3-phenyl-pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto

Abstract

The present invention relates to certain 3-phenyl-pyrazole derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggreagation, 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 a symptom, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep 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.

1 . A compound of Formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: 
         V is O, S, S(═O), S(═O) 2  or NR 10 ; 
         W is C 1-4  alkylene optionally substituted with 1 to 8 substituents selected independently from the group consisting of C 1-3  alkyl, C 1-4  alkoxy, carboxy, cyano, C 1-3  haloalkyl, halogen and oxo; or W is absent; 
         X is C(═O), C(═S) or absent; 
         Y is O, NR 11  or absent; 
         Z is C 1-4  alkylene, or C 3-6  cycloalkylene, each optionally substituted with 1 to 8 substituents selected independently from the group consisting of C 1-3  alkyl, C 1-4  alkoxy, carboxy, cyano, C 1-3  haloalkyl, halogen, hydroxyl, and oxo; or Z is absent; 
         R 1  is selected from the group consisting of H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl and C 3-7  cycloalkyl; 
         R 2  is selected from the group consisting of H, C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, C 2-8  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, haloalkyl, haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; 
         R 3  is selected from the group consisting of H, C 2-6  alkenyl, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C 2-6  alkenyl, C 1-6  alkyl, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 3-7  cycloalkyl, heteroaryl and phenyl groups are optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-5  acyl, C 1-5  acyloxy, C 2-6  alkenyl, C 1-4  alkoxy, C 1-8  alkyl, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-4  alkylcarboxamide, C 2-6  alkynyl, C 1-4  alkylsulfonamide, C 1-4  alkylsulfinyl, C 1-4  alkylsulfonyl, C 1-4  alkylthio, C 1-4  alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6  cycloalkyl, C 2-6  dialkylcarboxamide, halogen, C 1-4  haloalkoxy, C 1-4  haloalkyl, C 1-4  haloalkylsulfinyl, C 1-4  haloalkylsulfonyl, C 1-4  haloalkylthio, hydroxyl, nitro and sulfonamide; 
         R 4  is heterobicyclic, heterocyclic, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C 1-6  acyl, C 1-12  acyloxy, C 2-6  alkenyl, C 1-4  alkoxy, C 1-6  alkoxycarbonylamino, C 1-6  alkyl, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-4  alkylcarboxamide, C 2-6  alkynyl, C 1-4  alkylsulfonamide, C 1-4  alkylsulfinyl, C 1-4  alkylsulfonyl, C 1-4  alkylthio, C 1-4  alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6  cycloalkyl, C 3-7  cycloalkylcarbonyl, C 2-6  dialkylcarboxamide, formyl, halogen, C 1-4  haloalkoxy, haloalkyl, C 1-4  haloalkylsulfinyl, C 1-4  haloalkylsulfonyl, C 1-4  haloalkylthio, heteroaryl, hydroxyl, nitro, phenyl and sulfonamide; wherein said C 1-5  acyl, C 1-5  acyloxy, C 1-4  alkoxy, C 1-6  alkyl, C 1-4  alkylcarboxamide, amino, carbo-C 1-6 -alkoxy, and heteroaryl are each optionally substituted with substituents selected independently from the group consisting of C 1-6  alkyl, C 1-5  acyl, C 1-4  alkoxy, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-4  alkylcarboxamide, C 1-4  alkylsulfonyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6  cycloalkyl, halogen, C 1-4  haloalkoxy, C 1-4  haloalkyl, hydroxyl, and phenyl; 
         R 5 , R 6 , and R 7  are each selected independently from the group consisting of H, C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-6  alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, C 2-8  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl; 
         R 8  is C 1-8  alkyl, C 2-6  alkenyl, aryl, C 3-7  cycloalkyl, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-6  alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, C 2-8  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent substituents together with said aryl or said heteroaryl form a C 5-7  cycloalkyl optionally comprising 1 to 2 oxygen atoms and optionally substituted with F, Cl or Br; and wherein said C 2-6  alkenyl, C 1-6  alkyl, C 2-6  alkynyl, C 1-6  alkylamino, C 1-6  alkylimino, C 2-8  dialkylamino, heterocyclic, and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, thiol and nitro; and 
         R 9 , R 10 , and R 11  are each independently H or C 1-8  alkyl; 
         provided that said compound is other than N-[4-oxiranylmethoxy-3-(2H-pyrazol-3-yl)-phenyl]-acetamide. 
       
     
     
         2 . The compound according to  claim 1  having Formula (Ic): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein V is O. 
     
     
         4 . The compound according to  claim 1  wherein W is —CH 2 —, —CH 2 CH 2 —, —CH 2 C(═O)—, —CH 2 CH 2 CH 2 —, —C(CH 3 ) 2 C(═O)—, —CH 2 CH(CH 3 )—, —CH(CH 3 )CH 2 —, —C(CH 3 ) 2 CH 2 —, or —CH 2 C(CH 3 ) 2 —. 
     
     
         5 . The compound according to  claim 1 , wherein W is absent. 
     
     
         6 . The compound according to  claim 1 , wherein X is C(═O). 
     
     
         7 . The compound according to  claim 1 , wherein X is absent. 
     
     
         8 . The compound according to  claim 1 , wherein Y is NH, O or absent. 
     
     
         9 . The compound according to  claim 1 , wherein Z is absent, —CH 2 —, —CH(OH)—, —CF 2 —, —C(CH 3 ) 2 —, 1,1-cyclopropyl, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )—, or —C(═O)—. 
     
     
         10 . The compound according to  claim 1 , wherein R 1  is —CH 3 . 
     
     
         11 . The compound according to  claim 1 , wherein R 2  is H. 
     
     
         12 . The compound according to  claim 1 , wherein R 3  is H, F, Cl or Br. 
     
     
         13 . The compound according to  claim 1 , wherein R 4  is heterobicyclic, heterocyclic, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C 1-6  acyl, C 1-12  acyloxy, C 1-6  alkoxycarbonylamino, C 1-4  alkoxy, C 1-6  alkyl, C 1-4  alkylcarboxamide, C 1-4  alkylsulfonamide, C 1-4  alkylsulfonyl, C 1-4  alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, C 2-6  dialkylcarboxamide, formyl, halogen, C 1-4  haloalkyl, heteroaryl, hydroxyl and phenyl; wherein said C 1-5  acyl, C 1-5  acyloxy, C 1-4  alkoxy, C 1-6  alkyl, C 1-4  alkylcarboxamide, amino, carbo-C 1-6 -alkoxy and heteroaryl are each optionally substituted with substituents selected independently from the group consisting of C 1-6  alkyl, carbo-C 1-6 -alkoxy, carboxy, and phenyl. 
     
     
         14 . The compound according to  claim 1 , wherein R 4  is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl, 2,5-diaza-bicyclo[2.2.1]hept-2-yl, [1,4]oxazepan-4-yl, 1,1-dioxo-1λ 6 -thiomorpholin-4-yl, piperidin-2-yl, azepan-1-yl, pyrrolidin-3-yl, 3-oxo-piperazin-1-yl, 7-aza-bicyclo[2.2.1]hept-7-yl, and imidazol-1-yl each optionally substituted with substituents selected independently from the group consisting of CH 3 , C(═O)O-t-butyl, C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH, C(═O)NHCH 2 C(═O)OCH 3 , NHC(═O)CH 2 C(═O)OCH 3 , C(═O)NHCH 2 C(═O)OH, NHC(═O)CH 2 C(═O)OH, C(═O)OCH 3 , OC(═O)CH 2 CH 2 C(═O)OCH 3 , OC(═O)CH 2 CH 2 CH 2 CH 2 CH 3 , CH 2 C(═O)OCH 2 CH 3 , OCH 3 , CH 2 C(═O)OH, OC(═O)CH 2 CH 2 C(═O)OCH 3 , CH 2 CH 2 C(═O)OCH 3 , C(═O)CH 3 , and C(═O)OCH 2 -phenyl, C(═O)CH 2 CH 2 C(═O)OCH 3 , C(═O)CH 2 CH 2 C(═O)OH, F, phenyl, CH 2 C(═O)OCH 3 , S(═O) 2 CH 3 , OCH 2 -phenyl, CH 2 -phenyl, C(═O)NH 2 , CHO, —NH 2 , NHC(═O)CH 3 , C(═O)N(CH 3 ) 2 , NHS(═O) 2 CH 3 , —CF 3 , 3-methyl-[1,2,4]oxadiazol-5-yl, and CH(CH 3 ) 2 . 
     
     
         15 . The compound according to  claim 1 , wherein R 5 , R 6  and R 7  are all H. 
     
     
         16 . The compound according to  claim 1 , wherein R 8  is C 1-8  alkyl, C 2-6  alkenyl, aryl, C 3-7  cycloalkyl, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C 1-6  acyl, C 1-6  alkoxy, C 1-6  alkyl, cyano, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, and hydroxyl, or two adjacent substituents together with said aryl or said heteroaryl form a C 5-7  cycloalkyl optionally comprising 1 to 2 oxygen atoms and optionally substituted with F. 
     
     
         17 . The compound according to  claim 1 , wherein R 8  is selected from the group consisting of methyl, iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, phenyl, naphthalen-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, pyridin-2-yl, pyridin-3-yl, 1H-benzoimidazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl, benzothiophen-2-yl, thiazol-2-yl, isoxazol-3-yl, and pyridin-4-yl each optionally substituted with substituents selected independently from the group consisting of C(═O)CH 3 , OCH 3 , CH 3 , F, Cl, Br, CF 3 , hydroxyl, OCF 3 , and CN, or two adjacent substituents together with said phenyl form a C 5  cycloalkyl comprising 2 oxygen atoms and optionally substituted with F. 
     
     
         18 . The compound according to  claim 1 , wherein R 8  is selected from the group consisting of 4-chloro-phenyl, 2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl, 4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl, 4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl, 4-methyl-phenyl, 3-trifluoromethyl-phenyl, 3,5-difluoro-phenyl, 2,4-dichloro-phenyl, 4-chloro-2-trifluoromethyl-phenyl, 3,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, naphthalen-1-yl, 4-trifluoromethoxy-phenyl, 3-cyano-phenyl, 2-trifluoromethoxy-phenyl, 4-chloro-2-fluoro-phenyl, 2,3-difluoro-phenyl, 2,4,5-trifluoro-phenyl, 2,3,4-trifluoro-phenyl, 3,4-dichloro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 5-fluoro-2-trifluoromethyl-phenyl, 2-trifluoromethyl-phenyl, 3-methyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 4-chloro-3-fluoro-phenyl, 3-fluoro-4-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 3-chloro-4-fluoro-phenyl, 2,6-dichloro-phenyl, 4-cyano-phenyl, 2,5-dichloro-phenyl, and benzo[1,3]dioxol-5-yl. 
     
     
         19 . The compound according to  claim 1 , wherein R 8  is selected from the group consisting of methyl, iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, 3-methyl-butyl, cyclopropyl, cyclobutyl, and cyclopentyl. 
     
     
         20 . The compound according to  claim 1 , wherein R 8  is selected from the group consisting of pyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl, 3-hydroxy-pyridin-2-yl, 6-methyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl, 1H-benzoimidazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl, 5-chloro-thiophen-2-yl, benzothiophen-2-yl, thiazol-2-yl, 5-methyl-isoxazol-3-yl, and pyridin-4-yl. 
     
     
         21 . The compound according to  claim 1 , wherein R 9  is H. 
     
     
         22 . The compound according to  claim 1 , wherein R 11  is H. 
     
     
         23 . The compound according to  claim 1  having Formula (Ik): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: 
         W is —CH 2 —, —CH 2 CH 2 —, —CH 2 C(═O)—, —CH 2 CH 2 CH 2 —, —C(CH 3 ) 2 C(═O)—, —CH 2 CH(CH 3 )—, —CH(CH 3 )CH 2 —, —C(CH 3 ) 2 CH 2 —, or —CH 2 C(CH 3 ) 2 —; or W is absent; 
         X is C(═O) or absent; 
         Y is NH, O or absent; 
         Z is absent, —CH 2 —, —CH(OH)—, —CF 2 —, —C(CH 3 ) 2 —, 1,1-cyclopropyl, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )—, or —C(═O)—; 
         R 1  is C 1-6  alkyl; 
         R 3  is H or halogen; 
         R 4  is heterobicyclic, heterocyclic, or heteroaryl, each optionally substituted with substituents selected independently from the group consisting of C 1-6  acyl, C 1-12  acyloxy, C 1-4  alkoxy, C 1-6  alkoxycarbonylamino, C 1-6  alkyl, C 1-4  alkylcarboxamide, C 1-4  alkylsulfonamide, C 1-4  alkylsulfonyl, C 1-4  alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, C 2-6  dialkylcarboxamide, formyl, halogen, C 1-4  haloalkyl, heteroaryl, hydroxyl and phenyl; wherein said C 1-5  acyl, C 1-5  acyloxy, C 1-4  alkoxy, C 1-6  alkyl, C 1-4  alkylcarboxamide, amino, carbo-C 1-6 -alkoxy and heteroaryl are each optionally substituted with substituents selected independently from the group consisting of C 1-6  alkyl, carbo-C 1-6 -alkoxy, carboxy, and phenyl; and 
         R 8  is C 1-8  alkyl, C 2-6  alkenyl, aryl, C 3-7  cycloalkyl, or heteroaryl, each optionally substituted with substituents selected independently from the group consisting of C 1-6  acyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylsulfonyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-6  alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent substituents together with said aryl or said heteroaryl form a C 5-7  cycloalkyl optionally comprising 1 to 2 oxygen atoms and optionally substituted with F. 
       
     
     
         24 . The compound according to  claim 1  having Formula (Ik): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: 
         W is —CH 2 —, —CH 2 CH 2 —, —CH 2 C(═O)—, —CH 2 CH 2 CH 2 —, —C(CH 3 ) 2 C(═O)—, —CH 2 CH(CH 3 )—, —CH(CH 3 )CH 2 —, —C(CH 3 ) 2 CH 2 —, or —CH 2 C(CH 3 ) 2 —; or W is absent; 
         X is C(═O) or absent; 
         Y is NH, O or absent; 
         Z is absent, —CH 2 —, —CH(OH)—, —CF 2 —, —C(CH 3 ) 2 —, 1,1-cyclopropyl, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )—, or —C(═O)—; 
         R 1  is C 1-6  alkyl; 
         R 3  is H or halogen; 
         R 4  is heterobicyclic, heterocyclic, or heteroaryl, each optionally substituted with substituents selected independently from the group consisting of C 1-6  acyl, C 1-12  acyloxy, C 1-4  alkoxy, C 1-6  alkoxycarbonylamino, C 1-6  alkyl, C 1-4  alkylcarboxamide, C 1-4  alkylsulfonamide, C 1-4  alkylsulfonyl, C 1-4  alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, C 2-6  dialkylcarboxamide, formyl, halogen, C 1-4  haloalkyl, heteroaryl, hydroxyl and phenyl; wherein said C 1-5  acyl, C 1-5  acyloxy, C 1-4  alkoxy, C 1-6  alkyl, C 1-4  alkylcarboxamide, amino, carbo-C 1-6 -alkoxy and heteroaryl are each optionally substituted with substituents selected independently from the group consisting of C 1-6  alkyl, carbo-C 1-6 -alkoxy, carboxy, and phenyl; and 
         R 8  is selected from the group consisting of 4-chloro-phenyl, 2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl, 4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl, 4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl, 4-methyl-phenyl, 3-trifluoromethyl-phenyl, 3,5-difluoro-phenyl, 2,4-dichloro-phenyl, 4-chloro-2-trifluoromethyl-phenyl, 3,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, naphthalen-1-yl, 4-trifluoromethoxy-phenyl, 3-cyano-phenyl, 2-trifluoromethoxy-phenyl, 4-chloro-2-fluoro-phenyl, 2,3-difluoro-phenyl, 2,4,5-trifluoro-phenyl, 2,3,4-trifluoro-phenyl, 3,4-dichloro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 5-fluoro-2-trifluoromethyl-phenyl, 2-trifluoromethyl-phenyl, 3-methyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 4-chloro-3-fluoro-phenyl, 3-fluoro-4-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 3-chloro-4-fluoro-phenyl, 2,6-dichloro-phenyl, 4-cyano-phenyl, 2,5-dichloro-phenyl, and benzo[1,3]dioxol-5-yl. 
       
     
     
         25 . The compound according to  claim 1  having Formula (Io): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: 
         W is —CH 2 —, —CH 2 CH 2 — or —CH 2 C(═O)—; 
         R 1  is C 1-6  alkyl; 
         R 3  is H or halogen; 
         R 4  is pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl or pyridin-4-yl, each optionally substituted with substituents selected independently from the group consisting of CH 3 , C(═O)O-t-butyl, C(═O)OH, C(═O)OEt, NHC(═O)O-t-butyl, OH, C(═O)NHCH 2 C(═O)OCH 3 , NHC(═O)CH 2 C(═O)OCH 3 , C(═O)NHCH 2 C(═O)OH, NHC(═O)CH 2 C(═O)OH, C(═O)OCH 3 , OC(═O)CH 2 CH 2 C(═O)OCH 3 , OC(═O)CH 2 CH 2 CH 2 CH 2 CH 3 , CH 2 C(═O)OCH 2 CH 3 , OCH 3 , CH 2 C(═O)OH, OC(═O)CH 2 CH 2 C(═O)OCH 3 , CH 2 CH 2 C(═O)OCH 3 , C(═O)CH 3 , and C(═O)OCH 2 -phenyl; and 
         R 8  is selected from the group consisting of 1H-benzoimidazol-2-yl, benzooxazol-2-yl and benzothiazol-2-yl. 
       
