Carbamate compounds and methods of making and using same

Patent metadata

Field	Value
Publication number	US-11530189-B2
Application number	US-202117195351-A
Country	US
Kind code	B2
Filing date	Mar 8, 2021
Priority date	Jan 6, 2012
Publication date	Dec 20, 2022
Grant date	Dec 20, 2022

Abstract

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.

First claim

What is claimed is:

1. A method of treating epilepsy 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 pyrrolidine.

10. The method of claim 7 , wherein the 4-6 membered saturated heterocyclic ring is morpholine.

11. The method of claim 7 , wherein the 4-6 membered saturated heterocyclic ring is piperidine.

12. 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), and heteroaryl (optionally substituted by one, two or three moieties each independently selected from C 1-6 alkyl or halogen).

13. The method of claim 12 , wherein R 7 is substituted by two moieties independently selected from R h .

14. 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)—.

15. The method of claim 14 , wherein R 7 is substituted by two moieties independently selected from R h .

16. The method of claim 1 , wherein L 3 is —S(O) 2 —.

17. The method of claim 1 , wherein L 3 is —C(O)—.

18. The method of claim 1 , wherein L 3 is a bond.

19. 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.

20. 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]4-methyl]piperazine-1-carboxylate, or a pharmaceutically acceptable salt thereof.

21. 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.

22. 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.

23. 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.

24. 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.

Assignees

• H Lundbeck As
• Scripps Research Inst
• H Lundbecka/S

Inventors

• Cisar Justin S
• Grice Cheryl A
• Jones Todd K
• Niphakis Micah J
• Chang Jae Won
• Lum Kenneth M
• Cravatt Benjamin F

Classifications

• C07D271/06

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title