Metabotrophic glutamate receptor 5 modulators and methods 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 both 0;

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;

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

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

wherein

Q is CR 7 or N;

G is CH 2 or O;

R 1 and R 2 are independently hydrogen, alkyl, cyano, or heteroalkyl; or R 1 and R 2 together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; and

R 7 is selected from hydrogen and alkyl

provided that

when Q is N and G is CH 2 , then at least one of R 1 and R 2 is not hydrogen;

when Q is N, G is CH 2 , and one of R 1 and R 2 is methyl, then the other of R 1 and R 2 is not hydrogen or methyl;

when Q is N, G is CH 2 , and one of R 1 and R 2 is hydroxymethyl or methoxymethyl, then the other of R 1 and R 2 is not hydrogen; and

when Q is N, G is CH 2 , and R 1 and R 2 together with the atom to which they are attached form a heterocycloalkyl ring, then R 1 and R 2 together are not —(CH 2 ) 2 O(CH 2 ) 2 —.

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

wherein

m and n are both 0;

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;

when m and n are both 0 and both R 1 and R 4 are methyl, then at least one of R 1 , R 2 , R 5 and R 6 is not hydrogen; and

when m and n are both 0, one of R 5 and R 6 is hydroxymethyl or methoxymethyl, and the other of R 5 and R 6 is hydrogen, then at least one of R 1 , R 2 , R 3 , and R 4 is not hydrogen.

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

wherein

m and n are both 0;

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, heterocycloalkyl, aryl, or heteroaryl ring.

5. A compound selected from:

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A method of treating psychosis, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

8. A method of treating schizophrenia, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

9. A method of treating Alzheimer's disease, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.