS m/z 371
(M+H).sup.+, 369(M-H).sup.-.
[0103] The following compounds were prepared by using the same
procedure described in Example 2, substituting a suitable halide
for bromomethyl cyclopropane. In some cases, if the product was not
recrystallized from methanol or ethanol, the reaction mixture was
purified by flash column or preparative HPLC. [0104]
3-Amino-6-(3-chloro-propyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-dia-
za-s-indacene-2-carboxylic acid amide (3) [0105]
3-Amino-6-(tetrahydro-pyran-2-ylmethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1--
thia-6,8-diaza-s-indacene-2-carboxylic acid amide (4) [0106]
3-Amino-6-[5-(2-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-4-thiophen-2-
-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid
amide (5) [0107]
3-Amino-6-(3-methyl-butyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6-
,8-diaza-s-indacene-2-carboxylic acid amide (6) [0108]
3-Amino-6-(2-benzoyloxy-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8--
diaza-s-indacene-2-carboxylic acid amide (9) [0109]
3-Amino-6-phenethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-ind-
acene-2-carboxylic acid amide (10) [0110]
3-Amino-6-cyclohexylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaz-
a-s-indacene-2-carboxylic acid amide (11) [0111]
3-Amino-6-[2-(4-chloro-phenyl)-2-oxo-ethyl]-4-thiophen-2-yl-6,7-dihydro-H-
-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (12) [0112]
3-Amino-6-(3-hydroxy-2-methyl-propyl)-4-thiophen-2-yl-6,7-dihydro-5H-thia-
-6,8-diaza-s-indacene-2-carboxylic acid amide (13) [0113]
3-Amino-6-isobutyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-inda-
cene-2-carboxylic acid amide (14) [0114]
3-Amino-6-(2-hydroxy-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-dia-
za-s-indacene-2-carboxylic acid amide (15) [0115]
3-Amino-6-pentyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indace-
ne-2-carboxylic acid amide (16) [0116]
3-Amino-6-(2-methoxy-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-dia-
za-s-indacene-2-carboxylic acid amide (17) [0117]
3-Amino-6-carbethoxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaz-
a-s-indacene-2-carboxylic acid amide (18) [0118]
3-Amino-6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-thiophen-2-yl-
-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
(19)
Example 3
Synthesis of
3-amino-6-(3-morpholin-4-yl-propyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-
-6,8-diaza-s-indacene-2-carboxylic acid amide (27)
##STR00009##
[0119]
3-Amino-6-(3-chloro-propyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6-
,8-diaza-s-indacene-2-carboxylic acid amide (3)
[0120] A mixture of
3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carb-
oxylic acid amide hydrochloride (0.7 g, 2 mmol),
1-chloro-3-bromopropane (4 mmol), and triethylamine (2 ml) in 10 ml
of anhydrous DMF was heated at 60.degree. C. for 24 hours. The
solvent was removed in vacuo, and the residue was purified by
silica gel column (chloroform/methanol, 40:1) to give pure compound
as a yellow solid. .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 7.88 (d,
J=5.1 Hz, 1H), 7.29 (d, J=3.6 Hz, 1H), 7.27 (dd, J=3.6, 5.1 Hz,
1H), 7.22 (brs, 2H), 5.98 (brs, 2H), 4.00 (s, 2H), 3.77 (s, 2H),
3.67 (t, J=6.3 Hz, 2H), 2.78 (t, J=6.3 Hz, 2H), 1.90 (m, 2H). ES MS
m/z 393, 395 (M+H).sup.+.
3-Amino-6-(3-morpholin-4-yl-propyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia--
6,8-diaza-s-indacene-2-carboxylic acid amide (27)
[0121] A mixture of
3-amino-6-(3-chloro-propyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-dia-
za-s-indacene-2-carboxylic acid amide (78 mg, 0.2 mmol) and
morpholine (44 mg, 0.5 mmol) in 4 ml of ethanol was heated at
100.degree. C. for 24 hours. The solvent was removed in vacuo, and
the residue was purified by silica gel column (chloroform/methanol,
30:1) to give the pure compound as a yellow solid. .sup.1H-NMR (300
MHz, DMSO-d6): .delta. 7.88 (d, J=5.1 Hz, 1H), 7.29 (d, J=3.6 Hz,
1H), 7.27 (dd, J=3.6, 5.1 Hz, 1H), 7.22 (brs, 2H), 5.98 (brs, 2H),
4.59 (s, 2H), 4.35 (s, 2H), 3.80 (m, 4H), 3.67 (t, J=6.3 Hz, 2H),
3.20 (m, 4H), 3.15 (t, J=6.3 Hz, 2H), 2.00 (m, 2H). ES MS m/z 444
(M+H).sup.+, 442 (M-H).sup.-.
[0122] The following compounds were prepared by the same procedure
described in Example 3, substituting suitable nucleophilic reagents
for morpholine, as for compound 27. In some cases, if the product
was not recrystallized from methanol or ethanol, the reaction
mixture was purified by flash column chromatography or preparative
HPLC. [0123]
3-Amino-6-[3-(4-pyrimidin-2-yl-piperazin-1-yl)-propyl]-4-thiophen-2-yl-6,-
7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
(25) [0124]
3-Amino-6-[3-(2-methoxy-piperidin-1-yl)-propyl]-4-thiophen-2-yl-6,-
7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
(26) [0125]
3-Amino-6-[3-(2-hydroxy-propylamino)-propyl]-4-thiophen-2-yl-6,7-d-
ihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
(28)
Example 4
Synthesis of
3-amino-7-benzyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-1-thia-7,9-diaza-cycl-
openta[b]naphthalene-2-carboxylic acid amide (31)
##STR00010##
[0126]
3-Amino-2-carbamoyl-4-thiophen-2-yl-5,8-dihydro-6H-1-thia-7,9-diaza-
-cyclopenta[b]naphthalene-7-carboxylic acid tert-butyl ester
(30)
[0127] To a mixture of 2-cyano-3-thiophen-2-yl-thioacrylamide (4.38
g, 22.5 mmol) and 1-boc-3-piperidone (4.49 g, 22.5 mmol) in 200 ml
of anhydrous ethanol was added morpholine (3.94 g, 45 mmol) at room
temperature with stirring. The resulting mixture was heated to
reflux overnight. Then, 2-chloroacetamide (4.21 g, 45 mmol) and
K.sub.2CO.sub.3 (6.23 g, 45 mmol) was added. The reaction mixture
was continued to heat at 80.degree. C. overnight. The solvent was
removed in vacuo, and the residue was purified by silica gel column
(chloroform/methanol, 40:1) and recrystallized from methanol to
give a yellow crystalline product.
3-Amino-4-thiophen-2-yl-5,6,7,8-tetrahydro-1-thia-7,9-diaza-cyclopenta[b]n-
aphthalene-2-carboxylic acid amide (29)
[0128] To a suspension of
3-amino-2-carbamoyl-4-thiophen-2-yl-5,8-dihydro-6H-1-thia-7,9-diaza-cyclo-
penta[b]naphthalene-7-carboxylic acid tert-butyl ester (100 mg) in
10 ml of anhydrous methanol under argon 0.5 ml of acetyl chloride
was added dropwise, and the resulting mixture was stirred overnight
at room temperature. The reaction mixture was neutralized with 7N
ammonia in methanol and evaporated to dryness under vacuum. The
residue was purified by silica gel column (chloroform/methanol,
30:1) to give a yellow solid. .sup.1H-NMR (300 MHz, DMSO-d6):
.delta. 7.88 (d, J=5.1 Hz, 1H), 7.28 (dd, J=3.6, 5.1 Hz, 1H), 7.16
(d, J=3.6 Hz, 1H), 7.01 (brs, 2H), 5.64 (brs, 2H), 4.84 (brs, 1H),
3.16 (s, 2H), 2.94 (m, 2H), 1.86 (m, 2H). ES MS m/z 331
(M+H).sup.+, 329 (M-H).sup.-.
