Pyrazole MAGL inhibitors
Provided herein are pyrazole compounds and pharmaceutical compositions comprising the same. The compounds and compositions are useful as modulators of monoacylglycerol lipase (MAGL). Furthermore, the compounds and compositions are useful for the treatment of pain.
1. A method of treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I):
wherein:
R 1 is —C(O)OR 15 or —C(O)NR 10 R 11 ;
R 2 is H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 is
A is N or C(H);
Y is —CH 2 — or —C(O)—;
Z is —S—, —O—, or —N(R 18 )—;
R 4 is H, halogen, —OR 7 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —C(O)NR 8 R 9 , C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, —C 1-6 alkyl-C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl are optionally substituted with 1 or 2 R 14 ;
R 5 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, or phenyl;
R 6 is H, halogen, or C 1-6 alkyl;
R 7 is H, C 1-6 alkyl, C 1-6 haloalkyl, —C 1-6 alkyl-OH, C 2-9 heterocyloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl are optionally substituted with 1 or 2 R 14 ;
each R 8 and each R 9 are independently selected from H and C 1-6 alkyl; or R 8 and R 9 together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring;
R 10 and R 11 are each independently H or C 1-6 alkyl;
R 12 is H, halogen, or C 1-6 alkyl;
R 13 is H or C 1-6 alkyl;
each R 14 is independently selected from halogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C 1-6 alkyl-OH, C 3-8 cycloalkyl, —C(O)OH, —C(O)NR 8 R 9 , —SO 2 —C 1-6 alkyl, and —N(R 17 )C(O)—C 1-6 alkyl;
R 15 is H or C 1-6 alkyl;
R 17 is H or C 1-6 alkyl;
R 18 is H or C 1-6 alkyl;
n is 1;
m is 1;
p is 2; and
q is 0;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein R 3 is
3. The method of claim 2 wherein Y is —CH 2 —.
4. The method of claim 3 wherein R 13 is H.
5. The method of claim 4 wherein R 12 is H.
6. The method of claim 5 wherein A is C(H).
7. The method of claim 6 wherein R 6 is H.
8. The method of claim 7 wherein R 4 is halogen, —OR 7 , C 1-6 haloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl are optionally substituted with 1 or 2 R 14 .
9. The method of claim 8 wherein R 4 is halogen or C 2-9 heterocycloalkyl optionally substituted with 1 or 2 R 14 .
10. The method of claim 9 wherein R 4 is an unsubstituted C 2-9 heterocycloalkyl.
11. The method of claim 9 wherein R 5 is H, halogen, C 1-6 alkyl, C 1 - 6 haloalkyl, or C 1-6 haloalkoxy.
12. The method of claim 11 wherein R 2 is H.
13. The method of claim 12 wherein R 1 is —C(O)OR 15 .
14. The method of claim 13 , wherein R 15 is H.
15. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 wherein the compound of Formula (I) is:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the compound of Formula (I) is:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the compound of Formula (I) is:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 wherein the compound of Formula (I) is:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 wherein the compound of Formula (I) is:
or a pharmaceutically acceptable salt thereof.