Azepane derivatives and methods of treating hepatitis B infections

Patent metadata

Field	Value
Publication number	US-9505722-B2
Application number	US-201514694147-A
Country	US
Kind code	B2
Filing date	Apr 23, 2015
Priority date	Jan 16, 2014
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.

First claim

The invention claimed is:

1. A compound of Formula V:

or a pharmaceutically acceptable salt thereof;
wherein
each R 1 is, independently at each occurrence, halo, OH, —C 1 -C 6 alkyl, or —O—C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or OH;
each R 2 is, independently at each occurrence, halo, OH, —C 1 -C 6 alkyl, or —O—C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or OH;
Cy is

R 11 is, independently at each occurrence, —OH, —C 1 -C 6 alkyl, —OC(O)CH 3 , or —C 3 -C 10 cycloalkyl;
R 13 and R 14 , together with the carbons to which they are attached, join to form a cyclopropyl ring;
m is 1, 2, or 3;
n is 1, 2, or 3; and
x is 2 or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is, independently at each occurrence, halo.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is, independently at each occurrence, halo or —C 1 -C 6 alkyl, wherein the alkyl is optionally substituted 1-3 times with halo.

4. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

5. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of claim 1 .

6. A method of reducing the viral load associated with an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of claim 1 .

7. The method of claim 5 , further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of a HBV polymerase inhibitor, immunomodulatory agents, pegylated interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and a combination thereof.

8. The method of claim 7 , wherein the therapeutic agent is a reverse transcriptase inhibitor, and is at least one of Zidovudine, Didanosine, Zalcitabine, 2′,3′-dideoxyadenosine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, cidofovir, Efavirenz, Nevirapine, Delavirdine, and Etravirine.

9. The method of claim 7 , wherein the therapeutic agent is a TLR agonist, and wherein the TLR agonist is selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

10. The method of claim 7 , wherein the therapeutic agent is an interferon selected from the group consisting of interferon alpha (IFN-α), interferon beta (IFN-β), interferon lambda (IFN-λ), and interferon gamma (IFN-γ).

11. The method of claim 10 , wherein the interferon is interferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1.

12. The method of claim 10 , wherein the interferon-alpha-2a or interferon-alpha-2b is pegylated.

13. The method of claim 10 , wherein the interferon-alpha-2a is pegylated interferon-alpha-2a (PEGASYS).

14. The method of claim 5 , further comprising administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.

15. The method of claim 14 , wherein the HBV vaccine is selected from the group consisting of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, and SHANVAC B.

16. A method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a compound of claim 1 alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of HBV vaccine.

17. The method of claim 5 further comprising monitoring the HBV viral load of the subject, and wherein the method is carried out for a period of time such that the HBV virus is undetectable.

18. The compound of claim 1 , wherein
each R 1 is, independently at each occurrence, halo;
each R 2 is, independently at each occurrence, halo or —C 1 -C 6 alkyl, wherein the alkyl is optionally substituted 1-3 times with halo
Cy is

R 11 is, independently at each occurrence, —OH, —C 1 -C 6 alkyl, —OC(O)CH 3 , or —C 3 -C 10 cycloalkyl;
m is 1, 2, or 3;
n is 1 or 2; and
x is 2 or 3.

19. The compound of claim 1 , wherein Cy is

20. The compound of claim 1 , wherein n is 1 or 2.

Assignees

• Novira Therapeutics Inc

Inventors

• Hartman George D
• Kuduk Scott

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title