Pyrazole MAGL inhibitors
Provided herein are pyrazole compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL. Furthermore, the subject compounds and compositions are useful for the treatment of pain.
1. A compound of Formula (I):
wherein:
R 1 is —N(R 2 )C(O)R 15 or —N(H)SO 2 R 15 ;
R is H or C 1-6 alkyl;
R 3 is
A is N or C(H);
X is —O—, —N(R 16 )—, or —CH 2 N(R 16 )CH 2 —;
Y is —CH 2 — or —C(O)—;
Z is —S—, —O—, or —N(R 20 )—;
R 4 is H, halogen, —OR 7 , C 1-6 alkyl, C 1-6 alkyl-OH, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —O—C 3-8 cycloalkyl, —O—C 3-8 cycloalkyl-OH, —N(H)—C 1-6 alkyl-CO 2 H, —SO 2 R 17 , —CO 2 R 8 , —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, 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, C 1-9 heteroaryl are optionally substituted with 1 or 2 R 14 ;
R 5 is H, —CN, 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 3-8 cycloalkyl, 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 ;
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 is —O—C 1-6 haloalkyl, —O—C 1-6 alkyl-CO 2 H, —O—C 3-8 cycloalkyl, —O—C 3-8 cycloalkyl-CO 2 H, —N(H)—C 1-6 alkyl-CO 2 H, or —SO 2 R 17 ;
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, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C 1-6 alkyl-OH, C 3-8 cycloalkyl, —CO 2 R 8 , —C(O)NR 8 R 9 , —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkyl-OH, —SO 2 —C 1-6 alkyl, —N(R 8 )SO 2 —C 1-6 alkyl, and —N(R 8 )C(O)—C 1-6 alkyl;
R 15 is C 1-6 alkyl or C 3-8 cycloalkyl;
R 16 is H, C 1-6 alkyl, —C(O)—C 1-6 alkyl, or —CH 2 CO 2 H;
R 17 is C 1-6 alkyl or C 3-8 cycloalkyl;
R 18 and R 19 are independently selected from H and C 1-6 alkyl, wherein R 18 and R 19 are not both H;
R 20 is H or C 1-6 alkyl;
v is 0 or 1;
n is 0 or 1;
m is 0 or 1;
p is 0, 1, or 2;
q is 0, 1, or 2; and
w is 1 or 2;
or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 is
3. The compound of claim 2 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, p is 1, and w is 1.
4. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is C(H).
5. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is —CH 2 —.
6. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 6 is H.
7. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 13 is H.
8. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 12 is H.
9. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 is halogen, —OR 7 , C 1-6 alkyl-OH, —N(H)—C 1-6 alkyl-CO 2 H, C 1-6 alkynyl, C 1-6 haloalkyl, —CO 2 R 8 , —C(O)NR 8 R 9 , C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl are optionally substituted with 1 or 2 R 14 .
10. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 is halogen, —OR 7 , —N(H)—C 1-6 alkyl-CO 2 H, C 1-6 haloalkyl, —C(O)NR 8 R 9 , C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, or C 1-9 heteroaryl, wherein C 2-9 heterocycloalkyl or C 1-9 heteroaryl are optionally substituted with 1 or 2 R 14 .
11. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 is C 1-6 haloalkyl.
12. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 is —CF 3 .
13. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 is —N(H)—C 1-6 alkyl-CO 2 H.
14. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 is —C(O)NH 2 .
15. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 is H, —CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy.
16. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 is C 1-6 haloalkyl.
17. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 is —CF 3 .
18. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 2 )C(O)R 15 .
19. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 2 is H.
20. The compound of claim 1 , or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 15 is —CH 3 .
21. A compound selected from:
or a tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound of claim 1 , or a tautomer, A-oxide, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
23. A method of treating pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a tautomer, A-oxide, or a pharmaceutically acceptable salt thereof.
24. A method of treating a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from migraine, epilepsy/seizure disorder, neuromyelitis optica (NMO), Tourette syndrome, persistent motor tic disorder, persistent vocal tic disorder, and abdominal pain associated with irritable bowel syndrome.