IP Library › Granted Patent US 11,512,059
Granted Patent B2
US 11,512,059 · App. 17/212,302 · Granted Nov 29, 2022

Aminocyclobutanes as monoacylglycerol lipase modulators

Inventors: Michael K. Ameriks (San Diego, CA); Pablo Garcia-Reynaga (San Diego, CA)
Assignee: Janssen Pharmaceutica NV
C07D263/52
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Quick Facts
Patent No.
US 11,512,059
App. No.
17/212,302
Granted
Nov 29, 2022
Kind
B2
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, R 1 , R 2a , R 2b , R 3 and R 4 are defined herein.

Claims (87)

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]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(tert-Butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1r,3R)-3-(tert-Butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-Cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1r,3R)-3-Cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-Methyl-N-((1s,3S)-3-(4-(1-methylcyclopropyl)phenyl)cyclobutyl)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(4-(Sec-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-Methyl-N-((1s,3S)-3-(3-(1-methylcyclopropyl)phenyl)cyclobutyl)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(3-Ethyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(3-Cyclopropyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(3-Isopropyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(3-Chloro-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(3-Cyclopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(2,3-Dihydro-1H-inden-5-yl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

(2s,4S)-N-((1s,3S)-3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and

(2s,4S)-N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-ethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

16. A pharmaceutical composition comprising:

(A) a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, and

(B) at least one pharmaceutically acceptable excipient.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 9, 2021
From: AMERIKS, MICHAEL K.; GARCIA-REYNAGA, PABLO
To: JANSSEN RESEARCH & DEVELOPMENT, LLC
Reel/Frame 056484/0942 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 9, 2021
From: JANSSEN RESEARCH & DEVELOPMENT, LLC
To: JANSSEN PHARMACEUTICA NV
Reel/Frame 056485/0016 →
Continuity (2)
Provisional Application 63000298 · Mar 26, 2020
Related Publication 20210317094A1 · Oct 14, 2021