Pyrazolopyridine, pyrazolopyrazine, 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 method for the treatment of a neurotransmission dysfunction and other disease states 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 a formula:
wherein:
A is selected from C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or C 3 -C 12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N;
D, when present, is CH 2 , CR 3 R 4 , CONH, or CONR 3 ;
m is 0, 1 or 2;
R 1 is independently halogen;
R 2 is OC 1-10 alkyl (which may 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 at least one R 1 , R 2 and/or R 4 ), OHeteroaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), OC 1-10 alkylaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), OC 1-10 alkylheteroaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), or NR 3 R 4 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 3 R 4 , CO, S(O) 0-2 NR 3 R 4 ; R 3 and R 4 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 5 ;
R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl, benzyl, OC 1-10 alkyl (which may optionally contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), CN, CF 3 ;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.
2. The method of claim 1 , wherein the mammal is a human.
3. The method of claim 1 , wherein the dysfunction is Parkinson's disease.
4. method of claim 1 , wherein the dysfunction is schizophrenia, psychosis, “schizophrenia-spectrum” disorder, depression, bipolar disorder, cognitive disorder, delirium, amnestic disorder, anxiety disorder, attention disorder, obesity, eating disorder, or NMDA receptor-related disorder.
5. The method of claim 1 , wherein the dysfunction is Parkinson's disease; anxiety; motor effects after alcohol consumption; neurogenic fate commitment and neuronal survival; epilepsy; medulloblastoma; inflammation and metabolic disorders; and taste enhancing associated with glutamatergic dysfunction.
6. The method of claim 1 , wherein the mammal has been diagnosed with the dysfunction prior to the administering step.
7. The method of claim 1 , further comprising the step of identifying a mammal having a need for treatment of the dysfunction.
8. A compound having a structure represented by a formula:
wherein:
A is selected from C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or C 3 -C 12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N;
D, when present, is CH 2 , CR 3 R 4 , CONH, or CONR 3 ;
m is 0, 1 or 2;
R 1 is independently halogen;
R 2 is OC 1-10 alkyl (which may 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 at least one R 1 , R 2 and/or R 4 ), OHeteroaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), OC 1-10 alkylaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), OC 1-10 alkylheteroaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), or NR 3 R 4 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 3 R 4 , CO, S(O) 0-2 NR 3 R 4 ; R 3 and R 4 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 5 ;
R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl, benzyl, OC 1-10 alkyl (which may optionally contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), CN, CF 3 ;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.
9. A compound of claim 8 , wherein A is substituted or unsubstituted phenyl.
10. A compound of claim 9 , wherein R 1 is Cl.
11. A compound of claim 8 , wherein R 2 is NR 3 R 4 .
12. A compound of claim 11 , wherein R 3 is hydrogen and R 4 is heteroaryl.
13. A compound of claim 12 , wherein heteroaryl is substituted or unsubstituted pyridine, quinoline, pyrazine, pyrimidine, quinazoline, quinoxaline, napthyridine.
14. A compound of claim 8 , wherein R 2 is chosen from:
15. A compound of claim 8 , wherein R 2 is substituted or unsubstituted O-Aryl, O-alkylaryl, O—C 1-10 alkyl (which could contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), and O-heteroaryl.
16. A compound of claim 15 , wherein R 2 is —O—C (0-1) -aryl (optionally substituted with one or more R 4 ), or —O—C (0-1) -heteroaryl (optionally substituted with one or more R 4 ).
17. A compound of claim 16 , wherein heteroaryl is substituted or unsubstituted phenyl, pyridine, thiazole, cyclopentyl, cyclohexyl, pyrimidine, therahydroquinoline.
18. A compound of claim 8 , wherein R 2 is chosen from:
19. A compound of claim 8 , of the following formula:
20. A pharmaceutical composition comprising a compound having a structure represented by a formula:
wherein:
A is selected from C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or C 3 -C 12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N;
D, when present, is CH 2 , CR 3 R 4 , CONH, or CONR 3 ;
m is 0, 1 or 2;
R 1 is independently halogen;
R 2 is OC 1-10 alkyl (which may 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 at least one R 1 , R 2 and/or R 4 ), OHeteroaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), OC 1-10 alkylaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), OC 1-10 alkylheteroaryl (optionally substituted with at least one R 1 , R 2 and/or R 4 ), or NR 3 R 4 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 3 R 4 , CO, S(O) 0-2 NR 3 R 4 ; R 3 and R 4 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 5 ;
R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl, benzyl, OC 1-10 alkyl (which may optionally contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), CN, CF 3 ;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and
a pharmaceutically acceptable carrier.
21. The composition of claim 20 , wherein A is substituted or unsubstituted phenyl.
22. The composition of claim 20 , wherein R 1 is Cl.
23. The composition of claim 20 , wherein R 2 is NR 3 R 4 .
24. The composition of claim 23 , wherein R 3 is hydrogen and R 4 is heteroaryl.
25. The composition of claim 24 , wherein heteroaryl is substituted or unsubstituted pyridine, quinoline, pyrazine, pyrimidine, quinazoline, quinoxaline, napthyridine.
26. The composition of claim 20 , wherein R 2 is chosen from:
27. The composition of claim 20 , wherein R 2 is substituted or unsubstituted O-Aryl, O-alkylaryl, O—C 1-10 alkyl (which may optionally contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), and O-heteroaryl.
28. The composition of claim 27 , wherein R 2 is —O—C (0-1) -aryl (optionally substituted with one or more R 4 ), or —O—C (0-1) -heteroaryl (optionally substituted with one or more R 4 ).
29. The composition of claim 28 , wherein heteroaryl is substituted or unsubstituted phenyl, pyridine, thiazole, cyclopentyl, cyclohexyl, pyrimidine, therahydroquinoline.
30. The composition of claim 20 , wherein R 2 is chosen from:
31. The composition of claim 20 , wherein the compound is of the following formula:
32. The method of claim 1 , wherein the dysfunction is Parkinson's disease.
33. The method of claim 1 , wherein the dysfunction is multiple sclerosis.
34. The method of claim 1 , wherein the disfunction is diabetes.