Aryl aniline derivatives as beta2 adrenergic receptor agonists

Abstract

The invention provides novel β 2 adrenergic receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with β 2 adrenergic receptor activity, and processes and intermediates useful for preparing such compounds.

1 - 29 . (canceled) 
     
     
         30 . A process for preparing a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is —CH 2 OH or —NHCHO, and R 2  is hydrogen, 
 or R 1  and R 2  taken together are —NHC(═O)CH═CH—, or —CH═CHC(═O)NH—; 
 R 3  is —OH, and R 4  is hydrogen, 
 one of R 5  and R 6  is —[O—C 1-6 alkylenyl] n —NR 10 R 11  or C 1-6 alkylenyl-NR 12 R 13 , 
 and the other of R 5  and R 6  is selected from hydrogen, hydroxy, C 1-4 alkoxy, and C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with halo, 
 wherein
 each of R 10 , R 11 , R 12 , and R 13  is independently hydrogen or C 1-4 alkyl; or 
 R 10  and R 11 , together with the nitrogen atom to which they are attached, or R 10 , together with the nitrogen atom to which it is attached and a carbon atom of the adjacent C 1-6 alkylenyl, or R 12  and R 13 , together with the nitrogen atom to which they are attached, or R 12 , together with the nitrogen atom to which it is attached and a carbon atom of the adjacent C 1-6 alkylenyl, form a heterocyclic or heteroaryl ring having from 5 to 7 ring atoms, and optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein nitrogen is optionally substituted with —S(O) 2 —C 1-4 alkyl; and 
 n is 1, 2, or 3; and 
 
 each of R 7 , R 8 , and R 9  is hydrogen; 
 or a pharmaceutically-acceptable salt or stereoisomer thereof, 
 
       the process comprising:
 (a) reacting
 (i) a compound of formula (III): 
 
 
       
         
           
           
               
               
           
         
         with a compound of formula (IV): 
       
       
         
           
           
               
               
           
         
         in the presence of a transition metal catalyst; or
 (ii) a compound of formula (V): 
 
       
       
         
           
           
               
               
           
         
         with a compound of formula (VI): 
       
       
         
           
           
               
               
           
         
         wherein P 1  is a hydroxy-protecting group; and R 3a  is —OH or —OP 2 , wherein P 2  is a hydroxy-protecting group; one of A and B is a leaving group and the other of A and B is —NH 2 ; L is a leaving group; to provide a compound of formula (VII); 
       
       
         
           
           
               
               
           
         
         (b) removing the protecting group P 1  to provide a compound of formula (VIII): 
       
       
         
           
           
               
               
           
         
       
       and
 (c) when R 3a , is —OP 2 , removing the protecting group P 2  to provide a compound of formula (I), or a salt or stereoisomer thereof. 
 
     
     
         31 - 32 . (canceled) 
     
     
         33 . The process of  claim 30  wherein R 5  is —[O—C 1-6 alkylenyl] n —NR 10 R 11  or C 1-6 alkylenyl-NR 12 R 13  and R 6  is hydrogen. 
     
     
         34 . The process of  claim 30  wherein R 5  is C 1-4 alkoxy and R 6  is —[O—C 1-6 alkylenyl] n —NR 10 R 11  or C 1-6 alkylenyl-NR 12 R 13 . 
     
     
         35 . The process of  claim 30  wherein:
 R 5  is selected from —O—C 1-6 alkylenyl-NR 10 R 11  and C 1-6 alkylenyl-NR 12 R 13  and R 6  is hydrogen; or 
 R 5  is C 1-4 alkoxy and R 6  is —C 1-6 alkylenyl-NR 12 R 13 , 
 wherein each of R 10 , R 11 , R 12  and R 13  is independently hydrogen or C 1-4 alkyl, or R 10  and R 11 , together with the nitrogen atom to which they are attached, form a piperazinyl ring. 
 
     
     
         36 . The process of  claim 35  wherein R 1  and R 2  taken together are —NHC(═O)CH═CH— or —CH═CHC(═O)NH—. 
     
     
         37 . The process of  claim 36  wherein R 5  is —O—C 1-6 alkylenyl-NR 10 R 11  and R 6  is hydrogen. 
     
     
         38 . The process of  claim 37  wherein the process of step (a) comprises reacting a compound of formula (III) with a compound of formula (IV) to provide a compound of formula (VII).