# US 7,465,742 B2 · Heterocyclic compounds having anti-HBV activity

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- Number: US 7,465,742 B2
- Document ID: US7465742B2
- Status: Granted
- Kind: B2
- Application number: 11/347,145
- Filed: 2006-02-03
- Published: 2006-08-24
- Granted: 2008-12-16
- Earliest claimed: 2005-02-11
- Inventors: Huanming Chen; Robert Tam; Anneke K. Raney
- Web page: https://patentgrep.com/patent/US7465742B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 31/12: Antivirals
- C07D 495/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A compound of Formula I
wherein A is S, O, or N(CH3);
R1 and R2 are, independently, H, CH3, CF3, or CH3O;
R3 is H;
or R3 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms;
or R3 is C1-6 alkyl, C1-6 alkanoyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 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 CH3, OCH3, C(O)CH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and
d) with one group selected from C1-6 alkanoyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbamoyl, ethylcarbamoylmethyl, methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R3 is R4NHC(O), R4NHC(S), or R4NHCH2C(O), wherein R4 is C1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R3 alkyl groups, or R4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R4 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 CH3, OCH3, CO2CH3, OC(O)CH3, 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 R1 and R2 are both H, then R3 is not methyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein A is S, n is 1, m is 1, R1 is H, and R2 is H or CH3.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R3 is H or C1-6 alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbamoyl, N-phthalimido, or R3 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, CH3, CH3O, CN, CF3, and CH3C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R3 is C1-4 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.

### Claim 5 (depends on 2)

The compound of claim 2, wherein R3 is R4NHC(O), R4NHC(S), or R4NHCH2C(O), wherein R4 is C1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R3 alkyl groups, or R4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R4 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms.

### Claim 6 (depends on 1)

The compound of claim 1, wherein A is S, n is 2, m is 1, R1 is H, and R2 is H or CH3.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R3 is H or C1-4 alkyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein A is O, n is 1, m is 1, R1 is H, and R2 is H or CH3.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R3 is H or C1-6 alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbamoyl, N-phthalimido, or R3 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, CH3, CH3O, CN, CF3, and CH3C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R3 is C1-4 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.

### Claim 11 (depends on 8)

The compound of claim 8, wherein R3 is R4NHC(O), R4NHC(S), or R4NHCH2C(O), wherein R4 is C1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R3 alkyl groups, or R4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R4 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms.

### Claim 12

A compound of Formula II
wherein n is zero, 1, 2, or 3; A is S, O, or N(CH3);
B and B′ are either both H or jointly oxo;
R1 and R2 are, independently, H, CH3, CF3, or CH3O;
R3 is H;
or R3 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms;
or R3 is C1-6 alkyl, C1-6 alkanoyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 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 CH3, OCH3, C(O)CH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and
d) with one group selected from C1-6 alkanoyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R3 is R4NHC(O), R4NHC(S), or R4NHCH2C(O), wherein R4 is C1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R3 alkyl groups, or R4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R4 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and
R5 is H or C3 alkyl; or
R3 and R5, 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 R1, R2, R3, B, and B′ are not all H, and further provided that when A is S and R1 is methyl, then R2, R3, B, and B′ are not all H.

### Claim 13 (depends on 12)

A compound according to claim 12, wherein A is S, R5 is H; and wherein R3 is selected from H, C1-4 alkyl, C1-4 alkenyl, or C1-6 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 CH3, OCH3, CF3, and halo;
and n=0, 1, or 2.

### Claim 14 (depends on 13)

The compound of claim 13, wherein n=1 or 2, and R3 is hydrogen, methyl, methoxy, ethoxy, or allyl.

