5-position modified pyrimidines and their use

Abstract

The present disclosure relates to the field of nucleic acid chemistry, specifically to 5-position modified uridines as well as phosphoramidite and triphosphate derivatives thereof. The present disclosure also relates to methods of making and using the same.

What is claimed is: 
     
         1 . A compound selected from the compounds having the following structure or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of —(CH 2 ) n —R X1 ; 
         R X1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         *Denotes point of attachment of the R X1  group to (CH 2 ) n  connecting group 
         wherein 
         R X4  is selected from the group consisting of a branched or linear lower alkyl (C1-C20); halogen (F, Cl, Br, I); nitrile (CN); boronic acid (BO 2 H 2 ); carboxylic acid (COOH); carboxylic acid ester (COOR X2 ); primary amide (CONH 2 ); secondary amide (CONHR X2 ); tertiary amide (CONR X2 R X3 ); sulfonamide (SO 2 NH 2 ); N-alkylsulfonamide (SONHR X2 ); 
         wherein 
         R X2 , R X3  are independently selected from the group consisting of a branched or linear lower alkyl (C1-C20); phenyl (C 6 H 5 ); an R X4  substituted phenyl ring (R X4 C 6 H 4 ), wherein R X4  is defined above; a carboxylic acid (COOH); a carboxylic acid ester (COOR X5 ), wherein R X5  is a branched or linear lower alkyl (C1-C20); and cycloalkyl; 
         wherein n=2-10; 
         wherein 
         X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3  and -azido; 
         wherein 
         R′ is selected from the group consisting of —Ac; —P(N(iPr) 2 (O(CH 2 ) 2 )CN; —Bz and —SiMe 2 tBu; 
         wherein 
         R″ is selected from the group consisting of H, DMT and triphosphate (—P(O)(OH)—O—P(O)(OH)—O—P(O)(OH) 2 ) or a salt thereof. 
       
     
     
         2 . A compound according to  claim 1  having the following structure or a salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         3 . An oligonucleotide comprising at least one modified nucleotide having the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of —(CH 2 ) n —R X1 ; 
         R X1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         *Denotes point of attachment of the R X1  group to (CH 2 ) n  connecting group 
         wherein 
         R X4  is selected from the group consisting of a branched or linear lower alkyl (C1-C20); halogen (F, Cl, Br, I); nitrile (CN); boronic acid (BO 2 H 2 ); carboxylic acid (COOH); carboxylic acid ester (COOR X2 ); primary amide (CONH 2 ); secondary amide (CONHR X2 ); tertiary amide (CONR X2 R X3 ); sulfonamide (SO 2 NH 2 ); N-alkylsulfonamide (SONHR X2 ); 
         wherein 
         R X2  and R X3  are independently selected from the group consisting of a branched or linear lower alkyl (C1-C20); phenyl (C 6 H 5 ); an R X4  substituted phenyl ring (R X4 C 6 H 4 ), wherein R X4  is defined above; a carboxylic acid (COOH); a carboxylic acid ester (COOR X5 ), wherein R X5  is a branched or linear lower alkyl (C1-C20); and cycloalkyl; 
         wherein n=2-10; 
         wherein 
         X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3  and -azido. 
       
     
     
         4 . An oligonucleotide according to  claim 3 , wherein the oligonucleotide is selected from a ribonucleic acid or a deoxyribonucleic acid, optionally wherein said oligonucleotide further comprises at least one chemical modification comprising a chemical substitution at one or more positions independently selected from a ribose position, a deoxyribose position, a phosphate position, and a base position, optionally wherein said chemical modification is independently selected from the group consisting of a 2′-position sugar modification, a 2′-amino (2′-NH 2 ), a 2′-fluoro (2′-F), a 2′-O-methyl (2′-OMe), 2′-O-ethyl (2′-OEt), 2′-O-propyl (2′-OPr), 2′-O—CH 2 CH 2 OCH 3 , a 5-position pyrimidine modification, a backbone modification, methylation, a 3′ cap, and a 5′ cap. 
     
     
         5 . An aptamer comprising at least one modified nucleotide having the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         R is selected from the group consisting of —(CH 2 ) n —R X1 ; 
         R X1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         *Denotes point of attachment of the R X1  group to (CH 2 ) n  connecting group 
         wherein 
         R X4  is selected from the group consisting of a branched or linear lower alkyl (C1-C20); halogen (F, Cl, Br, I); nitrile (CN); boronic acid (BO 2 H 2 ); carboxylic acid (COOH); carboxylic acid ester (COOR X2 ); primary amide (CONH 2 ); secondary amide (CONHR X2 ); tertiary amide (CONR X2 R X3 ); sulfonamide (SO 2 NH 2 ); N-alkylsulfonamide (SONHR X2 ); 
         wherein 
         R X2  and R X3  are independently selected from the group consisting of a branched or linear lower alkyl (C1-C20); phenyl (C 6 H 5 ); an R X4  substituted phenyl ring (R X4 C 6 H 4 ), wherein R X4  is defined above; a carboxylic acid (COOH); a carboxylic acid ester (COOR X5 ), wherein R X5  is a branched or linear lower alkyl (C1-C20); and cycloalkyl; 
         wherein n=2-10; 
         wherein 
         X is selected from the group consisting of —H, —OH, —OMe, —O-allyl, —F, —OEt, —OPr, —OCH 2 CH 2 OCH 3  and -azido. 
       
     
     
         6 . An aptamer according to  claim 5 , wherein the aptamer is selected from a ribonucleic acid or a deoxyribonucleic acid, optionally wherein said aptamer further comprises at least one chemical modification comprising a chemical substitution at one or more positions independently selected from a ribose position, a deoxyribose position, a phosphate position, and a base position, optionally wherein said chemical modification is independently selected from the group consisting of a 2′-position sugar modification, a 2′-amino (2′-NH 2 ), a 2′-fluoro (2′-F), a 2′-O-methyl (2′-OMe), 2′-O-ethyl (2′-OEt), 2′-O-propyl (2′-OPr), 2′-O—CH 2 CH 2 OCH 3 , a 5-position pyrimidine modification, a backbone modification, methylation, a 3′ cap, and a 5′ cap.