IP Library › Patent Application 19197599

Patent Application

App. No. 19/197,599

DUAL MAGL AND FAAH INHIBITORS

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Patent No.: US None
App. No.: 19/197,599

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Abstract

Provided herein are compounds and pharmaceutical compositions comprising said compounds useful as modulators of MAGL and/or FAAH. The subject compounds and compositions are useful for the treatment of pain and neurological disorders.

Claims (78)

1 - 42 . (canceled)

43 . A compound having the structure of Formula (II):

wherein:

each R 1 is independently selected from halogen, —CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkyl-OR 7 , C 1-6 haloalkyl, C 3-8 cycloalkyl, —NR 5 R 6 , —C(O)NR 5 R 6 , —OR 7 , —SO 2 R 12 , —SF 5 , —SR 8 , aryl, and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and —C(O)NR 8 R 9 ; or two adjacent R 1 form a heterocycloalkyl ring optionally substituted with one or two R 11 ;

R 2 is C 1-6 alkyl;

R 3 is selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, —NR 8 R 9 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , and —NR 9 SO 2 R 8 ;

R 3a is selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl;

each R 5 and R 6 is independently selected from H, C 1-6 alkyl, and C 3-8 cycloalkyl; or R 5 and R 6 , together with the nitrogen to which they are attached, form a heterocycloalkyl optionally substituted with one or two R 10 ;

each R 7 is independently selected from H, C 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or two groups independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl;

each R 8 and R 9 is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and heteroaryl;

each R 10 is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, halogen, oxo, —CN, —C(O)OR B , —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 11 is independently selected from halogen and C 1-6 alkyl;

each R 12 is independently selected from C 1-6 alkyl and C 3-8 cycloalkyl;

m is 0, 1, 2, 3, 4, or 5;

n is 0, 1, 2, or 3;

p is 0 or 1; and

q is 0 or 1;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

44 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0 or 1.

45 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1 and R 2 is —CH 3 .

46 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

47 . The compound of claim 46 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1.

48 . The compound of claim 43 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is

49 . The compound of claim 48 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 1 or 2.

50 . A compound having the structure of Formula (III):

wherein:

R 3 is selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, —NR 8 R 9 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , and —NR 9 SO 2 R 8 ;

R 3a is selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl;

each R 1 and R 9 is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and heteroaryl;

each R 10 is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, halogen, oxo, —CN, —C(O)OR 8 , —C(O)R 8 , —C(O)NR 8 R 9 , —SO 2 R′, —NR 9 C(O)R 8 , and —NR 9 SO 2 R 8 ;

each R 11 is independently selected from halogen and C 1-6 alkyl;

each R 12 is independently selected from C 1-6 alkyl and C 3-8 cycloalkyl;

m is 0, 1, 2, 3, 4, or 5;

q is 0 or 1;

w is 1 or 2;

x is 0 or 1;

y is 0 or 1; and

z is 0 or 1;

wherein when y and z are 0, then x is 1 and w is 2;

when y and z are 1, then w is 1; and

when y is 1 and z is 0, or y is 0 and z is 1, then x is 1;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

51 . The compound of claim 50 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having the structure of Formula (IIIa):

52 . The compound of claim 50 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having the structure of Formula (IIIb):

53 . A compound having the structure of Formula (IV):

wherein:

R 3 is selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, —NR 8 R 9 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , and —NR 9 SO 2 R 8 ;

R 3a is selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl;

each R 1 and R 9 is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and heteroaryl;

each R 11 is independently selected from halogen and C 1-6 alkyl;

each R 12 is independently selected from C 1-6 alkyl and C 3-8 cycloalkyl;

m is 0, 1, 2, 3, 4, or 5; and

q is 0 or 1;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

54 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3 is C 1-6 haloalkyl, —CF 3 , halogen, —C(O)NH 2 , or —CN.

55 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0 or 1.

56 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, —NR 5 R 6 , —OR 7 , and heteroaryl.

57 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, aryl, and heteroaryl.

58 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5 and R 6 , together with the nitrogen to which they are attached, form:

a. a heterocycloalkyl optionally substituted with one or two R 10 ;

b. a heterocycloalkyl ring substituted with one or two R 10 independently selected from C 1-6 alkyl and —C(O)NR 8 R 9 ;

c. an unsubstituted heterocycloalkyl; or

d. a heterocycloalkyl selected from:

59 . The compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two adjacent R 1 form a heterocycloalkyl ring optionally substituted with one or two R 11 .

60 . A compound selected from:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

61 . A pharmaceutical composition comprising the compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

62 . A method of treating pain or a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 43 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.