PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO

• US 20100004264A1
• Filed: 10/02/2007
• Published: 01/07/2010
• Est. Priority Date: 10/03/2006
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Cherrier, Martin C., Teegarden, Bradley, Choi, Jin Sun Karoline, Dosa, Peter I., Xiong, Yifeng, Strah-Pleynet, Sonja, Ullman, Brett, Smith, Brian M.
• Granted Patent: US 9,434,692 B2
• Time in Patent Office: Days
• US Class Current: 514/254.05
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: 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
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/16 : Halogen atoms or nitro radicals
• CPC Class Codes: C07D 231/54 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond

Abstract

Pyrazole derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the serotonin 5HT_2A receptor. Formula (Ia). Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of insomnia and related sleep disorders, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette'"'"'s syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to the methods for the treatment of 5-HT_2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

Claims

1. A compound of Formula (Ia):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein;

R¹ and R² are each independently selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ alkylaryl, aryl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen, heteroaryl, and nitro; and

wherein C₁-C₆ alkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C₁-C₆ acyl, C₁-C₆ acyloxy, C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylcarboxamide, C₁-C₆ alkylsulfonamide, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, C₁-C₆ alkylureyl, C₁-C₆ alkylamino, C₂-C₆ alkynyl, amino, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano, C₃-C₇ cycloalkyl, C₂-C₆ dialkylamino, C₂-C₆ dialkylcarboxamide, C₂-C₆ dialkylsulfonamide, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ haloalkylthio, halogen, hydroxyl, nitro, sulfonamide and thiol;

or

R¹ and R² together with the carbon atoms to which they are bonded form a C₃-C₇ carbocyclyl or a C₃-C₇ heterocyclyl group each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C₁-C₆ acyl, C₁-C₆ acyloxy, C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylcarboxamide, C₁-C₆ alkylsulfonamide, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, C₁-C₆ alkylureyl, C₁-C₆ alkylamino, C₂-C₆ alkynyl, amino, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano, C₃-C₇ cycloalkyl, C₂-C₆ dialkylamino, C₂-C₆ dialkylcarboxamide, C₂-C₆ dialkylsulfonamide, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ haloalkylthio, halogen, hydroxyl, nitro, oxo, sulfonamide and thiol;

R³ is selected from the group consisting of H, C₁-C₆ alkyl and aryl; and

wherein aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C₁-C₆ acyl, C₁-C₆ acyloxy, C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylcarboxamide, C₁-C₆ alkylsulfonamide, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, C₁-C₆ alkylureyl, C₁-C₆ alkylamino, C₂-C₆ alkynyl, amino, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano, C₃-C₇ cycloalkyl, C₂-C₆ dialkylamino, C₂-C₆ dialkylcarboxamide, C₂-C₆ dialkylsulfonamide, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ haloalkylthio, halogen, hydroxyl, nitro, sulfonamide and thiol;

A and X are each —

CH₂CH₂—

, each optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C₁-C₄ alkoxy, C₁-C₃ alkyl, carboxy, cyano, C₁-C₃ haloalkyl, halogen, hydroxyl and oxo;

J is —

CH₂CH₂—

or —

C(═

NOMe)CH₂—

each optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C₁-C₄ alkoxy, C₁-C₃ alkyl, carboxy, cyano, C₁-C₃ haloalkyl, halogen, hydroxyl and oxo; and

Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C₁-C₆ acyl, C₁-C₆ acyloxy, C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylcarboxamide, C₁-C₆ alkylsulfonamide, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, C₁-C₆ alkylureyl, C₁-C₆ alkylamino, C₂-C₆ alkynyl, amino, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano, C₃-C₇ cycloalkyl, C₂-C₆ dialkylamino, C₂-C₆ dialkylcarboxamide, C₂-C₆ dialkylsulfonamide, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆ haloalkylthio, halogen, C₃-C₇ heterocyclyl, hydroxyl, nitro, sulfonamide and thiol;

provided that said compound is other than;

1-(4-(1H-pyrazole-3-carbonyl)piperazin-1-yl)-2-(4-fluoro-1H-indol-3-yl)ethane-1,2-dione.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, having Formula (Ic):

