Metabotropic glutamate receptor negative allosteric modulators (NAMs) and uses thereof

Patent metadata

Field	Value
Publication number	US-10597367-B2
Application number	US-201815950683-A
Country	US
Kind code	B2
Filing date	Apr 11, 2018
Priority date	Jun 10, 2014
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

Abstract

Provided herein are small molecule active metabotropic glutamate subtype-2 and -3 receptor negative allosteric modulators (NAMs), compositions comprising the compounds, and methods of using the compounds and compositions.

First claim

What is claimed is:

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (III):

wherein:
Z is ═N— or ═C(H)—;
R 1 is halogen, —OR 5 , —NO 2 , —CN, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or —CO 2 R 6 ;
each R 2 is independently halogen, —OR 5 , NO 2 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl;
R 3 is —X—R 4 ;
X is —O—, —S—, —S(O) 2 —, —N(R 7 )—, or —C≡C—;
R 4 is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R 5 is independently hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl;
R 6 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
R 7 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
each R 8 is independently halogen or substituted or unsubstituted C 1 -C 6 alkyl;
n is 1, 2, or 3; and
m is 0, 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIIa) or Formula (IIIb):

wherein R 3 is —X—R 4 ; and R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted or unsubstituted heteroaryl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 2 is halogen or —CH 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CF 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof having the structure:

9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient.

10. A method of treating a central nervous disorder (CNS), the method comprising the step of administering to a subject in need thereof, an effective amount of a compound of claim 1 , thereby treating the disorder.

11. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IV):

wherein:
Z is ═N— or ═C(H)—;
R 1 is halogen, —OR 5 , —NO 2 , —CN, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or —CO 2 R 6 ;
R 2 is halogen, —OR 5 , NO 2 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl;
R 3 is halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, unsubstituted heteroaryl, —C(O)NR 9 R 10 , or —X—R 4 ;
X is —O—, —S—, —S(O) 2 —, —N(R 7 )—, or —C≡C—;
R 4 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R 5 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
R 6 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
R 7 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
R 8 is halogen or substituted or unsubstituted C 1 -C 6 alkyl;
R 9 and R 10 are independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
n is 0, 1, 2, or 3; and
m is 0, 1, or 2.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, having the structure of Formula (IVa) or Formula (IVb):

wherein R 3 is halogen, unsubstituted heteroaryl, or —X—R 4 ; and R 4 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

13. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.

14. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted or unsubstituted heteroaryl.

15. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 2 is halogen or —CH 3 .

16. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CF 3 .

17. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein m is 0.

18. The compound of claim 11 , or a pharmaceutically acceptable salt thereof having the structure:

19. A pharmaceutical composition comprising a compound of claim 11 , or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient.

20. A method of treating a central nervous disorder (CNS), the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of claim 11 , thereby treating the disorder.

Assignees

• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Cosford Nicholas David Peter
• Raveendra-Panickar Dhanya
• Sheffler Douglas J
• Hutchinson John Howard
• Gadient Reto Andreas

Classifications

• C07D401/12

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

• C07D285/08

  1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles · CPC title

• C07D409/02

  containing two hetero rings · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• C07D413/04

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