Hepatitis B capsid assembly modulators

Patent metadata

Field	Value
Publication number	US-10590076-B2
Application number	US-201916438361-A
Country	US
Kind code	B2
Filing date	Jun 11, 2019
Priority date	Jun 11, 2018
Publication date	Mar 17, 2020
Grant date	Mar 17, 2020

Abstract

Described herein are hepatitis B capsid assembly modulators and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of hepatitis B.

First claim

What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:
Ring A is phenyl or pyridyl;
each R 11 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 12 is hydrogen or C 1 -C 6 alkyl;
R 13 is hydrogen, halogen, or C 1 -C 6 alkyl;
R 14 is hydrogen, halogen, or C 1 -C 6 alkyl;
R 15 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl;
R 16 is hydrogen or C 1 -C 6 alkyl;
R 17 is cyclohexyl optionally substituted with one, two, or three R 7 ;
n is 0-3;
each R 7 is independently halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C 1 -C 6 alkyl(aryl), —C 1 -C 6 alkyl(heteroaryl), —C 1 -C 6 alkyl(cycloalkyl), or —C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 7a ;
each R 7a is independently oxo, halogen, —CN, —OH, —OR a , —NR b R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; and
each R b and R c are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
or R b and R c are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 14 is hydrogen or C 1 -C 6 alkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 15 is C 1 -C 6 alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 12 is hydrogen.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 13 is hydrogen or C 1 -C 6 alkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Ring A is phenyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R 11 is independently halogen, or C 1 -C 6 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
n is 1 or 2.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 16 is hydrogen.

10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R 7 is independently halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)OR b , —C(═O)NR b R c , —C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one, two, or three R 7a .

11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R 7 is independently halogen, —CN, —OH, —OR a , —NR b R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl; wherein each alkyl is independently optionally substituted with one, two, or three R 7a .

12. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R 7a is independently halogen, —CN, —OH, —OR a , —NR b R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or heteroaryl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

15. A method of treating hepatitis B in a subject, comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

16. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R 7 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R 7 is independently —OH or C 1 -C 6 alkyl.

Assignees

• Venatorx Pharmaceuticals Inc

Inventors

• Burns Christopher J
• Coburn Glen
• Liu Bin
• Yao Jiangchao
• Benetatos Christopher
• Boyd Steven A
• Condon Stephen M
• Haimowitz Thomas

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D413/12

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

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/06

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