Pyrazolopyridine, pyrarolopyrazine, pyrazolopyrimidine, pyrazolothiophene and pyrazolothiazole compounds as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
Pyrazolopyridine, pyrazolopyrazine, pyrazolopyrimidine, pyrazolothiophene and pyrazolothiazole compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.
1. A compound having a structure represented by a formula:
wherein:
X is selected from CH, N or NH;
X 1 is selected from N or NH;
X 2 is independently selected from CH, N or NH;
m is 0, 1 or 2;
n is 1 or 2;
D, when present, is CH 2 , CR 3 R 4 , CONH, or CONR 3 ;
Y is selected from N, or NH;
W is NH;
A is selected from substituted or unsubstituted C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, pyridinyl, or phenyl;
R 1 is independently selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may optionally contain a C 3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R 4 ), OAryl (optionally substituted with one or more R 2 ), OHeteroaryl (optionally substituted with one or more R 2 ), NR 3 R 4 , CHR 3 R 4 , CONR 3 R 4 , COCR 3 R 4 , COAryl (optionally substituted with one or more R 2 ), COHeteroaryl (optionally substituted with one or more R 2 ), CN or CF 3 ;
R 2 is independently selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may optionally contain a C 3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R 4 ), OAryl (optionally substituted with one or more R 2 ), OHeteroaryl (optionally substituted with one or more R 2 ), NR 3 R 4 , CHR 3 R 4 , CONR 3 R 4 , COCR 3 R 4 , COAryl (optionally substituted with R 1 and/or R 2 ), COHeteroaryl (optionally substituted with one or more R 2 ), CN or CF 3 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
provided that when X 1-4 , Y, and Z are part of pyrazolopyridine, W is NH, m is 0, and A is phenyl, then R 1 is not Cl when R 2 is H and R 2 is not Cl when R 1 is H;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.
2. The compound of claim 1 , of the following formula:
3. The compound of claim 1 , wherein n is 2.
4. The compound of claim 1 , wherein X is N or CH.
5. The compound of claim 1 , wherein Y is NH.
6. The compound of claim 1 , wherein X 1 is N.
7. The compound of claim 1 , wherein A is substituted or unsubstituted and selected from phenyl, cyclohexane, or pyridine.
8. The compound of claim 7 , wherein R 1 and R 2 are independently hydrogen, halogen, methoxy, difluoromethoxy, nitrile, optionally substituted O-aryl, optionally substituted O-heteroaryl.
9. The compound of claim 8 , wherein O-aryl is O-phenyl or O-benzyl; and O-heteroaryl is O-pyrimidine, O-pyrazine, or O-pyridine.
10. The compound of claim 8 , wherein O-aryl or O-heteroaryl is optionally substituted with at least one halogen, at least one methyl, and/or CF 3 .
11. The compound of claim 1 , of the following formula:
12. A pharmaceutical composition comprising a compound having a structure represented by a formula:
wherein:
X is selected from CH, N or NH;
X 1 is selected from N or NH;
X 2 is independently selected from CH, N or NH;
m is 0, 1 or 2;
n is 1 or 2;
D, when present, is CH 2 , CR 3 R 4 , CONH, or CONR 3 ;
Y is selected from N, or NH;
W is NH;
A is selected from substituted or unsubstituted C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, pyridinyl, or phenyl;
R 1 is independently selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may optionally contain a C 3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R 4 ), OAryl (optionally substituted with one or more R 2 ), OHeteroaryl (optionally substituted with one or more R 2 ), NR 3 R 4 , CHR 3 R 4 , CONR 3 R 4 , COCR 3 R 4 , COAryl (optionally substituted with one or more R 2 ), COHeteroaryl (optionally substituted with one or more R 2 ), CN or CF 3 ;
R 2 is independently selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may optionally contain a C 3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R 4 ), OAryl (optionally substituted with one or more R 2 ), OHeteroaryl (optionally substituted with one or more R 2 ), NR 3 R 4 , CHR 3 R 4 , CONR 3 R 4 , COCR 3 R 4 , COAryl (optionally substituted with R 1 and/or R 2 ), COHeteroaryl (optionally substituted with one or more R 2 ), CN or CF 3 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
provided that when X 1-4 , Y, and Z are part of pyrazolopyridine, W is NH, m is 0, and A is phenyl, then R 1 is not Cl when R 2 is H and R 2 is not Cl when R 1 is H;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and
a pharmaceutically acceptable carrier.
13. The composition of claim 12 , wherein the compound is of the following formula:
14. The composition of claim 12 , wherein n is 2.
15. The composition of claim 12 , wherein X is N or CH.
16. The composition of claim 12 , wherein Y is N, or NH.
17. The composition of claim 12 , wherein X 1 is N, or S.
18. The composition of claim 12 , wherein A is substituted or unsubstituted and selected from phenyl, cyclohexane, pyrazine, pyrimidine, quinoline, thiazole, or pyridine.
19. The composition of claim 18 , wherein R 1 and R 2 are independently hydrogen, halogen, methoxy, difluoromethoxy, nitrile, optionally substituted O-aryl, optionally substituted O-heteroaryl.
20. The composition of claim 19 , wherein O-aryl is O-phenyl or O-benzyl; and O-heteroaryl is 0-pyrimidine, 0-pyrazine, or 0-pyridine.
21. The composition of claim 19 , wherein O-aryl or O-heteroaryl is optionally substituted with at least one halogen, at least one methyl, and/or CF 3 .
22. The composition of claim 12 , wherein the compound is of the following formula:
23. The compound of claim 1 , of the following formula:
provided that when W is NH, m is 0, and A is phenyl, then R 1 is not Cl when R 2 is H and R 2 is not Cl when R 1 is H.
24. A compound of claim 23 , wherein W is NH, A is phenyl, and R 1 is halo.
25. A compound of claim 23 , wherein R 2 is O-heteroaryl.
26. A compound of claim 1 , of the following formula:
27. The composition of claim 12 , wherein the compound is of the following formula:
provided that when W is NH, m is 0, and A is phenyl, then R 1 is not Cl when R 2 is H and R 2 is not Cl when R 1 is H.
28. A composition of claim 27 , wherein W is NH, A is phenyl, and R 1 is halo.
29. A composition of claim 27 , wherein R 2 is O-heteroaryl.
30. A composition of claim 27 , of the following formula:
31. A compound of the following formula: