Hepatitis B core protein allosteric modulators

Patent metadata

Field	Value
Publication number	US-10183936-B2
Application number	US-201515125911-A
Country	US
Kind code	B2
Filing date	Mar 13, 2015
Priority date	Mar 13, 2014
Publication date	Jan 22, 2019
Grant date	Jan 22, 2019

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

The invention claimed is:

1. A compound represented by:

wherein
Y is S(O) y , wherein y is 2;
R m′ and R m are each independently selected from the group consisting of H, halogen, C 1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C 2-6 alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR′R″, and hydroxyl;
R c is H;
R 78 is selected from the group consisting of H, 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)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, phenyl, heteroaryl, 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));
R 79 is selected from the group consisting of H, 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)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, phenyl, heteroaryl, 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));
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 4-6 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″;
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, C 1-6 alkoxy, NR′R″, —NR′—S(O) w , and S(O) w —NR′R″; 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 , and S(O) w —NR′R″; C 3-6 cycloalkyl 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 1-6 alkoxy, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, and NR′R″; phenyl may be 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), and heteroaryl may be 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 3-6 cycloalkyl, 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), and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein R 7 is selected from H and F.

3. The compound of claim 1 , wherein R 6 is selected from H and F.

4. The compound of claim 1 , wherein R 5 is selected from H and F.

5. The compound of claim 1 , wherein R 10 is selected from the group consisting of H, methyl and F.

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

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

8. 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 .

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

10. 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.

11. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound of claim 1 , and one or more other HBV agent each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.

Assignees

• Univ Indiana Res & Tech Corp
• Assembly Biosciences Inc

Inventors

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

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

• A61P1/16

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

• A61K31/553

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

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title