3-Amino-7-benzyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-1-thia-7,9-diaza-cyclo-
penta[b]naphthalene-2-carboxylic acid amide (31)
[0129] A mixture of
3-amino-4-thiophen-2-yl-5,6,7,8-tetrahydro-1-thia-7,9-diaza-cyclopenta[b]-
naphthalene-2-carboxylic acid amide (66 mg, 0.2 mmol), benzyl
bromide (38 mg, 0.22 mmol), and triethylamine (0.2 ml) in 2 ml of
anhydrous DMF was heated at 60.degree. C. for 24 hours. The solvent
was removed in vacuo, and the residue was purified by preparative
HPLC to give pure products as a yellow solid.
[0130] The following compounds were prepared by using the same
procedure described in Example 4 and substituting a suitable halide
for benzyl bromide as for compound 31. In some cases, if the
product was not recrystallized from methanol or ethanol, the
reaction mixture was purified by flash column or preparative HPLC.
[0131]
3-Amino-6-tert-butyloxycarbonyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno-
[2,3-b][1,6]naphthyridine-2-carboxylic acid amide (32) [0132]
3-Amino-6-benzyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-thieno[2,3-b]-
[1,6]naphthyridine-2-carboxylic acid amide (33)
Example 5
Synthesis of
3-amino-7-ethoxy-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e-
]pyridine-2-carboxylic acid amide (35)
##STR00011##
[0133]
3-Amino-7-ethoxy-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno-
[3,2-e]pyridine-2-carboxylic acid amide (35)
[0134] To a mixture of 2-cyano-3-thiophen-2-yl-thioacrylamide (0.39
g, 2 mmol), 2-ethoxy-cyclopentanone (0.26 g, 2 mmol) in 10 ml of
ethanol was added N-methylmorpholine (0.4 g, 4 mmol). The resulting
mixture was refluxed overnight, and 2-chloroacetamide (0.38 g, 4
mmol) and anhydrous potassium carbonate (0.55 g, 4 mmol) were added
with stirring. The reaction mixture was further heated at reflux
overnight. The cooled reaction mixture was poured into 50 ml of
ice-water, and the precipitate was filtered and washed with water
to give the crude product as a yellow solid. The product was
further purified by silica gel column to produce a yellow solid.
.sup.1H-NMR (300 MHz, DMSO-d6): .delta. 7.88 (dd, J=2.7, 3.6 Hz,
1H), 7.28-7.26 (m, 2H), 7.24 (brs, 2H), 5.8 (brs, 2H), 4.87 (dd,
J=4.5, 6.9 Hz, 1H), 3.79 (m, 1H), 3.65 (m, 1H), 3.43 (m, 1H), 2.77
(m, 1H), 2.35 (m, 1H), 1.98 (m, 1H), 1.31 (t, J=6.9 Hz, 3H). ES MS
m/z 360 (M+H).sup.+, 358 (M-H).sup.-.
[0135] The following compounds were prepared by the same procedure
described in Example 5, substituting a suitable cyclic ketone for
2-ethoxy-cyclopentanone as for compound 35. When flash column
chromatography was insufficient for purification, the crude product
was further purified by preparative HPLC. [0136]
3-Amino-7-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e-
]pyridine-2-carboxylic acid amide (37) [0137]
3-Amino-7-carbomethoxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]-
thieno[3,2-e]pyridine-2-carboxylic acid amide (40) [0138]
3-Amino-7-carbethoxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]th-
ieno[3,2-e]pyridine-2-carboxylic acid amide (41) [0139]
3-Amino-7-hexyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]-
pyridine-2-carboxylic acid amide (59) [0140]
3-Amino-7-heptyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e-
]pyridine-2-carboxylic acid amide (60) [0141]
3-Amino-7-cyclopentyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[-
3,2-e]pyridine-2-carboxylic acid amide (61) [0142]
3-Amino-8-(2-cyano-ethyl)-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b-
]quinoline-2-carboxylic acid amide (62) [0143]
3-Amino-8-isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinol-
ine-2-carboxylic acid amide (63) [0144]
3-Amino-8-benzyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinolin-
e-2-carboxylic acid amide (64) [0145]
3-Amino-8-propyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinolin-
e-2-carboxylic acid amide (65) [0146]
3-Amino-8-phenyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinolin-
e-2-carboxylic acid amide (66) [0147]
3-Amino-8-(3-methoxy-phenyl)-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,-
3-b]quinoline-2-carboxylic acid amide (67) [0148]
3-Amino-8-cyclohexyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quin-
oline-2-carboxylic acid amide (68) [0149]
3-Amino-8-methoxy-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinoli-
ne-2-carboxylic acid amide (69) [0150]
8-Allyl-3-amino-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinoline-
-2-carboxylic acid amide (70) [0151]
3-Amino-8-carbethoxymethyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3--
b]quinoline-2-carboxylic acid amide (71) [0152]
3-Amino-6-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinolin-
e-2-carboxylic acid amide (72) [0153]
3-Amino-6-ethyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinoline-
-2-carboxylic acid amide (73) [0154]
3-Amino-7-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinolin-
e-2-carboxylic acid amide (74) [0155]
3-Amino-4-(3-methyl-thiophen-2-yl)-5-oxo-5,6,7,8-tetrahydro-thieno[2,3-b]-
quinoline-2-carboxylic acid amide (75) [0156]
3-Amino-4-(thiophen-2-yl)-5-oxo-5,6,7,8-tetrahydro-thieno[2,3-b]quinoline-
-2-carboxylic acid amide (76) [0157]
3-Amino-4-(4-chloro-phenyl)-5-oxo-5,6,7,8-tetrahydro-thieno[2,3-b]quinoli-
ne-2-carboxylic acid amide (77) [0158]
3-Amino-5-oxo-4-thiophen-2-yl-1,4,5,6,7,8-hexahydro-thiochromeno[2,3-b]py-
rrole-2-carboxylic acid amide (78)
[0159] A by-product from synthesis of
3-amino-4-(thiophen-2-yl)-5-oxo-5,6,7,8-tetrahydro-thieno[2,3-b]quinoline-
-2-carboxylic acid amide (76)
Example 6
Synthesis of
3-amino-7-(2-morpholin-4-yl-2-oxo-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-c-
yclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide (38)
##STR00012##
[0160]
3-Amino-7-carboxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b-
]thieno[3,2-e]pyridine-2-carboxylic acid amide (36)
[0161] To a mixture of 2-cyano-3-thiophen-2-yl-thioacrylamide (6.3
g, 33 mmol), 2-oxocyclopentaneacetic acid (4.6 g, 33 mmol) in 70 ml
of ethanol was added N-methylmorpholine (6.6 g, 65 mmol). The
resulting mixture was refluxed overnight, then 2-chloroacetamide
(6.1 g, 65 mmol) and anhydrous potassium carbonate (9.0 g, 65 mmol)
was added with stirring. The reaction mixture was continued to
reflux overnight. The reaction mixture was cooled to room
temperature and the solid was filtered and washed with ethanol. The
sodium salt of product was dissolved in 100 ml of water and
neutralized with 10% hydrochloric acid to pH<6. The precipitate
was filtered and washed with water to give 3.7 g (31%) of pure
product as a yellow solid. .sup.1H-NMR (300 MHz, DMSO-d6): .delta.
12.24 (brs, 1H), 7.87 (d, J=5.1 Hz, 1H), 7.27-7.24 (m, 2H), 7.18
(brs, 2H), 5.93 (brs, 2H), 3.55 (m, 1H), 2.94 (dd, J=3.9, 16.2 Hz,
1H), 2.68 (m, 2H), 2.40 (m, 2H), 1.75 (m, 1H). ES MS m/z 374
(M+H).sup.+, 372 (M-H).sup.-.
3-Amino-7-(2-morpholin-4-yl-2-oxo-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-cy-
clopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide (38)
[0162] A solution of
3-amino-7-carboxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thien-
o[3,2-e]pyridine-2-carboxylic acid amide (75 mg, 0.2 mmol),
morpholine (19 mg, 0.22 mmol), and 1-hydroxybenzotriazole (30 mg,
0.22 mmol) in 2 ml of anhydrous DMF was cooled to 0.degree. C.,
then DCC (45 mg, 0.22 mmol) was added. The resulting mixture was
stirred at 0.degree. C. for 2 hours, then at room temperature for
48 hours. The solvent was removed in vacuo and the residue was
recrystallized from methanol to give a pure product as yellow
crystals. .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 7.87 (dd, J=1.2,
4.8 Hz, 1H), 7.27 (dd, J=3.6, 4.8 Hz, 1H), 7.23 (dd, J=1.2, 3.6 Hz,
1H), 7.18 (brs, 2H), 5.93 (brs, 2H), 3.61 (m, 1H), 3.55 (m, 4H),
3.47 (m, 4H), 3.04 (dd, J=3.9, 15.9 Hz, 1H), 2.71 (m, 2H), 2.57
(dd, J=9.3, 15.9 Hz, 1H), 2.39 (m, 1H), 1.75 (m, 1H). ES MS m/z 443
(M+H).sup.+, 441 (M-H)--.
[0163] The following compounds were prepared by the same procedure
described in Example 6, substituting a suitable amine for
morpholine as for compound 38. In some cases, if the product was
not recrystallized from methanol or ethanol, the reaction mixture
was purified by flash column or preparative HPLC. [0164]
3-Amino-7-[(2-hydroxy-2-phenyl-ethylcarbamoyl)-methyl]-4-thiophen-2-yl-6,-
7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide (39) [0165]
3-Amino-7-methylcarbamoylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta-
[b]thieno[3,2-e]pyridine-2-carboxylic acid amide (42) [0166]
3-Amino-7-{[(5-methyl-furan-2-ylmethyl)-carbamoyl]-methyl}-4-thiophen-2-y-
l-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide (43) [0167]
3-Amino-7-[(2-methoxy-benzylcarbamoyl)-methyl]-4-thiophen-2-yl-6,7-dihydr-
o-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide
(44) [0168]
3-Amino-7-{[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-4-thiophen-2-y-
l-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide (45) [0169]
3-Amino-7-[(2-pyridin-2-yl-ethylcarbamoyl)-methyl]-4-thiophen-2-yl-6,7-di-
hydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide
(46) [0170]
3-Amino-4-thiophen-2-yl-7-[(4-trifluoromethyl-benzylcarbamoyl)-met-
hyl]-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide (47) [0171]
3-Amino-7-[(3-methyl-butylcarbamoyl)-methyl]-4-thiophen-2-yl-6,7-dihydro--
5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide (48)
[0172]
3-Amino-7-dimethylcarbamoylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopen-
ta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide (49) [0173]
3-Amino-7-cyclobutylcarbamoylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclop-
enta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide (50) [0174]
3-Amino-7-cyclohexylcarbamoylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclop-
enta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide (51) [0175]
3-Amino-7-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-thiophen-2-yl-6,7--
dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide (52) [0176]
3-Amino-7-[2-oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-4-thioph-
en-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide (53) [0177]
4-[2-(3-Amino-2-carbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thi-
eno[3,2-e]pyridin-7-yl)-acetylamino]-piperidine-1-carboxylic acid
ethyl ester (54) [0178]
3-Amino-7-{[2-(1-methyl-pyrrolidin-2-yl)-ethylcarbamoyl]-methyl}-4-thioph-
en-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide (55) [0179]
1-[2-(3-Amino-2-carbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thi-
eno[3,2-e]pyridin-7-yl)-acetyl]-piperidine-4-carboxylic acid ethyl
ester (56) [0180]
3-Amino-7-[(3-morpholin-4-yl-propylcarbamoyl)-methyl]-4-thiophen-2-yl-6,7-
-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide (57) [0181]
3-Amino-7-{[3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl}-4-thioph-
en-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide (58)
Example 7
Synthesis of
3-amino-6-phenylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-d-
iaza-s-indacene-2-carboxylic acid amide (79)
##STR00013##
[0182]
3-amino-6-phenylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-
-6,8-diaza-s-indacene-2-carboxylic acid amide (79)
[0183] To 70 mg (0.22 mmol) of
3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carb-
oxylic acid amide hydrochloride in 3.0 ml of DMF was added dropwise
40 .mu.l of diisopropylethylamine and 26 .mu.l of phenyl
isothiocyanate with stirring at 0.degree. C. The resulting mixture
was continuously stirred at room temperature for 6 hours. The
solvent was removed in vacuo and the residue was recrystallized
from methanol to give the pure product as a yellow solid in 92%
yield: silica gel TLC (1:5 methanol-chloroform); .sup.1H NMR (300
MHz, DMSO-d6) .delta. 9.29 (s, 1H), 7.94 (d, 1H, J=4.8 Hz),
7.36-7.28 (m, 8H), 7.16-7.13 (m, 1H), 5.99 (s, 2H), 5.13 (s, 2H),
4.89 (s, 2H). ES MS m/z 452 (M+H).sup.+, 450 (M-H).sup.-.
[0184] The following compounds were prepared by using the same
procedure described in Example 7, substituting a suitable
isothiocyanate for phenyl isothiocyanate, as for compound 79. In
most cases, 1.0 equivalent of
3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carb-
oxylic acid amide hydrochloride in DMF was added dropwise 1.1
equivalent of diisopropylethylamine and 1.0 equivalent of
isothiocyanate at 0.degree. C. Then the resulting mixture was
stirred at room temperature for 4 to 16 hours and monitored by TLC.
The solvent was removed in vacuo and the residue was purified by a
silica gel column chromatography eluting with 10-25% methanol in
chloroform or recrystallized from methanol to give the pure
products as a yellow solid in 80-99% yield. [0185]
3-Amino-6-[(tetrahydro-furan-2-ylmethyl)-thiocarbamoyl]-4-thiophen-
-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid
amide (80) [0186]
3-Amino-6-cyclopentylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia--
6,8-diaza-s-indacene-2-carboxylic acid amide (81) [0187]
3-Amino-6-butylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-di-
aza-s-indacene-2-carboxylic acid amide (82) [0188]
3-Amino-4-thiophen-2-yl-6-p-tolylthiocarbamoyl-6,7-dihydro-5H-1-thia-6,8--
diaza-s-indacene-2-carboxylic acid amide (83) [0189]
3-Amino-6-benzylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-d-
iaza-s-indacene-2-carboxylic acid amide (84) [0190]
3-Amino-6-(3-methoxy-phenylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydro-5H--
1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (85) [0191]
3-Amino-6-(3-phenyl-propylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-
-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (86) [0192]
3-Amino-4-thiophen-2-yl-6-(3-trifluoromethyl-phenylthiocarbamoyl)-6,7-dih-
ydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (87)
[0193]
3-Amino-6-(4-fluoro-phenylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-
-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (88) [0194]
3-Amino-6-(3,5-dichloro-phenylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydro--
5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (89) [0195]
4-[(3-Amino-2-carbamoyl-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-in-
dacene-6-carbothioyl)-amino]-benzoic acid methyl ester (90) [0196]
3-Amino-6-cyclopropylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia--
6,8-diaza-s-indacene-2-carboxylic acid amide (91) [0197]
3-Amino-6-(3,5-dimethyl-phenylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydro--
5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (92) [0198]
3-Amino-6-(2-morpholin-4-yl-ethylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihyd-
ro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (93)
[0199]
3-Amino-6-(3-morpholin-4-yl-propylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihy-
dro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (94)
Example 8
3-amino-6-(4,5-dihydro-thiazol-2-yl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-
-6,8-diaza-s-indacene-2-carboxylic acid amide (95)
##STR00014##
[0200]
3-amino-6-(4,5-dihydro-thiazol-2-yl)-4-thiophen-2-yl-6,7-dihydro-5H-
-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (162)
[0201] To 20 mg (0.06 mmol) of
3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carb-
oxylic acid amide hydrochloride in 3.0 ml of DMF was added 51 ul of
1.0 M solution of diisopropylethylamine in THF and 7.3 mg (0.06
mmol) of 2-chloroethyl isothiocyanate at 0.degree. C. with
stirring. The resulting mixture was continuously stirred at room
temperature for 16 hours. The solvent was removed in vacuo to
dryness. The residue was recrystallized from methanol to give the
pure product as a yellow solid in 70% yield: silica gel TLC R.sub.f
0.80 (I: 8 methanol-chloroform); .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.97 (dd, 1H, J=6.0, 1.2 Hz), 7.37-7.30 (m,
4H), 6.00 (s, 2H), 5.07 (s, 2H), 4.82 (s, 2H), 3.98 (t, 2H, J=15.0
Hz), 3.68 (t, 2H, J=15.0 Hz). ES MS m/z 540 (M+H).sup.+, 538
(M-H).sup.-.
Example 9
3-amino-6-(4-cyanophenylcarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,-
8-diaza-s-indacene-2-carboxylic acid amide (106)
##STR00015##
[0202]
3-amino-6-(4-cyanophenylcarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1--
thia-6,8-diaza-s-indacene-2-carboxylic acid amide (106)
[0203] To 50 mg (0.158 mmol) of
3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carb-
oxylic acid amide hydrochloride in 3.0 ml of DMF was added dropwise
0.16 ml of 1.0 M solution of diisopropylethylamine in THF and 0.16
ml of 1.0 M solution of 4-cyanophenyl isocyanate in THF with
stirring at 0.degree. C. The resulting mixture was continuously
stirred at room temperature for 8 hours. The solvent was removed in
vacuo to dryness. The residue was recrystallized from methanol and
further purified by HPLC to give the pure product as a yellow solid
in 93.7% yield: silica gel TLC R.sub.f 0.80 (1:5
methanol-chloroform); .sup.1H NMR (DMSO-d.sub.6) .delta. 8.94 (s,
1H), 7.94 (d, 1H, J=3.0 Hz), 7.73-7.67 (m, 4H), 7.36-7.27 (m, 4H),
5.98 (s, 2H), 4.92 (s, 2H), 4.68 (s, 2H). ES MS m/z 461
(M+H).sup.+, 459 (M-H).sup.-.
[0204] The following compounds were prepared by using the same
procedure described in Example 9 and substituting a isocyanate for
4-cyanophenylcyanate as for compound 106. In some cases, if the
product was not recrystallized from methanol or ethanol, the
reaction mixture was purified by flash column chromatography or
preparative HPLC. [0205]
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dicar-
boxylic acid 2-amide 6-phenylamide (96) [0206]
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dicar-
boxylic acid 2-amide 6-benzylamide (97) [0207]
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dicar-
boxylic acid 2-amide 6-ethylamide (98) [0208]
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dicar-
boxylic acid 2-amide 6-[(4-phenyl-piperazin-1-ylmethyl)-amide] (99)
[0209]
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dicar-
boxylic acid 2-amide 6-thiophen-3-ylamide (100) [0210]
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dicar-
boxylic acid 2-amide 6-cyclohexylamide (101) [0211]
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dicar-
boxylic acid 2-amide 6-[(6-morpholin-4-yl-pyridin-3-yl)-amide]
(102)
Example 10
3-amino-6-(2-chloro-acetyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaz-
a-s-indacene-2-carboxylic acid amide (104)
##STR00016##
[0213] To 50 mg (0.158 mmol) of
3-amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carb-
oxylic acid amide hydrochloride in 3.0 ml of DMF was added dropwise
0.32 ml of 1.0 M solution containing diisopropylethylamine (DIPEA)
in THF and (0.16 mmol) of 2-chloroacetyl chloride in 1.0 ml of DMF,
according to standard procedures. The resulting mixture was
continuously stirred at room temperature for several hours, and the
progress of the reaction was monitored by TLC. The solvent was
removed under vacuum, and the residue was recrystallized from a
polar solvent. Similar procedures were used for
3-amino-6-[2-(4-benzyl-cyclohexylamino)-acetyl]-4-thiophen-2-yl-6,7-dihyd-
ro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (103) and
3-amino-6-(6-morpholin-4-yl-pyridine-3-carbonyl)-4-thiophen-2-yl-6,7-dihy-
dro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide (105).
In some cases, if the product was not recrystallized from methanol
or ethanol, the reaction mixture was purified by flash column
chromatography or preparative HPLC. All products were verified by
NMR spectroscopy.
Example 11
8-Amino-7-thiophen-2-yl-1,2,3,4,4a,5,6,11b-octahydro-10-thia-11-aza-cyclop-
enta[b]phenanthrene-9-carboxylic acid amide (107)
##STR00017##
[0214]
4-Thiophen-2-yl-2-thioxo-1,2,5,6,6a,7,8,9,10,10a-decahydro-benzo[h]-
quinoline-3-carbonitrile
[0215] A mixture of 2-cyano-3-thiophen-2-yl-thioacrylamide (290 mg,
1.533 nmol), trans-1-decalone (280 mg) and morpholine (2 drops) was
microwaved in a sealed vessel with the following condition: 300
watts, 75.degree. C., 300 psi, 5 min run time, 25 min hold time
without stirring. The resulting mixture was passed through a silica
gel column eluted with 5% acetone in chloroform to yield 180 mg
(36.0%) of the benzoquinoline product as an enantiomeric mixture.
