Carbamate compounds and methods of making and using same
This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from post-traumatic stress disorder comprising administering a disclosed compound or composition.
1. A method of treating pain in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound represented by:
wherein
L 3 is a bond, —CH 2 —, —S(O) 2 —, or —C(O)—;
R 7 is phenyl; wherein R 7 is optionally substituted by one, two, or three moieties independently selected from R h ;
R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl, heterocycle, and phenyl;
or R a and R b , when they occur together with the nitrogen to which they are attached, form a 4-6 membered saturated heterocyclic ring, which may have an additional heteroatom selected from O, S, and N, or a spirocyclic ring selected from 8-oxa-2-azaspiro[4.5]decane and 2,8-diazaspiro[4.5]decane, wherein the 4-6 membered saturated heterocyclic ring or the spirocyclic ring are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, C 1-6 alkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), hydroxyl, —C(O)—C 1-6 alkyl, —NH 2 , and —NH—C(O)—C 1-6 alkyl;
R c is selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl (optionally substituted by one, two, or three halogens), and C 1-6 alkoxy (optionally substituted by one, two, or three halogens); and
R h is selected from the group consisting of: halogen, phenyl (optionally substituted by one, two, or three moieties each independently selected from R c ), hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens), C 1-6 alkoxy (optionally substituted by one, two or three halogens), R a R b N—, R a —C(O)NR a —, R a R b N—SO 2 —, R a R b N—C(O)—, R a —S(O) w — (wherein w is 0, 1 or 2), R a —SO 2 —NR b —, and heteroaryl (optionally substituted by one, two or three moieties each independently selected from R c ); or a stereoisomer or pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein L 3 is a —CH 2 —.
3. The method of claim 1 , wherein L 3 is a —CH 2 —; and R h is selected from the group consisting of: halogen, phenyl (optionally substituted by one, two, or three moieties each independently selected from halogen, methyl, ethyl, propyl, t-butyl, and CF 3 ), C 1-6 alkyl (optionally substituted by one, two or three halogens), C 1-6 alkoxy (optionally substituted by one, two or three halogens), R a R b N—, R a R b N—C(O)—, and heteroaryl (optionally substituted by one, two or three moieties each independently selected from C 1-6 alkyl or halogen).
4. The method of claim 1 , wherein L 3 is a —CH 2 —; and R h is selected from the group consisting of: halogen, C 1-6 alkyl (optionally substituted by one, two or three halogens), C 1-6 alkoxy (optionally substituted by one, two or three halogens), and R a R b N—.
5. The method of claim 4 , wherein R 7 is substituted by two moieties independently selected from R h .
6. The method of claim 1 , wherein L 3 is a —CH 2 —; and R 7 is substituted by R a R b N- and a moiety selected from the group consisting of: halogen, C 1-6 alkyl (optionally substituted by one, two or three halogens), and C 1-6 alkoxy (optionally substituted by one, two or three halogens).
7. The method of claim 6 , wherein R a and R b , together with the nitrogen to which they are attached, form a 4-6 membered saturated heterocyclic ring, which may have an additional heteroatom selected from O, S, and N, and the 4-6 membered saturated heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, C 1-6 alkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), hydroxyl, —C(O)—C 1-6 alkyl, —NH 2 , and —NH—C(O)—C 1-6 alkyl.
8. The method of claim 7 , wherein the 4-6 membered saturated heterocyclic ring is selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine, and the 4-6 membered saturated heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, C 1-6 alkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), hydroxyl, —C(O)—C 1-6 alkyl, —NH 2 , and —NH—C(O)—C 1-6 alkyl.
9. The method of claim 7 , wherein the 4-6 membered saturated heterocyclic ring is piperidine.
10. The method of claim 1 , wherein L 3 is a —CH 2 —; and R h is selected from the group consisting of: halogen, C 1-6 alkyl (optionally substituted by one, two or three halogens), C 1-6 alkoxy (optionally substituted by one, two or three halogens), and R a R b N—C(O)—.
11. The method of claim 10 , wherein R 7 is substituted by two moieties independently selected from R h .
12. The method of claim 1 , wherein the compound is 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-(morpholin-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound is 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[3-fluoro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the compound is 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-acetamidopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate, or a solvate, hydrate, stereoisomer, or pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the compound is 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)benzyl)piperazine-1-carboxylate, or a solvate, hydrate, or pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the compound is 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(4-(methylsulfonyl)piperazin-1-yl)benzyl)piperazine-1-carboxylate, or a solvate, hydrate, or pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the pain is neuropathic pain.
19. The method of claim 1 , wherein the pain is inflammatory pain.