# US 11,993,601 B2 · Monoacylglycerol lipase modulators

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- Number: US 11,993,601 B2
- Document ID: US11993601B2
- Status: Granted
- Kind: B2
- Application number: 18/160,647
- Filed: 2023-01-27
- Published: 2023-08-03
- Granted: 2024-05-28
- Earliest claimed: 2018-09-28
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Michael K. Ameriks; Gang Chen; Chaofeng Huang; Brian Ngo Laforteza; Suchitra Ravula; Wei Zhang
- Web page: https://patentgrep.com/patent/US11993601B2

## CPC

- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- C07D 471/18: Bridged systems
- C07D 471/04: Ortho-condensed systems
- C07D 519/00: 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
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Bridged 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 R2, R3 R4, R5 and R6 are defined herein.

## Claims

### Claim 1

A method of treating a patient suffering from or diagnosed with a condition selected from the group consisting of major depressive disorder, treatment resistant depression, anxious depression and bipolar disorder, comprising administering to a patient in need thereof a compound, having the structure of Formula (I):
wherein
R2 is selected from the group consisting of:
(a)
(b) 6-membered heteroaryl selected from the group consisting of: pyridazin-4-yl; pyrazin-2-yl; pyrimidinyl; pyrimidinyl substituted with C1-4alkyl or OC1-4alkyl; and pyridinyl, wherein the pyridinyl is substituted with one or two substituents each independently selected from the group consisting of: halo, C1-4alkyl, OC1-4alkyl, OC1-4haloalkyl, C3-6cycloalkyl, NH2, CN, N(CH3)2,
(c) 5-membered heteroaryl selected from the group consisting of:
(d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:
(e) 6,6-fused bicyclic heteroaryl selected from the group consisting of:
and
(f)
wherein
Ra is selected from the group consisting of: H, halo, C1-4alkyl, OC1-4alkyl, C1-4haloalkyl and OC1-4haloalkyl;
Ra1 is selected from the group consisting of: C1-4alkyl, OC1-4alkyl, OC1-4haloalkyl, N(C═O)CH3, oxazol-2-yl, pyrimidin-2-yl, and 5-membered heteroaryl ring containing two, three, or four nitrogen members, wherein the 5-membered heteroaryl ring is optionally substituted with one Ra member;
Rb is H or C1-4akyl;
Rc is H or C1-4haloalkyl;
Rd is H or halo;
Rc is selected from the group consisting of: H, halo, C1-4akyl, C1-4haloalkyl, OC1-4alkyl, and C3-6cycloalkyl;
Rf is selected from the group consisting of: H, C1-4alkyl, CH2CH2OH, C1-4haloalkyl, cyclopropyl, phenyl, and phenyl substituted with CF3;
Rg is selected from the group consisting of: H, OC1-4alkyl and C1-4haloalkyl;
Ri is H, halo, C1-4alkyl, C1-4haloalkyl, OH, OC1-4alkyl, OC1-4haloalkyl, C3-6cycloalkyl;
Rj is selected from the group consisting of: H, halo, OCH3, OH, NH2, and NO2;
R3 is selected from the group consisting of:
(g) phenyl, wherein phenyl is independently substituted with one, two, or three members selected from the group consisting of: halo, C1-4alkyl, C1-4haloalkyl, and OC1-4alkyl;
(h) 5-(trifluoromethyl)-2-thienyl or 1-methylindo1-2-yl; and
(i) cyclopropyl; and
R4 is C1-4alkyl or C3-4cycloalkyl;
and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein R2 is
where Ra is H, halo, C1-4alkyl, or OC1-4alkyl; and Ra1 is C1-4alkyl, OC1-4alkyl, OC1-4haloalkyl, or (C═O)NHCH3.

### Claim 3 (depends on 1)

The method of claim 1, wherein R2 is

### Claim 4 (depends on 1)

The method of claim 1, wherein R2 is:
where Ra is H, halo, C1-4alkyl, OC1-4alkyl, or C1-4haloalkyl; and is

### Claim 5 (depends on 4)

The method of claim 4, wherein is:

### Claim 6 (depends on 4)

The method of claim 4, wherein Ra is: H, Cl, F, CH3, CF3, or OCH3.

### Claim 7 (depends on 4)

The method of claim 4, wherein Rb is: H or CH3.

### Claim 8 (depends on 4)

The method of claim 4, wherein Rc is: H or CF3.

### Claim 9 (depends on 4)

The method of claim 4, wherein Rd is: H, Cl, or F.

### Claim 10 (depends on 1)

The method of claim 1, wherein R2 is:

### Claim 11 (depends on 1)

The method of claim 1, wherein R2 is:

### Claim 12 (depends on 1)

The method of claim 1, wherein R2 is:

### Claim 13 (depends on 1)

The method of claim 1, wherein R2 is:

### Claim 14 (depends on 1)

The method of claim 1, wherein R2 is:

### Claim 15 (depends on 1)

The method of claim 1, wherein R2 is
wherein Ra is H, Cl, Br, F, or OCH3, and Ra1 is OCH3 or

### Claim 16 (depends on 1)

The method of claim 1, wherein R2 is:

### Claim 17 (depends on 1)

The method of claim 1, wherein the condition is major depressive disorder.

### Claim 18 (depends on 1)

The method of claim 1, wherein the condition is treatment resistant depression.

### Claim 19 (depends on 1)

The method of claim 1, wherein the condition is anxious depression.

### Claim 20 (depends on 1)

The method of claim 1, wherein the condition is bipolar disorder.