# US 7,745,458 B2 · Azabicyclo (3, 1, 0) hexan derivatives useful as modulators of dopamine D3 receptors

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- Number: US 7,745,458 B2
- Document ID: US7745458B2
- Status: Granted
- Kind: B2
- Application number: 12/064,123
- Filed: 2006-08-18
- Published: 2009-09-03
- Granted: 2010-06-29
- Earliest claimed: 2005-08-22
- Assignees: Glaxo Group Limited
- Inventors: Luca Arista; Anna Checchia; Gabriella Gentile; Dieter Hamprecht; Fabrizio Micheli
- Web page: https://patentgrep.com/patent/US7745458B2

## CPC

- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- 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 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- 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 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 25/36: Opioid-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel compounds of formula (I) or a salt thereof: wherein: p is 0, 1, 2, 3, 4 or 5; R1 is independently selected from a group consisting of: halogen, hydroxy, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkanoyl and SF5; n is 3 or 4; R2 is hydrogen or C1-4alkyl; n is 2 or 3; X is —CH2—, —O— or —S—; Z may be —CH— or N; A is a group P or P1, wherein P is and P1 is and Y is hydrogen, —OH, C1-4alkyl, haloC1-4alkyl, phenyl or a heteroaromatic group, wherein the phenyl and the heteroaromatic group are optionally substituted by one or two substituents selected from a group consisting of C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloC1-4alkoxy; processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D3 receptors, e.g. to treat substance related disorders, as antipsychotic agents premature ejaculation or cognition impairment.

## Claims

### Claim 1

A compound of formula (I) or a salt thereof:
wherein:
p in the group (R1)p is 0, 1, 2, 3, 4 or 5;
R1 is independently selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkanoyl and SF5;
n is 2 to 4;
R2 is hydrogen or C1-4alkyl;
X is —CH2—, —O— or —S—;
Z may be —CH— or N;
A is a group P or P1,
wherein P is;
and P1 is
and
Y is hydrogen, —OH, C1-4alkyl, haloC1-4alkyl, phenyl or a heteroaromatic group, wherein the phenyl and the heteroaromatic group are optionally substituted by one or two substituents selected from the group consisting of C1-4alkyl, haloC1-4alkyl, hydroxyl, C1-4alkoxy and haloC1-4alkoxy.

### Claim 2 (depends on 1)

A compound as claimed in claim 1, wherein p in the group (R1)p is 1.

### Claim 3 (depends on 1)

A compound as claimed in claim 1, wherein R1 is CF3.

### Claim 4 (depends on 1)

A compound as claimed in claim 1, wherein n is 3 and X is —CH2—, or n is 3 and X is —S—, or n is 3 and X is —O—.

### Claim 5 (depends on 1)

A compound as claimed in claim 1, wherein Y is hydrogen, haloC1-4alkyl, phenyl wherein the phenyl is optionally substituted by haloC1-4alkoxy, —OH or C1-4alkyl.

### Claim 6 (depends on 1)

A compound as claimed in claim 1, wherein A is the group P.

### Claim 7 (depends on 1)

A compound as claimed in claim 1 which is a compound of formula (IL) or a salt thereof:
(IL)
wherein p, R1, R2, n, X, A and Z are defined as above for compounds of formula (I).

### Claim 8 (depends on 1)

A compound as claimed in claim 1 which is a compound of formula (IN) or a salt thereof:
wherein X and Y are as defined for formula (I).

### Claim 9 (depends on 1)

A compound as claimed in claim 1 which is
(1S,5R)-3-[4-(4-phenyl-2-pyrimidinyl)butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
(1S,5R1)-[4-(trifluoromethyl)phenyl]-3-{4-[4-(trifluoromethyl)-2-pyrimidinyl]butyl}-3-azabicyclo[3.1.0]hexane;
(1S,5R)-3-[3-(2-pyrimidinylthio)propyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
(1S,5R)-3-[3-({4-[4-(methyloxy)phenyl]-2-pyrimidinyl}thio)propyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
2-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)oxy]-4(1H)-pyrimidinone;
2-[(3-{(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)thio]-4(1H)-pyrimidinone;
4-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)thio]-2(1H)-pyrimidinone;
(1S,5R)-3-{3-[(4-methyl-2-pyrimidinyl)thio]propyl}-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
(1S,5R)-3-{3-[(4-methyl-2-pyrimidinyl)thio]propyl}-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
2-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-4-pyrimidinol
2-[(3-{(1R,5R)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)thio]-4-pyrimidinol;
2-[(3-{(1S,5R)-1-[4-(1-methylethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)thio]-4-pyrimidinol;
or a salt thereof.

### Claim 10 (depends on 1)

A process for preparing a compound of formula (I) or a salt thereof as defined in claim 1, the process comprising:
(a) for compounds of formula (I) wherein X is —CH2— and R2 is hydrogen, reacting a compound of formula (II):
wherein n and A are as defined for formula (I), with a compound of formula (III):
wherein p, Z and R1 are as defined for formula (I); or
(b) for a compound of formula (I), wherein X is —S—, reacting a compound of formula (IV):
wherein p, R1, R2, Z and n are as defined for formula (I) and L is a leaving group, with a compound of formula (V):
HS-A (V)
wherein A is as defined for formula (I);
(b) for a compound of formula (I), wherein X is —O—, reacting a compound of formula (VI):
wherein p, R1, R2, Z and n are as defined for formula (I), with a compound of formula (VII):
wherein A is as defined for formula (I);
and thereafter optionally for process (a), (b) and for process (c):
(i) removing any protecting group(s); and/or
(ii) forming a salt; and/or
(iii) converting a compound of formula (I) or a salt thereof to another compound of formula (I) or a salt thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.