.sup.1H-NMR (300 MHz, DMSO-d6): .delta. 8.30 (brs, 1H) 7.86 (m,
1H), 7.24 (m, 2H), 1.0-3.5 (m, 14H).
8-Amino-7-thiophen-2-yl-1,2,3,4,4a,5,6,11b-octahydro-10-thia-11-aza-cyclop-
enta[b]phenanthrene-9-carboxylic acid amide (107)
[0216] To a solution of the above intermediate (180 mg, 0.55 mmol)
in ethanol (5 ml) was added potassium carbonate (114 mg, 0.83 mmol)
and 2-chloroacetamide (77.6 mg, 0.83 mmol). This solution was
heated at 80.degree. C. overnight with stirring. The resulting
solution was evaporated to dryness and passed through a silica gel
column eluted with 5% acetone in chloroform to yield 23.4 mg (11%)
of the amino-carboxamide. This product was determined to be an
enantiomeric mixture (55% and 42%) by analytical HPLC. .sup.1H-NMR
(300 MHz, DMSO-d6): .delta. 8.30 (brs, 1H), 7.87 (d, J=5.1 Hz, 1H),
7.2 (m, 3H), 5.74 (brs, 1H), 1.0-3.5 (m, 14H).
Particularly Preferred Compounds
[0217]
3-Amino-6-(2-benzoyloxy-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-t-
hia-6,8-diaza-s-indacene-2-carboxylic acid amide [0218]
3-Amino-6-pyridin-3-ylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-di-
aza-s-indacene-2-carboxylic acid amide [0219]
3-Amino-4-thiophen-2-yl-5,6,7,8-tetrahydro-1-thia-7,9-diaza-cyclopenta[b]-
naphthalene-2-carboxylic acid amide [0220]
3-Amino-7-ethoxy-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e-
]pyridine-2-carboxylic acid amide [0221]
3-Amino-7-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e-
]pyridine-2-carboxylic acid amide [0222]
3-Amino-7-[(2-hydroxy-2-phenyl-ethylcarbamoyl)-methyl]-4-thiophen-2-yl-6,-
7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide [0223]
3-Amino-8-(2-cyano-ethyl)-4-thiophen-2-yl-5,6,7,8-tetrahydro-thien-
o[2,3-b]quinoline-2-carboxylic acid amide [0224]
3-Amino-8-methoxy-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinoli-
ne-2-carboxylic acid amide [0225]
3-Amino-4-(3-methyl-thiophen-2-yl)-5-oxo-5,6,7,8-tetrahydro-thieno[2,3-b]-
quinoline-2-carboxylic acid amide [0226]
3-Amino-6-(4,5-dihydro-thiazol-2-yl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thi-
a-6,8-diaza-s-indacene-2-carboxylic acid amide
Preferred Uses of Contemplated Compounds and Compositions
[0227] Based on the unexpected discovery that numerous protein
kinase inhibitors may be employed as antiviral agents, the
inventors generally contemplate that known and novel kinase
inhibitors may be used as antiviral drugs and vice versa--antiviral
drugs as kinase inhibitors (e.g., in the treatment of diseases
known to be associated with dysregulation of kinases, especially
including neoplastic diseases). Thus, in one general aspect of the
inventive subject matter, all known kinase inhibitors, and
particularly those contemplated herein and/or involved in a
signaling cascade may be employed as antiviral agents (and vice
versa).
[0228] For example, various contemplated compounds exhibit
IKK.beta. inhibitory activity and have been demonstrated by the
inventors to be effective anti-HBV agents. However, it should be
recognized that numerous other kinase inhibitors may also
demonstrate an antiviral effect against a variety of viruses other
than HBV, and especially contemplated alternative viruses include
those in which the virus directly or indirectly interferes with the
host cell's signal transduction, and/or in which the viral
infection is associated with an inflammatory response of the host
(e.g., HCV). Still further, it should be recognized that
contemplated anti-HBV compounds may also be used as therapeutic
agents against diseases associated with IKK.beta. dysregulation
which may include, melanoma, mammary carcinoma, non-small cell lung
carcinoma, colorectal carcinoma, squamous-cell carcinoma, leukemia,
lymphoma, thyroid carcinoma, fibrosarcoma, pancreatic cancer,
prostate cancer, multiple myeloma, ovarian cancer, rheumatoid
arthritis, multiple sclerosis, psoriasis, or inflammatory
disorders.
[0229] Therefore, the inventors especially contemplate
pharmaceutical compositions in which contemplated kinase inhibitory
compounds are present at a concentration effective to inhibit or
reduce viral propagation in a patient's cell. The term "viral
propagation" as used herein especially includes reduction of viral
replication, synthesis, processing and/or assembly of viral
polypeptides, viral entry into the host cell, and release of viral
particles from an infected cell.
[0230] Contemplated Pharmaceutical Compositions
[0231] It is particularly preferred that contemplated compounds are
included in a pharmaceutical composition that is formulated with
one or more non-toxic pharmaceutically acceptable carriers. The
pharmaceutical compositions may be specially formulated for oral
administration in solid or liquid form, for parenteral injection,
or for rectal administration.
[0232] The pharmaceutical compositions of this invention can be
administered to humans and other animals orally, rectally,
parenterally, intracistemally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an
oral or nasal spray. The term "parenteral" administration as used
herein refers to modes of administration which include intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous and
intra-articular injection and infusion.
[0233] Pharmaceutical compositions for parenteral injection
preferably comprise pharmaceutically acceptable sterile aqueous or
non-aqueous solutions, dispersions, suspensions or emulsions as
well as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and non-aqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils (such as olive oil), and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0234] Contemplated compositions may also contain adjuvants such as
preservative, wetting agents, emulsifying agents, and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride, and the like, Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0235] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution, which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0236] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides) Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0237] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0238] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as
glycerol, d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, cetyl alcohol and glycerol
monostearate, h) absorbents such as kaolin and bentonite clay, and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0239] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and may also be of a
composition such that they release the active ingredient(s) only,
or preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
which can be used include polymeric substances and waxes. The
active compounds may also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[0240] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions may also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0241] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0242] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolizable lipid capable of
forming liposomes may be used. The present compositions in liposome
form may contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients, and the like.
The preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art. See, for example, Prescott, Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.
(1976), p. 33 et seq.
[0243] The compounds of the present invention may be used in the
form of pharmaceutically acceptable salts derived from inorganic or
organic acids. By "pharmaceutically acceptable salt" is meant those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well-known in the art. For
example, S. M. Berge, et al. describe pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
The salts may be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable acid. Representative
acid addition salts include, but are not limited to acetate,
adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate
(isethionate), lactate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups may be quaternized with such agents as
lower alkyl halides such as methyl, ethyl, propyl, and butyl
chlorides, bromides and iodides; dialkyl sulfates like dimethyl,
diethyl, dibutyl and diamyl sulfates; long chain halides such as
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides; arylalkyl halides like benzyl and phenethyl bromides and
others. Water or oil-soluble or dispersible products are thereby
obtained. Examples of acids which may be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric
acid and phosphoric acid and such organic acids as oxalic acid,
maleic acid, succinic acid and citric acid.
