IP Library › Granted Patent US 11,633,395

Granted Patent B2

US 11,633,395 · App. 16/764,962 · Granted Apr 25, 2023

Substituted pyrazolo[1,5-a]pyrazines as negative allosteric modulators of group II metabotropic glutamate receptor

Inventors: Yohei Ikuma (Osaka, JP); Kengo Tojo (Osaka, JP); Ryo Fukazawa (Osaka, JP); Shuji Masumoto (Osaka, JP)

Assignee: SUMITOMO PHARMA CO., LTD.

A61K31/4985 A61P25/28 C07D519/00

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 11,633,395
App. No.: 16/764,962
Granted: Apr 25, 2023
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Provided are a compound that is useful for the prevention of and/or as a treatment agent for a disease in which a group II mGlu receptor is involved; and a medical application of said compound. Provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Claims (220)

1. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof,

wherein:

Ring A is a saturated 4- to 10-membered heterocyclyl, C 6-10 aromatic carbocyclyl, or 5- to 10-membered aromatic heterocyclyl;

X is CR e or N;

R 1 is H, halogen, CN, C 1-4 alkyl, or a saturated C 3-6 carbocyclyl;

wherein the C 1-4 alkyl or saturated C 3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy;

R 2 is H, halogen, CN, C 1-4 alkyl, or a saturated C 3-6 carbocyclyl;

wherein the C 1-4 alkyl or saturated C 3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; or

R 1 and R 2 , taken together with the carbon atom to which they are attached, form a saturated C 3-4 carbocyclyl;

wherein the saturated C 3-4 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy;

R 3 is H, halogen, CN, C 1-6 alkyl, C 2-4 alkenyl, OH, C 1-4 alkoxy, C 1-4 alkylthio, a saturated C 3-6 carbocyclyl, C 3-6 cycloalkoxy, a saturated 4- to 6-membered heterocyclyl, or a 5- or 6-membered aromatic heterocyclyl;

wherein the C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, saturated 4- to 6-membered heterocyclyl, or 5- or 6-membered aromatic heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and

wherein the saturated C 3-6 carbocyclyl or C 3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and C 1-4 alkyl;

R 4 is H, halogen, CN, C 1-6 alkyl, C 2-4 alkenyl, OH, C 1-4 alkoxy, C 1-4 alkylthio, a saturated C 3-6 carbocyclyl, C 3-6 cycloalkoxy, a saturated 4- to 6-membered heterocyclyl, or a 5- or 6-membered aromatic heterocyclyl;

wherein the saturated C 3-6 carbocyclyl or C 3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and C 1-4 alkyl;

R 5 is H, halogen, CN, CH 2 C(O)NR a R b , C 1-6 alkyl, C(O)R d , C(O)NR a R b , C(O)OR d , NR a R b , NR d C(O)R c , NR d C(O)NR a R b , NR d C(O)OR c , NR d S(O) 2 R c , OH, C 1-6 alkoxy, C 1-6 alkylthio, a saturated C 3-6 carbocyclyl, C 3-6 cycloalkoxy, or a saturated 4- to 6-membered heterocyclyl;

wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or saturated 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy;

wherein the C 3-6 cycloalkoxy or saturated C 3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, OH, and C 1-4 alkoxy; and

wherein each C 1-4 alkoxy substituent of the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, saturated C 3-6 carbocyclyl, C 3-6 cycloalkoxy, or saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;

R 6 is H, halogen, CN, CH 2 C(O)NR a R b , C 1-6 alkyl, C(O)R d , C(O)NR a R b , C(O)OR d , NR a R b , NR d C(O)R c , NR d C(O)NR a R b , NR d C(O)OR c , NR d S(O) 2 R c , OH, C 1-6 alkoxy, C 1-6 alkylthio, a saturated C 3-6 carbocyclyl, C 3-6 cycloalkoxy, or a saturated 4- to 6-membered heterocyclyl;

each R a is independently H, C 1-4 alkyl, a saturated C 3-6 carbocyclyl, or a saturated 4- to 6-membered heterocyclyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; and

