New indole derivatives with 5-HT6 receptor affinity

Abstract

This invention relates to compounds which have generally 5-HT6 receptor affinity and which are represented by Formula I: wherein one of R 5 , R 6 or R 7 is a group of general Formula B, wherein W is a —CH— group or a nitrogen atom, and the other substituents are as defined herein; or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds, methods for their use as therapeutic agents, and methods of preparation thereof.

1 - 33 . (canceled)  
     
     
         34 . A compound of Formula I:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is —S(O) 0-2 -A, —C(O)-A, or —(CH 2 ) 0-1 -A, wherein A is selected from aryl and heteroaryl, said heteroaryl being a monovalent aromatic carbocyclic radical having one or two rings incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen, or sulfur, and said aryl and heteroaryl are each independently in each occurrence optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino;  
         R 2  is selected from hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, and C 1-6 -alkylthio;  
         R 3  is selected from hydrogen and C 1-6 -alkyl;  
         R 4  is selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 alkylthio, halo-C 1-6 -alkyl, cyano, and C 1-6 -alkylcarbonyl; and  
         one of R 5 , R 6  or R 7  is a group of general Formula B, wherein W is a —CH— group, and R 8 , R 9  and R 10  are each independently selected from hydrogen, C 1-10 -alkyl and benzyl;  
         
           
             
             
                 
                 
             
           
         
          and the others are each independently of each other selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 alkylthio, haloalkyl, cyano, and C 1-6 -alkylcarbonyl;  
         or individual isomers, racemic or non racemic mixtures of isomers, prodrugs, or pharmaceutically acceptable salts or solvates thereof.  
       
     
     
         35 . The compound of  claim 34 , wherein R 1  is —SO 2 -A.  
     
     
         36 . The compound of  claim 35 , wherein A is an aryl group.  
     
     
         37 . The compound of  claim 35 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         38 . The compound of  claim 34 , wherein R 1  is —S-A.  
     
     
         39 . The compound of  claim 34 , wherein A is an aryl group.  
     
     
         40 . The compound of  claim 34 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         41 . A compound of Formula I comprising:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is —SO 0-2 -A, —C(O)-A, or —(CH 2 ) 0-1 -A, wherein A is aryl or heteroaryl, said heteroaryl being a monovalent aromatic carbocyclic radical having one or two rings incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen, or sulfur; said aryl and heteroaryl are each independently in each occurrence optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino;  
         R 2  is selected from hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, and C 1-16 -alkylthio;  
         R 3  is selected from hydrogen and C 1-6 -alkyl;  
         R 7  is a group of general Formula B, wherein W is a —CH— group, and R 8 , R 9  and  
         R 10  are each independently selected from hydrogen and C 1 -C 10 -alkyl;  
         
           
             
             
                 
                 
             
           
         
          and R 4 , R 5  and R 6  are each independently of each other selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 alkylthio, halo-C 1-6 -alkyl, cyano, and C 1-6 -alkylcarbonyl;  
         or individual isomers, racemic or non racemic mixtures of isomers, prodrugs, or pharmaceutically acceptable salts or solvates thereof.  
       
     
     
         42 . The compound of  claim 41 , wherein R 1  is —SO 2 -A.  
     
     
         43 . The compound of  claim 42 , wherein A is aryl, optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         44 . The compound of  claim 42 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         45 . The compound of  claim 42 , wherein A is heteroaryl, said heteroaryl being a monovalent aromatic carbocyclic radical having one or two rings incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen, or sulfur, said heteroaryl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         46 . The compound of  claim 42 , wherein A is pyridinyl or benzothiazolyl, said pyridinyl or benzothiazolyl being each independently of each other optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 16-alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         47 . The compound of  claim 41 , wherein R 1  is —S-A.  
     
