Modulators of the NMDA receptor

Patent metadata

Field	Value
Publication number	US-11466027-B2
Application number	US-202016916769-A
Country	US
Kind code	B2
Filing date	Jun 30, 2020
Priority date	Jul 3, 2019
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The present invention is directed to novel modulators of the NMDA receptor. Separate aspects of the inventions are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat neurological disorders or neuropsychiatric disorders such as depression.

First claim

The invention claimed is:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of a hydrogen, halogen, C 1-4 haloalkyl, cyano, C 3-6 cycloalkyl, and C 1-4 alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, C 1-4 haloalkyl, cyano, C 3-6 cycloalkyl, and C 1-4 alkyl;
R 3 is selected from the group consisting of hydrogen, halogen, C 1-4 haloalkyl, cyano, C 3-6 cycloalkyl, and C 1-4 alkyl;
R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 hydroxyhaloalkyl, cyano, OR 6 , L-(OR 6 ), and R 7 ;
R 6 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and C 1-4 hydroxyhaloalkyl;
L represents a C 1-3 alkylene; and
R 7 is selected from the group consisting of C 3-6 cycloalkyl, phenyl, 4, 5, or 6 membered heterocycle, and 5 or 6 membered heteroaryl, wherein said cycloalkyl, phenyl, heterocycle or heteroaryl are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-3 alkyl, and C 1-3 alkoxy, wherein said C 1-3 alkyl and C 1-3 alkoxy are independently unsubstituted or substituted with 1, 2 or 3 F.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of a hydrogen, halogen, and C 1-4 alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl;
R 3 is selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl;
R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, OR 6 , and R 7 ;
R 6 is selected from the group consisting of C 1-4 alkyl, and C 1-4 haloalkyl; and
R 7 is selected from the group consisting of a C 3-6 cycloalkyl and phenyl, wherein said cycloalkyl and phenyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, wherein said C 1-3 alkyl and C 1-3 alkoxy are independently unsubstituted or substituted with 1, 2 or 3 F.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl, and halogen.

6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of hydrogen, fluoro, and methyl.

7. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are hydrogen.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 alkyl.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 fluoroalkyl.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl unsubstituted or substituted with C 1-3 alkyl.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 alkoxy.

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, halogen, and phenyl unsubstituted or substituted with ethyl.

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, isopropoxy, ethoxy, methoxy, cyclopropyl, fluoro, bromo, and ethylphenyl.

17. The compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , selected from the group consisting of:
(R)-2-amino-3-[[7-thieno[3,2-b]pyridine-2-carbonyl]amino]propanoic acid;
(R)-2-amino-3-[(7-ethylthieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[[7-(difluoromethyl)thieno[3,2-b]pyridine-2-carbonyl]amino]propanoic acid;
(R)-2-amino-3-[(7-cyclopropylthieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[(7-methylthieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[(7-isopropylthieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[[7-(2-ethylphenyl)thieno[3,2-b]pyridine-2-carbonyl]amino]propanoic acid;
(R)-2-amino-3-[(7-methoxythieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[[7-(trifluoromethyl)thieno[3,2-b]pyridine-2-carbonyl]amino]propanoic acid;
(R)-2-amino-3-[(7-ethoxythieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[(7-isopropoxythieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[(7-bromothieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[(7-hydroxymethylthieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid;
(R)-2-amino-3-[[7-(fluoromethyl)thieno[3,2-b]pyridine-2-carbonyl]amino]propanoic acid;
(R)-2-amino-3-[(6-fluoro-7-methyl-thieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid; and
(R)-2-amino-3-[(6,7-dimethylthieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid; or a pharmaceutically acceptable salt thereof.

18. The compound, or a pharmaceutically acceptable salt thereof, according to claim 1 wherein the compound is
(R)-2-amino-3-[(7-methylthieno[3,2-b]pyridine-2-carbonyl)amino]propanoic acid, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , and one or more pharmaceutically acceptable carriers or diluents.

Assignees

• H Lundbeck As

Inventors

• Kilburn John Paul
• Ascic Erhad
• Marigo Mauro
• David Laurent

Classifications

• B60W2510/20

  Steering systems · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P25/24

  Antidepressants · CPC title

• B60W30/06

  Automatic manoeuvring for parking · CPC title

• B62D15/0285 Primary

  Parking performed automatically · CPC title