wherein each saturated C 3-6 carbocyclyl and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, OH, and C 1-4 alkoxy;

each R b is independently H, C 1-4 alkyl, a saturated C 3-6 carbocyclyl, or a saturated 4- to 6-membered heterocyclyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; and

each R a and R b , taken together with the nitrogen atom to which they are attached, independently forms a saturated 4- to 6-membered heterocyclyl;

wherein each saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, OH, and C 1-4 alkoxy;

each R c is independently C 1-4 alkyl, a saturated C 3-6 carbocyclyl, or a saturated 4- to 6-membered heterocyclyl;

wherein each C 1-4 alkyl, saturated C 3-6 carbocyclyl, and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy;

each R d is independently H, C 1-4 alkyl, a saturated C 3-6 carbocyclyl, or a saturated 4- to 6-membered heterocyclyl;

R e is H, halogen, CN, C 1-6 alkyl, or C 1-6 alkoxy;

wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is chromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-benzodioxolyl, phenyl, 2,3-dihydro-1H-indenyl, naphthalenyl, thiophenyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolizinyl, imidazopyridinyl, benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one moiety has (S)-configuration at the 7-position.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H or C 1-4 alkyl;

wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; and

R 2 is H or C 1-4 alkyl;

wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; or

R 1 and R 2 , taken together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is H, halogen, CN, C 1-4 alkyl, OH, C 1-4 alkoxy, C 1-4 alkylthio, or C 3-6 cycloalkoxy;

wherein the C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkylthio is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and

wherein the C 3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and C 1-4 alkyl; and

R 4 is H, halogen, CN, C 1-4 alkyl, OH, C 1-4 alkoxy, C 1-4 alkylthio, or C 3-6 cycloalkoxy;

wherein the C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkylthio is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and

wherein the C 3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and C 1-4 alkyl.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 5 is H, halogen, CN, CH 2 C(O)NR a R b , C 1-4 alkyl, C(O)R d , C(O)NR a R b , C(O)OR d , NR a R b , NR d C(O)R c , NR d C(O)NR a R b , NR d C(O)OR c , NR d S(O) 2 R c , OH, C 1-4 alkoxy, or a saturated 4- to 6-membered heterocyclyl;

wherein the C 1-4 alkyl, C 1-4 alkoxy, or saturated 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; and

wherein each C 1-4 alkoxy substituent of the C 1-4 alkyl, C 1-4 alkoxy, or saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and

R 6 is H, halogen, CN, CH 2 C(O)NR a R b , C 1-4 alkyl, C(O)R d , C(O)NR a R b , C(O)OR d , NR a R b , NR d C(O)R c , NR d C(O)NR a R b , NR d C(O)OR c , NR d S(O) 2 R c , OH, C 1-4 alkoxy, or a saturated 4- to 6-membered heterocyclyl;

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

each R a is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; and

each R b is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; or

each R a and R b , taken together with the nitrogen atom to which they are attached, independently forms a saturated 4- to 6-membered heterocyclyl;

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R c is independently C 1-4 alkyl or a saturated C 3-6 carbocyclyl;

wherein each C 1-4 alkyl and saturated C 3-6 carbocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R d is independently H, C 1-4 alkyl, or a saturated C 3-6 carbocyclyl;

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R e is H, halogen, or C 1-4 alkyl;

wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

Ring A is chromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-benzodioxolyl, phenyl, 2,3-dihydro-1H-indenyl, naphthalenyl, thiophenyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolizinyl, imidazopyridinyl, benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl;

R 1 is H or C 1-4 alkyl;

wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy;

R 2 is H or C 1-4 alkyl;

wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; or

R 1 and R 2 , taken together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl;

R 3 is H, halogen, CN, C 1-4 alkyl, OH, C 1-4 alkoxy, C 1-4 alkylthio, or C 3-6 cycloalkoxy;

wherein the C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkylthio is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and

wherein the C 3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and C 1-4 alkyl;

