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

Patent metadata

Field	Value
Publication number	US-11447453-B2
Application number	US-202016817209-A
Country	US
Kind code	B2
Filing date	Mar 12, 2020
Priority date	Jun 10, 2014
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

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 (I):

wherein:
ring

is thiazolyl, thiadiazolyl, or triazolyl;
ring

is an aryl ring or heteroaryl ring;
R 1 is —CO 2 H, —CN, —C(O)NHOH, —C(O)NHOMe, —C(O)NHSO 2 Me, —NHC(O)Me, —C(O)NHMe,

each R 2 is independently halogen, —OR 5 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl;
each R 3 is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
each R 4 is independently halogen, —OR 5 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
or two R 4 taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 2 -C 8 heterocycloalkyl;
each R 5 is independently hydrogen, or substituted or unsubstituted C1-C6alkyl;
n is 0, 1, 2, or 3;
m is 0 or 1; and
p is 0, 1, 2, or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring

is thiazolyl, or thiadiazolyl.

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

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

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

wherein R 3 is substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted aryl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted phenyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring

is a phenyl ring.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring

is a heteroaryl ring.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
ring

is furanyl, thiophenyl, benzofuranyl, benzothiophenyl, or pyridinyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1 and R 4 is halogen, —CF 3 , or —OCH 3 .

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

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

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 2 is F.

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

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CO 2 H.

16. A compound of having the structure:

or a pharmaceutically acceptable salt thereof.

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

18. 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 1 , thereby treating the disorder.

19. The method of claim 18 , wherein the central nervous disorder is depression, treatment resistant depression (TRD), schizophrenia, anxiety, insomnia, psychosis, epilepsy, traumatic brain injury (TBI), bipolar disorder, post traumatic stress disorder (PTSD), neurogenesis, addictive disorder, or neurogenerative diseases.

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

• A61K31/426

  1,3-Thiazoles · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D271/06

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title

• C07D233/64

  with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine · CPC title