MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

1. A compound having a structure represented by a formula:

wherein A is selected from O or S;

wherein R 1 is pyridine, pyrimidine, thiazole, furan, thiophene, or pyrazine, optionally substituted with one or more R 8 , aryl, or a 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 8 ;

wherein R 4 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl optionally substituted with one or more R 7 ;

wherein R 4 and R 5 may cyclize to form a 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 8 ;

wherein R 5 is selected from: H, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl optionally substituted with one or more R 8 ;

wherein R 5 and R 6 may cyclize to form a 3-7 membered ring containing C, O, S or N, optionally substituted with one or more R 8 ;

wherein R 6 is selected from: H, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl optionally substituted with one or more R 8 , R 5 and R 6 may cyclize to form a 3-7 membered ring containing C, O, S or N, optionally substituted with one or more R 7 ;

wherein R 7 is selected from: H, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, OC 1-6 alkyl , aryl, heteroaryl, CN or CF 3 ; and

wherein R 8 is selected from OH, NR 1 R 2 , halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, OC 1-6 alkyl, CF 3 , or

a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , where R 1 is pyridine, optionally substituted with at least one fluoro, chloro and/or methoxy.

3. A compound of claim 1 , where R 1 is furan, optionally chloro-substituted.

4. A compound of claim 1 , where R 6 is methyl.

5. A compound of claim 1 , where R 4 is hydrogen, methyl, alkyl.

6. A compound of claim 1 , where R 7 is chloro, CF 3 , alkoxy.

7. A compound of claim 1 , where R 5 and R 6 are independently hydrogen, alkyl, cyclohexyl, methyl.

8. A compound of claim 7 , wherein R 5 is ethyl benzyl, tert-butyl carboxylate, acetyl, tert-butyl acetyl, furan acetyl.

9. A compound of claim 1 , where R 4 and R 5 cyclize to form a substituted or unsubstituted 5 or 6 membered ring.

10. A compound of claim 1 , where R 5 and R 6 cyclize to form a substituted or unsubstituted 5, 6, 7, or 8 membered ring.

11. A compound of claim 1 , having a structure represented by a formula:

12. A compound of claim 1 , having a structure represented by a formula:

wherein R 9 is C, O, S, SO 2 , SO 2 —C.

13. A compound of claim 1 , of the following formula, or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure represented by a formula:

wherein A is selected from O or S;

wherein R 1 is pyridine, pyrimidine, thiazole, furan, thiophene, pyrazine, optionally substituted with one or more R 8 , aryl, or a 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 8 ;

wherein R 4 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl optionally substituted with one or more R 7 ;

wherein R 4 and R 5 may cyclize to form a 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 8 ;

wherein R 5 is selected from: H, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl optionally substituted with one or more R 8 ;

wherein R 5 and R 6 may cyclize to form a 3-7 membered ring containing C, O, S or N, optionally substituted with one or more R 8 ;

wherein R 6 is selected from: H, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl optionally substituted with one or more R 8 , R 5 and R 6 may cyclize to form a 3-7 membered ring containing C, O, S or N, optionally substituted with one or more R 7 ;

wherein R 7 is selected from: H, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, OC 1-6 alkyl , aryl, heteroaryl, CN or CF 3 ; and

wherein R 8 is selected from OH, NR 1 R 2 , halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, OC 1-6 alkyl, CF 3 , or

a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

15. A composition of claim 14 , where R 1 is pyridine, optionally substituted with at least one fluoro, chloro and/or methoxy.

16. A composition of claim 14 , where R 1 is furan, optionally chloro-substituted.

17. A composition of claim 14 , where R 6 is methyl.

18. A composition of claim 14 , where R 4 is hydrogen, methyl, alkyl.

19. A composition of claim 14 , where R 7 is chloro, CF 3 , alkoxy.

20. A composition of claim 14 , where R 5 and R 6 are independently hydrogen, alkyl, cyclohexyl, methyl.

21. A composition of claim 14 , where R 4 and R 5 cyclize to form a substituted or unsubstituted 5 or 6 membered ring.

22. A composition of claim 14 , where R 5 and R 6 cyclize to form a substituted or unsubstituted 5, 6, 7,or 8 membered ring.

23. A composition of claim 14 , having a structure represented by a formula:

24. A composition of claim 14 , having a structure represented by a formula:

wherein R 9 is C, O, S, SO 2 , SO 2 —C.

25. A composition of claim 14 , of the following formula, or a pharmaceutically acceptable salt thereof:

26. A compound of claim 1 , of the following formula:

27. A compound of claim 11 , wherein R 7 is H or Cl.

28. A compound of claim 12 , wherein R 7 is H or Cl.

29. A compound of claim 11 , wherein R 4 is H or CH 3 ; R 7 is H or Cl; R 6 is CH 3 ; R 5 is C 1 alkyl substituted with R 8 ; and R 8 is cycloalkyl.

30. A compound of claim 29 , wherein the cycloalkyl is substituted with fluorine.

31. A compound of claim 11 , wherein R 5 is chosen from:

32. A composition of 14, wherein the compound is chosen from:

33. A composition of claim 23 , wherein R 7 is H or Cl.

34. A composition of claim 24 , wherein R 7 is H or Cl; and R 1 is pyridine.

35. A composition of claim 23 , wherein R 7 is H or Cl; R 6 is CH 3 ; R 5 is C 1 alkyl substituted with R 8 ; and R 8 is cycloalkyl.

36. A composition of claim 34 , wherein the cycloalkyl is substituted with fluorine.

37. A composition of claim 23 , wherein R 5 is chosen from:

38. A compound of claim 1 , having a structure represented by a formula:

wherein R 4 and R 5 cyclize to form a 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 8 ;

wherein R 6 is selected from: H, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl optionally substituted with one or more R 8 ; and

wherein R 8 , when present, is selected from OH, NR 1 R 2 , halogen, C 1-6 alkyl, C 3-10 cycloalkyl, CN, OC 1-6 alkyl, or CF 3 and

wherein W, X, Y, and Z are C or CH; R 7 is H or halogen; A is O; and R 1 is pyridine.

39. The compound of claim 1 , wherein R 8 is —NH 2 , —NHalkyl, or —NHcycloalkyl.

40. The composition of claim 14 , wherein R 8 is —NH 2 , —NHalkyl, or —NHcycloalkyl.