R 4 is H, halogen, CN, C 1-4 alkyl, OH, C 1-4 alkoxy, C 1-4 alkylthio, or C 3-6 cycloalkoxy;

wherein the C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkylthio is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and

wherein the C 3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and C 1-4 alkyl;

each R a is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; and

each R b is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; or

each R a and R b , taken together with the nitrogen atom to which they are attached, independently forms a saturated 4- to 6-membered heterocyclyl;

each R c is independently C 1-4 alkyl or a saturated C 3-6 carbocyclyl;

each R d is independently H, C 1-4 alkyl, or a saturated C 3-6 carbocyclyl;

R e is H, halogen, or C 1-4 alkyl;

wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

12. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein Ring A is 1,3-benzodioxolyl, phenyl, thiophenyl, pyridinyl, or quinolinyl.

13. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, CH 3 , CHF 2 , CF 3 , CH 2 OH, CH 2 OCH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or cyclopropyl; and

R 2 is H, CH 3 , CHF 2 , CF 3 , CH 2 OH, CH 2 OCH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or cyclopropyl; or

R 1 and R 2 , taken together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl.

14. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is H, halogen, CN, C 1-4 alkyl, or C 1-4 alkoxy;

wherein the C 1-4 alkyl or C 1-4 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and

R 4 is H, halogen, CN, C 1-4 alkyl, or C 1-4 alkoxy;

wherein the C 1-4 alkyl or C 1-4 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

15. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

R 5 is H, halogen, CN, C 1-4 alkyl, NR a R b , OH, C 1-4 alkoxy, or a saturated 4- to 6-membered heterocyclyl;

R 6 is H, halogen, CN, C 1-4 alkyl, NR a R b , OH, C 1-4 alkoxy, or a saturated 4- to 6-membered heterocyclyl;

16. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

each R a is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy; and

each R b is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy.

17. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein each R c is independently C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

18. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein each R d is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

19. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein R e is H, F, or C 1-4 alkyl;

wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

20. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

Ring A is 1,3-benzodioxolyl, phenyl, thiophenyl, pyridinyl, or quinolinyl;

R 1 is H, CH 3 , CHF 2 , CF 3 , CH 2 OH, CH 2 OCH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or cyclopropyl;

R 2 is H, CH 3 , CHF 2 , CF 3 , CH 2 OH, CH 2 OCH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or cyclopropyl; or

R 1 and R 2 , taken together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl;

R 3 is H, halogen, CN, C 1-4 alkyl, or C 1-4 alkoxy;

wherein the C 1-4 alkyl or C 1-4 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;

R 4 is H, halogen, CN, C 1-4 alkyl, or C 1-4 alkoxy;

wherein the C 1-4 alkyl or C 1-4 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;

R 5 is H, halogen, CN, C 1-4 alkyl, NR a R b , OH, C 1-4 alkoxy, or a saturated 4- to 6-membered heterocyclyl;

R 6 is H, halogen, CN, C 1-4 alkyl, NR a R b , OH, C 1-4 alkoxy, or a saturated 4- to 6-membered heterocyclyl;

each R a is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy;

each R b is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and C 1-4 alkoxy;

each R c is independently C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;

each R d is independently H or C 1-4 alkyl;

wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and

R e is H, F, or C 1-4 alkyl;

wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

21. The compound according to claim 1 , wherein the compound is of the following formula:

or a pharmaceutically acceptable salt thereof,

wherein:

X is CH or N;

R 3 is H, F, Cl, CHF 2 , CF 3 , or OCHF 2 ;

R 4 is H, F, Cl, CHF 2 , CF 3 , or OCHF 2 ;

R 5 is H or NH 2 ; and

R 6 is H or NH 2 .

22. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition according to claim 24 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 3 , or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical composition according to claim 26 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 11 , or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition according to claim 28 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 20 , or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition according to claim 30 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

32. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 21 , or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition according to claim 32 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 22 , or a pharmaceutically acceptable salt thereof.

