Cyclobutyl amide monoacylglycerol lipase modulators

Patent metadata

Field	Value
Publication number	US-11802111-B2
Application number	US-202117480493-A
Country	US
Kind code	B2
Filing date	Sep 21, 2021
Priority date	Sep 22, 2020
Publication date	Oct 31, 2023
Grant date	Oct 31, 2023

Abstract

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 depression, major depressive disorder, treatment resistant depression, anxious depression, autism spectrum disorders, Asperger syndrome, and bipolar disorder), cancers and eye conditions:

wherein R 1 , , R 3 , and L are as defined herein.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein
R 1 is C 1-4 alkyl or C 1-4 haloalkyl;
is

wherein m, n, o, and p are each independently 1 or 2; and
wherein is optionally substituted with one, two, and three R 2 members;
wherein each R 2 is independently H, halo, OH, C 1-4 alkyl, or OC 1-4 alkyl;

L is a bond, C 1-4 alkyl, C 1-4 haloalkyl, or O; and
R 3 is:
(a) phenyl optionally substituted with one, two or three members each independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 haloalkyl, N(C 1-4 alkyl) 2 , pyrrolidinyl, C 3-6 cycloalkyl, OC 3-6 cycloalkyl, 1H-pyrazol-1-yl, and 1-methyl-1H-imidazol-4-yl;
(b) a 6-membered heteroaryl optionally substituted with one, two, or three members each independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 haloalkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl substituted with C 1-4 alkyl or C 1-4 haloalkyl;
(c) a 5-membered heteroaryl optionally substituted with one, two, or three members each independently selected from C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 haloalkyl, and phenyl;
(d) a fused 5-6 heteroaryl or a fused 6-6 heteroaryl each optionally substituted with one, two, or three members each independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, and OC 1-4 haloalkyl; or
(e) 2,3-dihydro-1H-indenyl, 2,3-dihydrobenzofuranyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinyl, or 6,7-dihydro-5H-cyclopenta[b]pyridinyl;