     
     
         26 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of:
 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea (Compound 1);   N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)cyclopropanecarboxamide (Compound 271);   N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-3-fluoro-benzamide (Compound 637);   N-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-fluoro-4-methyl-benzamide (Compound 559);   1-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)-3-(3-chlorophenyl)urea (Compound 231);   1-(4-Chloro-benzyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-urea (Compound 666);   3-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide (Compound 512);   3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide (Compound 487);   1-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea (Compound 298);   1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-trifluoromethyl-benzyl)-urea (Compound 710);   1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-benzyl)-urea (Compound 734);   4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (Compound 281);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide (Compound 282);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide (Compound 435);   N-[4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-methyl-benzamide (Compound 546);   4-Fluoro-3-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-benzamide (Compound 547);   N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-3,4-difluoro-benzamide (Compound 579);   N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-3,4-difluoro-benzamide (Compound 585);   N-[4-[2-(3-Hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide (Compound 586);   3-Fluoro-N-[4-[2-(4-formyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide (Compound 752);   N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide (Compound 755);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-phenyl-acetamide) (Compound 762);   2-(3-Fluoro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (Compound 766);   2-(3-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (Compound 767);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-acetamide (Compound 768);   2-(3-Methoxy-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (Compound 769);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-m-tolyl-acetamide (Compound 770);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-p-tolyl-acetamide (Compound 771);   2-Benzo[1,3]dioxol-5-yl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (Compound 772);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide (Compound 794);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-thiophen-2-yl-acetamide (Compound 795);   1-[4-(2-Azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound 86);   1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea (Compound 267);   N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-methyl-butyramide (Compound 326);   Benzooxazol-2-yl-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amine (Compound 199);   5-Chloro-thiophene-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide (Compound 333);   3,4-Difluoro-N-[4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide (Compound 459);   N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-4-fluoro-3-methyl-benzamide (Compound 745);   1-(2-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea (Compound 65);   N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-fluoro-benzamide (Compound 455);   Cyclopentanecarboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide (Compound 310);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide (Compound 343);   N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenyl}-3-fluoro-benzamide (Compound 475);   3-Chloro-4-fluoro-N-[4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide (Compound 538);   N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-4-fluoro-benzamide (Compound 396);   N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide (Compound 660);   N-[4-[2-(4,4-Difluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide (Compound 778);   3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (Compound 729);   3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (Compound 733);   1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound 5);   1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea (Compound 145);   1-(2,4-Difluoro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea (Compound 219);   [4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamic acid isopropyl ester (Compound 352);   N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide (Compound 568);   N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide (Compound 606);   [3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-carbamic acid isopropyl ester (Compound 214);   [3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-carbamic acid isopropyl ester (Compound 215); and   N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide (Compound 527);   or a pharmaceutically acceptable salt, hydrate or solvate thereof.   
     
     
         27 . A pharmaceutical composition comprising a compound according to  claim 1  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 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 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 pharmaceutical composition according to  claim 27 . 
     
     
         31 . 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 pharmaceutical composition according to  claim 27 . 
     
     
         32 . 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 pharmaceutical composition according to  claim 27 . 
     
     
         33 . 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 pharmaceutical composition according to  claim 27 . 
     
     
         34 . The method according to  claim 33 , wherein said sleep disorder is a dyssomnia. 
     
     
         35 . The method according to  claim 33 , wherein said sleep disorder is a parasomnia. 
     
     
         36 . 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 pharmaceutical composition according to  claim 27 . 
     
     
         37 . 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 pharmaceutical composition according to  claim 27 . 
     
     
         38 . 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 pharmaceutical composition according to  claim 27 . 
     
     
         39 . 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 pharmaceutical composition according to  claim 27 . 
     
     
         39 .- 65 . (canceled) 
     
     
         66 . A process for preparing a composition comprising admixing a compound according to  claim 1  and a pharmaceutically acceptable carrier.