Azocane and azonane derivatives and methods of treating hepatitis B infections

Patent metadata

Field	Value
Publication number	US-10537580-B2
Application number	US-201715848639-A
Country	US
Kind code	B2
Filing date	Dec 20, 2017
Priority date	Mar 19, 2015
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

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 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 Formula I:

or a pharmaceutically acceptable salt thereof;
wherein
R 4 is H or C 1 -C 3 alkyl;
R 1 is, independently at each occurrence, —OH, halo, —CN, —NO 2 , —H 2 PO 4 , —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —O—C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, —C 3 -C 10 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, —C 1 -C 4 alkyl-(C 3 -C 10 cycloalkyl), —C 1 -C 4 alkyl-(C 3 -C 10 heterocycloalkyl), —C 1 -C 4 alkyl-(C 6 -C 10 aryl), or —C 1 -C 4 alkyl-(C 5 -C 9 heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted 1-5 times with halo, —OH, —CN, or —NO 2 ;
R 2 is, independently at each occurrence, —OH, halo, —CN, —NO 2 , R 6 , or OR 6 , wherein R 6 is, independently at each occurrence, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, —C 3 -C 10 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, —C 1 -C 4 alkyl-(C 3 -C 10 cycloalkyl), —C 1 -C 4 alkyl-(C 3 -C 10 heterocycloalkyl), —C 1 -C 4 alkyl-(C 6 -C 10 aryl), or —C 1 -C 4 alkyl-(C 5 -C 10 heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted 1-5 times with halo, —OH, —CN, or —NO 2 ;
Cy is

wherein
R 11 is, independently at each occurrence, —OH, halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —O—C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, —C 3 -C 10 heterocycloalkyl, C 6 -C 10 aryl, C 5 -C 9 heteroaryl, —C 1 -C 4 alkyl-(C 3 -C 10 cycloalkyl), —C 1 -C 4 alkyl-(C 3 -C 10 heterocycloalkyl), —C 1 -C 4 alkyl-(C 6 -C 10 aryl), or —C 1 -C 4 alkyl-(C 5 -C 9 heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted 1-5 times with halo, —OH, —CN, or —NO 2 , or two R 11 groups, together with the carbons to which they are attached, join to form a cyclic phosphate ring;
m is 0, 1, 2, 3, or 4;
x is 0, 1, 2, 3, 4, or 5; and
y is 0, 1, 2, 3, or 4.

2. The method of claim 1 , wherein:
R 4 is H;
m is 0, 1, 2, or 3;
x is 0, 1, 2, or 3; and
y is 0, 1, 2, or 3.

3. The method of claim 1 , wherein:
R 1 is, independently at each occurrence, —OH, halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —O—C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, —C 3 -C 10 heterocycloalkyl, —C 1 -C 4 alkyl-(C 3 -C 10 cycloalkyl), or —C 1 -C 4 alkyl-(C 3 -C 10 heterocycloalkyl), wherein the alkyl group is optionally substituted 1-5 times with halo or —OH.

4. The method of claim 1 , wherein:
R 2 is, independently at each occurrence, —OH, halo, —CN, —NO 2 , R 6 , or OR 6 , wherein R 6 is, independently at each occurrence, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, —C 3 -C 10 heterocycloalkyl, —C 1 -C 4 alkyl-(C 3 -C 10 cycloalkyl), or —C 1 -C 4 alkyl-(C 3 -C 10 heterocycloalkyl), wherein the alkyl group is optionally substituted 1-5 times with halo or —OH.

5. The method of claim 1 , wherein:
R 11 is, independently at each occurrence, —OH, halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —O—C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, —C 3 -C 10 heterocycloalkyl, —C 1 -C 4 alkyl-(C 3 -C 10 cycloalkyl), or —C 1 -C 4 alkyl-(C 3 -C 10 heterocycloalkyl), wherein the alkyl group is optionally substituted 1-5 times with halo or —OH.

6. The method of claim 1 , wherein:
R 11 is, independently at each occurrence, —OH, halo, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, or —C 3 -C 10 heterocycloalkyl.

7. The method of claim 1 , wherein:
R 4 is H;
each R 1 is, independently at each occurrence, —OH, halo, —CN, —NO 2 , or —C 1 -C 6 alkyl;
R 2 is selected from —OH, halo, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, and —C 3 -C 10 heterocycloalkyl, wherein the alkyl and cycloalkyl groups are optionally substituted 1-5 times with halo;
Cy is

wherein
R 11 is, independently at each occurrence, —OH or halo;
m is 0, 1 or 2; and
x is 0, 1, 2, or 3.

8. The method of claim 1 , wherein:
R 4 is H;
each R 1 is, independently at each occurrence, —OH or halo;
R 2 is selected from —OH, halo, and —C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted 1-5 times with halo;
Cy is

wherein
R 11 is, independently at each occurrence, —OH, halo, —C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, —C 3 -C 10 cycloalkyl, or —C 3 -C 10 heterocycloalkyl;
m is 0, 1 or 2; and
x is 0, 1, 2, or 3.

9. The method of claim 1 , wherein:
R 4 is H;
each R 1 is, independently at each occurrence, —OH or halo;
R 2 is selected from halo and —C 1 -C 3 alkyl, wherein the alkyl group is optionally substituted 1-3 times with halo;
Cy is

wherein
R 11 is, independently at each occurrence, —OH, halo, —C 1 -C 3 alkyl, —C 1 -C 4 heteroalkyl, —C 3 -C 7 cycloalkyl, or —C 3 -C 07 heterocycloalkyl;
m is 0, 1 or 2; and
x is 0, 1, 2, or 3.

10. The method of claim 1 , wherein:
R 4 is H;
each R 1 is, independently at each occurrence, halo;
R 2 is selected from halo and —C 1 alkyl, wherein the alkyl group is optionally substituted 1-3 times with halo;
Cy is

wherein
R 11 is, independently at each occurrence, —OH, halo, —C 1 -C 3 alkyl, or —C 3 -C 7 cycloalkyl;
m is 0, 1 or 2; and
x is 2 or 3.

11. The method of claim 1 , wherein:
R 4 is H;
each R 1 is, independently at each occurrence, halo;
R 2 is selected from halo and C 1 alkyl, wherein the alkyl group is optionally substituted 1-3 times with halo;
Cy is

wherein
R 11 is, independently at each occurrence, —OH, halo, —C 1 -C 3 alkyl, or —C 3 -C 7 cycloalkyl;
m is 0, 1 or 2; and
x is 2 or 3.

12. The method of claim 11 , wherein the compound is selected from:

13. The method of claim 1 , 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, capsid assembly modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, and an HBV vaccine, and a combination thereof.

Assignees

• Novira Therapeutics Inc

Inventors

• Hartman George D
• Kuduk Scott

Classifications

• A61P43/00

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

• A61P31/20

  for DNA viruses · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P1/16

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

• A61K38/212

  IFN-alpha · CPC title