Metabotrophic glutamate receptor 5 modulators and methods of use thereof

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

Q is CR 9 or N;

m and n are each 1;

X is F. Cl, Br, or I;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently hydrogen, X, alkyl, heteroalkyl, or alkenyl; or any two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 together with the atoms to which they are attached, form a cycloalkyl ring; and

R 9 is hydrogen or alkyl;

provided that

at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is either X, or alkyl or heteroalkyl substituted with at least one X; or a cycloalkyl ring formed by any two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 together with the atoms to which they are attached is substituted with at least one X;

at least one of R 3 and R 4 is not hydrogen;

When Q is CH, and R 1 , R 2 , R 4 , R 5 , and R 6 are all H, then R 3 is not CF 3 or F;

when Q is CH, and R 1 , R 2 , R 5 , and R 6 are all H, then R 3 and R 4 are not both F; and

when Q is CH, R 1 , R 2 , R 5 , and R 6 are all H, and R 3 is unsubstituted alkyl, then R 4 is not F.

2. A compound of formula (IV) or a pharmaceutically acceptable salt thereof:

wherein

m and n are each 1;

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, alkyl, or heteroalkyl; or

R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 together with the atom to which they are bonded form a cycloalkyl or heterocycloalkyl ring;

provided that

at least one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is not hydrogen; and

when one of R 3 and R 4 is methyl, and the other of R 3 and R 4 is hydrogen, then at least one of R 1 , R 2 , R 5 , and R 6 is not hydrogen.

3. A compound of formula (V) or a pharmaceutically acceptable salt thereof:

wherein

m and n are each 1 ;

Z is

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or alkyl;

Q is O or S;

R 7 and R 8 are hydrogen or alkyl; or R 7 and R 8 together with the atoms to which they are attached form a cyclolalkyl, heterocyeloalkyl, aryl, or heteroaryl ring;

provided that

when Z is

 Q is S, R 7 is methyl and R 8 is hydrogen, one of R 3 and R 4 is methyl, and the other of R 3 and R 4 is hydrogen, then at least one of R 1 , R 2 , R 5 and R 6 is not hydrogen.

4. A compound of formula (VI) or a pharmaceutically acceptable salt thereof:

wherein

m and n are each 1;

L is —R 8 C═CR 8 —, —OC(R 9 ) 2 or —C(O)NR 10 ;

X is F, Cl, Br, or I;

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, alkyl, or X;

R 7 is hydrogen or cyano;

each R 8 is hydrogen or X;

R 9 and R 10 are each independently hydrogen or alkyl;

provided that

when L is —HC═CH—, one of R 3 and R 4 is methyl, the other of R 3 and R 4 is hydrogen, R 1 , R 2 , R 5 , and R 6 are all hydrogen, and R 7 is hydrogen or cyano, then Pyr is

 and

when L is —HC═CH—, R 1 ,R 2 ,R 3 ,R 4 ,R 5 ,R 6 , and R 7 are all hydrogen, then Pyr is not 2—pyridyl.

5. A compound selected from:

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A method for modulating mGluR5 in a cell by contacting the cell with an effective amount of a compound of claim 1 .

8. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently hydrogen, X, or alkyl.

9. The compound of claim 8 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or alkyl.

10. The compound of claim 8 , wherein R 7 and R 8 are each independently hydrogen or X.

11. The compound of claim 10 , wherein X is F.

12. The compound of claim 2 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or alkyl.

13. The compound of claim 2 , wherein R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 together with the atom to which they are bonded form a heterocycloalkyl ring.

14. The compound of claim 4 , wherein R 7 is cyano.

15. The compound of claim 4 , wherein X is F.