3. The compound according to claim 1, or a pharmaceutically acceptable salt solvate or hydrate thereof, having Formula (Ie):

4. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein each R¹ and R² is selected independently from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ alkylaryl, aryl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen, heteroaryl and nitro.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein each R¹ and R² is selected independently from the group consisting of H, methyl, ethyl, isopropyl, t-butyl, 2-methylphenyl, phenyl, cyclopropyl, trifluoromethyl, fluoro, chloro, bromo, iodo, furan-2-yl and nitro.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R¹ is H, halogen or C₁-C₆ alkylaryl;

and R² is H, C₁-C₆ alkyl, aryl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, heteroaryl or nitro.

7. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R¹ is H, fluoro, chloro, bromo, iodo or 2-methylphenyl;

and R² is H, methyl, ethyl, isopropyl, t-butyl, phenyl, cyclopropyl, trifluoromethyl, furan-2-yl or nitro.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R¹ and R² together with the carbon atoms to which they are bonded form a C₃-C₇ carbocyclyl.

9. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R¹ and R² together with the carbon atoms to which they are bonded form a C₅ carbocyclyl.

10. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R³ is selected from the group consisting of H, C₁-C₆ alkyl and aryl;

and wherein aryl is optionally substituted with C₁-C₆ alkoxy.

11. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R³ is selected from the group consisting of H, C₁-C₆ alkyl and aryl;

and wherein aryl is optionally substituted with methoxy.

12. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R³ is selected from the group consisting of H, methyl, ethyl, t-butyl, phenyl and 4-methoxyphenyl.

13. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein A and X are each —

CH₂CH₂—

, each optionally substituted with C₁-C₃ alkyl.

14. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein A and X are each —

CH₂CH₂—

, each optionally substituted with methyl.

15. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein A and X are each independently —

CH₂CH₂—

or —

CH(CH₃)CH₂—

.

16. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein J is —

CH₂CH₂—

optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C₁-C₃ alkyl, hydroxyl, oxo and ═

NO—

C₁-C₃ alkyl.

17. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein J is —

CH₂CH₂—

optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of methyl, hydroxyl, oxo and ═

NOCH₃.

18. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein J is —

CH₂CH₂—

, —

C(═

NOCH₃)CH₂—

, —

C═

OCH₂—

, —

CH(CH₃)CH₂—

, —

C(CH₃)₂CH₂—

, or —

CHOHCH₂—

.

19. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen and heterocyclyl.

20. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, methanesulfonyl, trifluoromethoxy, trifluoromethyl, fluoro, chloro and pyrrolidin-1-yl.

21. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Ar is naphthyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-methanesulfonylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 6-chloro-1,3-dihydro-indol-2-one.

22. The compound according to claim 1, having Formula (Ic):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein;

R¹ is H, halogen or C₁-C₆ alkylaryl;

R² is H, C₁-C₆ alkyl, aryl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, heteroaryl, or nitro;

or

R¹ and R² together with the carbon atoms to which they are bonded form a C₃-C₇ carbocyclyl;

R³ is H, C₁-C₆ alkyl, aryl, or aryl substituted with C₁-C₆ alkoxy;

A and X are each —

CH₂CH₂—

, each optionally substituted with C₁-C₃ alkyl;

J is —

CH₂CH₂—

optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C₁-C₃ alkyl, hydroxyl, oxo and ═

NO—

C₁-C₃ alkyl; and

Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen and heterocyclyl.

23. The compound according to claim 1, having Formula (Ic):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein;

R¹ is H, fluoro, chloro, bromo, iodo or 2-methylphenyl;

R² is H, methyl, ethyl, isopropyl, t-butyl, phenyl, cyclopropyl, trifluoromethyl, furan-2-yl or nitro;

or

R¹ and R² together with the carbon atoms to which they are bonded form a C₅ carbocyclyl

R³ is H, methyl, ethyl, t-butyl, phenyl and 4-methoxyphenyl;

A and X are each independently —

CH₂CH₂—

or —

CH(CH₃)CH₂—

;

J is —

CH₂CH₂—

, —

C(═

NOMe)CH₂—

, —

C═

OCH₂—

, —

CH(CH₃)CH₂—

, —

C(CH₃)₂CH₂—

, or —

CHOHCH₂—

; and

Ar is naphthyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-methanesulfonylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 6-chloro-1,3-dihydro-indol-2-one.

