Monoacylglycerol lipase modulators

Patent metadata

Field	Value
Publication number	US-11820766-B2
Application number	US-202017132313-A
Country	US
Kind code	B2
Filing date	Dec 23, 2020
Priority date	Sep 28, 2018
Publication date	Nov 21, 2023
Grant date	Nov 21, 2023

Abstract

Fused compounds of Formula (I) and Formula (II), 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 R 1 , R 2 , R 2a , R 3 , R 3a , R 4 , and R 4a are defined herein.

First claim

What is claimed:

1. A compound of Formula (I),

wherein:
R 2 is selected from the group consisting of:
(a)

(b) pyridyl substituted with OC 1-4 haloalkyl;
(c) pyrazole or 1H-1,2,4-triazole each substituted with one or two members each independently selected from the group consisting of: H, Cl, C 1-4 alkyl, cyclopropyl and phenyl;
(d)

where X is selected from the group consisting of: O, S, NH, and NCH 3 ;
R a is H or halo;
R b is selected from the group consisting of: H, halo and CH 3 ;
R c is H or CF 3 ; and
R d is H or CH 3 ;

R 3 is selected from the group consisting of:
(a) Phenyl; or phenyl independently substituted with one or two members selected from the group consisting of: halo and OC 1-4 haloalkyl;
(b)

 and
(c) C 3-4 cycloalkyl; and
R 4 is selected from the group consisting of: C 1-4 alkyl;
with the proviso that when R 2 is

 then R 3 is cyclopropyl, and pharmaceutically acceptable salts, isotopes, N-oxides, and stereoisomers thereof.

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

3. A compound as claimed in claim 1 , wherein R 2 is

4. A compound as claimed in claim 1 , wherein R 2 is

5. A compound as claimed in claim 1 , wherein R 2 is

6. A compound as claimed in claim 1 , wherein R 2 is

7. A compound as claimed in claim 1 , wherein R 2 is

8. A compound as claimed in claim 1 , wherein R 2 is

9. A compound as claimed in claim 1 , wherein R 2 is

10. A compound as claimed in claim 1 , wherein R 2 is

11. A compound as claimed in claim 1 , wherein R 2 is

12. A compound as claimed in claim 1 , wherein R 2 is

13. A compound as claimed in claim 1 , wherein R 2 is

14. A compound as claimed in claim 1 , wherein R 3 is phenyl, 3,5-difluorophenyl, 3-chlorophenyl, 3-fluorophenyl, or 3-(difluoromethoxy)phenyl.

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

16. A compound as claimed in claim 1 , wherein R 4 is CH 3 .

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

18. A compound as claimed in claim 1 , wherein X is S.

19. A compound as claimed in claim 1 , wherein X is NH or NCH 3 .

20. A compound selected from the group consisting of:
(2-Methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(naphthalen-1-yl)methanone;
(3-Cyclopropyl-2-methyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,3-dichlorophenyl)methanone;
(3-Cyclopropyl-2-methyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(naphthalen-1-yl)methanone;
(2-Fluoro-3-(trifluoromethoxy)phenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Methoxy-6-(trifluoromethyl)phenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(3-Methoxy-5-(trifluoromethyl)phenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Methoxy-3-methylphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Ethyl-3-methoxyphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(3,4-Dimethoxyphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2,6-Dimethoxyphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(3,5-Dimethoxyphenyl)-(2-methyl-3-phenyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Chloro-3-hydroxyphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Chloro-3-methoxyphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(3-Chloro-2-methoxy-phenyl)-(2-methyl-3-phenyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Chloro-6-methoxyphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(3-Chloro-5-methoxyphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Amino-3-methylphenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-(1H-1,2,4-Triazol-1-yl)phenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Methyl-3-morpholinophenyl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(5-Chloro-1-methyl-1H-pyrazol-4-yl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(1,5-Dimethyl-1H-pyrazol-4-yl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-phenyl-1H-1,2,4-triazol-3-yl)methanone;
(6-(Difluoromethoxy)pyridin-2-yl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-(trifluoromethoxy)pyridin-2-yl)methanone;
5-(2-Methyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-6-carbonyl)-2H-benzo[b][1,4]oxazin-3 (4H)-one;
(4-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
Benzo[d][1,3]dioxol-4-yl(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
Benzo[d][1,3]dioxol-5-yl(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2,2-Difluorobenzo[d][1,3]dioxol-4-yl)(2-methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(2-Methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4H-thieno[3,2-b]pyrrol-2-yl)methanone;
(2-Methyl-3-phenyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-methylimidazo[

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Ameriks Michael K
• Chen Gang
• Huang Chaofeng
• Laforteza Brian Ngo
• Ravula Suchitra
• Southgate Emma Helen
• Zhang Wei

Classifications

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title