Metabotrophic glutamate receptor 5 modulators and methods of use thereof
Compounds that modulate GluR5 activity and methods of using the same are disclosed.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein
Q is CR 9 or N;
one of m and n is 0 and the other is 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 m is 1, n is 0, Q is CH, R 1 , R 2 , R 5 , and R 6 are all H, and R 3 is H or F, then R 4 is not F.
2. A compound of formula (III) or a pharmaceutically acceptable salt thereof:
wherein
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, alkyl, hydroxyl, alkenyl, heteroalkyl, or cyano; or
R 1 and R 2 or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; or
R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl ring;
R 5 is hydrogen or alkyl;
R 6 , R 7 , and R 8 are each independently hydrogen, CN, heteroalkyl, alkyl, or X; and
X is F, Cl, Br, or I;
provided that
R 3 and R 4 cannot together form ═CH 2 ;
when R 1 , R 2 , R 3 , and R 4 are all hydrogen, then at least one of R 5 , R 6 , R 7 , and R 8 is not hydrogen;
when both R 1 and R 2 are methyl, then at least one of R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is other than hydrogen;
when both R 3 and R 4 are methyl, then at least one of R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 is not hydrogen;
when one of R 1 , R 2 , R 3 , and R 4 is methyl, and the other three of R 1 , R 2 , R 3 , and R 4 are all hydrogen, then at least one of R 5 , R 6 , R 7 , and R 8 is not hydrogen;
when one of R 1 and R 2 is hydroxymethyl or methoxymethyl and the other of R 1 and R 2 is hydrogen, then at least one of R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is not hydrogen;
when one of R 3 and R 4 is hydroxymethyl, hydroxy, methoxy, methoxymethyl, or fluoro, and the other of R 3 and R 4 is hydrogen, then at least one of R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 is not hydrogen;
when one of R 3 and R 4 is methyl and the other of R 3 and R 4 is hydroxyl or methoxy, then at least one of R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 is not hydrogen;
when R 3 and R 4 are both F, then at least one of R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 is not hydrogen.
3. A compound of formula (IV) or a pharmaceutically acceptable salt thereof:
wherein
one of m and n is 0 and the other is 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;
when m is 0, n is 1, and both R 5 and R 6 are methyl, then at least one of R 1 , R 2 , R 3 , and R 4 is not hydrogen; and
when m is 1, n is 0, and both R 3 and R 4 are methyl, then at least one of R 1 , R 2 , R 5 , and R 6 is not hydrogen.
4. A compound of formula (V) or a pharmaceutically acceptable salt thereof:
wherein
one of m and n is 0 and the other is 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, heterocycloalkyl, aryl, or heteroaryl ring.
5. A compound of formula (VI) or a pharmaceutically acceptable salt thereof:
wherein
one of m and n is 0 and the other is 1;
L is —R 8 C═CR 8 —, —OC(R 9 ) 2 —, C(O)NR 10 —, or —NR 10 C(O)—;
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 m is 0, n is 1, L is —HC═CH—, R 1 , R 2 , R 3 , and R 4 are all hydrogen, R 5 and R 6 are both methyl, and R 7 is hydrogen or cyano, then Pyr is not
when m is 1, n is 0, L is —HC═CH—, R 1 , R 2 , R 5 , and R 6 are all hydrogen, R 3 and R 4 are both methyl, and R 7 is hydrogen or cyano, then Pyr is not
when m is 0, n is 1, L is —HC═CH—, R 1 , R 2 , R 5 , and R 6 are all hydrogen, R 3 and R 4 are both methyl, and R 7 is hydrogen or cyano, then Pyr is not and
when m is 1, n is 0, L is —HC═CH—, R 3 , R 4 , R 5 , and R 6 are all hydrogen, R 1 and R 2 are both methyl, and R 7 is hydrogen or cyano, then Pyr is not
6. A compound of formula (VII) or a pharmaceutically acceptable salt thereof:
wherein Z is
7. A compound selected from:
and a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
9. A method for treating a disorder or disease mediated by mGluR5, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
10. The method of claim 9 , wherein the disorder or disease mediated by mGluR5 is a neurological disorder.
11. The method of claim 10 , wherein the neurological disorder is a neurodegenerative disease, a neuropsychiatric disease, an affective disorder, a loss of cognitive function or a learning and memory disorder.
12. A method for treating psychosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
13. A method for treating schizophrenia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
14. A method for treating cognitive impairment associated with schizophrenia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
15. A method for treating Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
16. A method for treating a cognitive disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
17. A method for modulating mGluR5 in a subject by administering to the subject a therapeutically effective amount of a compound of claim 1 .
18. A method for modulating mGluR5 in a cell by contacting the cell with an effective amount of a compound of claim 1 .