24. The compound according to claim 1, having Formula (Ie):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein;

R¹ is H, halogen or C₁-C₆ alkylaryl;

R² is H, C₁-C₆ alkyl, aryl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, heteroaryl, or nitro;

or

R¹ and R² together with the carbon atoms to which they are bonded form a C₃-C₇ carbocyclyl;

R³ is H, C₁-C₆ alkyl, aryl, or aryl substituted with C₁-C₆ alkoxy;

A and X are each —

CH₂CH₂—

, each optionally substituted with C₁-C₃ alkyl;

J is —

CH₂CH₂—

optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C₁-C₃ alkyl, hydroxyl, oxo and ═

NO—

C₁-C₃ alkyl; and

Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C₁-C₆ alkoxy, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen and heterocyclyl.

25. The compound according to claim 1, having Formula (Ie):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein;

R¹ is H, fluoro, chloro, bromo, iodo or 2-methylphenyl;

R² is H, methyl, ethyl, isopropyl, t-butyl, phenyl, cyclopropyl, trifluoromethyl, furan-2-yl or nitro;

or

R¹ and R² together with the carbon atoms to which they are bonded form a C₅ carbocyclyl R³ is H, methyl, ethyl, t-butyl, phenyl or 4-methoxyphenyl;

A and X are each independently —

CH₂CH₂—

or —

CH(CH₃)CH₂—

;

J is —

CH₂CH₂—

, —

C(═

NOMe)CH₂—

, —

C═

OCH₂—

, —

CH(CH₃)CH₂—

, —

C(CH₃)₂CH₂—

, or —

CHOHCH₂—

; and

Ar is naphthyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-methanesulfonylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 6-chloro-1,3-dihydro-indol-2-one.

26. The compound according to claim 1 selected from the group consisting of:

2-[4-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

1-(4-Fluoro-phenyl)-2-[4-(2-methyl-5-phenyl-2H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

2-[4-(4-Bromo-2,5-dimethyl-2H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

5-{2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethyl}-6-chloro-1,3-dihydro-indol-2-one;

2-[(S)-4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[4-(4-Chloro-1-ethyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[(S)-4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

1-(4-Fluoro-phenyl)-2-[4-(1,4,5,6-tetrahydro-cyclopentapyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

2-[(R)-4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-2-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(3-fluoro-phenyl)-ethanone;

2-[(R)-4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-2-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Chloro-1-ethyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[4-(1-tert-Butyl-5-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-pyrrolidin-1-yl-phenyl)-ethanone;

1-(4-Fluoro-phenyl)-2-{4-[1-(4-methoxy-phenyl)-5-phenyl-1H-pyrazole-3-carbonyl]-piperazin-1-yl}-ethanone;

2-[4-(5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Chloro-1-methyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-methanesulfonyl-phenyl)-ethanone;

(4-Chloro-1-methyl-1H-pyrazol-3-yl)-{4-[2-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone O-methyl-oxime;

(4-Bromo-2,5-dimethyl-2H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

1-(4-Fluoro-phenyl)-2-[4-(1-methyl-4-o-tolyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-trifluoromethoxy-phenyl)-ethanone;

2-[4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(3-fluoro-phenyl)-ethanone;

1-(4-Fluoro-phenyl)-2-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

(4-Bromo-2-methyl-2H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[4-(5-Cyclopropyl-4-fluoro-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-trifluoromethyl-phenyl)-ethanone;

(4-Chloro-1-methyl-1H-pyrazol-3-yl)-{4-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

1-(4-Fluoro-phenyl)-2-[4-(1-methyl-5-trifluoromethyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[4-(5-Ethyl-4-fluoro-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-chloro-phenyl)-ethanone;

2-[4-(4-Chloro-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-(2-methyl-2H-pyrazol-3-yl)-methanone;

