Monoacylglycerol lipase modulators

Patent metadata

Field	Value
Publication number	US-11891387-B2
Application number	US-202117212377-A
Country	US
Kind code	B2
Filing date	Mar 25, 2021
Priority date	Mar 26, 2020
Publication date	Feb 6, 2024
Grant date	Feb 6, 2024

Abstract

Fused and bridged compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, 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, autism spectrum disorders, Asperger syndrome, bipolar disorder), cancers and eye conditions:

wherein R 1a , R 1b , R 2 , and R 3 , are defined herein.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein
R 1a is C 1-4 alkyl;
R 1b is H;
or R 1a and R 1b taken together form —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —;
R 2 is selected from:
(a) phenyl or pyridyl, each optionally substituted with one or two substituents selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C 3-6 cycloalkyl, or two adjacent ring substituents taken together with the carbons to which they are attached form a monocyclic cycloalkyl or hetercycloalkyl ring; and
(b) bicyclic heteroaryl optionally substituted with one or two substituents selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C 3-6 cycloalkyl; and

R 3 is 1H—C 1-4 alkyl-pyrazolyl, 1H—C 1-4 haloalkyl-pyrazolyl, 1H-pyridyl-pyrazolyl, 1H—(C 3 -6cycloalkyl)-pyrazolyl, or 1H—(C 3-6 cycloalkyl-methyl)-pyrazolyl, each pyrazolyl optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;
provided that when R 2 is phenyl or pyridyl, each optionally substituted with halo, C 1-4 alkyl, or C 1-4 haloalkyl, then (a) R 1a and R 1b are taken together form —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —;
or (b) R 3 is not 1H—C 1-4 alkyl-pyrazol-5-yl

 or 1H—C 1-4 haloalkyl-pyrazol-5-yl

 or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

2. The compound of claim 1 , wherein R 2 is selected from:
(a)

(b) a 5,6-fused or 6,5-fused heteroaryl selected from:

(c) a fused 6,6-heteroaryl selected from:

(d)

R 3 is a 5-membered heteroaryl ring selected from:

 wherein
R a is selected from: H, halo, C 1-4 alkyl, C 1-4 haloalkyl, and OC 1-4 alkyl;
R b is selected from: C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 haloalkyl,

each R c is independently selected from: halo, C 1-4 alkyl, and OC 1-4 alkyl;
R d is H or C 1-4 alkyl;
each R e is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl;
each R f is independently selected from: C 1-4 alkyl, C 1-4 haloalkyl, and OC 1-4 alkyl;
R g is C 1-4 alkyl, or C 1-4 haloalkyl; and
R h is selected from: H, C 1-4 alkyl, C 1-4 haloalkyl, and cycloalkyl;

n is 0, 1, or 2; and
m is 0, 1, or 2.

3. The compound of claim 1 , wherein R 1a is CH 3 and R 1b is H.

4. The compound of claim 1 , wherein R 1a and R 1b come together to form —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —.

5. The compound of claim 1 , wherein R 2 is:
(a)

 wherein R a is H, Cl, F, C 1-4 alkyl or C 1-4 haloalkyl; and R b is C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;
(b)

 wherein R a is Cl, F, or C 1-4 alkyl; and R b is

 or
(c)

6. The compound of claim 5 , wherein R 1a is CH 3 and R 2 is

wherein R a is Cl or F, and R b is OC 1-4 alkyl.

7. The compound of claim 1 , wherein R 2 is:
(a)

(b)

 or
(c)

8. The compound of claim 1 , wherein R 2 is

wherein each R c is independently selected from: F, CH 3 , and OCH 3 ; and
m and n are each independently 0 or 1.

9. The compound of claim 1 , wherein (a) R 1a is C 1-4 alkyl or R 1a and R 1b come together to form —CH 2 CH 2 CH 2 —, and (b) R 2 is

10. The compound as claimed in claim 1 or claim 2 , wherein R 3 is

11. The compound of claim 2 , wherein (a) m is 1 or 2; (b) n is 1 or 2; or (c) m and n are each 1.

12. The compound of claim 1 , wherein the compound is selected from:
(S)-(2,7-Dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-5-yl)methanone;
(S)-(3-(1,4-Dimethyl-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone;
(S)-(3-(1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone;
(S)-(2-Chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone;
(S)-(2,7-Dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoro-1H-indol-3-yl)methanone;
(S)-(2,7-Dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-3-yl)methanone;
(S)-(2,7-Dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylpyrazolo[1,5-a]pyridin-3-yl)methanone;
(S)-(2,7-Dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone;
(S)-(2,7-Dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-4-yl)methanone;
(S)-(2,7-Dimethyl-3-(1-methyl-3-(trifluorometh

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Ameriks Michael K
• Laforteza Brian Ngo
• Ravula Suchitra
• Schiffer Jamie M
• Stenne Brice M

Classifications

• C07D471/04 Primary

  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

• C07D491/10

  Spiro-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title