# US 11,897,872 B2 · Azaspirocycles as monoacylglycerol lipase modulators

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- Number: US 11,897,872 B2
- Document ID: US11897872B2
- Status: Granted
- Kind: B2
- Application number: 18/051,130
- Filed: 2022-10-31
- Published: 2023-07-20
- Granted: 2024-02-13
- Earliest claimed: 2020-03-26
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Jesus Alcazar; Michael K. Ameriks; Cynthia B. Berry; Pablo Garcia-Reynaga; Andrew V. Samant; J. A. Vega-Ramiro
- Web page: https://patentgrep.com/patent/US11897872B2

## CPC

- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 25/00: Drugs for disorders of the nervous system
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Azaspirocycle 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 X, R1, R2a, R2b, R3, m, n, o, and p are defined herein.

## Claims

### Claim 1

A method of treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I):
wherein
X is CH2 or O;
R1 is H;
R2a and R2b are each independently selected from H and C1-4alkyl;
R3 is selected from:
(i) phenyl, benzyl, or monocyclic heteroaryl, each optionally substituted with one, two, or three substituents selected from: halo, C1-6alkyl, C1-6haloalkyl, C1-6alkyl-OH, OC1-6alkyl, OC1-6haloalkyl, SC1-6alkyl, SF5, Si(CH3)3, NRaRb, C3-6cycloalkyl, OC3-6cycloalkyl, phenyl, O-phenyl, and O-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl is optionally substituted with one or two C1-4alkyl, C1-4haloalkyl, or halo groups; or two adjacent ring substituents on the phenyl, benzyl, or monocyclic heteroaryl, taken together with the atoms to which they are attached form a fused monocyclic C5-6cycloalkyl or heterocycloalkyl ring, each ring optionally substituted with one or two C1-4alkyl, C1-4haloalkyl, or halo groups;
wherein Ra and Rb are each independently H or C1-4alkyl;
(ii) a bicyclic heteroaryl optionally substituted with C1-4alkyl or halo; and
(iii) C3-6alkyl or C3-6cycloalkyl optionally substituted with C1-4alkyl, C1-4haloalkyl, or halo; and
n, m, o, and p are each independently 1 or 2;
or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein
R3 is selected from: C3-6cycloalkyl; C3-6cycloalkyl substituted with C1-4alkyl; phenyl; phenyl substituted with one or two members each independently selected from: halo, C1-6alkyl, C1-6 haloalkyl, OC1-6alkyl, OC1-6haloalkyl, and C3-6cycloalkyl optionally substituted with CH3 or CF3; pyridyl substituted with one or two members each independently selected from: halo, C1-6alkyl, and C1-6haloalkyl; pyrimidinyl substituted with C1-6alkyl;

### Claim 3 (depends on 1)

The method of claim 1, wherein X is CH2.

### Claim 4 (depends on 1)

The method of claim 1, wherein X is O.

### Claim 5 (depends on 1)

The method of claim 1, wherein (a) R2a and R2b are each H; of (b) R2a and R2b are each CH3; or (c) R2a is H and R2b is CH3.

### Claim 6 (depends on 1)

The method of claim 1, wherein R3 is:
(a) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
(b)
(c) R3 is phenyl, or phenyl substituted with one or two members each independently selected from: Cl, F, CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3, cyclopropyl, cyclopropyl substituted with CF3, and cyclobutyl;
(d)
or
(g) 4-trifluoromethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-cyclopropylphenyl.

### Claim 7 (depends on 1)

The method of claim 1, wherein:
(a) n and o are each 1;
(b) n and o are each 2;
(c) n is 1 and o is 2;
(d) m and p are each 1;
(e) m and p are each 2;
(f) m is 1 and p is 2;
(g) m, n, o, and p are each 1;
(h) m, n, and p are each 1 and o is 2;
(i) m, n, and o are each 1 and p is 2;
(j) n and o are each 2 and m and p are each 1;
(k) n and o are each 1 and m and p are each 2; or
(l) n, o, and p are each 2 and m is 1.

### Claim 8

A method of treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound selected from:
(2s,4s)-2-(2-Phenyl-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(p-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(3-Cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(m-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(3-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-[3-(Trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(2,4-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(2-(Tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-(2-(5-(tert-Butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
2-[2-[3-(Trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-[2-[4-[1-(Trifluoromethyl)cyclopropyl]phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-[2-[3-Chloro-4-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-[2-(2,5-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-[2-[4-Methoxy-3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(4-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-(2-(5-(tert-Butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-(2-(5-(tert-Butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-[2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4s)-2-(2-(5-(tert-Butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(2-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(4-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(3-Fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(6-(Trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(5-Fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(2-(tert-Butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(4-(tert-Butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-[2-(2-(tert-Butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(3,5-Difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-8-Methyl-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2r,4S*)-2-((R*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4R*)-2-((S*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2r,4S*)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2r,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-Cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2r,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3 0.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(2-(4-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(3-Isopropylphenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(rac)-(2r,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;
(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(2-Phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(m-Tolyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(3,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(3,5-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(2,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(3-Cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(3-Cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-(2,3-Dihydro-1H-inden-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-Phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(7-Phenyl-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and
(2s,4s)-2-(6-(1-Methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
and pharmaceutically acceptable salts, isotopes, N-oxides, and stereoisomers thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein the compound is selected from:
(2r,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;
(2s,4s)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
(2s,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and
(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;
and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound comprises the structure of Formula (IA):
wherein
X is CH2 or O;
R2a and R2b are each independently selected from H and CH3;
R3 is selected from: C3-6cycloalkyl; C3-6cycloalkyl substituted with C1-4alkyl; phenyl; phenyl substituted with one or two members each independently selected from: C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and
and
m and p are each independently 1 or 2;
or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound comprises the structure of Formula (TB):
wherein
X is O;
R3 is selected from: phenyl and phenyl substituted with C1-6alkyl; and
m and p are each 1;
or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound comprises the structure of Formula (IC):
wherein
X is CH2 or O;
R2a and R2b are each independently selected from H and CH3;
R3 is selected from: C3-6cycloalkyl; phenyl; phenyl substituted with one or two members each independently selected from: halo, C1-6alkyl, C1-6haloalkyl, OC1-6alkyl, OC1-6haloalkyl, and C3-6cycloalkyl; pyridyl substituted with one or two members each independently selected from: halo, C1-6alkyl, and C1-6haloalkyl; pyrimidinyl substituted with C1-6alkyl;
and
m and p are each independently 1 or 2;
or a pharmaceutically acceptable salt, isotope, N-oxide, or stereoisomer thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein the MGL receptor mediated disease, disorder, or condition is selected from: pain, psychiatric conditions, neurological conditions, cancers, and eye conditions.

### Claim 14 (depends on 1)

The method of claim 1, wherein the MGL receptor mediated disease, disorder or condition is selected from: major depressive disorder, treatment resistant depression, anxious depression, autism spectrum disorders, Asperger syndrome, and bipolar disorder.

### Claim 15 (depends on 1)

The method of claim 1, wherein the MGL receptor mediated disease, disorder or condition is inflammatory pain.