2-[4-(4-Fluoro-5-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-(4-phenethyl-piperazin-1-yl)-methanone;

(4-Chloro-1-methyl-1H-pyrazol-3-yl)-{4-[2-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

1-(4-Fluoro-phenyl)-2-[4-(5-isopropyl-2H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

(4-Chloro-1,5-dimethyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

1-(4-Fluoro-phenyl)-2-[4-(4-iodo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(3,4-difluoro-phenyl)-ethanone;

5-{2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-acetyl}-6-chloro-1,3-dihydro-indol-2-one;

1-(4-Fluoro-phenyl)-2-[4-(5-methyl-2H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone

(4-Bromo-1,5-dimethyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[4-(4-Bromo-5-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Bromo-1,5-dimethyl-1H-pyrazol-3-yl)-{(S)-4-[2-(4-fluoro-phenyl)-ethyl]-3-methyl-piperazin-1-yl}-methanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{(S)-4-[2-(4-fluoro-phenyl)-ethyl]-2-methyl-piperazin-1-yl}-methanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(2-chloro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-(5-isopropyl-2H-pyrazol-3-yl)-methanone;

2-[4-(4-Chloro-5-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{(S)-4-[2-(4-fluoro-phenyl)-ethyl]-3-methyl-piperazin-1-yl}-methanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{(R)-4-[2-(4-fluoro-phenyl)-ethyl]-2-methyl-piperazin-1-yl}-methanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(3-chloro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

(1,5-Dimethyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

2-[4-(4-Chloro-1,5-dimethyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Chloro-1-methyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-2-methyl-propyl]-piperazin-1-yl}-methanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-naphthalen-2-yl-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(2-methoxy-phenyl)-ethanone;

1-(4-Fluoro-phenyl)-2-[4-(5-furan-2-yl-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-(5-methyl-1H-pyrazol-3-yl)-methanone

2-[4-(4-Bromo-1,5-dimethyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

(4-Chloro-1-methyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-propyl]-piperazin-1-yl}-methanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-chloro-phenyl)-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(2-fluoro-phenyl)-ethanone;

1-(4-Fluoro-phenyl)-2-[4-(1-methyl-5-phenyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

(4-Bromo-1,5-dimethyl-1H-pyrazol-3-yl)-{(R)-4-[2-(4-fluoro-phenyl)-ethyl]-3-methyl-piperazin-1-yl}-methanone;

1-(4-Fluoro-phenyl)-2-[4-(1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{(R)-4-[2-(4-fluoro-phenyl)-ethyl]-3-methyl-piperazin-1-yl}-methanone;

1-(4-Fluoro-phenyl)-2-[4-(5-nitro-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-ethanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-piperazin-1-yl}-methanone;

2-[(S)-4-(4-Bromo-1,5-dimethyl-1H-pyrazole-3-carbonyl)-2-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[4-(2-Ethyl-5-methyl-2H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[(S)-4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-2-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(2,4-difluoro-phenyl)-ethanone;

2-[(S)-4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)-2-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone;

{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-methanone;

(4-Bromo-1-methyl-1H-pyrazol-3-yl)-{4-[2-(2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone; and

(4-Chloro-1-methyl-1H-pyrazol-3-yl)-{4-[2-(2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-methanone;

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

27. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

28. A method for treating a 5-HT_2A mediated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

29. The method according to claim 28, wherein said 5-HT_2A mediated disorder is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation.

30. A method for treating a sleep disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

31. The method according to claim 30, wherein said sleep disorder is a dyssomnia.

32. The method according to claim 30, wherein said sleep disorder is insomnia.

33. The method according to claim 30, wherein said sleep disorder is a parasomnia.

34. A method for increasing slow wave sleep in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

35. A method for improving sleep consolidation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

36. A method for improving sleep maintenance in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

37. A method for treating a condition associated with platelet aggregation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

38. A method for reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

39. A method for reducing the risk of blood clot formation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

40. A method for reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

41. A method for treating a diabetic-related disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

42. A method for treating progressive multifocal leukoencephalopathy in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

43. A method for treating hypertension in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

44. A method for treating pain in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 27.

45-80. -80. (canceled)