### Claim 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(CH3);
R1 and R2 are, independently, H, CH3, CF3, or CH3O;
R3 is H;
or R3 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms;
or R3 is C1-6 alkyl, C1-6 alkanoyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 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 CH3, OCH3, C(O)CH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and
d) with one group selected from C1-6 alkanoyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R3 is R4NHC(O), R4NHC(S), or R4NHCH2C(O), wherein R4 is C1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R3 alkyl groups, or R4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R4 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 CH3, OCH3, CO2CH3, OC(O)CH3, 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(CH3);
B and B′ are either both H or jointly oxo;
R1 and R2 are, independently, H, CH3, CF3, or CH3O;
R3 is H;
or R3 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms;
or R3 is C1-6 alkyl, C1-6 alkanoyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 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 CH3, OCH3, C(O)CH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and
d) with one group selected from C1-6 alkanoyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbamoyl, ethylcarbamoylmethyl methylcarbamoylmethyl, 2-hydroxy-2-phenyl-ethylcarbamoylmethyl, or N-phthalimido;
or R3 is R4NHC(O), R4NHC(S), or R4NHCH2C(O), wherein R4 is C1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R3 alkyl groups, or R4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R4 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms; and
R5 is H or C3 alkyl; or
R3 and R5, together with the ring carbon atoms to which they are attached, form an additional fused 5- or 6-membered cycloalkyl group.

### Claim 16 (depends on 15)

The method of claim 15, wherein a compound of formula I is administered where A is S, n is 1, m is 1, R1 is H, and R2 is H or CH3.

### Claim 17 (depends on 16)

The method of claim 16, wherein R3 is H or C1-6 alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbamoyl, N-phthalimido, or R3 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, CH3, CH3O, CN, CF3, and CH3C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms.

### Claim 18 (depends on 17)

The method of claim 17, wherein R3 is C1-4 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.

### Claim 19 (depends on 16)

The method of claim 16, wherein R3 is R4NHC(O), R4NHC(S), or R4NHCH2C(O), wherein R4 is C1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R3 alkyl groups, or R4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R4 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms.

### Claim 20 (depends on 15)

The method of claim 15, wherein wherein a compound of formula I is provided, and A is S, n is 2, m is 1, R1 is H, and R2 is H or CH3.

### Claim 21 (depends on 20)

The method of claim 20, wherein R3 is H or C1-4 alkyl.

### Claim 22 (depends on 15)

The method of claim 15, wherein a compound of formula I is administered, and A is O, n is 1, m is 1, R1 is H, and R2 is H or CH3.

### Claim 23 (depends on 22)

The method of claim 22, wherein R3 is H or C1-6 alkyl, optionally substituted with one or two substituents independently selected from halo, hydroxy, cyano, phenyl, pyridyl, benzoyl, benzoyl methyl, benzoyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbamoyl, N-phthalimido, or R3 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, CH3, CH3O, CN, CF3, and CH3C(O), wherein all methyl groups are optionally substituted 1-3 chlorine atoms.

### Claim 24 (depends on 23)

The method of claim 23, wherein R3 is C1-4 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.

### Claim 25 (depends on 22)

The method of claim 22, wherein R3 is R4NHC(O), R4NHC(S), or R4NHCH2C(O), wherein R4 is C1-6 alkyl, wherein said alkyl group may be straight-chain, branched, or cyclic, and is optionally substituted as described for R3 alkyl groups, or R4 is a five- or 6-membered aromatic ring containing 0-3 heteroatoms independently selected from O, N, and S, all R4 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 CH3, OCH3, CO2CH3, OC(O)CH3, CN, and halo, wherein all methyl groups are optionally substituted with 1, 2, or 3 halogen atoms.

### Claim 26 (depends on 15)

The method claim 15, wherein a compound of formula II is administered.

### Claim 27 (depends on 26)

The method of claim 26, wherein A is S, R5 is H; and wherein R3 is selected from H, C1-4 alkyl, C1-4 alkenyl, or C1-6 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 CH3, OCH3, CF3, and halo; and n=0, 1, or 2.

### Claim 28 (depends on 26)

The method of claim 26, wherein n=1 or 2, and R3 is H, methyl, methoxy, ethoxy or allyl.