# US 10,370,355 B2 · Tetrahydroisoquinoline derivatives

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,370,355 B2
- Document ID: US10370355B2
- Status: Granted
- Kind: B2
- Application number: 16/086,698
- Filed: 2017-04-07
- Published: 2019-04-11
- Granted: 2019-08-06
- Earliest claimed: 2016-04-13
- Assignees: Ucb Biopharma Sprl
- Applicants: UCB Biopharma SPRL
- Inventors: Ali Ates; Eric Jnoff; Laurent Provins; Anne Valade; Adrian Hall
- Web page: https://patentgrep.com/patent/US10370355B2

## CPC

- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/28: 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
- A61P 25/30: for treating abuse or dependence
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 217/06: with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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 (G1), (G2), (G3), (G4), (G5), and (G6), 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.

## Claims

### Claim 1

A compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein
R1, R2 and R3 represent independently hydrogen, halogen or cyano; or R1, R2 and R3 represent independently C1-6 alkyl or C1-6 alkoxy, either of which groups may be optionally substituted by one or more substituents;
R4 represents —N═S(O)RaRb, or R4 represents C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl or C3-7heterocycloalkyl, each of these groups which may be optionally substituted by one or more substituents;
Ra and Rb represent independently C1-6 alkyl, which group may be optionally substituted by one or more substituents; or Ra and Rb are linked together to form with the S atom to which they are attached a C3-7 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 (G1), (G2), (G3), (G4), (G5), and (G6),
wherein
the asterisk (*) represents the point of attachment of G to the remainder of the molecule;
V1 represents CH or N;
W1 and W2 represent independently CR9R10;
X represents O or NR11;
R5 represents halogen or cyano: or R5 represents C1-6 alkyl or C1-6 alkoxy, either of which group may be optionally substituted by one or more substituents;
R6 and R7 represent independently hydrogen, halogen or cyano; or R6 and R7 represent independently C1-6alkyl or C1-6 alkoxy, either of these groups which may be optionally substituted by one or more substituents;
R8 represents hydrogen, halogen or cyano; or R8 represents independently C1-6 alkyl, C3-8 cycloalkyl or C1-6 alkoxy, either of these groups which may be optionally substituted by one or more substituents;
R9 and R10 represent independently hydrogen or halogen; or R9 and R10 represent independently C1-6 alkyl, which group may be optionally substituted by one or more substituents; and
R11 represents hydrogen; or R11 represents C1-6alkyl, which group may be optionally substituted by one or more substituents.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1, R2 and R3 represent independently hydrogen, halogen or cyano: or R1, R2 and R3 represent independently unsubstituted C1-6 alkyl or unsubstituted C1-6 alkoxy; and
R4 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-λ6-sulfanilidene]amino-, or [oxido-λ4-oxathianylidene]amino-, [oxidotetrahydro-1H-1λ4-thiophenylidene]amino.

### Claim 4 (depends on 1)

The compound as claimed in claim 1 wherein (G) represents a fused heterocycle represented by formula (G1), (G5) or (G6), and
X represents O or NR11;
V1 represents CH or N;
R11 represents hydrogen or unsubstituted C1-6 alkyl;
R5 and R6 represent independently halogen;
R7 represents hydrogen; and
R8 represents hydrogen, cyano or unsubstituted C3-8 cycloalkyl.

### Claim 5 (depends on 1)

The compound as claimed in claim 1 wherein R4 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.

### Claim 6 (depends on 1)

The compound as claimed in claim 1 represented by formula (IC-a), or a pharmaceutically acceptable salt thereof,
wherein
R1, R2 and R3 represent independently hydrogen, halogen or cyano; or R1, R2 and R3 represent independently unsubstituted C1-6 alkyl or unsubstituted C1-6 alkoxy;
X represents O or NR11;
V1 represents CH or N;
R11 represents hydrogen or unsubstituted C1-6 alkyl;
R5 and R6 represent independently halogen;
R8 represents hydrogen, cyano or unsubstituted C3-8 cycloalkyl, and
R12 and R13 represent independently hydrogen, deuterium, methyl, fluoromethyl or difluoromethyl.

