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-xL proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-xL protein.

1 - 16 . (canceled) 
     
     
         17 . A process for preparing tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1 3,7 ]dec-2-yl]methyl}-1H-pyrazol-4-yl)picolinate (56F). 
       
         
           
           
               
               
           
         
         comprising:
 adding (trimethylsilyl)diazomethane dropwise to a solution of adamantane-2-carboxylic acid in ethyl acetate to produce methyl tricyclo[3.3.1.1 3,7 ]decane-2-carboxylate (56A), 
 
       
       
         
           
           
               
               
           
         
         
           adding lithium diisopropylamide dropwise to a solution of 56A in tetrahydrofuran at −78° C., followed by stirring the mixture of lithium diisopropylamide and 56A, adding 2-bromoethyl methyl ether to the mixture, allowing the mixture to warm to room temperature, and adding a saturated aqueous NH 4 Cl solution to the mixture to produce methyl 2-(2-methoxyethyl)tricyclo[3.3.1.1 3,7 ]decane-2-carboxylate (56B), 
         
       
       
         
           
           
               
               
           
         
         
           adding lithium aluminum hydride to a solution of 56B in tetrahydrofuran followed by adding sodium hydroxide to produce [2-(2-methoxyethyl)tricyclo[3.3.1.1 3,7 ]dec-2-yl]methanol (56C), 
         
       
       
         
           
           
               
               
           
         
         
           mixing together 56C, pyrazole, and cyanomethylenetributylphosphorane in toluene to produce 1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1 3,7 ]dec-2-yl]methyl}-1H-pyrazole (56D), 
         
       
       
         
           
           
               
               
           
         
         
           dissolving 56D in N,N-dimethylformamide and adding N-bromosuccinimide to the solution of 56D in N,N-dimethylformamide to produce 4-bromo-1-{[2-(2-methoxyethyl)tricyclo[3.3.1.1 3,7 ]dec-2-yl]methyl}-1H-pyrazole (56E) 
         
       
       
         
           
           
               
               
           
         
         
           heating a suspension of 56E, tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate, tris(dibenzylideneacetone)dipalladium(0), 1,3,5,7-tetramethyl-6-phenyl-2,4, 8-trioxa-6-phosphaadamantane, and potassium phosphate in tetrahydrofuran and water, followed by purifying 56F from the suspension.