[0244] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium and aluminum salts and the like and
nontoxic quaternary ammonia and amine cations including ammonium,
tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the like. Other representative organic amines useful
for the formation of base addition salts include ethylenediamine,
ethanolamine, diethanolamine, piperidine, piperazine and the like.
Preferred salts of the compounds of the invention include
phosphate, TRIS, and acetate.
[0245] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated, and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved. Generally, dosage levels of
about 1 to about 500, more preferably of about 5 to about 50 mg of
an active compound per kilogram of body weight per day are
administered orally to a mammalian patient. If desired, the
effective daily dose may be divided into multiple doses for
purposes of administration, e.g., two to four separate doses per
day.
EXAMPLES
[0246] The following examples are provided to illustrate the
inhibition of replication of IKK.beta. and HBV by compounds in the
invention. However, it should be appreciated that numerous
modifications of the compounds, assay, and virus may result in
similarly beneficial results. Consequently, the examples below are
given only to provide exemplary guidance to a practitioner.
IKK.beta. Cell-Based Assay
[0247] A cell-based assay screening system using an NF.kappa.B-Luc
cell line was designed to study IKK.beta. activity. The parental
cell line of NF.kappa.B-Luc is the 293 human embryonic kidney cell
line, which was transfected to express the firefly luciferase gene
under the control of an NF.kappa.B responsive element. Treatment of
NF.kappa.B-Luc cells with tumor necrosis alpha (TNF.alpha.) induces
activation of IKK.beta., leading to phosphorylation, ubiquitination
and degradation of I.kappa.B, and the subsequent translocation of
NF.kappa.B to the nucleus. Nuclear translocation of NF.kappa.B
results in its ability to initiate gene transcription, which can be
detected by the luciferase reporter system. Therefore, in this
system, inhibition of IKK enzymatic activity is expected to result
in inhibition of luciferase activity. For compound testing, 7500
NF.kappa.B-Luc cells were added per well of 384-well plates and
incubated for 16 hours at 37.degree. C. in a humidified incubator
with 5% CO.sub.2. Cells were pre-incubated with various
concentrations of compound diluted in MEM/10% FBS. After one hour,
cells were treated with 20 ng/mL TNF.alpha. diluted in MEM/10% FBS.
After a 4.5-hour incubation, cells were lysed and luciferase
activity was measured. IKK.beta. inhibitory activity was calculated
based on reduction of the luciferase signal and expressed as EC50
(effective concentration to reduce the luciferase signal by
50%).
IKK.beta. In Vitro Assay
[0248] For determination of IC50 values, an in vitro IKK.beta.
assay was designed to study IKK.beta. enzymatic activity in a
cell-free system. His-tagged human IKK.beta. expressed from a
baculovirus construct in Sf9 insect cells and Glutathione S
Transferase (GST)--I.kappa.B.alpha. fusion protein
(I.kappa.B.alpha. residues 1 through 54) expressed in E. coli were
purified and utilized in an in vitro radiolabel incorporation
assay. The reaction contained 25 mM HEPES, pH7.4, 50 mM NaCl, 1 mM
MgCl2, 0.2 mM EDTA and 2.5 mM DTT. Purified IKK.beta. (100 nM) was
pre-incubated with compound for 30 minutes at room temperature. The
kinase reaction was initiated by adding 5 .mu.M
GST-I.kappa.B.alpha. substrate, 1 .mu.M unlabeled ATP and 0.5
.mu.Ci .sup.33P-.gamma.-ATP. The reaction was allowed to proceed at
room temperature for 60 minutes and terminated by the addition 100
.mu.l 1% trichloroacetic acid (TCA). The reaction was transferred
to a 96-well glass fiber filter plate previously blocked with 1%
pyrophosphate. The filter plate was washed five times with water
and twice with absolute ethanol and dried. Liquid scintillation
cocktail was added to each well and radiolabel incorporation was
quantified using the Packard TopCount HTS Scintillation Counter.
Inhibition of IKK.beta. activity was calculated based on reduction
of the radioactive signal and reported as IC50 (inhibitory
concentration to reduce the signal by 50%).
HBV Screening Assay
[0249] HepG2 cells were transduced using a baculovirus to deliver
the HBV genome essentially as previously described (Delaney et al.
in Hepatology 1998; 28: 1134-1146). Transduced cells were cultured
in supplemented EMEM media with 10% fetal bovine serum in a 5% CO2
incubator at 37.degree. C. for three days in the presence of test
compounds. The cells were lysed in a buffer containing 0.5% NP-40
and 500 mg/ml proteinase K. A solid-phase hybridization was
performed to capture the viral DNA and to label the target DNA with
Digoxigenin-labeled DNA probes. The viral DNA was detected by
ELISA, using horseradish peroxidase-conjugated anti-digoxigenin
antibodies.
[0250] The EC50 values were determined using ExcelFit software from
the inhibition values of a titration curve for each compound. For
CC50 determinations, the same titration of compounds was
co-cultured with non-transduced HepG2 for three days under the
conditions described above. The Promega CellTiter 96 Aqueous One
Solution Cell Proliferation Assay was used to measure cell
proliferation/viability. The CC50 values were determined using
ExcelFit software from the inhibition values of the titration curve
for each compound.
