Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases

Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

1 .- 32 . (canceled) 
     
     
         33 . A process for preparing methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidin-1-yl)benzoate (263H): 
       
         
           
           
               
               
           
         
         by a process comprising:
 mixing tert-butyl 4-hydroxy-4-(2-(trifluoromethylsulfonyloxy)benzyl)piperidine-1-carboxylate (263D): 
 
       
       
         
           
           
               
               
           
         
         with 4-chlorophenylboronic acid, K 3 PO 4 , and 
         [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) in 2-methyltetrahydrofuran to produce tert-butyl 4-((4′-chlorobiphenyl-2-yl)methyl)-4-hydroxypiperidine-1-carboxylate (263E): 
       
       
         
           
           
               
               
           
         
         
           adding sodium hydride to 263E in tetrahydrofuran, followed by adding hexamethylphosphoramide and iodomethane, to produce tert-butyl-4-((4′-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidine-1-carboxylate (263F): 
         
       
       
         
           
           
               
               
           
         
         
           adding triethyl silane to a solution of 263F in dichloromethane and trifluoroacetic acid, and mixing to produce 4-((4′-chlorobiphenyl-2-yl)methyl)-4-methoxypiperidine (263G): 
         
       
       
         
           
           
               
               
           
         
         and
 adding methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (3H): 
 
       
       
         
           
           
               
               
           
         
         and base in dimethylsulfoxide to 263G in solution and stirring to produce 263H. 
       
     
     
         34 . The process of  claim 33 , which further comprises preparing tert-butyl 4-hydroxy-4-(2-(trifluoromethylsulfonyloxy)benzyl)piperidine-1-carboxylate (263D) by a process comprising:
 adding tert-butyl 4-oxopiperidine-1-carboxylate to a mixture of sodium hydride and trimethylsulfoxonium iodide in dimethyl sulfoxide and tetrahydrofuran to produce tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (263A):   
       
         
           
           
               
               
           
         
         adding (2-(benzyloxy)phenyl)magnesium bromide to a solution of 263A and CuI in tetrahydrofuran at 0° C., followed to produce tert-butyl 4-(2-(benzyloxy)benzyl)-4-hydroxypiperidine-1-carboxylate (263B): 
       
       
         
           
           
               
               
           
         
         adding 263B and methanol to Raney Nickel under 30 psi pressure and hydrogen, and mixing to produce tert-butyl 4-hydroxy-4-(2-hydroxybenzyl)piperidine-1-carboxylate (263C): 
       
       
         
           
           
               
               
           
         
         and 
         mixing together 263C, N-phenylbis(trifluoromethanesulfonimide), and base in dichloromethane to produce 263D. 
       
     
     
         35 . The process of  claim 33  or  34 , which further comprises preparing methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (3H) by a process comprising:
 adding lithium hexamethyldisilazide in tetrahydrofuran to 5-bromo-1H-pyrrolo[2,3-b]pyridine in tetrahydrofuran followed by adding triisopropylchlorosilane and mixing to produce 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3F): 
 
       
         
           
           
               
               
           
         
         adding BuLi to 3F in tetrahydrofuran at −78° C., followed by adding trimethylborate and allowing the mixture to warm to room temperature to produce 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (3G): 
       
       
         
           
           
               
               
           
         
         mixing 3G together with methyl 2,4-difluorobenzoate and K 3 PO 4  in diglyme to produce 3H.