Hepatitis B core protein modulators

Patent metadata

Field	Value
Publication number	US-10968211-B2
Application number	US-201916426727-A
Country	US
Kind code	B2
Filing date	May 30, 2019
Priority date	Sep 15, 2015
Publication date	Apr 6, 2021
Grant date	Apr 6, 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 compound represented by:

wherein
Y is O;
R Z is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
R m′ and R m are each independently selected from the group consisting of H, C 1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), and C 2-6 alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl);
R c is selected from the group consisting of H, C 1-6 alkyl and C 2-6 alkenyl;
R 77 is selected from the group consisting of H, halogen, cyano, and C 1-6 alkyl;
R 78 is phenyl (optionally substituted with one, two, three or four substituents each independently selected from the group consisting of R 73 );
X 2 is selected from the group consisting of S(O) w (wherein w is 0, 1, or 2), O, —C(O)— and NR′,
R 79 is selected from the group consisting of H, hydroxyl, halogen, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, NR′R′, —C(O)—O—C 1-6 alkyl, carboxy and C 1-6 alkyl), —C(O)—NR′R″, —C(═NH)—NR′R″, heteroaryl, phenyl (optionally substituted by one or more substituents selected from the group consisting of halogen, NR′R′, —C(O)—O—C 1-6 alkyl, carboxy, C 1-6 alkoxy, and C 1-6 alkyl), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, NR′R″, —C(O)—C 1-6 alkyl, C 3-6 cycloalkyl, —NR′—C(O)— C 1-6 alkyl, NR′—C(O)— O—C 1-6 alkyl, —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));
R 73 is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, oxo, C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, NR′R′, —C(O)—O—C 1-6 alkyl, carboxy and C 1-6 alkyl), —C(O)—NR′—C 1-6 alkyl, —C(═NH)—NR′R″, heteroaryl, phenyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, carboxy, oxo, NR′R″, —C(O)—C 1-6 alkyl, —C 3-6 cycloalkyl, NR′—C(O)— C 1-6 alkyl, NR′—C(O)— O—C 1-6 alkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), —S(O) w —NR′R″ (where w is 1, 2 or 3), —NR′—S(O) w — C 1-6 alkyl (where w is 0, 1 or 2), C(O)—NR′— C 1-6 alkyl, C(O)—C 1-3 alkylene-NR′— C(O)—O— C 1-6 alkyl, X 2 — R 79 ; and X 2 —C 1-6 alkylene-R 79 ;
R′ is selected, independently for each occurrence, from H, methyl, ethyl, cyclopropyl, cyclobutyl, and propyl;
R″ is selected, independently for each occurrence, from H, methyl, ethyl, propyl, (optionally substituted by hydroxyl), butyl (optionally substituted by hydroxyl), —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 optionally substituted by one, two or more substituents selected from the group consisting of halogen, hydroxyl, NH 2 , —C(O)—O—C 1-3 alkyl, —C(O)—C 1-3 alkyl, carboxy, oxo, and C 1-3 alkyl;
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 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR′R″;
wherein for each occurrence, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, NR′R″, —NR′—S(O) w — C 1-2 alkyl (where w is 0, 1 or 2), NR′—C(O)—C 1-3 alkyl, NR′—C(O)— O—C 1-3 alkyl, 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 1-3 alkyl, NR′R″, —NR′—S(O) w — C 1-2 alkyl (where w is 0, 1 or 2), and S(O) w —NR′R″ (where w is 0, 1 or 2); C 1-6 alkylene may be optionally substituted by a substituent selected from the group consisting of C 3-6 cycloalkyl, hydroxyl, cyano, and halogen;
and pharmaceutically acceptable salts and N-oxides thereof.

2. The compound of claim 1 , wherein R 77 is selected from the group consisting of H, CH 3 and CF 3 .

3. The compound of claim 1 , wherein R 7 is H or halogen.

4. The compound of claim 1 , wherein R 10 is H, halogen or methyl.

5. The compound of claim 1 , wherein R m′ and R m are each H.

6. The compound of claim 1 , wherein R Z is H.

7. The compound of claim 1 , wherein each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is H.

8. The compound of claim 1 , wherein R 77 is H.

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

10. 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 .

11. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from a compound of claim 1 , and optionally administering one or more additional compounds.

12. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a compound of claim 1 , and administering another HBV capsid assembly promoter.

Assignees

• Assembly Biosciences Inc
• Univ Indiana Res & Tech Corp

Inventors

• Turner Jr William W
• Arnold Lee D
• Maag Hans
• Li Leping
• Bures Mark G
• Haydar Simon Nicolas
• Francis Samson

Classifications

• C07D417/12 Primary

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

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K45/06 Primary

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

• C07D281/16 Primary

  [b, f]-condensed · CPC title