Heterocyclic compounds having anti-HBV activity
View Patent ↗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.
1. A compound of Formula I
wherein A is S, O, or N(CH 3 );
R 1 and R 2 are, independently, H, CH 3 , CF 3 , or CH 3 O;
R 3 is H;
or R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms;
or R 3 is C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkenyl, C 1-6 alkoxy, C 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 3 , OCH 3 , C(O)CH 3 , CO 2 CH 3 , OC(O)CH 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 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, ethylcarbamoylmethyl, methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R 3 is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4 is C 1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3 alkyl groups, or R 4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 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 1 and R 2 are both H, then R 3 is not methyl.
2. The compound of claim 1 , wherein A is S, n is 1, m is 1, R 1 is H, and R 2 is H or CH 3 .
3. The compound of claim 2 , wherein R 3 is H or C 1-6 alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, N-phthalimido, or R 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 3 , CH 3 O, CN, CF 3 , and CH 3 C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms.
4. The compound of claim 3 , wherein R 3 is C 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 3 is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4 is C 1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3 alkyl groups, or R 4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 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 1 is H, and R 2 is H or CH 3 .
7. The compound of claim 6 , wherein R 3 is H or C 1-4 alkyl.
8. The compound of claim 1 , wherein A is O, n is 1, m is 1, R 1 is H, and R 2 is H or CH 3 .
9. The compound of claim 8 , wherein R 3 is H or C 1-6 alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, N-phthalimido, or R 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 3 , CH 3 O, CN, CF 3 , and CH 3 C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms.
10. The compound of claim 9 , wherein R 3 is C 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 3 is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4 is C 1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3 alkyl groups, or R 4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms.
12. A compound of Formula II
wherein n is zero, 1, 2, or 3; A is S, O, or N(CH 3 );
B and B′ are either both H or jointly oxo;
R 1 and R 2 are, independently, H, CH 3 , CF 3 , or CH 3 O;
R 3 is H;
or R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms;
or R 3 is C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkenyl, C 1-6 alkoxy, C 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 3 , OCH 3 , C(O)CH 3 , CO 2 CH 3 , OC(O)CH 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 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R 3 is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4 is C 1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3 alkyl groups, or R 4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and
R 5 is H or C 3 alkyl; or
R 3 and R 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 1 , R 2 , R 3 , B, and B′ are not all H, and further provided that when A is S and R 1 is methyl, then R 2 , R 3 , B, and B′ are not all H.
13. A compound according to claim 12 , wherein A is S, R 5 is H; and wherein R 3 is selected from H, C 1-4 alkyl, C 1-4 alkenyl, or C 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 3 , OCH 3 , CF 3 , and halo;
and n=0, 1, or 2.
14. The compound of claim 13 , wherein n=1 or 2, and R 3 is hydrogen, methyl, methoxy, ethoxy, or allyl.
15. A method of treating an HBV infection, comprising administering to a person in need of treatment thereof a therapeutically effective amount of a compound of Formula I or a compound of formula II, where formula I is
wherein A is S, O, or N(CH 3 );
R 1 and R 2 are, independently, H, CH 3 , CF 3 , or CH 3 O;
R 3 is H;
or R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms;
or R 3 is C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkenyl, C 1-6 alkoxy, C 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 3 , OCH 3 , C(O)CH 3 , CO 2 CH 3 , OC(O)CH 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 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R 3 is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4 is C 1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3 alkyl groups, or R 4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 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
wherein n is zero, 1, 2, or 3; A is S, O, or N(CH 3 );
B and B′ are either both H or jointly oxo;
R 1 and R 2 are, independently, H, CH 3 , CF 3 , or CH 3 O;
R 3 is H;
or R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms;
or R 3 is C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkenyl, C 1-6 alkoxy, C 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 3 , OCH 3 , C(O)CH 3 , CO 2 CH 3 , OC(O)CH 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 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R 3 is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4 is C 1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3 alkyl groups, or R 4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 3 , CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and
R 5 is H or C 3 alkyl; or
R 3 and R 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 administered where A is S, n is 1, m is 1, R 1 is H, and R 2 is H or CH 3 .
17. The method of claim 16 , wherein R 3 is H or C 1-6 alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, N-phthalimido, or R 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 3 , CH 3 O, CN, CF 3 , and CH 3 C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms.
18. The method of claim 17 , wherein R 3 is C 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 3 is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4 is C 1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3 alkyl groups, or R 4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 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 wherein a compound of formula I is provided, and A is S, n is 2, m is 1, R 1 is H, and R 2 is H or CH 3 .
21. The method of claim 20 , wherein R 3 is H or C 1-4 alkyl.
22. The method of claim 15 , wherein a compound of formula I is administered, and A is O, n is 1, m is 1, R 1 is H, and R 2 is H or CH 3 .
23. The method of claim 22 , wherein R 3 is H or C 1-6 alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, N-phthalimido, or R 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 3 , CH 3 O, CN, CF 3 , and CH 3 C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms.
24. The method of claim 23 , wherein R 3 is C 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 3 is R 4 NHC(O), R 4 NHC(S), or R 4 NHCH 2 C(O), wherein R 4 is C 1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R 3 alkyl groups, or R 4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R 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 3 , OCH 3 , CO 2 CH 3 , OC(O)CH 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 administered.
27. The method of claim 26 , wherein A is S, R 5 is H; and wherein R 3 is selected from H, C 1-4 alkyl, C 1-4 alkenyl, or C 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 3 , OCH 3 , CF 3 , and halo; and n=0, 1, or 2.
28. The method of claim 26 , wherein n=1 or 2, and R 3 is H, methyl, methoxy, ethoxy or allyl.