Pyrazolopyridine, Pyrazolopyrazine, Pyrazolopyrimidine, Pyrazolothiophene and Pyrazolothiazole Compounds as MGLUR4 Allosteric Potentiators, Compositions, and Methods of Treating Neurological Dysfunction

A compound having a structure represented by a formula:

• wherein:
• X is selected from S, CR5, N or NR5;
• X1 is selected from S, CR5, N or NR5;
• X2 is independently selected from S, CR5, N or NR5;
• X3 is C or N;
• X4 is C or N;
• m is 0, 1 or 2;
• n is 1 or 2;
• D, when present, is CH2, CR3R4, CONH, or CONR3;
• Y is selected from N, NH or NR5;
• Z is N, NR5, CR5;
• W is selected from S, O, NH, or NR5;
• A is selected from C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3-C1-2 heterocycloalkyl or C3-C12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N;
• R1 is independently selected from hydrogen, halogen, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which would contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with R1 and/or R2), OHeteroaryl (optionally substituted with R1 and/or R2), NR3R4, CR3R4, CONR3R4, COCR3R4, COAryl (optionally substituted with R1 and/or R2), COHeteroaryl (optionally substituted with R1 and/or R2), S(O)0-2NR3R4, S(O)0-2CR3R4, CN or CF3;
• R2 is independently selected from hydrogen, halogen, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which would contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with R1 and/or R2), OHeteroaryl (optionally substituted with R1 and/or R2), NR3R4, CR3R4, CONR3R4, COCR3R4, COAryl (optionally substituted with R1 and/or R2), COHeteroaryl (optionally substituted with R1 and/or R2), S(O)0-2NR3R4, S(O)0-2CR3R4, CN or CF3;
• 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, CONR3R4, S(O)0-2NR3R4;
• R4 is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF3, CONR3R4, CO, S(O)0-2NR3R4;
• 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, C1-6 alkyl, C3-10 cycloalkyl, aryl, heteroaryl, benzyl, OC1-10 alkyl (which could contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), CN, CF3;
• provided that when X1-4, Y, and Z are part of pyrazolopyridine, W is NH, m is 0, and A is phenyl, then R1 is not Cl when R2 is H;
• or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

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

• wherein:
• X is selected from S, CR5, N or NR5;
• X1 is selected from S, CR5, N or NR5;
• X2 is independently selected from S, CR5, N or NR5;
• X3 is C or N;
• X4 is C or N;
• m is 0, 1 or 2;
• n is 1 or 2;
• D, when present, is CH2, CR3R4, CONH, or CONR3;
• Y is selected from N, NH or NR5;
• Z is N, NR5, CR5;
• W is selected from S, O, NH, or NR5;
• A is selected from C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3-C12 heterocycloalkyl or C3-C12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N;
• R1 is independently selected from hydrogen, halogen, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which would contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with R1 and/or R2), OHeteroaryl (optionally substituted with R1 and/or R2), NR3R4, CR3R4, CONR3R4, COCR3R4, COAryl (optionally substituted with R1 and/or R2), COHeteroaryl (optionally substituted with R1 and/or R2), S(O)0-2NR3R4, S(O)0-2CR3R4, CN or CF3;
• R2 is independently selected from hydrogen, halogen, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which would contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with R1 and/or R2), OHeteroaryl (optionally substituted with R1 and/or R2), NR3R4, CR3R4, CONR3R4, COCR3R4, COAryl (optionally substituted with R1 and/or R2), COHeteroaryl (optionally substituted with R1 and/or R2), S(O)0-2NR3R4, S(O)0-2CR3R4, CN or CF3;
• 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, CONR3R4, S(O)0-2NR3R4;
• R4 is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF3, CONR3R4, CO, S(O)0-2NR3R4;
• 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, C1-6 alkyl, C3-10 cycloalkyl, aryl, heteroaryl, benzyl, OC1-10 alkyl (which could contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), CN, CF3;
• provided that when X1-4, Y, and Z are part of pyrazolopyridine, W is NH, m is 0, and A is phenyl, then R1 is not Cl when R2 is H;
• or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and
• a pharmaceutically acceptable carrier.

A method for the treatment of a neurotransmission dysfunction or other disease state associated with mGluR4 activity in a mammal comprising the step of co-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:
• X is selected from S, CR5, N or NR5;
• X1 is selected from S, CR5, N or NR5;
• X2 is independently selected from S, CR5, N or NR5;
• X3 is C or N;
• X4 is C or N;
• m is 0, 1 or 2;
• n is 1 or 2;
• D, when present, is CH2, CR3R4, CONH, or CONR3;
• Y is selected from N, NH or NR5;
• Z is N, NR5, CR5;
• W is selected from S, O, NH, or NR5;
• A is selected from C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3-C12 heterocycloalkyl or C3-C12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N;
• R1 is independently selected from hydrogen, halogen, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which would contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with R1 and/or R2), OHeteroaryl (optionally substituted with R1 and/or R2), NR3R4, CR3R4, CONR3R4, COCR3R4, COAryl (optionally substituted with R1 and/or R2), COHeteroaryl (optionally substituted with R1 and/or R2), S(O)0-2NR3R4, S(O)0-2CR3R4, CN or CF3;
• R2 is independently selected from hydrogen, halogen, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which would contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with R1 and/or R2), OHeteroaryl (optionally substituted with R1 and/or R2), NR3R4, CR3R4, CONR3R4, COCR3R4, COAryl (optionally substituted with R1 and/or R2), COHeteroaryl (optionally substituted with R1 and/or R2), S(O)0-2NR3R4, S(O)0-2CR3R4, CN or CF3;
• 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, CONR3R4, S(O)0-2NR3R4;
• R4 is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF3, CONR3R4, CO, S(O)0-2NR3R4;
• 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, C1-6 alkyl, C3-10 cycloalkyl, aryl, heteroaryl, benzyl, OC1-10 alkyl (which could contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), CN, CF3;
• or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof with (i) with a drug having a known side-effect of increasing metabotropic glutamate receptor activity, (ii) with a drug known to treat a disorder associated with increasing metabotropic glutamate receptor activity and/or (iii) a drug known to treat the neurotransmission dysfunction or other disease state associated with potentiation of mGluR4.