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

Abstract

Pyrazolc 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 la 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.

1 - 80  (canceled) 
     
     
         81 . A method for treating a 5-HT 2A  mediated disorder in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound having Formula (Ie): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: 
         R 1  bis H, halogen or C 1 -C 6  alkylaryl; 
         R 2  is H, C 1 -C 6  alkyl, aryl, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkyl, heteroaryl, or nitro; or 
         R 1  and R 2  together with the carbon atoms to which they are bonded form a C 3 -C 7  carbocyclyl; 
         R 3  is H, C 1 -C 6  alkyl, aryl, or aryl substituted with C 1 -C 6  alkoxy; 
         A and X are each —CH 2 CH 2 —, each optionally substituted with C 1 -C 3 alkyl; 
         J is —CH 2 CH 2 — optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1 -C 3  alkyl, hydroxyl, oxo and ═NO—C 1 -C 3  alkyl; 
         Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6  alkylsulfonyl, C 1 -C 6  haloalkoxy, halogen and C 3 -C 7 heterocyclyl; 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; and 
         wherein the 5-HT 2A  mediated disorder is selected from the group consisting of agitation, dementia, Alzheimer's disease, Lewy Body disease. Parkinson's disease, Huntington's disease, platelet aggregation, reducing the risk of blood clot formation, treating a diabetic-related disorder, treating progressive multifocal leukoencephalopathy, hypertension, pain, and sleep disorders. 
       
     
     
         82 . A method for treating a condition in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound having Formula (Ie): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein. 
         R 1  bis H, halogen or C 1 -C 6  alkylaryl; 
         R 2  is H, C 1 -C 6  alkyl, aryl, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkyl, heteroaryl, or nitro; or 
         R 1  and R 2  together with the carbon atoms to which they are bonded form a C 3 -C 7  carbocyclyl; 
         R 3  is H, C 1 -C 6  alkyl, aryl, or aryl substituted with C 1 -C 6  alkoxy; 
         A and X are each —CH 2 CH 2 —, each optionally substituted with C 1 -C 3 alkyl; 
         J is —CH 2 CH 2 — optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1 -C 3  alkyl, hydroxyl, oxo and ═NO—C 1 -C 3  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 C 1 -C 6 alkoxy, C 1 -C 6  alkylsulfonyl, C 1 -C 6  haloalkoxy, halogen and C 3 -C 7 heterocyclyl; 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; and 
         wherein the condition is selected from the group consisting of a condition associated with platelet aggregation, a diabetic-related disorder, progressive multifocal leukoencephalopathy ;  hypertension, and pain. 
       
     
     
         83 . A method for reducing the risk of a condition in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound having Formula (Ie): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: 
         R 1  bis H, halogen or C 1 -C 6  alkylaryl; 
         R 2  is H, C 1 -C 6  alkyl, aryl, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkyl, heteroaryl, or nitro; or 
         R 1  and R 2  together with the carbon atoms to which they are bonded form a C 3 -C 7  carbocyclyl; 
         R 3  is H, C 1 -C 6  alkyl, aryl, or aryl substituted with C 1 -C 6  alkoxy; 
         A and X are each —CH 2 CH 2 —, each optionally substituted with C 1 -C 3 alkyl; 
         J is —CH 2 CH 2 — optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1 -C 3  alkyl, hydroxyl, oxo and ═NO—C 1 -C 3  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 C 1 -C 6 alkoxy, C 1 -C 6  alkylsulfonyl, C 1 -C 6  haloalkoxy, halogen and C 3 -C 7 heterocyclyl; 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; and 
         wherein the condition is selected from the group consisting of blood clot formation, blood clot formation in an angioplasty or coronary bypass surgery, and blood clot formation in an individual suffering from atrial fibrillation.