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

A method for treating a 5-HT2A 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:
• R1 bis 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-C3alkyl;
• 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;
• Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C1-C6alkoxy, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, halogen and C3-C7heterocyclyl;
• 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-HT2A 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.

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.
• R1 bis 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-C3alkyl;
• 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-C6alkoxy, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, halogen and C3-C7heterocyclyl;
• 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.

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:
• R1 bis 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-C3alkyl;
• 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-C6alkoxy, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, halogen and C3-C7heterocyclyl;
• 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.