Isoquiniline and napthalene-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

1. A compound having a structure of the following formula:

wherein the variables are substituted or unsubstituted and:

W is CH, CD, N, C-alkyl, C-halogen; X is N, CH, CD, or C-alkyl;

X is N, CH, CD, or C-alkyl;

X 1 is CH, CD, C-R 2 , N, or is N and together with R 1 forms a 5 or 6 membered ring;

X 2 is CH, CD, C-R 2 , or N, or together with R 3 forms a 5 or 6 membered ring;

Y is N, CH, CD, or C-alkyl;

Z 2 is CH, CD, C-alkyl, N, C-halogen, or C-alkoxy;

R is halogen, CN, Me, alkyl, OMe, or alkoxy;

R 1 is alkyl, alkene, cycloalkyl, NR 4 R 5 , aryl, halogen, CF 3 , cycloheteroalkyl, alkoxy, OH, CN, Oalkyl, Oaryl, Oheteroaryl, NHalkyl, NHaryl, NHheteroaryl, heteroaryl, CH 2F , CHF 2 , CO-heterocyclyl, CO—NH-alkyl, CO—NH-methoxyalkyl, CO-amino, CO-aryl, CO-heteroaryl, CO-aminocycloalkyl, CO-amino-alkoxy, CO-alkyl, Nalkylalkyl, NH-alkoxy, or together with X 1 forms a 5 or 6 membered ring;

R 2 is H, halogen, alkyl, alkoxy, OMe, CONH 2 , or CN;

R 3 is H, alkyl, alkene, cycloalkyl, aryl, heteroaryl, alkoxy, hydroxyl, amino, aminoalkoxy, halogen, or together with X 2 forms a 5 or 6 membered ring;

R 4 is H, alkyl, cycloalkyl, aryl, heteroaryl, alkyl-aryl, or methoxyalkyl;

R 5 is H, alkyl, cycloalkyl, aryl, or heteroaryl;

or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

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

or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

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

wherein:

R 1A is amino, piperazine, piperazine-ethanone, NH-methylsulfonylalkyl, pyrrolidine, fluoropyrrolidine, NH-cyclobutyl, NH-fluorocyclobutyl, NH-difluorocyclobutyl, piperazine, sulfonylpiperazine, methylsulfonylpiperazine, thiazepan, dioxothiazepan, pyrrolidine, sulfonylpyrrolidine, oxazepan, methylsulfonylpyrrolidine, difluoropyrrolidin, piperidine, piperidine-carboxamide, fluoropiperidine, alkylpiperidine, difluoropiperidine, CO-amino, amino-alkyl, dihydrothiazone, morpholine, thiomorpholino, dioxothiomorpholino, amino-alkoxy, amino-cycloalkyl, methoxyalkyl, pyrazolo, azaspiroheptane, or difluoroazaspiroheptanealkyl; and

R 1B is alkyl-tetrahydropyran, alkyl, alkyl-dimethylamino, phenyl, trifluoromethylphenyl, amino-alkyl, pyrazole, or alkoxyphenyl;

or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

4. A compound of claim 1 , wherein R 1 is piperidine, methyl-piperidine, piperazine, pyrimidine, piperazine-pyrimidine, pyrimidine, pyrazole, triazole, pyrazole-alkyl, amino-triflouroalkyl, morpholine, thiophene, aminobenzyl, aminocycloalkyl, triflouromethylpyrrolidine, pyrrolidine, pyrimidine-carbonyl, trifluoromethylpyrrolidinecarbonyl, pyrrolo-pyridine, carbonyl-morpholine, benzopyrazole, benzotrimethylpyrazole, azetidine, difluoroazetidine, amino-pyrrolidine, or amino-alkoxy.

5. A compound of claim 1 , wherein R 3 is trifluoroalkyl, pyrazole, methylpyrazole, pyridine, fluoropyridine, furan, fluoroalkyl, cyclopropyl, cyclopentyl, amino, amino-alkyl-cycloalkyl, or dialkylamino.

6. A compound of claim 1 , wherein:

cycloalkyl is cyclobutyl, cyclopropyl, or cyclopentyl; and

cycloheteroalkyl is piperazine, pyrrolidin, thiazepin, piperazin-ethanone, azaspiroheptane, oxazepan, tetrahydropyran, morpholino, thiomorpholino, or dioxothiomorpholino.

7. A compound of claim 1 , wherein:

heteroaryl is pyrazole, triazol, isoxazol, thiophen, pyrozolopyrimidine, imidazole, indazole, indazole, pyrazolo-pyridin, or tetramethyl-furopyrazole.

