IP Library Granted Patent US 10,752,584
Granted Patent B2
US 10,752,584 · App. 16/082,747 · Granted Aug 25, 2020

Elimination of hepatitis B virus with antiviral agents

Inventors: Raymond F. Schinazi (Atlanta, GA); Sebastien Boucle (Smyrna, GA); Franck Amblard (Tucker, GA); Ozkan Sari (Decatur, GA); Leda Bassit (Smyrna, GA)
Assignee: Emory University
C07D207/34A61K31/40A61K31/41A61K31/4178A61K31/4184A61K31/4192A61K31/427A61K31/454A61K31/496A61K31/506A61K31/5377A61K45/06A61P31/20C07D207/36C07D249/04C07D401/06C07D401/12C07D403/06C07D403/12C07D417/12
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Quick Facts
Patent No.
US 10,752,584
App. No.
16/082,747
Granted
Aug 25, 2020
Kind
B2
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.

Claims (41)

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.

Assignments (2)
CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF ASSIGNEE SHOULD BE "THE UNITED STATES GOVERNMENT AS REPRESENTED BY THE DEPARTMENT OF VETERANS AFFAIRS" PREVIOUSLY RECORDED ON REEL 054151 FRAME 0348. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Dec 10, 2020
From: EMORY UNIVERSITY
To: THE UNITED STATES GOVERNMENT AS REPRESENTED BY THE DEPARTMENT OF VETERANS AFFAIRS
Reel/Frame 054676/0553 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 17, 2020
From: BOUCLE, SEBASTIEN; AMBLARD, FRANCK; SARI, OZKAN; BASSIT, LEDA; SCHINAZI, RAYMOND F.
To: EMORY UNIVERSITY
Reel/Frame 053242/0849 →
Continuity (2)
Provisional Application 62305865 · Mar 9, 2016
Related Publication 20190241514A1 · Aug 8, 2019
Cited By (1)
US 12,599,582