Hepatitis B antiviral agents

Patent metadata

Field	Value
Publication number	US-10196376-B2
Application number	US-201715612240-A
Country	US
Kind code	B2
Filing date	Jun 2, 2017
Priority date	Dec 21, 2011
Publication date	Feb 5, 2019
Grant date	Feb 5, 2019

Abstract

The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.

First claim

The invention claimed is:

1. A compound of Formula VI:

or pharmaceutically acceptable salts thereof;
wherein
R 4 is H or C 1 -C 6 alkyl;
G 1 is H or C 1 -C 6 alkyl;
wherein each R 5 is independently selected at each occurrence from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, —CN, —NO 2 , -(L) m -SR 9 , -(L) m -S(═O)R 9 , -(L) m -S(═O) 2 R 9 , -(L) m -NHS(═O) 2 R 9 , -(L) m -C(═O)R 9 , -(L) m -OC(═O)R 9 , -(L) m CO 2 R 8 , -(L) m -OCO 2 R 8 , -(L) m -CH(R 8 ) 2 , -(L) m -N(R 8 ) 2 , -(L) m -C(═O)N(R 8 ) 2 , -(L) m -OC(═O)N(R 8 ) 2 , -(L) m -NHC(═O)NH(R 8 ), -(L) m -NHC(═O)R 9 , -(L) m -NHC(═O)OR 9 , -(L) m -C(OH)(R 8 ) 2 , -(L) m C(NH 2 )(R 8 ) 2 , —C 1 -C 6 haloalkyl, —C 1 -C 6 dihaloalkyl, and —C 1 -C 6 trihaloalkyl;
L is independently, at each occurrence, a bivalent radical selected from —(C 1 -C 3 alkylene)-, —(C 3 -C 7 cycloalkylene)-, —(C 1 -C 3 alkylene) m -O—(C 1 -C 3 alkylene) m -, or —(C 1 -C 3 alkylene) m -NH—(C 1 -C 3 alkylene) m -;
each R 8 is independently, at each occurrence, H, C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 dihaloalkyl, —C 1 -C 6 trihaloalkyl, 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), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1-5 substituents selected from R 2 ;
R 9 is C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 dihaloalkyl, —C 1 -C 6 trihaloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, a 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), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring is optionally substituted with 1-5 substituents selected from R 2 ;
R 10 is OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, a 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), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring is optionally substituted with 1-5 substituents selected from R 2 ;
R 11 is a bond or C 1 -C 3 alkylene, wherein the C 1 -C 3 alkylene is optionally substituted with 1-3 substituents selected from R 2 ;
R 2 is independently selected at each occurrence from the group consisting of halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 heteroalkyl, and C(O)—C 1 -C 6 alkyl;
w is 0, 1, or 2;
x is 0, 1, 2, 3, or 4;
y is 2, 3, or 4;
z is 0, 1, 2, or 3; and
m is 0, 1, or 2.

2. The compound of claim 1 , wherein
each R 5 is independently selected at each occurrence from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, —CN, —NO 2 , —C 1 -C 6 haloalkyl, —C 1 -C 6 dihaloalkyl, and —C 1 -C 6 trihaloalkyl;
R 10 is OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, —C 1 -C 6 haloalkyl, —C 1 -C 6 dihaloalkyl, —C 1 -C 6 trihaloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, a 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), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring is optionally substituted with 1-5 substituents selected from R 2 ;
R 11 is a bond or C 1 -C 3 alkylene, wherein the C 1 -C 3 alkylene is optionally substituted with 1-3 substituents selected from R 2 ; and
R 2 is independently selected at each occurrence from the group consisting of halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 heteroalkyl, C(O) —C 1 -C 6 alkyl, and C(O) —C 1 -C 6 alkoxy.

3. The compound of claim 1 , wherein
each R 5 is independently selected at each occurrence from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl;
R 10 is OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 fluoroalkyl, C 1 -C 6 difluoroalkyl, C 1 -C 6 trifluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, a 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), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring is optionally substituted with 1-5 substituents selected from R 2 ;
R 11 is a bond or C 1 -C 3 alkylene;
R 2 is independently selected at each occurrence from the group consisting of halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 heteroalkyl, and C(O) —C 1 -C 6 alkyl.

4. The compound of claim 1 , wherein R 5 is 3-F, 3-Cl, 3-CH 3 , 3-CH 2 F, 3-CHF 2 , 4-F, 3-CH 3 -4-F, 3-Cl-4-F, 3-Br-4-F, 3,4,5-trifluoro, 3,4,5-trichloro, or 3-chloro-4,5-difluoro.

5. The compound of claim 1 , wherein w is 1 or 2.

6. The compound of claim 1 , wherein
R 11 is a bond or C 1 -C 3 alkylene;
R 10 is OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, —C 1 -C 6 chloroalkyl, —C 1 -C 6 dichloroalkyl, —C 1 -C 6 trichloroalkyl, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 difluoroalkyl, —C 1 -C 6 trifluoroalkyl, C 3 -C 10 cycloalkyl, a C 3 -C 10 heterocycloalkyl, or phenyl, wherein the C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, or phenyl groups are optionally substituted with 1-5 substituents selected from halo, —C 1 -C 6 alkyl, and —C 1 -C 6 alkoxy; and
z is 0 or 1.

7. The compound of claim 1 , wherein the compound of Formula VI is of the Formula VIa:

or pharmaceutically acceptable salts thereof;
wherein G 1 is independently selected at each occurrence from CH 3 , OCH 3 , halo, CF 3 , CCl 3 , CH 2 Cl, CCI 2 H, CF 2 H, CH 2 F, and CF 3 ;
G 2 is H, C 1 -C 4 alkyl, or halo;
G 3 is OH, CH 2 OH, or CH 2 CH 2 OH;
G 4 is H, OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, —C 1 -C 6 chloroalkyl, —C 1 -C 6 dichloroalkyl, —C 1 -C 6 trichloroalkyl, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 difluoroalkyl, —C 1 -C 6 trifluoroalkyl, or phenyl, wherein the phenyl group is optionally independently substituted with 1-5 substituents selected from halo, —C 1 -C 6 alkyl, and —C 1 -C 6 alkoxy; and
y is 2 or 3.

8. The compound of claim 1 , wherein the compound of Formula VI is of the Formula VIb:

or pharmaceutically acceptable salts thereof;
wherein X is halo;
G 1 is hydrogen or halo;
G 2 is H, C 1 -C 4 alkyl, or halo; and
G 4 is H, halo, C 1 -C 4 alkyl, or OH.

9. A composition comprising a compound according to claim 1 , or a salt thereof.

10. The composition of claim 9 , wherein the composition is pharmaceutical and further comprises at least one pharmaceutically acceptable carrier.

11. A

Assignees

• Novira Therapeutics Inc

Inventors

• Hartman George D
• Flores Osvaldo A

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

• A61P31/12

  Antivirals · CPC title

• A61P1/16

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

• C07D207/14

  Nitrogen atoms not forming part of a nitro radical · CPC title