Indolone compounds and their use as AMPA receptor modulators

Patent metadata

Field	Value
Publication number	US-10604484-B2
Application number	US-201615569313-A
Country	US
Kind code	B2
Filing date	Apr 28, 2016
Priority date	Apr 29, 2015
Publication date	Mar 31, 2020
Grant date	Mar 31, 2020

Abstract

Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof,

Also provided herein are pharmaceutical compositions, comprising compounds of Formula (I), and methods of using compounds of Formula (I).

First claim

What is claimed:

1. A compound of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof,

wherein
R 1 is H or halo;
R 6 is a member selected from the group consisting of: H, halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 alkoxy, —C 1-5 haloalkoxy, and —CN;
Z 1 and Z 2 are independently C or N;
wherein only one Z 1 or Z 2 may be N;
(A) when Z 1 and Z 2 are C; then
R 2 is a member selected from the group consisting of: -halo, —C 1-5 haloalkoxy, —C 1-5 haloalkyl, —CN, and —CH 2 CN;
R 3 is a member selected from the group consisting of: H, halo, —C 1-5 alkyl, —CN, and —CH 2 CN;
R 4 is a member selected from the group consisting of: H, halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —CN, and —CO 2 C 1-5 alkyl; and
R 5 is a member selected from the group consisting of: halo; —CH═CH 2 ; —C 1-5 haloalkyl; —C 1-5 haloalkoxy; —CH 2 CN; —CH(CH 3 )CN; —C(CH 3 ) 2 CN; —O—CH 2 CN; —CO 2 C 1-5 alkyl; —O-benzyl; —O-cyclopropyl, —O—CH 2 -cyclopropyl; —O-azetidine substituted with —CO 2 tBu; —O-thiazole, cyclopropyl substituted with —CN; -cyclobutyl substituted with —CN; phenyl; phenyl substituted with —F, —CN, or —OCH 3 ; cyclopropyl, pyridyl; pyridyl substituted with —F, —OCH 3 or —CF 3 ; 1-(2-methoxyethyl)pyrazol-4-yl; 3,5-dimethylisoxazol-4-yl; 2-isopropylpyrazol-3-yl; 1H-pyrazol-4-yl; 1,5-dimethylpyrazol-4-yl); pyrimidin-5-yl; —NHCH 2 -furyl; —O—CH 2 cyclopropyl substituted with two —F; and 1-methylpyrazol-4-yl;

(B) when Z 1 and Z 2 are C and R 2 is C 1-5 alkyl; then
R 3 is selected from the group consisting of: H, —C 1-5 haloalkyl, —CN, and —CO 2 C 1-5 alkyl;
R 4 is selected from the group consisting of: H, halo, —CN, and —CO 2 C 1-5 alkyl; and
R 5 is selected from the group consisting of: H, halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 alkoxy, —C 1-5 haloalkoxy, —CN, —CO 2 C 1-5 alkyl, phenyl, 4-fluorophenyl, and 2-fluorophenyl;

(C) when Z 1 and Z 2 are C and R 2 is —C 1-5 alkoxy; then
R 3 is selected from the group consisting of: H, halo, and —CO 2 C 1-5 alkyl;
R 4 is selected from the group consisting of: H, halo, —C 1-5 alkyl, and —C 1-5 haloalkyl; and
R 5 is selected from the group consisting of: halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 haloalkoxy, quinolinyl, —O-benzyl, and —O—CH 2 -phenyl substituted with —F;

(D) when Z 1 and Z 2 are C and R 5 is H; then
R 2 is selected from the group consisting of: halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 alkoxy, —C 1-5 haloalkoxy, —CH 2 (C═O)NH(CH 3 ), and —CN;
R 3 is selected from the group consisting of: halo, —CN, —CH 2 CN, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 alkoxy, —C 1-5 haloalkoxy, —CO 2 C 1-5 alkyl, piperidine substituted with —OCH 3 , —O-azetidine substituted with —CO 2 tBu, —O—CH 2 cyclopropyl substituted with two —F, and —O-cyclopropyl; and
R 4 is selected from the group consisting of: H, halo, —CN, —C 1-5 alkyl, —C 1-5 haloalkyl, and —CO 2 C 1-5 alkyl;

(E) when one of Z 1 or Z 2 is N;
R 2 is a member selected from the group consisting of: halo, —C 1-5 alkyl, and —C 1-5 alkoxy;
R 3 is H or —C 1-5 haloalkyl; and
R 4 is a member selected from the group consisting of: H and —C 1-5 haloalkoxy;
R 5 is a member selected from the group consisting of: —C 1-5 alkyl, —C 1-5 haloalkoxy, and -halo; and
wherein when Z 1 is N, R 3 is absent;

or
(F) when Z 1 and Z 2 are C, and R 3 and R 5 are H; then
R 2 is a member selected from the group consisting of: halo, —C 1-5 alkyl and —C 1-5 alkoxy; and
R 4 is a member selected from the group consisting of: halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —CN and —CO 2 C 1-5 alkyl.