or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

2. The compound of claim 1 , wherein R 1 is CH 3 , CH 2 CH 3 , or CF 2 H.

3. The compound of claim 1 , wherein is

4. The compound of claim 1 , wherein is

 or is

5. The compound of claim 1 , wherein is

6. The compound of claim 1 , wherein R 2 is H, or is OH, or is OCH 3 , or is CH 3 , or is CH 2 CH 3 , or is F.

7. The compound of claim 1 , wherein R 2 is H, OH, OCH 3 , CH 3 , CH 2 CH 3 , or F, and is

8. The compound of claim 1 , wherein L is a bond, or is CH 2 , or is CH(CH 3 ), or is CF 2 , or is O.

9. The compound of claim 1 , wherein R 3 is:
phenyl optionally substituted with one two, or three members each independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, OC 1-4 haloalkyl, N(CH 3 ) 2 , pyrrolidin-1-yl, 1H-pyrazol-1-yl, 1-methyl-1H-imidazol-4-yl, C 3-6 cycloalkyl, and OC 3-6 cycloalkyl; or
phenyl substituted with one or two members independently selected from Cl, F, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , CHF 2 , CF 3 , CF 2 CH 3 , OCHF 2 , OCF 3 , N(CH 3 ) 2 , cyclopropyl, cyclobutyl, O-cyclopropyl 1H-pyrazol-1-yl, pyrrolidin-1-yl, and 1-methyl-1H-imidazol-4-yl; or
phenyl, o-tolyl, m-tolyl, p-tolyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-(tert-butyl)phenyl, 3-(tert-butyl)phenyl, 4-(tert-butyl)phenyl, 3-(difluoromethyl)phenyl, 4-(difluoromethyl)phenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 3-(1,1-difluoroethyl)phenyl, 4-(1,1-difluoroethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-(difluoromethoxy)phenyl, 4-(difluoromethoxy)phenyl, 2-(trifluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 2-cyclopropylphenyl, 3-cyclopropylphenyl, 4-cyclopropylphenyl, 3-cyclobutylphenyl, 4-cyclopropoxyphenyl, 3-(1H-pyrazol-1-yl)phenyl, 4-(1H-pyrazol-1-yl)phenyl, 3-(1-methyl-1H-imidazol-4-yl)phenyl, or 3-(pyrrolidin-1-yl)phenyl; or
2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, 2,3-dimethylphenyl, 3-ethyl-5-methylphenyl, 3-fluoro-4-methylphenyl, 2-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-2-methylphenyl, 2-fluoro-6-methylphenyl, 3-fluoro-5-methylphenyl, 2-fluoro-5-methylphenyl, 5-fluoro-2-methylphenyl, 2-fluoro-3-methylphenyl, 4-fluoro-2-methylphenyl, 3-fluoro-5-isopropylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-4-methylphenyl, 3-chloro-2-methylphenyl, 4-chloro-3-ethylphenyl, 3-(difluoromethyl)-5-methylphenyl, 3-(difluoromethyl)-4-methylphenyl, 4-(difluoromethyl)-3-methylphenyl, 2-methyl-5-(trifluoromethyl)phenyl, 4-methyl-3-(trifluoromethyl)phenyl, 3-methyl-5-(trifluoromethyl)phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 2-methyl-3-(trifluoromethyl)phenyl, 2-methyl-6-(trifluoromethyl)phenyl, 5-methyl-2-(trifluoromethyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 3-methyl-2-(trifluoromethyl)phenyl, 2-methyl-4-(trifluoromethyl)phenyl, 3-ethyl-5-(trifluoromethyl)phenyl, 2-isopropyl-3-(trifluoromethyl)phenyl, 3-isopropyl-2-(trifluoromethyl)phenyl, 3-fluoro-5-methoxyphenyl, 2-fluoro-3-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 3-ethoxy-5-fluorophenyl, 3-chloro-5-methoxyphenyl, 4-chloro-3-methoxyphenyl, 2-chloro-3-methoxyphenyl, 2-methoxy-3-methylphenyl, 3-methoxy-5-methylphenyl, 3-methoxy-2-methylphenyl, 4-methoxy-3-methylphenyl, 3-methoxy-4-methylphenyl, 5-methoxy-2-methylphenyl, 3-ethyl-5-methoxyphenyl, 3-ethyl-2-methoxyphenyl, 3-(tert-butyl)-4-methoxyphenyl, 2-(difluoromethyl)-4-methoxyphenyl, 4-(difluoromethyl)-2-methoxyphenyl, 4-methoxy-2-(trifluoromethyl)phenyl, 3-ethoxy-4-methylphenyl, 3-ethoxy-2-methylphenyl, 3-isopropoxy-2-methylphenyl, 4-(difluoromethoxy)-2-methylphenyl, 3-(difluoromethoxy)-5-methylphenyl, 5-(difluoromethoxy)-2-methylphenyl, 3-(difluoromethoxy)-4-methylphenyl, 4-(difluoromethoxy)-3-methylphenyl, 2-methyl-4-(trifluoromethoxy)phenyl, 3-methyl-5-(trifluoromethoxy)phenyl, 4-methyl-3-(trifluoromethoxy)phenyl, 3-methyl-4-(trifluoromethoxy)phenyl, 4-methoxy-3-(trifluoromethyl)phenyl, 3-methoxy-5-(trifluoromethyl)phenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 4-ethoxy-3-(trifluoromethyl)phenyl, 3-ethoxy-5-(trifluoromethyl)phenyl, 3-chloro-5-(trifluoromethoxy)phenyl, 3-ethyl-5-(trifluoromethoxy)phenyl, 3-(dimethylamino)-5-(trifluoromethyl)phenyl, 3-(dimethylamino)-4-(trifluoromethyl)phenyl, 4-cyclopropyl-3-fluorophenyl, 3-cyclopropyl-2-fluorophenyl, 5-cyclopropyl-2-fluorophenyl, 3-cyclopropyl-4-fluorophenyl, 3-cyclopropyl-2-methylphenyl, 3-cyclopropyl-5-methylphenyl, 4-cyclopropyl-3-methylphenyl, 2-cyclopropyl-3-methylphenyl, 3-cyclopropyl-4-methylphenyl, 4-cyclopropyl-2-methylphenyl, 3-cyclopropyl-5-methoxyphenyl, 3-cyclopropyl-4-methoxyphenyl, 4-cyclopropyl-3-methoxyphenyl, 3-cyclopropoxy-2-methylphenyl, 3-fluoro-5-methoxy-4-methylphenyl, 2,5-difluoro-3-methoxyphenyl, or 2,3-difluoro-5-methoxyphenyl; or

10. The compound of claim 1 , wherein R 3 is:
pyrazin-2-yl substituted with C(CH 3 ) 3 ; pyrimidin-2-yl substituted with CF or C(CH 3 ) 3 ; or pyridine optionally substituted with one, two or three members each independently selected from Cl, F, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Alcazar Jesus
• Ameriks Michael K
• Berry Cynthia B
• Garcia-Reynaga Pablo
• Laforteza Brian Ngo
• Samant Andrew V

Classifications

• C07D205/12 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title