PRIMARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO

摘要

The present invention pertains to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT2A 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, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, 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-HT2A serotonin receptor associated disorders in combination with other pharmaceutical agents administered separately or together.

主权项

1. A method for modulating the activity of a 5-HT2A serotonin receptor by contacting the receptor with a compound of Formula (Ia): or a pharmaceutically acceptable salt, hydrate or solvate thereof;wherein:
X is O or S; V is O or NH; W is C1-4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C1-3 alkyl, C1-4 alkoxy, carboxy, cyano, C3-7 cycloalkyl, C1-3 haloalkyl, halogen, oxo and imino, wherein said C1-3 alkyl is optionally substituted with C1-3 alkylsulfonyl; Z is C1-4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C1-3 alkyl, C1-4 alkoxy, carboxy, cyano, C1-3 haloalkyl, halogen and oxo; or Z is absent; R1 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-7 cycloalkyl; R2 is selected from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; R3 is selected from the group consisting of H, C2-6 alkenyl, C1-6 alkyl, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C2-6 alkenyl, C1-6 alkyl, C2-6 alkynyl, C1-6 alkylsulfonamide, C3-7 cycloalkyl, heteroaryl and phenyl groups are optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C1-5 acyl, C1-5 acyloxy, C2-6 alkenyl, C1-4 alkoxy, C1-8 alkyl, C1-6 alkylamino, C2-8 dialkylamino, C1-4 alkylcarboxamide, C2-6 alkynyl, C1-4 alkylsulfonamide, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkylthio, C1-4 alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-6 cycloalkyl, C2-6 dialkylcarboxamide, halogen, C1-4 haloalkoxy, C1-4 haloalkyl, C1-4 haloalkylsulfinyl, C1-4 haloalkylsulfonyl, C1-4 haloalkylthio, hydroxyl, nitro and sulfonamide; R4a is H; R4b is H, C1-12 acyl, carbo-C1-6-alkoxy, or C(═O)O-aryl, wherein said C1-12 acyl, carbo-C1-6-alkoxy, and —C(═O)O-aryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C1-6 alkylcarboxamide, amino, C1-6 alkylamino, C2-8 dialkylamino, C1-6 alkylimino, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, halogen, nitro, and phenyl; or R4b is —CO(═O)CRaRbOC(═O)Rc, wherein Ra, Rb and Rc are each independently selected from H, or C1-6 alkyl; R5, R6 and R7 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, C1-6 alkylimino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclyl, hydroxyl, thiol, and nitro; and R8 is C1-8-alkyl, aryl, C3-10 cycloalkyl, heteroaryl, or heterocyclyl each optionally substituted with substituents selected independently from the group consisting of C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, C1-6 alkylimino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heteroaryl, heterocyclyl, hydroxyl, thiol, nitro, phenoxy and phenyl, wherein said C2-6 alkenyl, C1-6 alkyl, C2-6 alkynyl, C1-6 alkylamino, C1-6 alkylimino, C2-8 dialkylamino, heteroaryl, heterocyclyl, phenyl, and phenoxy, and each said substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclyl, hydroxyl, thiol and nitro.