Hepatitis B viral assembly effectors

Patent metadata

Field	Value
Publication number	US-10273228-B2
Application number	US-201615566633-A
Country	US
Kind code	B2
Filing date	Apr 15, 2016
Priority date	Apr 17, 2015
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

Abstract

Novel assembly effector compounds having a therapeutic effect against hepatitis B viral (HBV) infection are disclosed. Assembly effector molecules described herein can lead to defective viral assembly and also may affect other viral activities associated with chronic HBV infection. Also disclosed is a process to synthesize disclosed compounds, method of treatment of HBV by administration of disclosed compounds, and use of these compounds in the manufacture of medicaments against HBV.

First claim

We claim:

1. A pharmaceutical composition comprising: (i) a compound of Formula 1 having the structure:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

is selected from the group consisting of

Y is selected from the group consisting of a bond, —O—, —S(O) w , and —N(R′)—;
X is selected from the group consisting of phenyl, naphthyl, and heteroaryl; wherein X is optionally substituted with one, two, three, or four R 2 groups;
provided that at least one of

or X is a heteroaryl;
R 1 is independently for each occurrence selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, halogen, cyano, —OH, —C(O)H, —CO 2 R′, —C(O)N(R′)(R″), —C(O)C 1 -C 6 alkyl, —N(R′)(R″), —NO 2 , —N(R′)C(O)C 1 -C 6 alkyl, —N(R′)S(O) w —C 1 -C 6 alkyl, and —S(O) w —N(R′)(R″);
q is 0, 1, 2, 3 or 4;
w is 0, 1 or 2;
R′ is independently for each occurrence selected from the group consisting of —H and —C 1 -C 6 alkyl;
R″ is independently for each occurrence selected from the group consisting of —H and —C 1 -C 6 alkyl; or
R′ and R″ are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic or heteroaryl ring, each of which is optionally substituted with an oxo group;
R 2 is independently for each occurrence selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, halogen, oxo, cyano, —OH, —C(O)H, —CO 2 R′, —C(O)N(R′)(R″), —C(O)C 1 -C 6 alkyl, —N(R′)(R″), —NO 2 , —N(R′)C(O)C 1 -C 6 alkyl, —S(O) w —C 1 -C 6 alkyl, —N(R′)S(O) w —C 1 -C 6 alkyl, and —S(O) w —N(R′)(R″); and
R 3 is selected from the group consisting of —H, —C 1 -C 6 alkyl, —N(R′)(R″), —N(R′)C 1 -C 6 alkyl-N(R′)(R″), —N(R)—C 1 -C 6 alkyl-OR′, —OH, —C 1 -C 6 alkoxy, —O—C 1 -C 6 alkyl-OR′, —O-heterocyclyl, —O-heteroaryl, —O—C 1 -C 6 alkyl-heteroaryl, —C 1 -C 6 alkyl-heteroaryl, heterocyclyl, and heteroaryl, wherein heterocyclyl and heteroaryl are optionally substituted with one or two C 1 -C 6 alkyl or halogen;
wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy may be independently for each occurrence optionally substituted with one, two, or three halogens; and
(ii) optionally, a pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1 , wherein

is phenyl.

3. The pharmaceutical composition of claim 1 , wherein X is selected from the group consisting of

4. The pharmaceutical composition of claim 1 , wherein X is phenyl.

5. The pharmaceutical composition of claim 1 , wherein R 1 is independently for each occurrence selected from the group consisting of —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, halogen, cyano, —OH, —CO 2 R′, and —N(R′)(R″).

6. The pharmaceutical composition of claim 1 , wherein R 1 is independently for each occurrence selected from the group consisting of —CH 3 , —Et, i-Pr, —CF 3 , —OMe, —OCF 3 , F, Cl, Br, —NH 2 , —NHMe, and —NMe 2 .

7. The pharmaceutical composition of claim 1 , wherein q is 1, 2, or 3.

8. The pharmaceutical composition of claim 1 , wherein R 2 is independently for each occurrence selected from the group consisting of —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, halogen, oxo, cyano, —OH, —CO 2 R′, and —N(R′)(R″).