     
         48 . The compound of  claim 47 , wherein A is aryl, optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         49 . The compound of  claim 47 , wherein A is phenyl optionally substituted with one or more optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         50 . A compound of Formula I comprising:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is —S(O) 0-2 -A, —C(O)-A, or —(CH 2 ) 0 -A, wherein A is aryl or heteroaryl, said heteroaryl being a monovalent aromatic carbocyclic radical having one or two rings incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen, or sulfur; and said aryl and heteroaryl are each independently of each other in each occurrence optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 16-alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino;  
         R 2  is selected from hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, and C 1-6 -alkylthio;  
         R 3  is selected from hydrogen and C 1-6 -alkyl;  
         R 5  is a group of general formula B, wherein W is a —CH— group, and R 8 , R 9  and R 10  are each independently selected from hydrogen and C 1-10 -alkyl;  
         
           
             
             
                 
                 
             
           
         
          and R 4 , R 6  and R 7  are each independently of each other selected from hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 alkylthio, haloC 1-6 -alkyl, cyano, and C 1-6 -alkylcarbonyl;  
         or individual isomers, racemic or non racemic mixtures of isomers, prodrugs, or pharmaceutically acceptable salts or solvates thereof.  
       
     
     
         51 . The compound of  claim 50 , wherein R 1  is —SO 2 -A.  
     
     
         52 . The compound of  claim 51 , wherein A is aryl.  
     
     
         53 . The compound of  claim 51 , wherein A is phenyl optionally substituted with one or more optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 16-alkylsulfonylamino.  
     
     
         54 . The compound of  claim 50 , wherein R 1  is —S-A.  
     
     
         55 . The compound of  claim 54 , wherein A is aryl, optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         56 . The compound of  claim 54 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         57 . The compound of  claim 42 , wherein R 2 , R 3 , R 4 , R 5  and R 6  are hydrogen.  
     
     
         58 . The compound of  claim 57 , wherein A is phenyl optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, thio-C 1-6 -alkyl, halo, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulfonyl, halo-C 1-6 -alkylsulfonyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, C 1-6 -alkylaminocarbonyl, C 1-6 -alkylcarbonylamino, C 1-6 -alkylaminosulfonyl, and C 1-6 -alkylsulfonylamino.  
     
     
         59 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of  claim 34  in admixture with at least one pharmaceutically acceptable carrier.  
     
     
         60 . A method of treating a subject that has a disease state selected from schizophrenia, depression, memory disorders, attention deficit disorder, and Alzheimer's disease, wherein said method comprises administering to said subject a therapeutically effective amount of the compound of  claim 34 .  
     
     
         61 . A method for treating a subject that has a disorder of the gastrointestinal tract, said method comprising administering to said subject a therapeutically effective amount of the compound of  claim 34 .  
     
     
         62 . A process for preparing a compound as claimed in claim  1 , said process comprising 
 i) reacting a compound having a general Formula 4                          wherein P is a protecting group and W, R 2 , R 4 , R 9  and R 10  are as recited in  claim 34 ,    with a compound of general formula (A-S) 2 , wherein A is aryl or heteroaryl′   ii) optionally alkylating the nitrogen of the indole group,    iii) removing the protecting group P;    to provide a compound of Formula I,                           wherein R 8  is hydrogen, and A, W, R 2 , R 3 , R 4 , R 9 , and R 10  are as recited in  claim 34 , and    iv) optionally alkylating to provide a compound of the general Formula I, wherein    R 8  is C 1-10 -alkyl, and A, W, R 2 , R 3 , R 4 , R 9 , and R 10  are as recited in  claim 34 .    
     
     
         63 . A process for preparing a compound as claimed in claim  1  which comprises 
 i) reacting a compound having a general Formula 4 
                     
  wherein P is a protecting group and W, R 2 , R 4 , R 9  and R 10  are as recited in  claim 34;   
 with a compound of general formula (A-S) 2 , wherein A is aryl or heteroaryl, to provide an adduct 4a  
                     
 ii) oxidizing the sulfur atom of 4a;  
 iii) optionally alkylating the nitrogen of the indole group of oxidized 4a;  
 iv) removing of the protecting group P;  
 to provide a compound of Formula I,  
                     
  wherein R 8  is hydrogen, and W, A, R 2 , R 3 , R 4 , R 9 , and R 10  are as recited in  claim 34 , and  
 v) optionally alkylating to provide a compound of the general Formula I, wherein R 8  is C 1-10 -alkyl, and W, A, R 2 , R 2 , R 4 , R 9 , and R 10  are as recited in  claim 34.