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

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.

1 . 80 . (canceled) 
     
     
         81 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ie): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
 R 1  is 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 
 a pharmaceutically acceptable carrier. 
 
     
     
         82 . The pharmaceutical composition of  claim 81 , wherein the therapeutically effective amount is from about 0.001 milligrams to about 1,000 milligrams. 
     
     
         83 . The pharmaceutical composition of  claim 81 , wherein the pharmaceutical composition is formulated for a mode of administration selected from the group consisting of oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal, parenteral (including intramuscular, sub-cutaneous and intravenous), inhalation, insufflation, and transdermally. 
     
     
         84 . The pharmaceutical composition of  claim 81 , wherein the pharmaceutical composition is administered in a unit dose selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, elixirs, gels, suppositories, sterile injectable solutions, and transdermal patches. 
     
     
         85 . The pharmaceutical composition of  claim 81 , wherein the pharmaceutically acceptable salt is selected from the group of acid addition salts consisting of acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, and p-toluenesulfonic. 
     
     
         86 . A method of treating a 5-HT2A mediated disorder, 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, in an individual, comprising administering to said individual a therapeutically effective amount of a pharmaceutical composition according to  claim 81 . 
     
     
         87 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ic): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or hydrate thereof;
 wherein: 
 R 1  is 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 
 a pharmaceutically acceptable carrier. 
 
     
     
         88 . The pharmaceutical composition of  claim 87 , wherein the therapeutically effective amount is from about 0.001 milligrams to about 1,000 milligrams. 
     
     
         89 . The pharmaceutical composition of  claim 87 , wherein the pharmaceutical composition is formulated for a mode of administration selected from the group consisting of oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal, parenteral (including intramuscular, sub-cutaneous and intravenous), inhalation, insufflation, and transdermally. 
     
     
         90 . The pharmaceutical composition of  claim 87 , wherein the pharmaceutical composition is administered in a unit dose selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, elixirs, gels, suppositories, sterile injectable solutions, and transdermal patches. 
     
     
         91 . The pharmaceutical composition of  claim 87 , wherein the pharmaceutically acceptable salt is selected from the group of acid addition salts consisting of acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, and p-toluenesulfonic. 
     
     
         92 . A method of treating a 5-HT2A mediated disorder, 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, in an individual, comprising administering to said individual a therapeutically effective amount of a pharmaceutical composition according to  claim 87 . 
     
     
         93 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ic): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or hydrate thereof;
 wherein: 
 R 1  is H, fluoro, chloro, bromo, iodo or 2-methylphenyl; 
 R 2  is H, methyl, ethyl, isopropyl, t-butyl, phenyl, cyclopropyl, trifluoromethyl, furan-2-yl or nitro; or 
 R 1  and R 2  together with the carbon atoms to which they are bonded form a Cs carbocyclyl 
 R 3  is H, methyl, ethyl, t-butyl, phenyl or 4-methoxyphenyl; 
 A and X are each independently —CH 2 CH 2 — or —CH(CH 3 )CH 2 —; 
 J is —CH 2 CH 2 —, —C(═NOMe)CH 2 —, —C═OCH 2 —, —CH(CH 3 )CH 2 —, —C(CH 3 )2CH 2 —, or —CHOHCH 2 —; and 
 Ar is naphthyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-methanesulfonylphenyl, 4-trifluoromethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, or 4-chlorophenyl; and 
 a pharmaceutically acceptable carrier. 
 
     
     
         94 . The pharmaceutical composition of  claim 93 , wherein the therapeutically effective amount is from about 0.001 milligrams to about 1,000 milligrams. 
     
     
         95 . The pharmaceutical composition of  claim 93 , wherein the pharmaceutical composition is formulated for a mode of administration selected from the group consisting of oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal, parenteral (including intramuscular, sub-cutaneous and intravenous), inhalation, insufflation, and transdermally. 
     
     
         96 . The pharmaceutical composition of  claim 93 , wherein the pharmaceutical composition is administered in a unit dose selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, elixirs, gels, suppositories, sterile injectable solutions, and transdermal patches. 
     
     
         97 . The pharmaceutical composition of  claim 93 , wherein the pharmaceutically acceptable salt is selected from the group of acid addition salts consisting of acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, and p-toluenesulfonic. 
     
     
         98 . A method of treating a 5-HT2A mediated disorder, 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, in an individual, comprising administering to said individual a therapeutically effective amount of a pharmaceutical composition according to  claim 93 .