Benzisoxazoles and azabenzisoxazoles as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction

摘要

Benzisoxazole and azabenzisoxazole 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.

主权项

1. A method for the treatment of Parkinson's disease, parkinsonism, and disease states involving akinesia or bradykinesia 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 aryl or heteroaryl or a 3-8 membered ring comprising C, O, S, and/or N;R is selected from hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), NR3R4, CONR3R4, S(O)0-2NR3R4, CN or CF3;R1 is independently selected from hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), NR3R4, CR3R4, CONR3R4, S(O)0-2NR3R4, CN; CF3, or S(O)0-2C1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), COC1-10alkyl; R2 is independently selected from hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), NR3R4, CR3R4, CONR3R4, S(O)0-2NR3R4, CN or CF3, or S(O)0-2C1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), COC1-10alkyl; R1 and R2 can optionally cyclize to form a ring comprising C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3-C12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R4; R3 is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF3; R4 is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF3; R3 and R4 can optionally cyclize to form a ring comprising C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3-C12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R5; R5 is selected from hydrogen, halogen, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), CN, CF3; provided that R1 cannot be CF3 when R2 is H and R2 cannot be CF3 when R1 is H; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.