Ethers, secondary amines and derivatives thereof as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto

Abstract

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.

What is claimed is: 
     
         1 . A compound of Formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof, 
       
       wherein:
 V is O or NH; 
 W is C 1-4  alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C 1-3  alkyl, C 1-4  alkoxy, carboxy, cyano, C 3-7  cycloalkyl, C 1-3  haloalkyl, halogen, and oxo; 
 Q is —NR 4a R 4b  or —OR 4c , wherein:
 R 4a  is H, C 1-12  acyl, carbo-C 1-12 -alkoxy, or C(═O)O-aryl, wherein said C 1-12  acyl, carbo-C 1-12 -alkoxy, and —C(═O)O-aryl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-5  acyloxy, C 1-6  alkylcarboxamide, amino, C 1-6  alkylamino, C 2-s  dialkylamino, C 1-6  alkylimino, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, halogen, nitro, and phenyl; 
 R 4b  is C 1-6  alkyl, aryl, C 3-7  cycloalkyl, C 1-6  haloalkyl, heterocyclyl, or heteroaryl, wherein each is optionally substituted with 1, 2, 3, 4, or 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, imino, nitro, sulfonamide and phenyl; and 
 R 4c  is H, or R 4c  is C 1-6  alkyl, C 1-12  acyl, aryl, C 3-7  cycloalkyl, C 1-6  haloalkyl, heterocyclyl, or heteroaryl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-8  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, C 1-6  alkylamino, C 2-8  dialkylamino, 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, heterocyclyl, hydroxyl, imino, nitro, sulfonamide and phenyl; 
 
 Z is C 1-4  alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 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 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, C 1-6  haloalkyl, C 1-6  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, 2, 3, 4, or 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 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, heterocyclyl, hydroxyl, thiol, and nitro; 
 and 
 R 8  is C 1-8 -alkyl, aryl, C 3-10  cycloalkyl, heteroaryl, or heterocyclyl 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 3-7  cycloalkyloxy, 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, heteroaryl, heterocyclyl, hydroxyl, thiol, nitro, phenoxy and phenyl, 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, 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 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, heterocyclyl, hydroxyl, thiol and nitro. 
 
     
     
         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 — optionally substituted with 1 to 2 substituents selected independently from the group consisting of C 1-3  alkyl and oxo. 
     
     
         5 . The compound according to  claim 1 , wherein W is —CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, or —CH 2 C(═O)—. 
     
     
         6 . The compound according to  claim 1 , wherein Z is absent. 
     
     
         7 . The compound according to  claim 1 , wherein Z is —CH 2 — or —CH 2 CH 2 —. 
     
     
         8 . The compound according to  claim 1 , wherein R 1  is C 1-6  alkyl. 
     
     
         9 . The compound according to  claim 1 , wherein R 1  is —CH 3 . 
     
     
         10 . The compound according to  claim 1 , wherein R 2  is H. 
     
     
         11 . The compound according to  claim 1 , wherein R 3  is H, Cl, or Br. 
     
     
         12 . The compound according to  claim 1 , wherein Q is —NR 4a R 4b . 
     
     
         13 . The compound according to  claim 12 , wherein R 4a  is H, 
     
     
         14 . The compound according to  claim 12 , wherein R 4a  is C 1-12  acyl, or carbo-C 1-12 -alkoxy each optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-5  acyloxy, C 1-6  alkylcarboxamide, amino, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-6  alkylimino, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, halogen, nitro, and phenyl. 
     
     
         15 . The compound according to  claim 12 , wherein R 4b  is C 1-6  alkyl, C 3-7  cycloalkyl, C 1-6  haloalkyl, heterocyclyl, or heteroaryl, and each is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-4  alkoxy, C 1-8  alkyl, C 1-4  alkylsulfonyl, amino, carbo-C 1-6 -alkoxy, carboxamide, cyano, hydroxyl, imino, and phenyl. 
     
     
         16 . The compound according to  claim 12 , wherein:
 R 4a  is H; and   R 4b  is C 1-6  alkyl, C 3-7  cycloalkyl, C 1-6  haloalkyl, heterocyclyl, or heteroaryl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-4  alkoxy, C 1-8  alkyl, C 1-4  alkylsulfonyl, amino, carbo-C 1-6 -alkoxy, carboxamide, cyano, hydroxyl, imino, and phenyl.   
     
     
         17 - 32 . (canceled) 
     
     
         33 . A method for treating a 5-HT 2A  associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         34 . A method for treating platelet aggregation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         35 . A method for treating asthma, a diabetic-related disorder, progressive multifocal leukoencephalopathy, hypertension, or pain in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         36 . 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 . 
     
     
         37 - 45 . (canceled) 
     
     
         46 . A process for preparing a composition comprising admixing a compound according to  claim 1  and a pharmaceutically acceptable carrier.