9. The pharmaceutical composition of claim 1 , wherein R 2 is independently for each occurrence selected from the group consisting of —CH 3 , —Et, i-Pr, —CF 3 , oxo, —OMe, —OCF 3 , F, Cl, Br, —NH 2 , —NHMe, and —NMe 2 .

10. The pharmaceutical composition of claim 1 , wherein X is optionally substituted with one, two, or three R 2 groups.

11. The pharmaceutical composition of claim 1 , wherein R 3 is independently for each occurrence selected from the group consisting of —H, —N(R′)(R″), —NH—C 1 -C 6 alkyl-N(C 1 -C 6 alkyl) 2 , —NH—C 1 -C 6 -alkyl-OR′, —OH, —C 1 -C 6 alkoxy, —O—C 1 -C 6 alkyl-OR′, heterocyclyl, and heteroaryl, wherein heterocyclyl and heteroaryl are optionally substituted with one or two C 1 -C 6 alkyl or halogen.

12. The pharmaceutical composition of claim 1 , wherein R 3 is independently for each occurrence selected from the group consisting of —H, —CH 3 , —Et, i-Pr, —N(CH 3 ) 2 , —NH(i-Pr), —NH(t-Bu), —N(CH 3 )(t-Bu), —NH(CH 3 ), —NH(CH 2 CH 2 OH), —NH—CH 2 CH 2 —N(CH 3 ) 2 , —OMe, —OCH 2 CH 2 OH,

13. A pharmaceutical composition comprising: (i) a compound of Formula 1-A having the structure:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y is selected from the group consisting of a bond, —O—, —S(O) w —, and —N(R′)—;
X is heteroaryl optionally substituted with one, two, three, or four R 2 groups;
R 1 is independently for each occurrence selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, halogen, cyano, —OH, —C(O)H, —CO 2 R′, —C(O)N(R′)(R″), —C(O)C 1 -C 6 alkyl, —N(R′)(R″), —NO 2 , —N(R′)C(O)C 1 -C 6 alkyl, —N(R′)S(O) w —C 1 -C 6 alkyl, and —S(O) w —N(R′)(R″);
q is 0, 1, 2, 3 or 4;
w is 0, 1 or 2;
R′ is independently for each occurrence selected from the group consisting of —H and —C 1 -C 6 alkyl;
R″ is independently for each occurrence selected from the group consisting of —H and —C 1 -C 6 alkyl; or
R′ and R″ are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic or heteroaryl ring, each of which is optionally substituted with an oxo group;
R 2 is independently for each occurrence selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, halogen, oxo, cyano, —OH, —C(O)H, —CO 2 R′, —C(O)N(R′)(R″), —C(O)C 1 -C 6 alkyl, —N(R′)(R″), —NO 2 , —N(R′)C(O)C 1 -C 6 alkyl, —N(R′)S(O) w —C 1 -C 6 alkyl, and —S(O) w —N(R′)(R″); and
R 3 is selected from the group consisting of —H, —C 1 -C 6 alkyl, —N(R′)(R″), —N(R′)C 1 -C 6 alkyl-N(R′)(R″), —N(R)—C 1 -C 6 alkyl-OR′, —OH, —C 1 -C 6 alkoxy, —O—C 1 -C 6 alkyl-OR′, —O-heterocyclyl, —O-heteroaryl, —O—C 1 -C 6 alkyl-heteroaryl, —C 1 -C 6 alkyl-heteroaryl, heterocyclyl, and heteroaryl, wherein heterocyclyl and heteroaryl are optionally substituted with one or two C 1 -C 6 alkyl or halogen;
wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy may be independently for each occurrence optionally substituted with one, two, or three halogens; and

(ii) optionally, a pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising: (i) a compound of Formula 1 having the structure:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

is selected from the group consisting of phenyl, naphthyl, and heteroaryl;
Y is —

Assignees

• Univ Indiana Res & Tech Corp
• Assembly Biosciences Inc

Inventors

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

Classifications

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D239/48

  Two nitrogen atoms · CPC title

• A61P31/20

  for DNA viruses · CPC title