Hepatitis B core protein modulators

Patent metadata

Field	Value
Publication number	US-10766890-B2
Application number	US-201615760387-A
Country	US
Kind code	B2
Filing date	Sep 15, 2016
Priority date	Sep 15, 2015
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

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 compound represented by:

wherein
Y is S(O) y , wherein y is 2;
R z is H;
R m′ and R m are each H;
R 21 is selected for each occurrence from the group consisting of H, and C 1-6 alkyl;
q is 0, 1, or 2;
R 22 is selected from the group consisting of hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, —C(O)—NR′R″, —C(═NH)—NR′R″, X 2 -phenyl (optionally substituted by one, two or three substituents represented by R 63 ), phenyl (optionally substituted by one, two or three substituents represented by R 63 ), 5-6 membered monocyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 63 ), 9-10 membered bicyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 73 ), C 3-6 cycloalkyl, —S(O) w -C 1-6 alkyl (where w is 0, 1 or 2), —S(O) w —NR′R″ (where w is 0, 1 or 2), and —NR′—S(O) w , (where w is 0, 1 or 2);
R′ is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
R″ is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, —C(O)-methyl and —C(O)-ethyl, or R′ and R″ taken together with the nitrogen to which they are attached may form a 4-7 membered heterocycle;
each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR′R″;
R 63 is selected independently at each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, heterocycle (optionally substituted by halogen or NR′R′), —C(O)—NR′R″, —C(═NH)—NR′R″, heteroaryl, phenyl, benzyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, C 3-6 cycloalkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), —S(O) w —NR′R″ (where w is 0, 1 or 2), —NR′—S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), X 2 —R 69 ;
R 69 is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, heterocycle (optionally substituted by halogen or NR′R′),), —C(O)—NR′R″, —C(═NH)—NR′R″, heteroaryl, phenyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, C 3-6 cycloalkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), —S(O) w —NR′R″ (where w is 0, 1 or 2), and —NR′—S(O) w — C 1-6 alkyl (where w is 0, 1 or 2),
X 2 is selected from S(O) w (wherein w is 0, 1, or 2), O, CH 2 , or NR′;
wherein for each occurrence, C 1-6 alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 2-6 alkenyl, C 2-6 alkynyl, NR′R″, —NR′—S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), and S(O) w —NR′R″(where w is 0, 1 or 2); C 1-6 alkoxy 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, NR′R″, —NR′—S(O) w — C 1-6 alkyl (where w is 0,1 or 2), and S(0) w —NR′R″ (where w is 0, 1 or 2);
and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein R 22 is selected from the group consisting of NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, —C(O)—NR′R″, —C(═NH)—NR′R″, X 2 -phenyl (optionally substituted by one, two or three substituents represented by R 63 ), phenyl (optionally substituted by one, two or three substituents represented by R 63 ), C 3-6 cycloalkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), —S(O) w —NR′R″ (where w is 0, 1 or 2), and —NR′—S(O) w , (where w is 0, 1 or 2).

3. The compound of claim 1 , wherein R 22 is selected from the group consisting of X 2 -phenyl (optionally substituted by one, two or three substituents represented by R 63 ), phenyl (optionally substituted by one, two or three substituents represented by R 63 ), 5-6 membered monocyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 63 ), and 9-10 membered bicyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 73 ).

4. The compound of claim 1 , wherein R 22 is —X 2 -phenyl (optionally substituted by one, two or three substituents represented by R 63 ).

5. The compound of claim 1 , wherein R 22 is phenyl (optionally substituted by one, two or three substituents represented by R 63 ).

6. The compound of claim 1 , wherein R 22 is a 5-6 membered monocyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 63 ) or a 9-10 membered bicyclic heteroaryl (optionally substituted by one, two or three substituents represented by R 73 ).

7. The compound of claim 1 , wherein q is 0.

8. The compound of claim 1 , represented by:

wherein R 21 is selected from the group consisting of H and C 1-6 alkyl.

9. The compound of claim 1 , wherein the compound is represented by:

wherein R 21 is selected from the group consisting of H and CH 3 .

10. The compound of claim 1 , wherein the compound is represented by:

wherein X 2 is selected from the group consisting of O, CH 2 , and S, and R 21 is selected from the group consisting of H and CH 3 .

11. The compound of claim 1 , wherein R 22 is represented by a substituent selected from the group consisting of:

wherein each R 22 is optionally substituted by one, two or three substituents represented by R 63 .

12. The compound of claim 1 , wherein
R 63 is selected independently at each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1-6 alkyl-OH, —C(O)—O—C 1-6 alkyl, —C(O)—NR′R″, —C(═NH)—NR′R″, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, C 3-6 cycloalkyl, —S(O) w —C 1-6 alkyl (where w is 0,1 or 2), —S(O) w —NR′R″ (where w is 0, 1 or 2), —NR′—S(O) w — C 1-6 alkyl (where w is 0, 1 or 2) and —NR′—S(O) w , (where w is 0, 1 or 2) and X 2 —C 1-6 alkylene-R 69 .

13. The compound of claim 1 , wherein
R 63 is selected independently at each occurrence from the group consisting of H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, C 1-6 alkyl-NR′R″, —O—C 1-6 alkyl-NR′R″, —C 1-6 alkyl-OH, —C(O)—NR′R″, C 1-6 alkoxy, carboxy, NR′R″, and benzyl.

14. A pharmaceutically acceptable composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.

15. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering an effective amount of a compound of claim 1 .

Assignees

• Assembly Biosciences Inc
• Univ Indiana Res & Tech Corp

Inventors

• Turner William
• Maag Hans
• Francis Samson

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/12 Primary

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

• A61K45/06 Primary

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

• A61P31/20

  for DNA viruses · CPC title

• C07D403/12

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