Spirocycle compounds and methods of making and using same
Provided herein are spirocycle compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL and/or ABHD6. Furthermore, the subject compounds and compositions are useful for the treatment of pain.
1. A compound of Formula (Ia):
wherein:
R 1 is H or C 1-6 alkyl;
R 2 is H or C 1-6 alkyl;
each R 3 is independently selected from C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkynyl, halogen, —CN, C 1-6 haloalkyl, C 1-6 aminoalkyl, heterocycloalkyl, —C 1-6 alkyl(heterocycloalkyl), heteroaryl, —SF 5 , —NR 5 R 6 , —OR 7 , —CO 2 R 8 , —C(O)R 8 , and —C(O)NR 8 R 9 , wherein heterocycloalkyl and —C 1-6 alkyl(heterocycloalkyl) are optionally substituted with one or two R 4 ; or two adjacent R 3 form a heterocycloalkyl ring optionally substituted with one, two, or three R 4 ;
each R 4 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, halogen, oxo, —CN, —CO 2 R 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 5 and R 6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl(heterocycloalkyl), —C 1-6 alkyl-C(O)(heterocycloalkyl), heterocycloalkyl, aryl, and heteroaryl; or R 5 and R 6 , together with the nitrogen to which they are attached, form a heterocycloalkyl ring optionally substituted with one, two, or three R 10 ;
each R 7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl, —C 1-6 alkyl(heterocycloalkyl), —C 1-6 alkyl-C(O)(heterocycloalkyl), heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or two groups selected from oxo, C 1-6 alkyl, C 1-6 haloalkyl, CO 2 H, and C(O)NH 2 ;
each R 8 and R 9 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, aryl, and heteroaryl; or R 8 and R 9 , together with the nitrogen to which they are attached, form a heterocycloalkyl ring optionally substituted with one or two groups selected from C 1-6 alkyl, C 1-6 haloalkyl, CO 2 H, and C(O)NH 2 ;
each R 10 is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, halogen, oxo, —CN, —CO 2 R 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 ;
p is 0, 1, 2, 3, 4, or 5;
n is 0 or 1; and
m is 1 or 2; provided that when n is 0, then m is 2; and when n is 1, then m is 1;
or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from C 1-6 alkyl, C 2-6 alkynyl, halogen, —CN, C 1-6 haloalkyl, heterocycloalkyl, —C 1-6 alkyl(heterocycloalkyl), heteroaryl, —SF 5 , —NR 5 R 6 , —OR′, —CO 2 R 8 , and —C(O)NR 8 R 9 .
3. The compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both H.
4. The compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both —CH 3 .
5. The compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from C 1-6 alkyl, halogen, C 1-6 haloalkyl, —C 1-6 alkyl(heterocycloalkyl), —NR 5 R 6 , —OR 7 , —CO 2 R 8 , and —C(O)NR 8 R 9 .
6. The compound of claim 5 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from halogen, C 1-6 haloalkyl, —NR 5 R 6 , and —OR 7 .
7. The compound of claim 5 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the nitrogen to which they are attached, form a heterocycloalkyl ring substituted with one or two R 10 independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, halogen, —CO 2 R 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 .
8. The compound of claim 7 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the nitrogen to which they are attached, form a heterocycloalkyl ring substituted with one or two R 10 independently selected from C 1-6 alkyl and —CO 2 H.
9. The compound of claim 5 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the nitrogen to which they are attached, form an unsubstituted heterocycloalkyl ring.
10. The compound of claim 5 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the nitrogen to which they are attached, form a heterocycloalkyl ring optionally substituted with one, two, or three R 10 selected from:
11. The compound of claim 5 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 7 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, —C 1-6 alkyl(heterocycloalkyl), —C 1-6 alkyl-C(O)(heterocycloalkyl), heterocycloalkyl, and heteroaryl.
12. The compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein two adjacent R 3 form a heterocycloalkyl ring optionally substituted with one or two R 4 .
13. The compound of claim 1 , wherein p is 2.
14. The compound of claim 1 , wherein p is 1.
15. The compound of claim 1 , wherein n is 0 and m is 2.
16. The compound of claim 1 , wherein n is 1 and m is 1.
17. A compound selected from:
or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
19. A method of treating pain, epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optica (NMO), Tourette syndrome, Alzheimer's disease, or abdominal pain associated with irritable bowel syndrome in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof.