Tetrahydroisoquinoline derivatives

Patent metadata

Field	Value
Publication number	US-10370355-B2
Application number	US-201716086698-A
Country	US
Kind code	B2
Filing date	Apr 7, 2017
Priority date	Apr 13, 2016
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

The present invention relates to tetrahydroisoquinoline derivatives according to formula (I), wherein G represents a fused heterocyclic system selected from the groups represented by formula (G 1 ), (G 2 ), (G 3 ), (G 4 ), (G 5 ), and (G 6 ), 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 , R 2 and R 3 represent independently hydrogen, halogen or cyano; or R 1 , R 2 and R 3 represent independently C 1-6 alkyl or C 1-6 alkoxy, either of which groups may be optionally substituted by one or more substituents;
R 4 represents —N═S(O)R a R b , or R 4 represents C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-7 heterocycloalkyl, each of these groups which may be optionally substituted by one or more substituents;
R a and R b represent independently C 1-6 alkyl, which group may be optionally substituted by one or more substituents; or R a and R b are linked together to form with the S atom to which they are attached a C 3-7 heterocycloalkyl, which group may be optionally substituted by one or more substituents;
G represents a fused heterocyclic system selected from the groups represented by formula (G 1 ), (G 2 ), (G 3 ), (G 4 ), (G 5 ), and (G 6 ),

wherein
the asterisk (*) represents the point of attachment of G to the remainder of the molecule;
V 1 represents CH or N;
W 1 and W 2 represent independently CR 9 R 10 ;
X represents O or NR 11 ;
R 5 represents halogen or cyano: or R 5 represents C 1-6 alkyl or C 1-6 alkoxy, either of which group may be optionally substituted by one or more substituents;
R 6 and R 7 represent independently hydrogen, halogen or cyano; or R 6 and R 7 represent independently C 1-6 alkyl or C 1-6 alkoxy, either of these groups which may be optionally substituted by one or more substituents;
R 8 represents hydrogen, halogen or cyano; or R 8 represents independently C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkoxy, either of these groups which may be optionally substituted by one or more substituents;
R 9 and R 10 represent independently hydrogen or halogen; or R 9 and R 10 represent independently C 1-6 alkyl, which group may be optionally substituted by one or more substituents; and
R 11 represents hydrogen; or R 11 represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents.

2. The compound as claimed in claim 1 represented by formula (IA), or a pharmaceutically acceptable salt thereof,

3. The compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 , R 2 and R 3 represent independently hydrogen, halogen or cyano: or R 1 , R 2 and R 3 represent independently unsubstituted C 1-6 alkyl or unsubstituted C 1-6 alkoxy; and
R 4 represents (hydroxy)ethyl, (fluoro)(hydroxy)ethyl, (difluoro)(hydroxy)ethyl, (methyl)(hydroxy)(difluoro)ethyl, (methyl)(hydroxy)(fluoro)ethyl, (hydroxy)(fluoromethyl)(fluoro)ethyl, (methyl)(hydroxy)ethyl, (hydroxy)(methyl)propyl, (hydroxy)(methyl)butyl, (hydroxy)cyclobutyl, (hydroxy)azetidinyl, (hydroxy)piperidinyl, methoxy, ethoxy, propoxy, difluoromethoxy, [(dimethyl)oxido-λ 6 -sulfanilidene]amino-, or [oxido-λ 4 -oxathianylidene]amino-, [oxidotetrahydro-1H-1λ 4 -thiophenylidene]amino.

4. The compound as claimed in claim 1 wherein (G) represents a fused heterocycle represented by formula (G 1 ), (G 5 ) or (G 6 ), and
X represents O or NR 11 ;
V 1 represents CH or N;
R 11 represents hydrogen or unsubstituted C 1-6 alkyl;
R 5 and R 6 represent independently halogen;
R 7 represents hydrogen; and
R 8 represents hydrogen, cyano or unsubstituted C 3-8 cycloalkyl.

5. The compound as claimed in claim 1 wherein R 4 represents (hydroxy)ethyl, (fluoro)(hydroxy)ethyl, (difluoro)(hydroxy)ethyl, (methyl)(hydroxy)(difluoro)ethyl, (methyl)(hydroxy)(fluoro)ethyl, (hydroxy)(fluoromethyl)(fluoro)ethyl or (methyl)hydroxy)ethyl.

6. The compound as claimed in claim 1 represented by formula (IC-a), or a pharmaceutically acceptable salt thereof,

wherein
R 1 , R 2 and R 3 represent independently hydrogen, halogen or cyano; or R 1 , R 2 and R 3 represent independently unsubstituted C 1-6 alkyl or unsubstituted C 1-6 alkoxy;
X represents O or NR 11 ;
V 1 represents CH or N;
R 11 represents hydrogen or unsubstituted C 1-6 alkyl;
R 5 and R 6 represent independently halogen;
R 8 represents hydrogen, cyano or unsubstituted C 3-8 cycloalkyl, and
R 12 and R 13 represent independently hydrogen, deuterium, methyl, fluoromethyl or difluoromethyl.

7. The compound as claimed in claim 1 represented by formula (ID-a), or a pharmaceutically acceptable salt thereof,

wherein
R 1 , R 2 and R 3 represent independently hydrogen, halogen or cyano or R 1 , R 2 and R 3 represent independently unsubstituted C 1-6 alkyl or unsubstituted C 1-6 alkoxy;
X represents O or NR 11 ;
V 1 represents CH or N;
R 11 represents hydrogen or unsubstituted C 1-6 alkyl;
R 5 and R 6 represent independently halogen;
R 8 represents hydrogen, cyano or unsubstituted C 3-8 cycloalkyl, and
R 12 and R 13 represent independently hydrogen, deuterium, methyl, fluoromethyl or difluoromethyl.

8. The compound as claimed in claim 6 wherein X represents —NR 11 and R 11 is hydrogen or methyl.

9. The compound as claimed in claim 7 wherein X represents —NR 11 and R 11 is hydrogen.

10. The compound as claimed in claim 1 represented by formula (IE-a), or a pharmaceutically acceptable salt thereof,

wherein
R 1 , R 2 and R 3 represent independently hydrogen, halogen or cyano; or R 1 , R 2 and R 3 represent independently unsubstituted C 1-6 alkyl or unsubstituted C 1-6 alkoxy;
R 5 and R 6 represent independently halogen;
R 7 represents hydrogen;
R 8 represents hydrogen, cyano or unsubstituted C 3-8 cycloalkyl; and
R 12 and R 13 represent independently hydrogen, deuterium, methyl, fluoromethyl or difluoromethyl.

11. The compound as claimed in claim 1 wherein R 1 , R 2 and R 3 represent independently hydrogen.

12. The compound as claimed in claim 1 wherein R 5 and R 6 represent independently chloro.

13. The compound as claimed in claim 1 wherein R 8 and R 7 represents hydrogen.

14. The compound as claimed in claim 1 which is selected from the group consisting of
2-(3,5-dichloro-1,2-benzoxazol-4-yl)-1-[(1S)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S)-5-[(1R)-2-fluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S)-5-[(1S)-2-fluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S)-5-[(1R)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S)-5-[(1S)-2,2-difluoro-1-hydroxy-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]e

Assignees

• Ucb Biopharma Sprl

Inventors

• Ates Ali
• Jnoff Eric
• Provins Laurent
• Valade Anne
• Hall Adrian

Classifications

• A61P43/00

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

• A61P25/30

  for treating abuse or dependence · 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

• A61P25/18

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