### Claim 7 (depends on 1)

The compound as claimed in claim 1 represented by formula (ID-a), or a pharmaceutically acceptable salt thereof,
wherein
R1, R2 and R3 represent independently hydrogen, halogen or cyano or R1, R2 and R3 represent independently unsubstituted C1-6 alkyl or unsubstituted C1-6 alkoxy;
X represents O or NR11;
V1 represents CH or N;
R11 represents hydrogen or unsubstituted C1-6 alkyl;
R5 and R6 represent independently halogen;
R8 represents hydrogen, cyano or unsubstituted C3-8 cycloalkyl, and
R12 and R13 represent independently hydrogen, deuterium, methyl, fluoromethyl or difluoromethyl.

### Claim 8 (depends on 6)

The compound as claimed in claim 6 wherein X represents —NR11 and R11 is hydrogen or methyl.

### Claim 9 (depends on 7)

The compound as claimed in claim 7 wherein X represents —NR11 and R11 is hydrogen.

### Claim 10 (depends on 1)

The compound as claimed in claim 1 represented by formula (IE-a), or a pharmaceutically acceptable salt thereof,
wherein
R1, R2 and R3 represent independently hydrogen, halogen or cyano; or R1, R2 and R3 represent independently unsubstituted C1-6 alkyl or unsubstituted C1-6 alkoxy;
R5 and R6 represent independently halogen;
R7 represents hydrogen;
R8 represents hydrogen, cyano or unsubstituted C3-8 cycloalkyl; and
R12 and R13 represent independently hydrogen, deuterium, methyl, fluoromethyl or difluoromethyl.

### Claim 11 (depends on 1)

The compound as claimed in claim 1 wherein R1, R2 and R3 represent independently hydrogen.

### Claim 12 (depends on 1)

The compound as claimed in claim 1 wherein R5 and R6 represent independently chloro.

### Claim 13 (depends on 1)

The compound as claimed in claim 1 wherein R8 and R7 represents hydrogen.

### Claim 14 (depends on 1)

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]ethanone;
2-(3,5-dichloro-1H-imidazol-4-yl)-1-[(1S)-5-[2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-2-methyl-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-2-methyl-indazol-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-1-methyl-1H-indazol-4-yl)-1-[(1S)-5-[(1R)-2,2-difluoro-1-hydroxyethyl]-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(3,5-dichloro-1-methyl-1H-indazol-4-yl)-1-[(1S)-5-[(1S)-2,2-difluoro-1-hydroxyethyl]-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone;
2-(3,5-dichloro-2-methyl-indazol-4-yl)-1-[(1S)-5-[2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1H-pyrazolo[3,4-b]pyridin-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-pyrazolo[3,4-b]pyridin-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-pyrazolo[3,4-b]pyridin-4-yl)-1-[(1S)-5-[2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1H-pyrazolo[3,4-b]pyridin-4-yl)-1-[(1S)-5-[2-fluoro-1-(fluoromethyl)-1-hydroxy-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1-methyl-pyrazolo[3,4-b]pyridin-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-1-methyl-pyrazolo[3,4-b]pyridin-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-1-methyl-pyrazolo[3,4-b]pyridin-4-yl)-1-[(1S)-5-[2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1-methyl-pyrazolo[3,4-b]pyridin-4-yl)-1-[(1S)-5-[2-fluoro-1-(fluoromethyl)-1-hydroxy-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1-methyl-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-1-methyl-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-1-methyl-indazol-4-yl)-1-[(1S)-5-[2,2-difluoro-1-hydroxy-1-methyl-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S)-5-[2-fluoro-1-(fluoromethyl)-1-hydroxy-ethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
2-(3,5-dichloropyrazolo[1,5-a]pyridin-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-dichloropyrazolo[1,5-a]pyridin-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-6-cyclopropyl-pyrazolo[1,5-a]pyridin-4-yl)-1-[(1S)-5-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone; and
3,5-dichloro-4-[2-[(1S)-5-(2,2-difluoro-1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]pyrazolo[1,5-a]pyridine-6-carbonitrile.

### Claim 15 (depends on 1)

A method of treating a subject with a disease or condition mediated by a D1 receptor, the method comprising administering to the subject a therapeutically effect amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the disease or condition is cognitive and negative symptoms in schizophrenia, cognitive and negative symptoms in schizophrenia, cognitive impairment related to classical antipsychotic therapy, impulsivity, attention disorder with hyperactivity (ADHD), Parkinson's disease and related movement disorders, dystonia, Huntington's disease, dementia with Lewy Body, Alzheimer's disease, age-related cognitive decline, mild cognitive impairment (MCI), drug addiction, sleep disorders or apathy.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.