35. The pharmaceutical composition according to claim 34 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 23 , or a pharmaceutically acceptable salt thereof.

37. The pharmaceutical composition according to claim 36 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.

38. A method for negatively modulating allosteric activity of a Group II metabotropic glutamate receptor in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

39. The method according to claim 38 , wherein the Group II metabotropic glutamate receptor is metabotropic glutamate receptor subtype 2.

40. The method according to claim 38 , wherein the patient has a disease involving a Group II metabotropic glutamate receptor selected from the group consisting of a neurodegenerative disease and a psychiatric disease.

41. The method according to claim 40 , wherein the neurodegenerative disease or psychiatric disease is selected from the group consisting of acute stress disorder, Alzheimer's disease, anxiety disorder, autism spectrum disorder, bipolar disorder, a bipolar-related disorder, cognitive dysfunction, dementia, depressive disorder, drug dependence, major depressive disorder, obesity, obsessive-compulsive disorder, pain, posttraumatic stress disorder, schizophrenia, seizure, sleep disorder, and tremor.

42. The method according to claim 38 , wherein the method further comprises administering to the patient at least one additional therapeutic agent.

43. The method according to claim 38 , wherein the method further comprises administering to the patient at least one antipsychotic drug.

44. A method for negatively modulating allosteric activity of a Group II metabotropic glutamate receptor in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound according to claim 3 , or a pharmaceutically acceptable salt thereof.

45. The method according to claim 44 , wherein the Group II metabotropic glutamate receptor is metabotropic glutamate receptor subtype 2.

46. The method according to claim 44 , wherein the patient has a disease involving a Group II metabotropic glutamate receptor selected from the group consisting of a neurodegenerative disease and a psychiatric disease.

47. The method according to claim 46 , wherein the neurodegenerative disease or psychiatric disease is selected from the group consisting of acute stress disorder, Alzheimer's disease, anxiety disorder, autism spectrum disorder, bipolar disorder, a bipolar-related disorder, cognitive dysfunction, dementia, depressive disorder, drug dependence, major depressive disorder, obesity, obsessive-compulsive disorder, pain, posttraumatic stress disorder, schizophrenia, seizure, sleep disorder, and tremor.

48. The method according to claim 44 , wherein the method further comprises administering to the patient at least one antipsychotic drug.

49. A method for negatively modulating allosteric activity of a Group II metabotropic glutamate receptor in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound according to claim 11 , or a pharmaceutically acceptable salt thereof.

50. The method according to claim 49 , wherein the Group II metabotropic glutamate receptor is metabotropic glutamate receptor subtype 2.

51. The method according to claim 49 , wherein the patient has a disease involving a Group II metabotropic glutamate receptor selected from the group consisting of a neurodegenerative disease and a psychiatric disease.

52. The method according to claim 51 , wherein the neurodegenerative disease or psychiatric disease is selected from the group consisting of acute stress disorder, Alzheimer's disease, anxiety disorder, autism spectrum disorder, bipolar disorder, a bipolar-related disorder, cognitive dysfunction, dementia, depressive disorder, drug dependence, major depressive disorder, obesity, obsessive-compulsive disorder, pain, posttraumatic stress disorder, schizophrenia, seizure, sleep disorder, and tremor.

53. The method according to claim 49 , wherein the method further comprises administering to the patient at least one antipsychotic drug.

54. A method for negatively modulating allosteric activity of a Group II metabotropic glutamate receptor in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound according to claim 20 , or a pharmaceutically acceptable salt thereof.

55. The method according to claim 54 , wherein the Group II metabotropic glutamate receptor is metabotropic glutamate receptor subtype 2.

56. The method according to claim 54 , wherein the patient has a disease involving a Group II metabotropic glutamate receptor selected from the group consisting of a neurodegenerative disease and a psychiatric disease.