Test Results for Selected Contemplated Compounds
[0251] Table I below lists selected compounds with their structures
and corresponding antiviral activity (EC50 in .mu.M). Antiviral
activity was determined using assays as described above. All tested
compounds had a CC50 value of greater than 50.000 .mu.M. ND means
not determined. (Legend: A: <1 .mu.M, B: 1-10 .mu.M, C: >10
.mu.M)
TABLE-US-00001 TABLE 1 No. Name Structure EC50 1
3-Amino-6-tert-butyloxycarbonyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,-
8-diaza-s-indacene-2-carboxylic acid amide ##STR00018## C 2
3-Amino-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-car-
boxylic acidamide ##STR00019## B 3
3-Amino-6-(3-chloro-propyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-di-
aza-s-indacene-2-carboxylic acid amide ##STR00020## B 4
3-Amino-6-(tetrahydro-pyran-2-ylmethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-
-thia-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00021## C 5
3-Amino-6-[5-(2-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-4-thiophen--
2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid
amide ##STR00022## B 6
3-Amino-6-(3-methyl-butyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-dia-
za-s-indacene-2-carboxylic aicd amide ##STR00023## C 7
3-Amino-6-pyridin-2-ylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-d-
iaza-s-indacene-2-carboxylic acid amide ##STR00024## C 8
3-Amino-6-cyclopropylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-di-
aza-s-indacene-2-carboxylic acid amide ##STR00025## C 9
3-Amino-6-(2-benzoyloxy-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-
-diaza-s-indacene-2-carboxylic acid amide ##STR00026## B 10
3-Amino-6-phenethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-i-
ndacene-2-carboxylic acid amide ##STR00027## C 11
3-Amino-6-cyclohexylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-di-
aza-s-indacene-2-carboxylic acid amide ##STR00028## B 12
3-Amino-6-[2-(4-chloro-phenyl)-2-oxo-ethyl]-4-thiophen-2-yl-6,7-dihydro-
-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acidamide ##STR00029##
B 13
3-Amino-6-(3-hydroxy-2-methyl-propyl)-4-thiophen-2-yl-6,7-dihydro-5H--t-
hia-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00030## B 14
3-Amino-6-isobutyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-in-
dacene-2-carboxylic acid amide ##STR00031## C 15
3-Amino-6-(2-hydroxy-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-d-
iaza-s-indacene-2-carboxylic acid amide ##STR00032## B 16
3-Amino-6-pentyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-inda-
cene-2-carboxylic acid amide ##STR00033## C 17
3-Amino-6-(2-methoxy-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-d-
iaza-s-indacene-2-carboxylic acid amide ##STR00034## C 18
3-Amino-6-carbethoxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-di-
aza-s-indacene-2-carboxylic acid amide ##STR00035## C 19
3-Amino-6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-thiophen-2--
yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid
amide ##STR00036## C 20
3-Amino-6-pyridin-3-ylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8--
diaza-s-indacene-2-carboxylic acid amide ##STR00037## A 21
3-Amino-6-benzyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-diaza-s-inda-
cene-2-carboxylic acid amide ##STR00038## B 22
3-Amino-6-(2-methyl-benzyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-d-
iaza-s-indacene-2-carboxylic acid amide ##STR00039## B 23
3-Amino-6-(3-fluoro-benzyl)-4-thipohen-2-yl-6,7-dihydro-5H-1-thia-6,8-d-
iaza-s-indacene-2-carboxylic acid amide ##STR00040## C 24
3-Amino-6-(3,5-dimethoxy-benzyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia--
6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00041## C 25
3-Amino-6-[3-(4-pyrimidin-2-yl-piperazin-1-yl)-propyl]-4-thiophen-2-yl--
6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylicacid amide
##STR00042## C 26
3-Amino-6-[3-(2-methoxy-piperidin-1-yl)-propyl]-4-thiophen-2-yl-6,7-dih-
ydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acidamide
##STR00043## C 27
3-Amino-6-(3-morpholin-4-yl-propyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-th-
ia-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00044## C 28
3-Amino-6-[3-(2-hydroxy-propylamino)-propyl]-4-thiophen-2-yl-6,7-dihydr-
o-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acidamide
##STR00045## C 29
3-Amino-4-thiophen-2-yl-5,6,7,8-tetrahydro-1-thia-7,9-diaza-cyclopenta[-
b]naphthalene-2-carboxylic acidamide ##STR00046## A 30
3-Amino-7-tert-butyloxycarbonyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-1-th-
ia-7,9-diaza-cyclopenta[b]naphthalene-2-carboxylic acid amide
##STR00047## C 31
3-Amino-7-benzyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-1-thia-7,9-diaza-cy-
clopenta[b]naphthalene-2-carboxylic acidamide ##STR00048## ND 32
3-Amino-6-tert-butyloxycarbonyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thie-
no[2,3-b][1,6]naphthyridine-2-carboxylic acidamide ##STR00049## C
33
3-Amino-6-benzyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-thieno[2,3--
b][1,6]naphthyridine-2-carboxylic acidamide ##STR00050## C 34
6-Acetyl-3-amino-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b][1,6]n-
aphthyridine-2-carboxylic acid amide ##STR00051## C 35
3-Amino-7-ethoxy-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-
-e]pyridine-2-carboxylic acid amide ##STR00052## A 36
3-Amino-7-carboxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thi-
eno[3,2-e]pyridine-2-carboxylic acid amide ##STR00053## C 37
3-Amino-7-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-
-e]pyridine-2-carboxylic acid amide ##STR00054## A 38
3-Amino-7-(2-morpholin-4-yl-2-oxo-ethyl)-4-thiophen-2-yl-6,7-dihydro-5H-
-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide
##STR00055## C 39
3-Amino-7-[(2-hydroxy-2-phenyl-ethylcarbamoyl)-methyl]-4-thiophen-2-yl--
6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide ##STR00056## C 40
3-Amino-7-carbomethoxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[-
b]thieno[3,2-e]pyridine-2-carboxylic acid amide ##STR00057## C 41
3-Amino-7-carbethoxymethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]-
thieno[3,2-e]pyridine-2-carboxylic acid amide ##STR00058## C 42
3-Amino-7-methylcarbamoylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopen-
ta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide ##STR00059## B
43
3-Amino-7-{[(5-methyl-furan-2-ylmethyl)-carbamoyl]-methyl}-4-thiophen-2-
-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide ##STR00060## C 44
3-Amino-7-[(2-methoxy-benzylcarbamoyl)-methyl]-4-thiophen-2-yl-6,7-dihy-
dro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide
##STR00061## C 45
3-Amino-7-{[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-4-thiophen-2-yl-6,7-
-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide ##STR00062## C 46
3-Amino-7-[(2-pyridin-2-yl-ethylcarbamoyl)-methyl]-4-thiophen-2-yl-6,7--
dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide ##STR00063## C 47
3-Amino-4-thiophen-2-yl-7-[(4-trifluoromethyl-benzylcarbamoyl)-methyl]--
6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide ##STR00064## C 48
3-Amino-7-[(3-methyl-butylcarbamoyl)-methyl]-4-thiophen-2-yl-6,7-dihydr-
o-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide
##STR00065## C 49
3-Amino-7-dimethylcarbamoylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclop-
enta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide ##STR00066## C
50
3-Amino-7-cyclobutylcarbamoylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-cycl-
openta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide ##STR00067##
C 51
3-Amino-7-cyclohexylcarbamoylmethyl-4-thiophen-2-yl-6,7-dihydro-5H-cycl-
openta[b]thieno[3,2-e]pyridine-2-carboxylic acid amide ##STR00068##
C 52
3-Amino-7-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-thiophen-2-yl-6,-
7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic acid
amide ##STR00069## C 53
3-Amino-7-[2-oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-4-thiophen-2--
yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide ##STR00070## C 54
4-[2-(3-Amino-2-carbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]t-
