Azaspirocycles as monoacylglycerol lipase modulators

Patent metadata

Field	Value
Publication number	US-11897872-B2
Application number	US-202218051130-A
Country	US
Kind code	B2
Filing date	Oct 31, 2022
Priority date	Mar 26, 2020
Publication date	Feb 13, 2024
Grant date	Feb 13, 2024

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, R 1 , R 2a , R 2b , R 3 , m, n, o, and p are defined herein.

First claim

What is claimed is:

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 CH 2 or O;
R 1 is H;
R 2a and R 2b are each independently selected from H and C 1-4 alkyl;
R 3 is selected from:
(i) phenyl, benzyl, or monocyclic heteroaryl, each optionally substituted with one, two, or three substituents selected from: halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-OH, OC 1-6 alkyl, OC 1-6 haloalkyl, SC 1-6 alkyl, SF 5 , Si(CH 3 ) 3 , NR a R b , C 3-6 cycloalkyl, OC 3-6 cycloalkyl, phenyl, O-phenyl, and O-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl is optionally substituted with one or two C 1-4 alkyl, C 1-4 haloalkyl, 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 C 5-6 cycloalkyl or heterocycloalkyl ring, each ring optionally substituted with one or two C 1-4 alkyl, C 1-4 haloalkyl, or halo groups;
wherein R a and R b are each independently H or C 1-4 alkyl;

(ii) a bicyclic heteroaryl optionally substituted with C 1-4 alkyl or halo; and
(iii) C 3-6 alkyl or C 3-6 cycloalkyl optionally substituted with C 1-4 alkyl, C 1-4 haloalkyl, 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.

2. The method of claim 1 , wherein
R 3 is selected from: C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with C 1-4 alkyl; phenyl; phenyl substituted with one or two members each independently selected from: halo, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl, OC 1-6 haloalkyl, and C 3-6 cycloalkyl optionally substituted with CH 3 or CF 3 ; pyridyl substituted with one or two members each independently selected from: halo, C 1-6 alkyl, and C 1-6 haloalkyl; pyrimidinyl substituted with C 1-6 alkyl;

3. The method of claim 1 , wherein X is CH 2 .

4. The method of claim 1 , wherein X is O.

5. The method of claim 1 , wherein (a) R 2a and R 2b are each H; of (b) R 2a and R 2b are each CH 3 ; or (c) R 2a is H and R 2b is CH 3 .

6. The method of claim 1 , wherein R 3 is:
(a) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
(b)

(c) R 3 is phenyl, or phenyl substituted with one or two members each independently selected from: Cl, F, CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 , cyclopropyl, cyclopropyl substituted with CF 3 , and cyclobutyl;
(d)

 or
(g) 4-trifluoromethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-cyclopropylphenyl.

7. 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.

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-(te

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Alcazar Jesus
• Ameriks Michael K
• Berry Cynthia B
• Garcia-Reynaga Pablo
• Samant Andrew V
• Vega-Ramiro J A

Classifications

• C07D413/06 Primary

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

• C07D401/06

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/06

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

• C07D413/14

  containing three or more hetero rings · CPC title