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

or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

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

or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

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

or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

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

or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

12. A compound having a structure of the following formula:

wherein the variables are substituted or unsubstituted, and:

X 1 is CH, CD, C-R 2 , N, or is N and together with R 1 forms a 5 or 6 membered ring;

X 2 is CH, CD, C-R 2 , or N;

R is halogen, CN, Me, alkyl, OMe, or alkoxy;

R 1 is H, alkyl, alkene, cycloalkyl, NR 4 R 5 , aryl, halogen, CF 3 , cycloheteroalkyl, alkoxy, OH, CN, Oalkyl, Oaryl, Oheteroaryl, NHalkyl, NHaryl, NHheteroaryl, heteroaryl, CH 2 F, CHF 2 , CO—NH-alkyl, CO—NH-methoxyalkyl, CO-amino, CO-aryl, CO-heteroaryl, CO-aminocycloalkyl, CO-amino-alkoxy, CO-alkyl, Nalkylalkyl, NH-alkoxy, or together with X 1 forms a 5 or 6 membered ring;

R 2 is H, halogen, alkyl, alkoxy, or OMe;

R 3 is H, alkyl, cycloalkyl, aryl, or heteroaryl;

R 4 is H, alkyl, cycloalkyl, aryl, heteroaryl, alkyl-aryl, or methoxyalkyl;

R 5 is H, alkyl, cycloalkyl, aryl, heteroaryl;

or a pharmaceutically acceptable salt thereof.

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

14. A method for potentiating mGluR4 activity in a mammal comprising the step of administering to the mammal at least one compound of claim 1 in a dosage and amount effective to potentiate mGluR4 activity in the mammal.

15. The method of claim 14 , wherein the mammal is a human.

16. The method of claim 14 , wherein the mammal has Parkinson's disease.

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

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

22. A compound of the following formula:

wherein the variables are substituted or unsubstituted, and:

R is halogen, CN, Me, alkyl, OMe, or alkoxy;

R 1 is H, alkyl, alkene, cycloalkyl, NR 4 R 5 , aryl, halogen, CF 3 , cycloheteroalkyl, alkoxy, OH, CN, Oalkyl, Oaryl, Oheteroaryl, NHalkyl, NHaryl, NHheteroaryl, heteroaryl, CH 2 F, CHF 2 , CO—NH-alkyl, CO—NH-methoxyalkyl, CO-amino, CO-aryl, CO-heteroaryl, CO-aminocycloalkyl, CO-amino-alkoxy, CO-alkyl, Nalkylalkyl, or NH-alkoxy;

R 2 is H, halogen, alkyl, alkoxy, OMe, CONH 2 , or CN;

R 3 is H, alkyl, alkene, cycloalkyl, aryl, heteroaryl, alkoxy, hydroxyl, amino, aminoalkoxy, or halogen;

R 4 is H, alkyl, cycloalkyl, aryl, heteroaryl, alkyl-aryl, or methoxyalkyl;

R 5 is H, alkyl, cycloalkyl, aryl, or heteroaryl;

or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

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

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

25. A pharmaceutical composition comprising a compound having a structure represented by a formula:

wherein the variables are substituted or unsubstituted, and:

R is halogen, CN, Me, alkyl, OMe, or alkoxy;

R 1 is H, alkyl, alkene, cycloalkyl, NR 4 R 5 , aryl, halogen, CF 3 , cycloheteroalkyl, alkoxy, OH, CN, Oalkyl, Oaryl, Oheteroaryl, NHalkyl, NHaryl, NHheteroaryl, heteroaryl, CH 2F , CHF 2 , CO—NH-alkyl, CO—NH-methoxyalkyl, CO-amino, CO-aryl, CO-heteroaryl, CO-aminocycloalkyl, CO-amino-alkoxy, CO-alkyl, Nalkylalkyl, or NH-alkoxy;

R 2 is H, halogen, alkyl, alkoxy, OMe, CONH 2 , or CN;

R 3 is H, alkyl, alkene, cycloalkyl, aryl, heteroaryl, alkoxy, hydroxyl, amino, aminoalkoxy, or halogen;

R 4 is H, alkyl, cycloalkyl, aryl, heteroaryl, alkyl-aryl, or methoxyalkyl;

R 5 is H, alkyl, cycloalkyl, aryl, or heteroaryl;

or a pharmaceutically acceptable salt thereof or an N-oxide thereof, and a pharmaceutically acceptable carrier.

26. The composition of claim 25 , wherein the compound is of the following formula:

27. The composition of claim 26 , wherein the compound is of the following formula: