Tetrahydroisoquinoline derivatives

Patent metadata

Field	Value
Publication number	US-10105359-B2
Application number	US-201515517795-A
Country	US
Kind code	B2
Filing date	Oct 6, 2015
Priority date	Oct 8, 2014
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

The present invention relates to tetrahydroisoquinoline derivatives according to formula (I), which are Positive Allosteric Modulators of D1 and accordingly of benefit as pharmaceutical agents for the treatment of diseases in which D1 receptors play a role.

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein
R 1 is hydrogen, halogen, cyano or hydroxy; C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl or (C 1-6 -alkylsulfonyl)amino, any of which groups is optionally substituted by one or more substituents;
R 2 is hydrogen, cyano, or halogen; or C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, (C 1-6 alkylsulfonyl)amino(C 1-6 alkyl), C 1-6 alkylamido, (C 1-6 alkylacyl)amino, (C 1-6 alkylacyl)amino(C 1-6 alkyl), or heteroaryl, any of which groups is optionally substituted by one or more substituents; or
R 1 and R 2 are linked together to form with the adjacent aromatic group a heterocycle of formula (i):

wherein R 2b is hydrogen or C 1-6 alkylsulfonyl;
R 3 is halogen, C 1-6 alkyl, C 1-6 alkoxy or cyano;
R 4 is hydrogen, halogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyloxy or C 1-6 alkylaminocarbonyloxy;
R 4′ is hydrogen, halogen or C 1-6 alkyl; or R 4 and R 4′ together form an oxo group;
R 5 is hydrogen, cyano or hydroxy; or C 1-6 alkyl; C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfonylamino; C 1-6 -alkylsulfonylamino(C 1-6 alkyl), heterocycle, C 1-6 alkylacylamino(C 1-6 alkyl), C 1-6 alkylureido(C 1-6 alkyl), C 1-6 alkylcarbamate(C 1-6 alkyl); amido; C 1-6 alkoxycarbonyloxy(C 1-6 alkyl); amino group; N-cyano-S—(C 1-6 -alkyl)sulfonimidoyl, N,S-(di-C 1-6 -alkyl)sulfonimidoyl, aminosulfinyl; C 1-6 -alkylsulfinyl; aminosulfonyl; (di-C 1-6 -alkyl)(oxido)-λ 6 -sulfanylidene-amino, amino(C 1-6 alkyl), or amido(C 1-6 alkyl); any of which groups is optionally substituted by one or more substituents;
R 6 is hydrogen;
R 7 is hydrogen or (C 1-6 alkylsulfonyl)amino;
X is CR 9 or N; wherein R 9 is hydrogen, halogen or C 1-6 -alkyl substituted by hydroxy;
Z is CH or N;
provided the compound is not
(2-(2-fluorophenyl)-1-[(1R)-1-methyl-3,4-dihydro-2(1H)-isoquinolinyl]-1-ethanone.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, hydroxy, C 1-6 -alkyl hydroxy, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl or (C 1-6 -alkylsulfonyl)amino.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, halogen, C 1-6 alkyl unsubstituted or substituted by one or more halogens, C 1-6 -alkyl hydroxy, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, cyano, C 1-6 alkylamido, pyrazolyl, or a group of formula —CH 2 R 2a , —NHR 2a or —CH 2 NHR 2a wherein R 2a is selected from C 1-6 alkylacyl or C 1-6 alkylsulfonyl.

4. The compound according to claim 2 represented by formula (I-A-A) or a pharmaceutically acceptable salt thereof,

wherein
R 2 and R 3 are independently halogen or cyano, and
R 5 is hydrogen, cyano or hydroxy; or C 1-6 alkyl, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfonylamino; C 1-6 -alkylsulfonylamino(C 1-6 alkyl), heterocycle, C 1-6 alkylacylamino(C 1-6 alkyl); C 1-6 alkylureido(C 1-6 alkyl), C 1-6 alkylcarbamate(C 1-6 alkyl), amido, C 1-6 alkoxycarbonyloxy(C 1-6 alkyl), amino; N-cyano-S—(C 1-6 -alkyl)sulfonimidoyl, 10 N,S-(di-C 1-6 -alkyl)sulfonimidoyl, aminosulfinyl, C 1-6 -alkylsulfinyl; aminosulfonyl, alkyl)(oxido)-6-sulfanylidene-amino; amino(C 1-6 alkyl) or amido(C 1-6 alkyl), any of which groups may be optionally substituted by one or more substituents.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is chloro or cyano.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is chloro or cyano.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein R 5 is hydrogen, hydroxy, hydroxymethyl, (methylsulfanyl)methyl, 1-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 3,5-dimethyl-1,2-oxazol-4-yl, (methylsulfonyl)amino, [(methylsulfonyl)amino]methyl, 2-[(methylsulfonyl)amino]ethyl, (2,2,2-trifluoroethyl)carbamoyl, dipropan-2-ylcarbamoyl, 4H-1,2,4-triazol-3-ylcarbamoyl, (2,5-dimethylpyrrolidin-1-yl)carbonyl, [4-(trifluoromethyl)piperidin-1-yl]carbonyl, methyl-sulfonyl, (methoxymethyl)sulfonyl, ethylsulfonyl, propan-2-ylsulfonyl, (tetrahydro-2H-pyran-4-ylmethyl)sulfonyl, methylsulfamoyl, (cyanomethyl)sulfamoyl, ethylsulfamoyl, (2,2,2-trifluoroethyl)sulfamoyl, propan-2-ylsulfamoyl or (4H-1,2,4-triazol-3-yl)sulfamoyl.

8. The compound of formula (I) according to claim 1 selected from the group consisting of
2-(2,6-dichlorophenyl)-1-(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone;
2-(2,6-dichlorophenyl)-1-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(2,6-dichlorophenyl)-1-[(1R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(3,5-dichloropyridin-4-yl)-1-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
N-{(1R)-2-[(2,6-dichlorophenyl)acetyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl}methanesulfonamide;
N-{(1S)-2-[(2,6-dichlorophenyl)acetyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl}methanesulfonamide;
2,4-dichloro-3-{2-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}benzonitrile;
2-(2,6-dichlorophenyl)-1-(4,4-difluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone;
2-(2,6-dichlorophenyl)-1-[4,4-difluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(2,6-dichlorophenyl)-1-(1,4,4-trimethyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone;
2-(3-bromo-2,6-dichlorophenyl)-1-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(3,5-dichloropyridin-4-yl)-1-[(1S)-5-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
N-{(1S)-2-[(2-chloro-6-methylphenyl)acetyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl}methanesulfonamide;
N-{(1S)-2-[(2-chloro-6-cyanophenyl)acetyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl}methanesulfonamide;
2-(3,5-dichloro-2-methoxypyridin-4-yl)-1-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(2-bromo-6-methoxyphenyl)-1-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(3-chloro-5-methylpyridin-4-yl)-1-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
3-chloro-2-{2-[(1 S,4R)-4-hydroxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}benzonitrile;
2-(2,6-dichlorophenyl)-1-[(1 S,4R)-4-hydroxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
3-chloro-2-{2-[(1 S,4S)-4-hydroxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}benzonitrile;
2-(2,6-dichlorophenyl)-1-[(1 S,4 S)-4-hydroxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(3,5-dichloropyridin-4-yl)-1-[(1S)-1-methyl-5-(methylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
3-chloro-2-{2-[(1S)-1-methyl-5-(methylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}benzonitrile;
2-(3,5-dichloropyridin-4-yl)-1-[(1 S,4R)-4-hydroxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(2,6-dichloro-4-fluorophenyl)-1-[(1 S,4 S)-4-hydroxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(2-chloro-6-methoxyphenyl)-1-[(1S)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-[2-chloro-6-(trifluoromethyl)phenyl]-1-[(1S)-1-methyl-3,4-dihyd

Assignees

• Ucb Biopharma Sprl

Inventors

• Valade Anne
• Jnoff Eric
• Ates Ali
• Burssens Pierre
• Skolc David
• Sands Zara
• Mathieu Benoit

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• 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

• A61P25/20

  Hypnotics; Sedatives · CPC title