Dual MAGL and FAAH inhibitors
Provided herein are compounds and pharmaceutical compositions comprising said compounds useful as modulators of MAGL and/or FAAH. The subject compounds and compositions are useful for the treatment of pain and neurological disorders.
1. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having the structure of Formula (I):
wherein:
is
each R 1 is independently selected from halogen, —CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkyl-OR 7 , C 1-6 haloalkyl, C 3-8 cycloalkyl, —NR 5 R 6 , —C(O)NR 5 R 6 , —OR 7 , —SO 2 R 12 , —SF 5 , —SR 8 , aryl, and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and —C(O)NR 8 R 9 ; or two adjacent R 1 form a heterocycloalkyl ring optionally substituted with one or two R 11 ;
R 2 is C 1-6 alkyl;
R 3 is selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, —NR 8 R 9 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , and —NR 9 SO 2 R 8 ;
R 3a is selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 4 is independently selected from H and C 1-6 alkyl;
each R 5 and R 6 is independently selected from H, C 1-6 alkyl, and C 3-8 cycloalkyl; or R 5 and R 6 , together with the nitrogen to which they are attached, form a heterocycloalkyl optionally substituted with one or two R 10 ;
each R 7 is independently selected from H, C 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 8 and R 9 is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and heteroaryl;
each R 10 is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, halogen, oxo, —CN, —C(O)OR 8 , —C(O)R 8 , —C(O)NR 8 R 9 , —SO 2 R 8 , —NR 9 C(O)R 8 , and —NR 9 SO 2 R 8 ;
each R 11 is independently selected from halogen and C 1-6 alkyl;
each R 12 is independently selected from C 1-6 alkyl and C 3-8 cycloalkyl;
m is 0, 1, 2, 3, 4, or 5;
n is 0, 1, 2, or 3;
p is 0 or 1; and
q is 0 or 1;
or a pharmaceutically acceptable salt or solvate thereof,
wherein the level of monoacylglycerol lipase (MAGL) and/or the level of fatty acid amide hydrolase (FAAH) in a biological sample from the subject is decreased after administration of the therapeutically effective amount of the compound to the subject as compared to the level of MAGL and/or the level of FAAH in a biological sample from the subject prior to the administration, thereby treating the subject.
2. The method of claim 1 , wherein R 2 is —CH 3 .
3. The method of claim 1 , wherein
is
4. The method of claim 3 , wherein m is 1 or 2.
5. The method of claim 1 , wherein R 3 is C 1-6 haloalkyl.
6. The method of claim 5 , wherein R 3 is —CF 3 .
7. The method of claim 1 , wherein R 3 is halogen.
8. The method of claim 1 , wherein R 3 is —C(O)NH 2 .
9. The method of claim 1 , wherein R 3 is —CN.
10. The method of claim 1 , wherein q is 0.
11. The method of claim 1 , wherein q is 1.
12. The method of claim 1 , wherein each R 1 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and —OR 7 .
13. The method of claim 12 , wherein R 7 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, aryl, and heteroaryl.
14. The method of claim 13 , wherein R 7 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
15. The method of claim 1 , wherein each R 4 is H.
16. The method of claim 1 , wherein the compound having the structure of Formula (I) is selected from:
or a pharmaceutically acceptable salt or solvate thereof.