Monoacylglycerol lipase modulators

Patent metadata

Field	Value
Publication number	US-11708359-B2
Application number	US-202117171559-A
Country	US
Kind code	B2
Filing date	Feb 9, 2021
Priority date	Feb 10, 2020
Publication date	Jul 25, 2023
Grant date	Jul 25, 2023

Abstract

3.1.0 and 4.1.0 Azabicycle compounds of Formula (I), pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, bipolar disorder), cancers and eye conditions.wherein X, Y, R1, R2a, and R2b are defined herein.

First claim

What is claimed:

1. A compound of Formula (I),

wherein
X is CH 2 or O;
Y is selected from the group consisting of:

R 1 is H;
R 2a and R 2b are each independently H;
R 3 is selected from the group consisting of: 2,3-dihydro-1H-indene; pyridyl substituted with C 1-6 alkyl; phenyl; and phenyl substituted with one or two members each independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkyl substituted with OH, C 1-6 alkyl substituted with CO 2 H, C 1-6 haloalkyl, OC 1-6 haloalkyl, C 3-6 cycloalkyl, O-phenyl, and C 3-6 cycloalkyl substituted with CH 3 ;
R a and R b are each independently selected from the group consisting of: H and halo; and
R c is H or CH 3 ;
and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

2. A compound as claimed in claim 1 , wherein X is CH 2 .

3. A compound as claimed in claim 1 , wherein X is O.

4. A compound as claimed in claim 1 , wherein Y is

5. A compound as claimed in claim 1 , wherein Y is

6. A compound as claimed in claim 1 , wherein Y is

7. A compound as claimed in claim 1 , wherein R a and R b are H.

8. A compound as claimed in claim 1 , wherein R a and R b are each independently selected from the group consisting of: H and Cl.

9. A compound as claimed in claim 1 , wherein R a and R b are F.

10. A compound as claimed in claim 1 , wherein R 3 is

11. A compound as claimed in claim 1 , wherein R 3 is phenyl, or phenyl substituted with one or two members each independently selected from the group consisting of: Cl, F, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 2 CH 2 OH, C(CH 3 ) 2 CH 2 CO 2 H, CF 3 , OCF 3 , cyclopropyl, cyclopropyl substituted with CH 3 , and O-phenyl.

12. A compound as claimed in claim 1 , wherein R 3 is

13. A compound as claimed in claim 1 , wherein R 3 is 3-tert-butylphenyl, 4-tert-butylphenyl, 4-methyl-3-trifluoromethylphenyl, or 3,4-dimethylphenyl.

14. A compound as claimed in claim 1 , selected from the group consisting of:
(rac)-(25,45)-2-(1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa azaspiro[3.4]octan-6-one;
(2s,4*R)-2-((1*S,5*R)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa azaspiro[3.4]octan-6-one;
(2s,4*S)-2-((1*R,5*S)-1-(p-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(25,45)-2-(1-Phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(25,45)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4*S)-2-((1*R,5*S)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4*R)-2-((1*S,5*R)-1-(3-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(25,45)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4*S)-2-((1*R,5*S)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4*R)-2-((1*S,5*R)-1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2r,45)-2-(1-(4-Isopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;
(rac)-(2r,45)-2-(1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl) azaspiro[3.4]octan-6-one;
(2r,4*S)-2-((1*R, 5*S)-1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl) azaspiro[3.4]octan-6-one;
(2r,4*R)-2-((1*S, 5*R)-1-(4-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl) azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-(tert-Butyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(4-Cyclopropylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(o-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(m-Tolyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(4-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(4-(Trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(4-Methyl-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2r,4s)-2-(1-(4-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(4-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-Phenoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-Chloro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl) oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-(1-Methylcyclopropyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(4-Cyclopropyl-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(2-Methyl-4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-Methyl-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(1-(3-Fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4S)-2-((1R,5S,6S)-6-(3-(Trifluoromethoxy)phenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4S)-2-((1R,6S)-6-Phenyl-3-azabicyclo[4.1.0]heptane-3-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4R)-2-((1S,6R)-6-Phenyl-3-azabicyclo[4.1.0]heptan

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Ameriks Michael K
• Berry Cynthia B
• Garcia-Reynaga Pablo
• Laforteza Brian Ngo
• Liang Jimmy T

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/06

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

• C07D403/06

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

• C07D413/06 Primary

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

• C07D401/08 Primary

  linked by a carbon chain containing alicyclic rings · CPC title