2. The compound of claim 1 , wherein R 1 is H.

3. The compound of claim 1 , wherein R 1 is halo.

4. The compound of claim 1 , wherein R 1 is —Br or —F.

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

6. The compound of claim 1 , wherein R 6 is H, halo, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , and —CN.

7. The compound of claim 1 , wherein R 1 and R 6 are H.

8. The compound of claim 1 , wherein Z 1 and Z 2 are C and R 2 , R 3 , R 4 , and R 5 are defined according to (A) of claim 1 .

9. The compound of claim 1 , wherein Z 1 and Z 2 are C and R 2 , R 4 , and R 5 are defined according to (A) of claim 1 , and R 3 is H, —Cl, —CN, —CH 3 , or —CH 2 CN.

10. The compound of claim 1 , wherein Z 1 and Z 2 are C, R 2 , R 4 , and R 5 are defined according to (A) of claim 1 , and R 3 is H, —CN.

11. The compound of claim 1 , wherein Z 1 and Z 2 are C, R 2 and R 3 are defined according to (A) of claim 1 , and R 5 is —Cl, —Br, —F, —CH 2 CN, —CH(CH 3 )CN, —OCF 2 H, —OCF 3 , —CH═CH 2 , —O—CH 2 CF 3 , —O—CH 2 CF 2 H, —OCH(CH 3 )CF 3 , —CF 3 , —O-benzyl, —CO 2 CH 3 , —OCH 2 CN, cyclopropyl, phenyl,

12. The compound of claim 1 , wherein Z 1 and Z 2 are C, R 2 and R 3 , are defined according to (A) of claim 1 , and R 5 is —Cl, —Br, —F, —CH 2 CN, —CH(CH 3 )CN, —OCF 2 H, or —OCF 3 .

13. The compound of claim 1 , wherein Z 1 and Z 2 are C, and R 2 , R 3 , R 4 , and R 5 are defined according to (B) of claim 1 .

14. The compound of claim 1 , wherein Z 1 and Z 2 are C and R 2 , R 3 , R 4 , and R 5 are defined according to (C) of claim 1 .

15. The compound of claim 1 , wherein Z 1 and Z 2 are C and R 2 , R 3 , R 4 , and R 5 are defined according to (D) of claim 1 .

16. The compound of claim 1 , wherein Z 1 is N, Z 2 is C, and R 2 , R 4 , and R 5 are defined according to (E) of claim 1 .

17. The compound of claim 1 , wherein Z 1 is C, Z 2 is N, and R 2 , R 4 , and R 5 are defined according to (E) of claim 1 .

18. The compound of claim 1 , wherein Z 2 is C, Z 1 is N, R 4 is H, R 5 is defined according to (E) of claim 1 , and R 2 is —Cl, —OCH 3 , or —CH 3 .

19. The compound of claim 14 , wherein R 6 is —H, —F, or —CH 3 .

20. The compound of claim 1 , as defined in (A), having the structure of Formula (II), and pharmaceutically acceptable salts, N-oxides, or solvates thereof,

wherein
R 2 is halo, —C 1-5 haloalkoxy or —CN; and
R 5 is halo, —CH 2 CN, or —C(CH 3 ) 2 CN.

21. The compound of claim 1 , as defined in (B), having the structure of Formula (II), and pharmaceutically acceptable salts, N-oxides, or solvates thereof,

wherein
R 2 is —C 1-5 alkyl; and
R 5 is halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 haloalkoxy or —CN.

22. The compound of claim 1 , as defined in (C), having the structure of Formula (II), and pharmaceutically acceptable salts, N-oxides, or solvates thereof,

R 2 is —C 1-5 alkoxy; and
R 5 is —C 1-5 haloalkoxy.

23. A compound of claim 1 having the structure of Formula (III), and pharmaceutically acceptable salts, N-oxides, or solvates thereof,

wherein

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Ameriks Michael K
• Ravula Suchitra
• Savall Bradley M
• Swanson Devin M
• Ziff Jeannie M
• Shireman Brock T

Classifications

• A61P23/00

  Anaesthetics · CPC title

• A61P25/24

  Antidepressants · CPC title

• C07D417/12

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

• C07D403/12

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

• A61K31/404

  Indoles, e.g. pindolol · CPC title