Azepane derivatives and methods of treating hepatitis B infections

Patent metadata

Field	Value
Publication number	US-9873671-B2
Application number	US-201615277421-A
Country	US
Kind code	B2
Filing date	Sep 27, 2016
Priority date	Jan 16, 2014
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

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 III:

or a pharmaceutically acceptable salt thereof;
wherein
R 4 is H or —C 1 -C 3 alkyl;
each 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, aryl, 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-(aryl), or —C 1 -C 4 alkyl-(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 —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, aryl, 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-(aryl), or —C 1 -C 4 alkyl-(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

R 7 and R 8 are, independently at each occurrence, —C 1 -C 6 alkyl, aryl, heteroaryl, —C 1 -C 4 alkyl-(aryl), or —C 1 -C 4 alkyl-(heteroaryl), wherein the aryl or heteroaryl groups are optionally substituted with —C 1 -C 3 alkyl;
or R 7 and R 8 join to form a 3- to 10-membered ring;
R 11 is, independently at each occurrence, —OH, halo, —CN, —NO 2 , ═O, —OC(O)CH 3 , —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, —O—C 3 -C 10 cycloalkyl, —C 3 -C 10 heterocycloalkyl, aryl, 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-(aryl), or —C 1 -C 4 alkyl-(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 12 is, independently at each occurrence, H or —C 1 -C 6 alkyl;
R 13 and R 14 , together with the carbons to which they are attached, join to form a cyclopropyl ring;
m is 0, 1, 2, 3, or 4;
n is 1, 2, 3, or 4; and
x is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is H or —C 1 -C 3 alkyl;
each 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, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted 1-3 times with halo, —OH, —CN, or —NO 2 ;
R 2 is —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, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted 1-3 times with halo, —OH, —CN, or —NO 2 ;
Cy is

R 7 and R 8 are, independently at each occurrence, —C 1 -C 6 alkyl, aryl, heteroaryl, —C 1 -C 4 alkyl-(aryl), or —C 1 -C 4 alkyl-(heteroaryl);
or R 7 and R 8 join to form a 3- to 7-membered ring;
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, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted 1-3 times with halo, —OH, —CN, or —NO 2 ;
R 12 is, independently at each occurrence, H or —C 1 -C 6 alkyl;
m is 0, 1, 2, or 3;
n is 1, 2, or 3; and
x is 0, 1, 2, or 3.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is H or C 1 -C 3 alkyl;
each R 1 is, independently at each occurrence, OH, halo, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, or —O—C 1 -C 6 heteroalkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or —OH;
each R 2 is, independently at each occurrence, OH, halo, R 6 , or OR 6 , wherein R 6 is, independently at each occurrence, —C 1 -C 6 alkyl, —C 3 -C 10 cycloalkyl, —C 1 -C 4 alkyl-(C 3 -C 10 cycloalkyl), wherein the alkyl and cycloalkyl groups are optionally substituted 1-3 times with halo or —OH;
Cy is

R 11 is, independently at each occurrence, OH, halo, —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C 1 -C 6 heteroalkyl, or —O—C 1 -C 6 heteroalkyl, wherein the alkyl group is optionally substituted 1-3 times with halo or —OH;
R 12 is, independently at each occurrence, H or —C 1 -C 6 alkyl;
m is 0, 1, 2, or 3;
n is 1, 2, or 3; and
x is 0, 1, 2, or 3.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are, independently at each occurrence, —C 1 -C 6 alkyl, phenyl, pyridyl, benzyl, or pyridylmethyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are, independently at each occurrence, —C 1 -C 6 alkyl, wherein the —C 1 -C 6 alkyl groups join to form a 3- to 7-membered ring.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is, independently at each occurrence, halo and x is 1, 2, or 3.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 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.

9. 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 3 alkyl-OH and y is 1 or 2.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —OR 6 , wherein R 6 is —C 1 -C 6 alkyl or —C 3 -C 10 cycloalkyl, wherein the alkyl and cycloalkyl groups are optionally substituted 1-2 times with halo or OH.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein each R 11 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.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is —O—C 1 -C 3 alkyl, and n is 1.

14. The

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

• A61P1/16

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

• C07D403/12

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

• A61K45/06

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