Hepatitis B core protein allosteric modulators

Patent metadata

Field	Value
Publication number	US-10947224-B2
Application number	US-201815965655-A
Country	US
Kind code	B2
Filing date	Apr 27, 2018
Priority date	Mar 13, 2014
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.

First claim

What is claimed is:

1. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula 1:

wherein:
T is selected from the group consisting of —C(O)—, —CH 2 —C(O)—, —N(C(O)—CH 3 )—, —NH—, —O—, and —S(O) z —, where z is 0, 1 or 2;
Y is NR Y ;
R Y is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
R L is selected from the group consisting of H, methyl, and —C(O)—C 1-3 alkyl;
L is a bond or C 1-4 straight chain alkylene optionally substituted by one or two substituents each independently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), ethenyl, hydroxyl, NR′R″, phenyl, heterocycle, and halogen and wherein the C 1-4 straight chain alkylene may be interrupted by an —O—;
R 2 is selected from the group consisting of:
i) H,
ii) phenyl or naphthyl (wherein the phenyl or naphthyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR′R″, —C(O)—NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR′R″, C(O)—NR′R″, —C(O)—C 1-6 alkoxy, —S(O) w —C 1-6 alkyl (where w is 1, 2 or 3), S(O) w —NR′R″ (where w is 1, 2 or 3), —NR′—S(O) w and —S(O) w —NR′R″ (where w is 1, 2 or 3)), heteroaryl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR′R″, C(O)—NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, —S(O) w —C 1-6 alkyl (where w is 1, 2 or 3), NR′—S(O) w , and —S(O) w —NR′R″ (where w is 1, 2 or 3)), C 3-6 cycloalkyl, —S(O) w —C 1-6 alkyl (where w is 1, 2 or 3), —S(O) w —NR′R″ (where w is 1, 2 or 3), and —NR′—S(O) w , (where w is 1, 2 or 3)),
iii) 5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (wherein the 5-6 membered heteroaryl may be optionally substituted: a) on a carbon with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR′R″, C(O)—NR′R″, —C(O)—OH, —C(O)—C 1-6 alkoxy, —S(O) w —C 1-6 alkyl (where w is 1, 2 or 3), —NR′—S(O) w , and —S(O) w —NR′R″ (where w is 1, 2 or 3)), heteroaryl, heterocycle, NR′R″, —C(O)—NR′R″, —C(O)—C 1-6 alkoxy, —S(O) w —C 1-6 alkyl (where w is 1, 2 or 3), —NR′—S(O) w , and —S(O) w —NR′R″ (where w is 1, 2 or 3), and/or b) on a nitrogen by R′),
iv) C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 3-10 cycloalkyl (optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, NR′R″, —C(O)—NR′R″, —CNR′, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, and —C(O)—C 1-6 alkoxy, and wherein the C 3-10 cycloalkyl may optionally be a bridged cycloalkyl), and
v) a 4-6 membered heterocycloalkyl having one or two heteroatoms each independently selected from O, N and S (wherein the 4-6 membered heterocycloalkyl may be optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, NR′R″, —C(O)—NR′R″, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, and —C(O)—C 1-6 alkoxy);

R′ is selected, independently for each occurrence, from H, methyl, ethyl, propyl, phenyl, and benzyl;
R″ is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, carboxybenzyl, —C(O)-methyl and —C(O)-ethyl, or R′ and R″ taken together may form a 4-6 membered heterocycle;
each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, hydroxyl, nitro, cyano, NR′R″, —C(O)—NR′R″, —S(O) w —C 1-6 alkyl (where w is 1, 2 or 3), —NR′—S(O), and —S(O) w —NR′R″ (where w is 0, 1 or 2), C 1-6 alkoxy, —C(O)—OH, —C(O)—C 1-6 alkyl, and —C(O)—C 1-6 alkoxy;
wherein for each occurrence in any one or more of R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 :
i) C 1-6 alkyl may be optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, phenyl, NR′R″, —C(O)—NR′R″, S(O) w -methyl (where w is 1, 2 or 3), —NR′—S(O), and S(O) w —NR′R″ (where w is 0, 1 or 2);
ii) C 1-6 alkoxy may be optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, phenyl, NR′R″, —C(O)—NR′R″, S(O) w —C 1-6 alkyl (where w is 1, 2 or 3), —NR′—S(O) w , and S(O) w —NR′R″ (where w is 0, 1 or 2); and
iii) C 3-6 cycloalkyl may be optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, and NR′R″; or

a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein L is —CH 2 —.

3. The method of claim 1 , wherein L is C 2-3 alkylene.

4. The method of claim 1 , wherein L is selected from the group consisting of —CH 2 —CH 2 —, —CH 2 (CH 2 )—CH 2 —, —CH 2 —CH 2 (OH)—, —CH 2 —CH 2 (CH 3 OH)—, and —CH 2 —CH 2 (OH)—CH 2 —.

5. The method of claim 1 , wherein L is a bond.

6. The method of claim 1 , wherein L is —C 2-3 alkylene-O—.

7. The method of claim 1 , wherein L is —O—.

8. The method of claim 1 , wherein R 2 is phenyl or 5-6 membered heteroaryl.

9. The method of claim 1 , wherein R 2 is phenyl.

10. The method of claim 1 , wherein R 2 is phenyl substituted by one or two substituents each selected from the group consisting of fluorine, chlorine, C 1-6 alkyl (optionally substituted by one, two or three fluorines), C 1-6 alkoxy (optionally substituted by one, two or three fluorines), hydroxyl, NR′R″, —S(O) 2 —NR′R″, heteroaryl, and phenyl (optionally substituted by halogen or hydroxyl).

11. The method of claim 1 , wherein R 2 is phenyl substituted by

12. The method of claim 1 , wherein R 2 is a 5-6 membered heteroaryl.

13. The method of claim 12 , wherein R 2 is selected from the group consisting of:

14. The method of claim 12 wherein R 2 is selected from the group consisting of:

wherein
R 32 is selected from the group consisting of H, halogen, phenyl, and C 1-6 alkyl (optionally substituted by one, two or three halogens);
R 52 is selected from the group consisting of H, halogen, phenyl, and C 1-6 alkyl (optionally substituted by one, two or three halogens); and
R 42 is selected from the group consisting of H, halogen, phenyl, C 1-6 alkyl (optionally substituted by one, two or three halogen

Assignees

• Univ Indiana Res & Tech Corp
• Assembly Biosciences Inc

Inventors

• Turner Jr William W
• Arnold Lee Daniel
• Maag Hans
• Zlotnick Adam

Classifications

• A61P31/12

  Antivirals · CPC title

• C07D413/12

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

• C07D281/16

  [b, f]-condensed · CPC title

• C07D281/14 Primary

  [b, e]-condensed · CPC title

• C07D243/38

  [b, e]- or [b, f]-condensed with six-membered rings · CPC title