Indazole and azaindazole substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

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

wherein the variables are substituted when permissible or unsubstituted and:

X and Y together form:

Z is N, CH, CD, or C-halogen, C-Me, C—O-Me, C—CN;

R is independently chosen from H, Cl, F, CN, alkyl, cycloalkyl, Me, OMe, alkoxy;

X 1 is N, C, CH, CD, CR 1 ;

X 2 is N, NR 1 , or NR 2 ;

X 3 is N, C, CH, CD, CR 1 ;

provided that one of X 1 or X 3 is C or CR 1 ;

R 1 is independently H, alkyl, cycloalkyl, phenyl, halogen, CF 3 , Cl, CD 3 , CD 2 R, CDRR 2 , aryl, heteroaryl, SO 2 R 3 , O—R, O-aryl, O-heteroaryl, NHR, NR 2 R 2 , perfluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH 2 heteroaryl), alkenyl, alkyl-cycloalkyl, O-alkyl-cycloalkyl, CH 2 -cycloalkyl, CH 2 —CF 3 , hydroxyalkyl, alkyl-alkoxy, alkyl-heterocycloalkyl, alkyl-heteroaryl, alkyl-carboxylic acid, CO—CF 3 , alkyl-CO—O-alkyl, CO-alkyl-sulfonyl-alkyl, CO-heterocycloalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, alkoxy-heterocycloalkyl, O-alkoxy, O-phenyl, O-alkoxyphenyl, O-dioxothianyl, hydroxyl, alkoxy, O-alkyl-heteroaryl, O-alkyl-heterocycloalkyl, alkoxy-heteroalkyl, methyl sulfonyl, O-heterocycloalkyl, O-alkoxy-heterocycloalkyl, O-alkoxyaryl, alkoxy-heteroaryl, alkyl-phenyl, heterocycloalkyl, O—CD 3 , O—CD 2 R, hydroxyl, amino, CO-alkyl, CO-cycloalkyl, CO-alkyl-cycloalkyl, CO-amino-alkyl-sulfonylmethyl, CO-amino-cycloalkyl;

R 2 is independently H, heteroaryl, alkyl, phenyl, aryl, O-heterocycloalkyl, alkoxy-heterocycloalkyl, O-alkoxy-heterocycloalkyl, O-alkoxyaryl, O-heteroaryl, alkoxy-heteroaryl, alkoxy, alkoxy-heterocycloalkyl, alkyl-phenyl, heterocycloalkyl, O—CD 3 , O—CD 2 R, hydroxyl, amino, cycloalkyl, CH 2 -cycloalkyl, CO-alkyl; heterocycloalkyl, H, CF 3 , halogen, CD 3 , CD 2 R, CDRR 2 , SO 2 R 3 , OR, O-aryl, NHR, NR 1 R 1 , perfluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH 2 heteroaryl), alkenyl, alkyl-cycloalkyl, CH 2 -cycloalkyl, CH 2 —CF 3 , hydroxyalkyl, alkyl-alkoxy, alkyl-heterocycloalkyl, alkyl-heteroaryl, O-alkyl-heteroaryl, alkyl-carboxylic acid, CO—CF 3 , alkyl-CO—O-alkyl, CO-alkyl-sulfonyl-alkyl, CO-heterocycloalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, O-dioxothianyl, methyl sulfonyl;

R 3 is H, alkyl, alkoxyphenyl, pyridinyl, nitrilepyridinyl, chloropyridinyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R, when present, is F.

3. The compound of claim 1 , wherein Z is N, CH, CD, or C—Cl.

4. The compound of claim 1 , of the following formula:

5. The compound of claim 1 , of the following formula:

6. The compound of claim 5 , wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein R 1 is H, alkyl, cycloalkyl, heterocycloalkyl, alkyl-cycloalkyl, trifluoroalkyl, hydroxyalkyl, alkyl-alkoxy; and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein R 1 is H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, CO—CF 3 , CD 2 -alkyl, alkyl-heteroaryl, alkyl-cycloalkyl, and R 2 is H, alkyl, cycloalkyl, heterocycloalkyl, alkyl-phenyl.

