Libraries of heteroaryl-containing macrocyclic compounds and methods of making and using the same

Abstract

The present disclosure relates to novel macrocyclic compounds and libraries thereof containing heteroaryl moieties that are useful as research tools for drug discovery efforts. The present disclosure also relates to methods of preparing these compounds and libraries and methods of using these libraries, such as in high throughput screening. In particular, these libraries are useful for evaluation of bioactivity at existing and newly identified pharmacologically relevant targets, including G protein-coupled receptors, nuclear receptors, enzymes, ion channels, transporters, transcription factors, protein-protein interactions and nucleic acid-protein interactions. As such, these libraries can be applied to the search for new pharmaceutical agents for the treatment and prevention of a range of medical conditions.

1 - 53 . (canceled) 
     
     
         54 . A compound having the following structure: 
       
         
           
           
               
               
           
         
       
       wherein: W is selected from the group consisting of NH—PG 1  and NH 2 , Y is selected from the group consisting of CHO, CH 2 —OH and CH 2 —OPG 2 ; Z is selected from the group consisting of NH—PG 3  and NH 2 , PG 1 , PG 2  and PG 3  are independently an activating or protecting group; and X is optionally present and, when present, is a halogen. 
     
     
         55 . The compound of  claim 54 , wherein W is NHPG 1 . 
     
     
         56 . The compound of  claim 54 , wherein Y is CH 2 —OH. 
     
     
         57 . The compound of  claim 54 , wherein Y is CHO. 
     
     
         58 . The compound of  claim 54 , wherein Z is NHPG 3 . 
     
     
         59 . The compound of  claim 54 , wherein X is fluorine. 
     
     
         60 . The compound of  claim 54 , wherein PG 1  is selected from the group consisting of t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc). 
     
     
         61 . The compound of  claim 54 , wherein PG 1  is selected from the group consisting of 2-nitrobenzenesulfonyl (Nos), 4-nitro-benzenesulfonyl, 2,4-dinitrobenzenesulfonyl and benzothiazolylsulfonyl (Bts). 
     
     
         62 . The compound of  claim 54 , wherein PG 2  is selected from the group consisting of tetrahydropyranyl (THP), tert-butyldimethylsilyl (TBDMS), benzyl (Bn), acetyl (Ac) and benzoyl (Bz). 
     
     
         63 . The compound of  claim 54 , wherein PG 3  is selected from the group consisting of t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc). 
     
     
         64 . The compound of  claim 54 , wherein PG 3  is selected from the group consisting of 2-nitrobenzenesulfonyl (Nos), 4-nitro-benzenesulfonyl, 2,4-dinitrobenzenesulfonyl and benzothiazolylsulfonyl (Bts). 
     
     
         65 . The compound of  claim 54  having the following structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein PG 1  and PG 3  are independently an activating or protecting group. 
     
     
         66 . The compound of  claim 65  wherein PG 1  is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc). 
     
     
         67 . The compound of  claim 65  wherein PG 3  is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc). 
     
     
         68 . The compound of  claim 54  having the following structure: 
       
         
           
           
               
               
           
         
         wherein PG 1  is an activating or protecting group. 
       
     
     
         69 . The compound of  claim 68  wherein PG 1  is 9-fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (Boc). 
     
     
         70 . A method of using at least one compound of  claim 54 , the method comprising reacting the at least one compound with at least one another compound for the synthesis of one or more macrocyclic compounds or a macrocyclic library. 
     
     
         71 . The method of  claim 70  wherein a plurality of compounds of claim  1  is used. 
     
     
         72 . The method of  claim 70  wherein the synthesis is of a macrocyclic compound. 
     
     
         73 . The method of  claim 70  wherein the synthesis is of a macrocyclic library.