Heterocyclic Sulfone MGLUR4 Allosteric Potentiators, Compositions, and Methods of Treating Neurological Dysfunction

A compound having a structure represented by a formula:

• wherein:
• W is selected from O, S, CR4, N or NR4;
• Y is selective from O, S, CR4, N or NR4;
• Z is selective from O, S, N, NR4 or CR4;
• X1 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
• X2 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
• X3 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3;
• X4 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3, aryl optionally substituted with R4, heteroaryl optionally substituted with R4;
• R is selected from heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
• R1 is selected from CR2R3 aryl optionally substituted with one or more R4, CR2R3 heteroaryl optionally substituted with one or more R4, heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
• R2 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
• R3 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
• and
• R4 is selected from H, OH, NR2R3, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, alkoxy, CF3;
• R5 is selected from H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CF, CF2, CF3, C1-6 alkyl-hydroxyl;
• and
• n is 0-6;
• 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:
• W is selected from O, S, CR4, N or NR4;
• Y is selective from O, S, CR4, N or NR4;
• Z is selective from O, S, N, NR4 or CR4;
• X1 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
• X2 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
• X3 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3;
• X4 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3, aryl optionally substituted with R4, heteroaryl optionally substituted with R4;
• R is selected from heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
• R1 is selected from CR2R3 aryl optionally substituted with one or more R4, CR2R3 heteroaryl optionally substituted with one or more R4, heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
• R2 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
• R3 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
• and
• R4 is selected from H, OH, NR2R3, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, alkoxy, CF3;
• R5 is selected from H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CF, CF2, CF3, C1-6 alkyl-hydroxyl;
• and
• n is 0-6;
• 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:
• W is selected from O, S, CR4, N or NR4;
• Y is selective from O, S, CR4, N or NR4;
• Z is selective from O, S, N, NR4 or CR4;
• X1 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
• X2 is selected from carbonyl, thiocarbonyl, CH2, CR2R3, NR4, S, SO, SO2;
• X3 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3;
• X4 is selected from carbonyl, thiocarbonyl, S, SO, SO2, CH2, CR2R3, aryl optionally substituted with R4, heteroaryl optionally substituted with R4;
• R is selected from heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
• R1 is selected from CR2R3 aryl optionally substituted with one or more R4, CR2R3 heteroaryl optionally substituted with one or more R4, heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;
• R2 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
• R3 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R8;
• and
• R4 is selected from H, OH, NR2R3, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, alkoxy, CF3;
• R5 is selected from H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CF, CF2, CF3, C1-6 alkyl-hydroxyl;
• and
• n is 0-6;
• or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof with (i) a drug having a known side-effect of increasing metabotropic glutamate receptor activity, (ii) 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.