Hepatitis B capsid assembly modulators

Patent metadata

Field	Value
Publication number	US-11247965-B2
Application number	US-201816771387-A
Country	US
Kind code	B2
Filing date	Dec 10, 2018
Priority date	Dec 11, 2017
Publication date	Feb 15, 2022
Grant date	Feb 15, 2022

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 (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:
Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
Ring B is;

R 1 is —F, —Cl, —OH, or —OR a ;
R 2 is hydrogen, —F, —Cl, —CN, —OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, or C 3-8 cycloalkyl;
R 3 is hydrogen or C 1-6 alkyl;
each R 4 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR b R c , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-7 heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl(aryl), C 1-6 alkyl(heteroaryl), C 1-6 alkyl(C 3- 8cycloalkyl), or C 1-6 alkyl(C 2-7 heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 12 ;
or two R 4 on adjacent atoms are taken together with the atoms to which they are attached to form a carbocycle ring or a heterocycle ring; each optionally substituted with one, two, or three R 12 ;
each R 5 is independently hydrogen, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR b R c , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-7 heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl(aryl), C 1-6 alkyl(heteroaryl), C 1-6 alkyl(C 3-8 cycloalkyl), or C 1-6 alkyl(C 2-7 heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 13 ;
or two R 5 on adjacent atoms are taken together with the atoms to which they are attached to form a carbocycle ring or a heterocycle ring; each optionally substituted with one, two, or three R 13 ;
R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 2-15 heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl(aryl), C 1-6 alkyl(heteroaryl), C 1-6 alkyl(C 3-8 cycloalkyl), or C 1-6 alkyl(C 2-7 heterocycloalkyl); wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 10 ;
or R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a C 2-15 heterocycloalkyl or a C 2-15 heterocycloalkenyl; wherein each heterocycloalkyl and heterocycloalkenyl is independently optionally substituted with one, two, or three R 11 ;
m is an integer from 0 to 5;
n is an integer from 0 to 4;
each R 10 is independently oxo, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR b R c , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , —B(OR d ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-7 heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl(aryl), C 1-6 alkyl(heteroaryl), C 1-6 alkyl(C 3-8 cycloalkyl), or C 1-6 alkyl(C 2-7 heterocycloalkyl);
each R 11 is independently oxo, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR b R c , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —NR b S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —CH 2 C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , —NR b C(═O)CH 2 NR b R c , —C(═O)CH 2 NR b C(═O)NR b R c , —OP(═O)(OR b )(OR b ), —B(OR d ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 1-6 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-7 heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl(aryl), C 1-6 alkyl(heteroaryl), C 1-6 alkyl(C 3-8 cycloalkyl), or C 1-6 alkyl(C 2-7 heterocycloalkyl);
each R 12 and R 13 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR b R c , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, or C 3-8 cycloalkyl;
each R a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 2-7 heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl(aryl), C 1-6 alkyl(heteroaryl), C 1-6 alkyl(C 3-8 cycloalkyl), or C 1-6 alkyl(C 2-7 heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, halogen, —OH, C 1-6 alkyl, or C 1-6 haloalkyl;
each R b and R c is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 2-7 heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl(aryl), C 1-6 alkyl(heteroaryl), C 1-6 alkyl(C 3-8 cycloalkyl), or C 1-6 alkyl(C 2-7 heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, halogen, —OH, C 1-6 alkyl, or C 1-6 haloalkyl;
or R b and R c are taken together with the nitrogen atom to which they are attached to form a C 2-7 heterocycloalkyl optionally substituted with one, two, or three oxo, halogen, —OH, C 1-6 alkyl, or C 1-6 haloalkyl; and
each R d is independently hydrogen or C 1-6 alkyl;
or two R d are taken together to form a C 2-7 heterocycloalkyl optionally substituted with one, two, or three halogen, —OH, or C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 1 is —F or —OH.

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

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3 is hydrogen or methyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is aryl or heteroaryl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 4 is independently halogen, —CN, —OR a , —NO 2 , —C(═O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, or C 3-8 cycloalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 1 to 3.

8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 5 is independently hydrogen, halogen, —CN, —OR a , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, or C 1-6 alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or

Assignees

• Venatorx Pharmaceuticals Inc

Inventors

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

Classifications

• A61P31/20 Primary

  for DNA viruses · CPC title

• C07D295/185

  from aliphatic carboxylic acids · CPC title

• C07D223/08

  Oxygen atoms · CPC title

• C07D211/70

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D213/40

  Acylated substituent nitrogen atom · CPC title