Metabotropic glutamate receptor positive allosteric modulators (PAMS) and uses thereof
Provided herein are small molecule active metabotropic glutamate subtype-2 and -3 receptor positive allosteric modulators (PAMS), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (I):
wherein:
R 1 is —OH, —NHOR 5 , —NHSO 2 R 4 , —NR 4 R 5 or R 4 ;
L 1 is absent;
R 2 is hydrogen, halogen, nitro, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
n is 0, 1, 2, 3, or 4;
R 3 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
X is —OH, —OR 4 , halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
Z is —OH, —OR 4 , halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
R 4 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and
R 5 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
or R 4 and R 5 taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C 2 -C 8 heterocycloalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is absent; and
Z is halogen, or C 1 -C 6 alkyl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is absent; and
Z is —CH 3 , or —CH 2 CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of formula (Ia) or formula (Ib):
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —OH or —NR 4 R 5 ;
X is —OH, —OR 4 , C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 2 is hydrogen, halogen, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl; and
R 3 is C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —OH;
R 2 is F, Cl, —CH 3 , or —OCH 3 ;
X is —OH; and
R 3 is —CH(CH 3 ) 2 , —C(CH 3 ) 3 , or cyclopentyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
9. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):
wherein:
R 1 is —OH, —OR 4 , —NHOR 5 , —NHSO 2 R 4 , —NR 4 R 5 or R 4 ;
or —C(═O)R 1 is a carboxylic acid bioisostere having the structure
Ring A is a substituted or unsubstituted monocyclic 5-, or 6- heteroaryl selected from the group consisting of: furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl;
L 2 is absent, —O—(C 1 -C 6 alkylene)—, —S—, or —S—(C 1 -C 6 alkylene)—;
R 2 is hydrogen, halogen, nitro, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
n is 0, 1, 2, 3, or 4;
R 3 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
X is —OH, —OR 4 , halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
Z is halogen, or C 1 -C 6 alkyl;
R 4 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R 5 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
or R 4 and R 5 taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C 2 -C 8 heterocycloalkyl.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
Z is —CH 3 , or —CH 2 CH 3 ; and
L 2 is absent, —O—(CH 2 )—, or —S—(CH 2 )—.
11. A compound, or a pharmaceutically acceptable salt thereof, having the following structure:
wherein:
R 1 is —OH, —OR 4 , —NHOR 5 , —NHSO 2 R 4 , —NR 4 R 5 or R 4 ;
or —C(=O)R 1 is a carboxylic acid bioisostere having the structure
Ring A is selected from a group consisting of:
L 2 is absent, —O—(CH 2 )—, or —S—(CH 2 )—;
R 2 is hydrogen, halogen, nitro, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
n is 0, 1, 2, 3, or 4;
R 3 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
X is —OH, —OR 4 , halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
Z is —CH 3 , or —CH 2 CH 3 ;
R 4 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R 5 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted aryl;
or R 4 R 5 taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C 2 -C 8 heterocycloalkyl.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —OH, —OCH 3 , —OCH 2 CH 3 , or —N(R 4 R 5 );
X is —OH, —OR 4 , C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 2 is hydrogen, halogen, —CN, —OH, —OR 4 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 fluoroalkyl; and
R 3 is C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl.
13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is F, Cl, —CH 3 , or —OCH 3 ; and
R 3 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is —CH(CH 3 ) 2 , —C(CH 3 ) 3 , or cyclopentyl.
15. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
17. A method of treating Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, or an addictive disorder in a subject, the method comprising the step of administering to a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.
19. A method of treating Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, or an addictive disorder in a subject, the method comprising the step of administering to a subject in need thereof a compound of claim 9 , or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.
21. A pharmaceutical composition comprising a compound of claim 9 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
22. A method of treating Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, or an addictive disorder in a subject, the method comprising the step of administering to a subject in need thereof a compound of claim 11 , or a pharmaceutically acceptable salt thereof.
23. The method of claim 22 , wherein the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.
24. A pharmaceutical composition comprising a compound of claim 11 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.