PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
First Claim
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;
orR1 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.
1 Assignment
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Accused Products
Abstract
Pyrazole derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the serotonin 5HT2A 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-HT2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.
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Citations
45 Claims
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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;
orR1 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; andAr 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)
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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.
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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.
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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.
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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.
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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.
- CH2CH2—
-
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.
- CH2CH2—
-
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—
.
- CH2CH2—
-
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.
- CH2CH2—
-
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.
- CH2CH2—
-
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—
.
- CH2CH2—
-
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.
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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.
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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;
orR1 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; andAr 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;
orR1 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—
; andAr 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;
orR1 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; andAr 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;
orR1 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—
; andAr 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.
-
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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.
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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.
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28. A method for treating a 5-HT2A 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.
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29. The method according to claim 28, wherein said 5-HT2A mediated disorder is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation.
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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.
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31. The method according to claim 30, wherein said sleep disorder is a dyssomnia.
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32. The method according to claim 30, wherein said sleep disorder is insomnia.
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33. The method according to claim 30, wherein said sleep disorder is a parasomnia.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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45-80. -80. (canceled)
Specification