1-heteroaryl-indoline-4-carboxamides as modulators of GPR52 useful for the treatment or prevention of disorders related thereto

Patent metadata

Field	Value
Publication number	US-9676758-B2
Application number	US-201615143026-A
Country	US
Kind code	B2
Filing date	Apr 29, 2016
Priority date	Apr 29, 2015
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

The present invention relates to compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of GPR52. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a GPR52-mediated disorder (e.g., Huntington's disease, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD), or Tourette's syndrome); an extrapyramidal or movement disorder; a motor disorder; a hyperkinetic movement disorder; a psychotic disorder; catatonia; a mood disorder; a depressive disorder; an anxiety disorder; obsessive-compulsive disorder (OCD); an autism spectrum disorder; a prolactin-related disorder (e.g., hyperprolactinemia); a neurocognitive disorder; a trauma- or stressor-related disorder (e.g., posttraumatic stress disorder (PTSD)); a disruptive, impulse-control, or conduct disorder; a sleep-wake disorder; a substance-related disorder; an addictive disorder; a behavioral disorder; hypofrontality; an abnormality in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathway; decreased activity in the striatum; cortical dysfunction; neurocognitive dysfunction; and conditions related thereto.

First claim

We claim:

1. A compound selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, and N-oxides thereof:

wherein:
Y is selected from: —CH 2 —, —O—, and —S—;
Ring A is pyridinediyl or pyrazine-2,6-diyl;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H or halogen;
R 3 is aryl or heteroaryl, wherein each ring is optionally substituted with one or more groups selected independently from: C 1 -C 6 acyl, C 1 -C 6 acyloxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarboxamide, C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, hydroxyl, and hydroxy-C 1 -C 6 -alkyl; and said C 1 -C 6 alkyl is optionally substituted with one or more groups selected independently from: C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, and oxo;
R 4 is H; and
R 5 is selected from: H, C 1 -C 6 alkyl, heteroaryl, heteroaryl-C 1 -C 6 alkyl, heterocyclyl, and heterocyclyl-C 1 -C 6 alkyl; and each group is optionally substituted with one or more groups selected independently from: C 1 -C 6 alkoxy, C 1 -C 6 alkylcarboxamide, C 1 -C 6 alkyl, cyano, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, C 1 -C 6 haloalkyl, halogen, hydroxyl, hydroxy-C 1 -C 6 -alkoxy, hydroxy-C 1 -C 6 -alkyl, and oxo.

2. The compound according to claim 1 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein Y is —CH 2 —.

3. The compound according to claim 2 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein Ring A is

4. The compound according to claim 2 , or an N-oxide or pharmaceutically acceptable salt thereof, wherein Ring A is:

5. The compound according to claim 2 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein Ring A is:

6. The compound according to claim 2 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein Ring A is:

7. The compound according to claim 2 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazine-2,6-diyl of the formula:

8. The compound according to claim 2 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein R 1 is H or methyl.

9. The compound according to claim 8 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

10. The compound according to claim 8 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein R 2 is H or fluoro.

11. The compound according to claim 10 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

12. The compound according to claim 10 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl optionally substituted with one or more groups selected independently from: acetoxy, acetyl, chloro, cyano, (dimethylamino)methyl, ethoxy, fluoro, hydroxy, hydroxymethyl, methoxy, methyl, methylcarbamoyl, trifluoromethoxy, and trifluoromethyl.

13. The compound according to claim 12 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: 3-((dimethylamino)methyl)phenyl, 3-(trifluoromethoxy)phenyl, 3-(trifluoromethyl)phenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 3,5-difluoro-4-methoxyphenyl, 3,5-difluorophenyl, 3-acetoxyphenyl, 3-acetyl-4-fluorophenyl, 3-acetylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, 3-chloro-5-fluorophenyl, 3-chloro-5-methoxyphenyl, 3-cyano-4-fluorophenyl, 3-cyano-5-fluorophenyl, 3-fluoro-4-(hydroxymethyl)phenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-5-methoxyphenyl, 3-methoxyphenyl, 4-acetyl-3-fluorophenyl, 4-acetylphenyl, 4-chloro-3-fluorophenyl, 4-chloro-3-methoxyphenyl, 4-cyano-3-fluorophenyl, 4-ethoxy-3-fluorophenyl, 4-fluoro-3-(hydroxymethyl)phenyl, 4-fluoro-3-(methylcarbamoyl)phenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 4-fluoro-3-hydroxyphenyl, 4-fluoro-3-methoxyphenyl, 4-methoxy-3-(trifluoromethyl)phenyl, and 4-methoxy-3-methylphenyl.

