Benzoxazepin oxazolidinone compounds and methods of use

Abstract

Described herein are benzoxazepin oxazolidinone compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation. Also described are methods of making the benzoxazepin oxazolidinone compounds having the Formula I structure.

We claim: 
     
         1 . A process for the preparation of compound 8, having the structure: 
       
         
           
           
               
               
           
         
         or stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein: 
         R 1  is selected from —CH 3 , —CH 2 CH 3 , cyclopropyl, and cyclobutyl; 
         R 2  is selected from —CH 3 , —CHF 2 , —CH 2 F, and —CF 3 ; 
         comprising reacting compound 7, having the structure: 
       
       
         
           
           
               
               
           
         
         with HN(R 2 )CH(R 1 )CO 2 H and a copper catalyst, followed by ammonium chloride, and HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) to form 8. 
       
     
     
         2 . The process of  claim 1  wherein the copper catalyst to form 8 is CuI. 
     
     
         3 . The process of  claim 1  wherein R 1  is —CH 3 . 
     
     
         4 . The process of  claim 1  wherein R 2  is —CHF 2 . 
     
     
         5 . The process of  claim 1  wherein compound 8 has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The process of  claim 1  wherein compound 7 is prepared by a process comprising reacting compound 6, having the structure: 
       
         
           
           
               
               
           
         
         with a 4-substituted oxazolidin-2-one having the structure: 
       
       
         
           
           
               
               
           
         
         and a copper catalyst to form 7. 
       
     
     
         7 . The process of  claim 6  wherein the 4-substituted oxazolidin-2-one is (S)-4-difluoromethyloxazolidin-2-one. 
     
     
         8 . The process of  claim 6  wherein the copper catalyst to form 7 is selected from CuI and Cu(OAc) 2 . 
     
     
         9 . The process of  claim 6  further comprising reacting compound 6 with trans-N,N′-dimethyl-1,2-cyclohexane diamine.