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 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoic acid (265J): 
       
         
           
           
               
               
           
         
       
       the process comprising
 mixing benzyl 9-(4-chlorophenyl)-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate (265F): 
 
       
         
           
           
               
               
           
         
       
       in dichloromethane together with methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(piperazin-1-yl)benzoate (15F) and sodium triacetoxyborohydride to produce benzyl 8-((4-(3-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-9-(4-chlorophenyl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate (265G): 
       
         
           
           
               
               
           
         
         stirring together 265G, tetrahydrofuran and 20% Pd(OH) 2 —C under 30 psi pressure at room temperature, followed by filtering the mixture and evaporating the solvent to produce methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate (265H): 
       
       
         
           
           
               
               
           
         
         adding 1,3-difluoroacetone and sodium triacetoxyborohydride to a solution of 265H in dichloromethane and mixing to produce methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate (265I): 
       
       
         
           
           
               
               
           
         
       
       and
 adding LiOH H 2 O to 265I in solution and stirring to produce 265J. 
 
     
     
         34 . The process of  claim 33 , which further comprises preparing benzyl 9-(4-chlorophenyl)-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate (265F) by a process comprising:
 contacting benzyl 4-formylpiperidine-1-carboxylate with piperidine to produce benzyl 4-(piperidin-1-ylmethylene)piperidine-1-carboxylate (265A):   
       
         
           
           
               
               
           
         
         mixing but-3-enone and 265A in a solution, followed by adding acetic acid to the solution and mixing, to produce benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (265B); 
         stirring together 265B, tetrahydrofuran and 5% Pt—C under 30 psi pressure at room temperature, followed by filtering and concentrating the filtrate to produce benzyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (265C): 
       
       
         
           
           
               
               
           
         
         contacting 265C with Dess-Martin periodinane to produce benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (265D): 
       
       
         
           
           
               
               
           
         
         adding phosphorus oxychloride dropwise to a solution comprising 265D in N,N-dimethylformamide and dichloromethane at 0° C. and mixing to produce benzyl 9-chloro-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate (265E): 
       
       
         
           
           
               
               
           
         
       
       and
 mixing together 265E, 4-chlorophenylboronic acid, palladium(II) acetate, K 2 CO 3  and tetrabutylammonium bromide and water and stirring the mixture at 50° C., followed by diluting the mixture, washing and drying to produce a residue from which is obtained 265F. 
 
     
     
         35 . The process of  claim 33  or  34 , which further comprises preparing methyl 2-(1 H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(piperazin-1-yl)benzoate (15F): 
       
         
           
           
               
               
           
         
       
       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 methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (3H) 
       
       
         
           
           
               
               
           
         
       
       and
 heating a mixture of 3H and piperazine in dimethylsulfoxide to 110° C. for 24 hours, and allowing the mixture to cool to room temperature to produce 15F.