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-(5-methyl-1-((1-morpholinocyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate (160F), 
       
         
           
           
               
               
           
         
       
       comprising:
 combining ethyl 1-aminocyclohexanearboxylate hydrogen chloride, triethylamine, and 1-bromo-2-(2-bromoethoxy)ethane (4.21 mL) in N,N-dimethylformamide at 95° C. to produce ethyl 1-morpholinocyclohexanecarboxylate (160A), 
 
       
         
           
           
               
               
           
         
         adding lithium aluminum hydride dropwise to a solution of 160A in diethyl ether at 0° C., followed by allowing the mixture to warm to room temperature, stirring at room temperature, and cooling to 0° C. followed by adding water and 15% aqueous NaOH solution to the mixture to produce (1-morpholinocyclohexyl)methanol (160B), 
       
       
         
           
           
               
               
           
         
         adding 1H-pyrazole and cyanomethylenetributylphosphorane to a solution of 160B in toluene to produce 4-(1-((1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine (160C), 
       
       
         
           
           
               
               
           
         
         adding n-butyllithium in hexanes dropwise to a solution of 160C at −45° C., followed by allowing the mixture to warm to −20° C. and adding iodomethane dropwise to produce 4-(1-((5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine (160D), 
       
       
         
           
           
               
               
           
         
         dissolving 160D in N,N-dimethylformamide and adding N-bromosuccinimide to the solution of 160D in N,N-dimethylformamide to produce 4-(1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine (160E) 
       
       
         
           
           
               
               
           
         
         heating a suspension of 160E, 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 160F from the suspension.