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

wherein R 1 is H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl; and R 2 is H, alkyl, cycloalkyl, heterocycloalkyl.

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

wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, heteroaryl; and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, heteroaryl; and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein R 1 is H, alkyl, cycloalkyl; and R 2 is H, alkyl, alkyl-cycloalkyl, alkyl-heteroaryl, CD 3 .

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

wherein R is H, Cl, F, CN, alkyl, cycloalkyl, Me, OMe, alkoxy; R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, heteroaryl; and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein Z is N, C—H, C-Me, C—O-Me; R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, CN, methyl sulfonyl, O-alkoxy, O-heterocycloalkyl, heterocycloalkyl, alkoxy-heterocycloalkyl, halogen, and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroaryl, alkyl-acetic acid, heterocycloalkyl, CD 3 .

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

wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkenyl.

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

wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkoxy, alkyl-cycloalkyl, R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, heterocycloalkyl.

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

wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein Z is N, CH, CD, C-halogen, C—O-Me; R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, methylsulfonyl; and R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroaryl, CD 3 .

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

wherein R 1 is O—R, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, CO—CF 3 , alkyl-CO—O-alkyl, CO-alkyl-sulfonyl-alkyl, CO-heterocycloalkyl, CO—NH-cycloalkyl, O-alkoxy, O-phenyl, O-alkoxyphenyl, O-dioxothianyl, O-alkyl-heteroaryl, O-alkyl-heterocycloalkyl, O-heterocycloalkyl, O-alkoxy-heterocycloalkyl, O-alkoxyaryl, O—CD 3 , O—CD 2 R, CO-alkyl, CO-cycloalkyl, CO-alkyl-cycloalkyl, CO-amino-alkyl-sulfonylmethyl, CO-amino-cycloalkyl.

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

wherein R may be optionally present and when present is F; R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkoxy, hydroxyl, cycloalkyl, methysulfonyl; R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroaryl.

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

wherein R may be optionally present and when present is O—Me; R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkyl-heteroaryl; or

a compound of claim 1 , of the following formula:

wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R 2 is alkyl, alkyl-cycloalkyl, alkylheteroaryl.

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

wherein R is F; R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, CD 3 .

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

wherein R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein Y is N or CH; Z is CH, CD, C—Cl, N; R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, alkenyl, CD 3 , alkyl, alkyl-heteroaryl; and R 3 is H, alkyl, cycloalkyl, alkyl-cycloalkyl.

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

wherein Y is N or CH; Z is CH, C—Cl, or N.

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

Z is CH, CD, C—Cl, N; R is optionally and independently present, and when present is H, alkyl, F; R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R 3 is H, alkyl, cycloalkyl, alkyl-cycloalkyl, CD 3 .

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

R 1 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; R 2 is H, alkyl, cycloalkyl, alkyl-cycloalkyl; and R 3 is alkoxy phenyl, pyridinyl, nitrilepyridinyl, chloropyridinyl.

29. A compound of claim 1 , where X 1 is N and R 1 is alkyl, alkenyl, CH2-cycloalkyl, cycloalkyl, CH 2 —CF 3 , hydroxyalkyl, heterocycloalkyl, alkyl-alkoxy, heteroaryl, alkyl-heterocycloalkyl, alkyl-heteroaryl, alkyl-carboxylic acid, CD 3 , CO—CF 3 , alkyl-CO—O-alkyl.

30. A compound of claim 1 , where X 1 is CH and R 1 is CO-alkyl-sulfonyl-alkyl, CO-heterocycloalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, alkoxy-heterocycloalkyl, O-alkoxy, O-dioxothianyl, hydroxyl, alkoxy, cycloalkyl, O-heteroalkyl, alkoxy-heteroalkyl, methyl sulfonyl.

31. A compound of claim 7 , where R 1 is cyclopentylmethyl, cyclobutylmethyl, cyclobutyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, methoxyethyl.