hiano[3,2-e]pyridin-7-yl)-acetylamino]-piperidine-1-carboxylic acid
ethyl ester ##STR00071## C 55
3-Amino-7-{[2-(1-methyl-pyrrolidin-2-yl)-ethylcarbamoyl]-methyl}-4-thio-
phen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide ##STR00072## C 56
1-[2-(3-Amino-2-carbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]t-
hieno[3,2-e]pyridin-7-yl)-acetyl]-piperidine-4-carboxylic acid
ethyl ester ##STR00073## C 57
3-Amino-7-[(3-morpholin-4-yl-propylcarbamoyl)-methyl]-4-thiophen-2-yl-6-
,7-dihydro-5H-cyclopenta[b]thiano[3,2-e]pyridine-2-carboxylic acid
amide ##STR00074## C 58
3-Amino-7-{[3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl}-4-thio-
phen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylic
acid amide ##STR00075## C 59
3-Amino-7-hexyl-4-thiophen-2-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]p-
yridine-2-carboxylic acid amide ##STR00076## C 60
3-Amino-7-heptyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-
-e]pyridine-2-carboxylic acid amide ##STR00077## C 61
3-Amino-7-cyclopentyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[b]thien-
o[3,2-e]pyridine-2-carboxylic acid amide ##STR00078## B 62
3-Amino-8-(2-cyano-ethyl)-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-
-b]quinoline-2-carboxylic acid amide ##STR00079## C 63
3-Amino-8-isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quin-
oline-2-carboxylic acid amide ##STR00080## B 64
3-Amino-8-benzyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]uinoli-
ne-2-carboxylic acid amide ##STR00081## C 65
3-Amino-8-propyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinol-
ine-2-carboxylic acid amide ##STR00082## B 66
3-Amino-8-phenyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinol-
ine-2-carboxylic acid amide ##STR00083## B 67
3-Amino-8-(3-methoxy-phenyl)-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[-
2,3-b]quinoline-2-carboxylic acid amide ##STR00084## C 68
3-Amino-8-cyclohexyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]qu-
inoline-2-carboxylic acid amide ##STR00085## C 69
3-Amino-8-methoxy-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quino-
line-2-carboxylic acid amide ##STR00086## A 70
8-Allyl-3-amino-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinoli-
ne-2-carboxylic acid amide ##STR00087## B 71
3-Amino-8-carbethoxymethyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,-
3-b]quinoline-2-carboxylic acid amide ##STR00088## C 72
3-Amino-6-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinol-
ine-2-carboxylic acid amide ##STR00089## C 73
3-Amino-6-ethyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinoli-
ne-2-carboxylic acid amide ##STR00090## C 74
3-Amino-7-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-thieno[2,3-b]quinol-
ine-2-carboxylic acid amide ##STR00091## C 75
3-Amino-4-(3-methyl-thiophen-2-yl)-5-oxo-5,6,7,8-tetrahydro-thieno[2,3--
b]quinoline-2-carboxylic acid amide ##STR00092## A
76
3-Amino-4-(thiophen-2-yl)-5-oxo-5,6,7,8-tetrahydro-thieno[2,3-b]quinoli-
ne-2-carboxylic acid amide ##STR00093## B 77
3-Amino-4-(4-chloro-phenyl)-5-oxo-5,6,7,8-tetrahydro-thieno[2,3-b]quino-
line-2-carboxylic acid amide ##STR00094## C 78
3-Amino-5-oxo-4-thiophen-2-yl-1,4,5,6,7,8-hexahydro-thiochromeno[2,3-b]-
pyrrole-2-carboxylic acid amide ##STR00095## C 79
3-Amino-6-phenylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-
-diaza-s-indacene-2-carboxylic acid amide ##STR00096## C 80
3-Amino-6-[(tetrahydro-furan-2-ylmethyl)-thiocarbamoyl]-4-thiophen-2-yl-
-6,7-dihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
##STR00097## C 81
3-Amino-6-cyclopentylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thi-
a-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00098## B 82
3-Amino-6-butylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8--
diaza-s-indacene-2-carboxylic acid amide ##STR00099## B 83
3-Amino-4-thiophen-2-yl-6-p-tolylthiocarbamoyl-6,7-dihydro-5H-1-thia-6,-
8-diaza-s-indacene-2-carboxylic acidamide ##STR00100## C 84
3-Amino-6-benzylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8-
-diaza-s-indacene-2-carboxylic acid amide ##STR00101## B 85
3-Amino-6-(3-methoxy-phenylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydro-5-
H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00102##
C 86
3-Amino-6-(3-phenyl-propylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydro-5H-
-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00103## B
87
3-Amino-4-thiophen-2-yl-6-(3-trifluoromethyl-phenylthiocarbamoyl)-6,7-d-
ihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
##STR00104## C 88
3-Amino-6-(4-fluoro-phenylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydro-5H-
-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00105## C
89
3-Amino-6-(3,5-dichloro-phenylthiocarbamoyl)-4-thiophen-2-yl-6,7-dihydr-
o-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
##STR00106## C 90
4-[(3-Amino-2-carbaomyl-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s--
indacene-6-carbothioyl)-amino]benzoic acid methylester ##STR00107##
C 91
3-Amino-6-cyclopropylthiocarbamoyl-4-thiophen-2-yl-6,7-dihydro-5H-1-thi-
a-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00108## B 92
3-Amino-6-(3,5-dimethyl-phenylthiopcarbamoyl)-4-thiophen-2-yl-6,7-dihyd-
ro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
##STR00109## C 93
3-Amino-6-(2-morpholin-4-yl-ethylthiocarbamoyl)-4-thiophen-2-yl-6,7-dih-
ydro-5H-1-thia-6,8-diaza-s-indacene-2-c arboxylic acid amide
##STR00110## C 94
3-Amino-6-(3-morpholin-4-yl-propylthiocarbamoyl)-4-thiophen-2-yl-6,7-di-
hydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acid amide
##STR00111## C 95
3-Amino-6-(4,5-dihydro-thiazol-2-yl)-4-thiophen-2-yl-6,7-dihydro-5H-1-t-
hia-6,8-diaza-s-indacene-2-carboxylic acid amide ##STR00112## A 96
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dic-
arboxylicacid 2-amide 6-phenylamide ##STR00113## C 97
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dic-
arboxylicacid 2-amide 6-benzylamide ##STR00114## C 98
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dic-
arboxylicacid 2- amide 6-ethylamide ##STR00115## A 99
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-dic-
arboxylicacid 2-amide 6-[(4-phenyl-piperazin-1-ylmethyl)-amide]
##STR00116## C 100
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-di-
carboxylicacid 2-amide 5-thiophen-3-ylamide ##STR00117## A 101
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-di-
carboxylicacid 2-amide 6-cyclohexylamide ##STR00118## C 102
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-di-
carboxylicacid 2-amide 6-[(6-morpholin-4-yl-pyridin-3-yl)-amide]
##STR00119## C 103
3-Amino-6-[2-(4-benzyl-cyclohexylamin)-acetyl]-4-thiophen-2-yl-6,7-dih-
ydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylic acidamide
##STR00120## B 104
3-Amino-6-(2-chloro-acetyl)-4-thiophen-2-yl-6,7-dihydro-5H-1-thia-6,8--
diaza-s-indacene-2-carboxylic acid amide ##STR00121## B 105
3-Amino-6-(6-morpholin-4-yl-pyridine-3-carbonyl)-4-thiophen-2-yl-6,7-d-
ihydro-5H-1-thia-6,8-diaza-s-indacene-2-carboxylicacid amide
##STR00122## C 106
3-Amino-4-thiophen-2-yl-5,7-dihydro-1-thia-6,8-diaza-s-indacene-2,6-di-
carboxylicacid 2-amide 6-[(4-cyano-phenyl)-amide] ##STR00123## C
107
8-Amino-7-thiophen-2-yl-1,2,3,4,4a,5,6,11b-octahydro-10-thia-11-aza-cy-
clopenta[b]phenanthrene-9-carboxylic acid amide ##STR00124## C
[0252] Thus, specific embodiments and applications of protein
kinase inhibitors have been disclosed. It should be apparent,
however, to those skilled in the art that many more modifications
besides those already described are possible without departing from
the inventive concepts herein. The inventive subject matter,
therefore, is not to be restricted except in the spirit of the
disclosure. Moreover, all terms employed herein should be
interpreted in the broadest possible manner consistent with the
context. In particular, the terms "comprises" and "comprising"
should be interpreted as referring to elements, components, or
steps in a non-exclusive manner, indicating that the referenced
elements, components, or steps may be present, or utilized, or
combined with other elements, components, or steps that are not
expressly referenced.
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