Aminocyclobutanes as monoacylglycerol lipase modulators

Patent metadata

Field	Value
Publication number	US-11512059-B2
Application number	US-202117212302-A
Country	US
Kind code	B2
Filing date	Mar 25, 2021
Priority date	Mar 26, 2020
Publication date	Nov 29, 2022
Grant date	Nov 29, 2022

Abstract

Aminocyclobutane compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing 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 and R4 are defined herein.

First claim

What is claimed is:

1. 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;

R 4 is C 1-6 alkyl;
or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

2. A compound of Formula (I):

wherein
X is CH 2 or O;
R 1 is H;
R 2a and R 2b are each H;
R 3 is selected from: C 1-6 alkyl (optionally C 3-6 alkyl); C 3-6 cycloalkyl; benzyl; phenyl; phenyl substituted with one or two members each independently selected from: halo, C 1-6 alkyl, OC 1-6 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl substituted with CH 3 or CF 3 ; 2,3-dihydro-1H-inden-5-yl; bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and 5,6,7,8-tetrahydronaphthalen-2-yl; and
R 4 is C 1-6 alkyl;
or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

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

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

5. The compound of claim 1 , wherein R 3 is tert-butyl.

6. The compound of claim 1 , wherein R 3 is

7. The compound of claim 1 , wherein R 3 is

8. The compound of claim 1 , wherein R 3 is benzyl, phenyl, or phenyl substituted with one or two members each independently selected from: F, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 3 , cyclopropyl, cyclopropyl substituted with CH 3 or CF3, and cyclobutyl.

9. The compound of claim 1 , wherein R 3 is

10. The compound of claim 1 , wherein R 3 is 3,5-dimethylphenyl, 3-ethyl-5-methylphenyl, 4-ethyl-3-methylphenyl, 3-isopropylphenyl, or 3-tert-butylphenyl.

11. The compound of claim 1 , wherein X is O, and R 2a and R 2b are each H.

12. The compound of claim 1 , wherein X is CH 2 , and R 2a and R 2b are each H.

13. The compound of claim 1 , wherein X is O and R 3 is phenyl substituted with one or two members each independently selected from: F, C 1-6 alkyl, OCH 3 , cyclopropyl, cyclopropyl substituted with CH 3 or CF3, and cyclobutyl.

14. The compound of claim 1 , wherein R 4 is CH 3 or CH 2 CH 3 .

15. A compound selected from:
(2s,4S)-N-Methyl-6-oxo-N-((1s,3S)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-Methyl-6-oxo-N-((1r,3R)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3-Cyclobutylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(4-(tert-Butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1r,3R)-3-(4-(tert-Butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3-(tert-Butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2r,4S)-N-((1s,3S)-3-(3-(tert-Butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3,5-Dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1r,3R)-3-(3,5-Dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3-Isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3-Methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1r,3R)-3-(3-Methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(4-Isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3-(tert-Butyl)-4-fluorophenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-Methyl-6-oxo-N-((1s,3S)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-Methyl-6-oxo-N-((1r,3R)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-Methyl-6-oxo-N-((1s,3S)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-Methyl-6-oxo-N-((1r,3R)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-Methyl-6-oxo-N-((1s,3S)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-Methyl-6-oxo-N-((1r,3R)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3-Ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(2,3-Dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1r,3R)-3-(2,3-Dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(4-Cyclopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3,4-Dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3-Fluoro-4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(4-Fluoro-3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(2,4-Dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(4-Ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(4-Ethyl-3-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(4-Cyclopropyl-3-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3S)-3-(3-Cyclopropyl-4-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-Methyl-6-oxo-N-((1s,3S)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1r,3S)-3-Benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;
(2s,4S)-N-((1s,3R)-3-Benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octa

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Ameriks Michael K
• Garcia-Reynaga Pablo

Classifications

• C07D263/52 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/423

  condensed with carbocyclic rings · CPC title