Elimination of hepatitis B virus with antiviral agents

Patent metadata

Field	Value
Publication number	US-10752584-B2
Application number	US-201716082747-A
Country	US
Kind code	B2
Filing date	Mar 9, 2017
Priority date	Mar 9, 2016
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

Abstract

The present invention is directed to compounds, compositions and methods for preventing, treating or curing Hepatitis B (HBV) infection in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof as pharmaceutical compositions and methods for treatment, prevention or eradication of HBV infection.

First claim

We claim:

1. A compound of the following formula:

or a pharmaceutically acceptable salt, wherein:
when R 1 and R 1′ are attached to a carbon, they are, independently, hydrogen, halogen, SF 5 , CF 3 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, cyano, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 hydroxyalkyl;
when R 1 and R 1′ are attached to a nitrogen, they are, independently, hydrogen, C 2-6 alkoxy, C 3-6 alkoxyalkyl, C 2-6 alkenyl, alkoxycarbonyl, carbonylalkyl, carbonyl aryl, C 1-6 alkyl, heterocyclylalkyl, C 2-6 hydroxyalkyl, or S(O) 2 R′;
each R′ is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, or if two R′ reside on the same nitrogen atom, they can come together to form a C 3-6 ring optionally containing a N, O, or S heteroatom;
the R′ groups, when other than H, can optionally be substituted with one or more substituents, which substituents are, independently, halo, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, or phosphonate;
u and v are independently 0, 1, 2, 3, 4, or 5;
I is phenyl, a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a five-membered heteroaromatic ring containing one, two, or three heteroatoms, which are, independently, N, O, or S, a C 4-14 bicyclic ring, alkylheteroaryl, or alkylaryl;
J is a five-membered heteroaromatic ring containing one, two, or three heteroatoms, which are, independently, N, O, or S;
W is

R 12 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and
R 13 is C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a C 4-14 bicyclic ring, or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S;
R 13 is optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, CF 3 , SF 5 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C(O)R′, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, azido, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 alkyl, cycloalkyl, arylalkoxycarbonyl, carboxyl, halo alkyl, heterocyclylalkyl, C 1-6 hydroxyalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, where substituents on the substituted aryl and the substituted heteroaryl are selected from the group consisting of halogen, SF 5 , CF 3 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C(O)R′, C 1-6 alkoxy, cyano, azido, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, and C 1-6 alkyl;
or R 12 and R 13 together with the nitrogen to which they are attached form a 3 to 4 membered ring optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, CF 3 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C 1-6 alkoxy, cyano, azido, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, and C 1-6 hydroxyalkyl.

2. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 , wherein the compound is:

and pharmaceutically acceptable salts thereof.

4. The compound of claim 2 is:

and pharmaceutically-acceptable salts thereof.

5. The compound of claim 2 is:

and pharmaceutically-acceptable salts thereof.

6. The compound of claim 2 is:

and pharmaceutically-acceptable salts thereof.

7. The compound of claim 1 , wherein R 12 is hydrogen.

8. The compound of claim 1 , wherein R 13 is C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl.

9. The compound of claim 8 , wherein R 13 is C 2-6 alkenyl.

10. The compound of claim 8 , wherein R 13 is C 2-6 alkynyl.

11. The compound of claim 8 , wherein R 13 is aryl.

12. The compound of claim 8 , wherein R 13 is heteroaryl.

13. The compound of claim 1 , wherein J is pyrrolyl.

14. The compound of claim 1 , wherein I is phenyl.

15. The compound of claim 1 , wherein u is 3.

16. The compound of claim 1 , wherein R 1 is C 1-6 alkyl.

17. The compound of claim 1 , wherein v is 2.

18. The compound of claim 1 , wherein R 1′ is halogen.

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically-acceptable carrier.

20. A method for treating a host infected with HBV, or reducing the biological activity of an infection with HBV in host, comprising administering an effective amount of a compound of claim 1 to the host in need of treatment thereof.

21. A method for treating a host infected with the West Nile Virus infection, or reducing the biological activity of an infection with West Nile Virus in a host, comprising administering an effective amount of a compound of claim 1 to the host in need of treatment thereof.

22. A method for treating a host infected with a flaviviridae virus, or reducing the biological activity of an infection with one of these viruses in a host, comprising administering an effective amount of a compound of claim 1 to the host in need of treatment thereof.

23. The method of claim 20 , wherein the treating a host infected with HBV or the reducing the biological activity of an infection with HBV in a host suppresses HDV infection.

Assignees

• Univ Emory

Inventors

• Schinazi Raymond F
• Boucle Sebastien
• Amblard Franck
• Sari Ozkan
• Bassit Leda

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title