14. The compound according to claim 12 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from: H, (oxetan-3-yl)methyl, 1H-pyrazol-4-yl, 1-hydroxybutan-2-yl, 2-(1H-imidazol-1-yl)ethyl, 2-(1H-imidazol-5-yl)ethyl, 2-(imidazolidin-1-yl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-4-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl, 2-hydroxypropyl, 3-hydroxypropan-2-yl, 3-hydroxypropyl, ethyl, 2-hydroxyethyl, methyl, piperidin-3-yl, piperidin-4-yl, propan-2-yl, propyl, pyridin-4-yl, pyrrolidin-3-yl, and tetrahydrofuran-3-yl; and each group is optionally substituted with one or more groups selected independently from: 2-hydroxyethoxy, 2-hydroxyethyl, acetamido, cyano, dimethylamino, fluoro, hydroxy, hydroxymethyl, methoxy, methyl, methylamino, oxo, and trifluoromethyl.

15. The compound according to claim 14 , or an N-oxide or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from: H, (2R,3S)-1,3-dihydroxybutan-2-yl, (3-(hydroxymethyl)oxetan-3-yl)methyl, (dimethylamino)ethyl, (R)-2,3-dihydroxypropyl, (R)-2-fluoro-3-hydroxypropyl, (R)-2-hydroxy-2-(pyridin-3-yl)ethyl, (R)-2-hydroxy-3-methoxypropyl, (R)-2-hydroxypropyl, (R)-2-oxopyrrolidin-3-yl, (R)-2-oxotetrahydrofuran-3-yl, (S)-2,3-dihydroxypropyl, (S)-2-fluoro-3-hydroxypropyl, (S)-2-hydroxy-2-(pyridin-3-yl)ethyl, (S)-2-hydroxy-3-methoxypropyl, (S)-2-hydroxypropyl, (S)-2-oxopyrrolidin-3-yl, (S)-2-oxotetrahydrofuran-3-yl, (S)-3,3,3-trifluoro-2-hydroxypropyl, (S)-3-fluoro-2-hydroxypropyl, (S)-tetrahydrofuran-3-yl, 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, 1-(2-hydroxyethyl)piperidin-4-yl, 1,3-dihydroxypropan-2-yl, 1,3-dimethoxypropan-2-yl, 1-methyl-1H-pyrazol-4-yl, 1-methylpiperidin-4-yl, 2-(1H-imidazol-1-yl)ethyl, 2-(1H-imidazol-5-yl)ethyl, 2-(2-hydroxyethoxy)ethyl, 2-(2-oxoimidazolidin-1-yl)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl, 2-acetamidoethyl, 2-cyanoethyl, 2-fluoroethyl, 2-hydroxy-2-(pyridin-2-yl)ethyl, 2-hydroxy-2-(pyridin-4-yl)ethyl, 2-hydroxyethyl, 2-morpholinoethyl, 3-(dimethylamino)-2-hydroxypropyl, 3-(methylamino)-3-oxopropyl, 3-hydroxypropyl, 6-oxopiperidin-3-yl, cyanomethyl, methyl, and pyridin-4-yl.

16. The compound according to claim 1 , according to Formula (Im):

or an N-oxide or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from: —CH 2 —, —O—, and —S—;
R 1 is H or methyl;
R 2 is H or fluoro;
R 3 is selected from: 1H-indol-4-yl, 2-(trifluoromethyl)pyridin-4-yl, 2,3-dihydrobenzofuran-5-yl, 2-chloropyrimidin-5-yl, 2-methoxypyrimidin-5-yl, 3-((dimethylamino)methyl)phenyl, 3-(trifluoromethoxy)phenyl, 3-(trifluoromethyl)phenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 3,5-difluoro-4-methoxyphenyl, 3,5-difluorophenyl, 3,5-dimethylisoxazol-4-yl, 3-acetoxyphenyl, 3-acetyl-4-fluorophenyl, 3-acetylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, 3-chloro-5-fluorophenyl, 3-chloro-5-methoxyphenyl, 3-cyano-4-fluorophenyl, 3-cyano-5-fluoropheny

Assignees

• Arena Pharm Inc
• Arena Pharmaceutical Inc

Inventors

• Xiong Yifeng
• Grottick Andrew J
• Korman Henry
• Lehmann Juerg
• Ren Albert S
• Semple Graeme
• Bagnol Didier Jc

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title