57. The method according to claim 56 , wherein the neurodegenerative disease or psychiatric disease is selected from the group consisting of acute stress disorder, Alzheimer's disease, anxiety disorder, autism spectrum disorder, bipolar disorder, a bipolar-related disorder, cognitive dysfunction, dementia, depressive disorder, drug dependence, major depressive disorder, obesity, obsessive-compulsive disorder, pain, posttraumatic stress disorder, schizophrenia, seizure, sleep disorder, and tremor.

58. The method according to claim 54 , wherein the method further comprises administering to the patient at least one antipsychotic drug.

59. A method for negatively modulating allosteric activity of a Group II metabotropic glutamate receptor in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound according to claim 21 , or a pharmaceutically acceptable salt thereof.

60. The method according to claim 59 , wherein the Group II metabotropic glutamate receptor is metabotropic glutamate receptor subtype 2.

61. The method according to claim 59 , wherein the patient has a disease involving a Group II metabotropic glutamate receptor selected from the group consisting of a neurodegenerative disease and a psychiatric disease.

62. The method according to claim 61 , wherein the neurodegenerative disease or psychiatric disease is selected from the group consisting of acute stress disorder, Alzheimer's disease, anxiety disorder, autism spectrum disorder, bipolar disorder, a bipolar-related disorder, cognitive dysfunction, dementia, depressive disorder, drug dependence, major depressive disorder, obesity, obsessive-compulsive disorder, pain, posttraumatic stress disorder, schizophrenia, seizure, sleep disorder, and tremor.

63. The method according to claim 59 , wherein the method further comprises administering to the patient at least one antipsychotic drug.

64. A method for negatively modulating allosteric activity of a Group II metabotropic glutamate receptor in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound according to claim 22 , or a pharmaceutically acceptable salt thereof.

65. The method according to claim 64 , wherein the Group II metabotropic glutamate receptor is metabotropic glutamate receptor subtype 2.

66. The method according to claim 64 , wherein the patient has a disease involving a Group II metabotropic glutamate receptor selected from the group consisting of a neurodegenerative disease and a psychiatric disease.

67. The method according to claim 66 , wherein the neurodegenerative disease or psychiatric disease is selected from the group consisting of acute stress disorder, Alzheimer's disease, anxiety disorder, autism spectrum disorder, bipolar disorder, a bipolar-related disorder, cognitive dysfunction, dementia, depressive disorder, drug dependence, major depressive disorder, obesity, obsessive-compulsive disorder, pain, posttraumatic stress disorder, schizophrenia, seizure, sleep disorder, and tremor.

68. The method according to claim 64 , wherein the method further comprises administering to the patient at least one antipsychotic drug.

69. A method for negatively modulating allosteric activity of a Group II metabotropic glutamate receptor in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of the compound according to claim 23 , or a pharmaceutically acceptable salt thereof.

70. The method according to claim 69 , wherein the Group II metabotropic glutamate receptor is metabotropic glutamate receptor subtype 2.

71. The method according to claim 69 , wherein the patient has a disease involving a Group II metabotropic glutamate receptor selected from the group consisting of a neurodegenerative disease and a psychiatric disease.

72. The method according to claim 71 , wherein the neurodegenerative disease or psychiatric disease is selected from the group consisting of acute stress disorder, Alzheimer's disease, anxiety disorder, autism spectrum disorder, bipolar disorder, a bipolar-related disorder, cognitive dysfunction, dementia, depressive disorder, drug dependence, major depressive disorder, obesity, obsessive-compulsive disorder, pain, posttraumatic stress disorder, schizophrenia, seizure, sleep disorder, and tremor.

73. The method according to claim 69 , wherein the method further comprises administering to the patient at least one antipsychotic drug.

Assignments (2)

CHANGE OF NAME Recorded Jun 3, 2022

From: SUMITOMO DAINIPPON PHARMA CO., LTD.

To: SUMITOMO PHARMA CO., LTD.

Reel/Frame 060096/0689 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 18, 2020

From: TOJO, KENGO; FUKAZAWA, RYO; MASUMOTO, SHUJI; IKUMA, YOHEI

To: SUMITOMO DAINIPPON PHARMA CO., LTD.

Reel/Frame 053526/0009 →