32. A compound of claim 8 , wherein R 1 is heteroaryl and heteroaryl is pyridinyl.

33. A compound of claim 10 , wherein R 1 is heteroaryl and heteroaryl is pyridinepyrazolyl.

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

35. A compound of formula 1, of the following formula:

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

40. A compound of claim 1 , wherein heteroaryl in R 1 is substituted or unsubstituted and chosen from isoxazolyl, methyl-isoxazolyl, alkyl-isoxazolyl, benzoisoxazolyl, quinnolinyl, pyridinyl, nitrilepyridinyl, or chloropyridinyl.

41. A compound of claim 19 , of the following formula:

and pharmaceutically acceptable salts thereof.

42. A compound of claim 22 , of the following formula:

and pharmaceutically acceptable salts thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

45. A method for the treatment of a neurotransmission dysfunction associated with mGluR4 activity in a mammal comprising the step of administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by the formula:

wherein the variables are substituted when permissible or unsubstituted and:

X and Y together form:

Z is N, CH, CD, or C-halogen, C-Me, C—O-Me, C—CN;

R is independently chosen from H, Cl, F, CN, alkyl, cycloalkyl, Me, OMe, alkoxy;

X 1 is N, C, CH, CD, CR 1 ;

X 2 is N, NR 1 , or NR 2 ;

X 3 is N, C, CH, CD, CR 1 ;

provided that one of X 1 or X 3 is C or CR 1 ;

R 1 is independently H, alkyl, cycloalkyl, phenyl, halogen, CF 3 , Cl, CD 3 , CD 2 R, CDRR 2 , aryl, heteroaryl, SO 2 R 3 , O—R, O-aryl, O-heteroaryl, NHR, NR 2 R 2 , perfluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH 2 heteroaryl), alkenyl, alkyl-cycloalkyl, O-alkyl-cycloalkyl, CH 2 -cycloalkyl, CH 2 —CF 3 , hydroxyalkyl, alkyl-alkoxy, alkyl-heterocycloalkyl, alkyl-heteroaryl, alkyl-carboxylic acid, CO—CF 3 , alkyl-CO—O-alkyl, CO-alkyl-sulfonyl-alkyl, CO-heterocycloalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, alkoxy-heterocycloalkyl, O-alkoxy, O-phenyl, O-alkoxyphenyl, O-dioxothianyl, hydroxyl, alkoxy, O-alkyl-heteroaryl, O-alkyl-heterocycloalkyl, alkoxy-heteroalkyl, methyl sulfonyl, O-heterocycloalkyl, O-alkoxy-heterocycloalkyl, O-alkoxyaryl, alkoxy-heteroaryl, alkyl-phenyl, heterocycloalkyl, O—CD 3 , O—CD 2 R, hydroxyl, amino, CO-alkyl, CO-cycloalkyl, CO-alkyl-cycloalkyl, CO-amino-alkyl-sulfonylmethyl, CO-amino-cycloalkyl;

R 2 is independently H, heteroaryl, alkyl, phenyl, aryl, O-heterocycloalkyl, alkoxy-heterocycloalkyl, O-alkoxy-heterocycloalkyl, O-alkoxyaryl, O-heteroaryl, alkoxy-heteroaryl, alkoxy, alkoxy-heterocycloalkyl, alkyl-phenyl, heterocycloalkyl, O—CD 3 , O—CD 2 R, hydroxyl, amino, cycloalkyl, CH 2 -cycloalkyl, CO-alkyl; heterocycloalkyl, H, CF 3 , halogen, CD 3 , CD 2 R, CDRR 2 , SO 2 R 3 , OR, O-aryl, NHR, NR 1 R 1 , perfluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH 2 heteroaryl), alkenyl, alkyl-cycloalkyl, CH 2 -cycloalkyl, CH 2 —CF 3 , hydroxyalkyl, alkyl-alkoxy, alkyl-heterocycloalkyl, alkyl-heteroaryl, O-alkyl-heteroaryl, alkyl-carboxylic acid, CO—CF 3 , alkyl-CO—O-alkyl, CO-alkyl-sulfonyl-alkyl, CO-heterocycloalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, O-dioxothianyl, methyl sulfonyl;

R 3 is H, alkyl, alkoxyphenyl, pyridinyl, nitrilepyridinyl, chloropyridinyl;

or a pharmaceutically acceptable salt thereof;

wherein the dysfunction is Parkinson's disease.