Nucleotide analogs

Abstract

Nucleotide analogs characterized by the presence of an amidate linked amino acid or an ester linked group which is bonded to the phosphorus atom of phosphonate nucleotide analogs are disclosed. The analogs comprise a phosphoamidate or ester bond that is hydrolyzed in vivo to yield a corresponding phosphonate nucleotide analog. Methods and intermediates for their synthesis and use are described.

What is claimed is:  
     
         1 . A compound of the formula I  
       
         
           
           
               
               
           
         
       
       or a physiologically acceptable salt thereof, wherein 
 L 1  and L 2  are independently an amino acid or polypeptide residue bonded to the phosphorus atom of the compound by an amidate bond, or L 1  and L 2  are independently an oxyester, thioester, a substituted or unsubstituted amine, or hydroxy, provided that one or both of L 1  and L 2  is an amino acid or polypeptide residue and provided that any carboxyl group that is linked by less than 5 atoms to the amidate N is esterified or amidated and the dotted lines represent facultative bonds;  
 Z is —CHR 7 —R 11 —(CH 2 ) m1 —C(R 8 )((CH 2 )m2(R 9 ))—(CH 2 ) m3 —R 10 —(CH 2 )m4-, C 6 H 4 eH 2 —, CHR 7 —O—CHR 7 —O—CHR 7 —, —CHR 7 —(CHR 13 ) m1 —CHR 14 —R 10 —,  
                     
 R 7  is H or C 1 -C 4  alkyl;  
 R 8 =R 7  or C 2 -C 4  alkenyl, azidomethyl or azidoethyl;  
 R 9  is halogen (F, Cl, Br or I), H or OH;  
 R 10  is O, CH 2  or a chemical bond;  
 R 11  is O, S, CH 2 , CHF, CF 2 ;  
 Q is C(R 12 ) 2 —CH 2 —, —C(R 12 ) 2 —O, —CR 12 =CR 12 —, or —C≡C—, wherein each R 12  is independently H, or halogen;  
 R 13  is H, halogen, OH, CH 3 , CH 2 OH, or C 3 —Cl 2  acyloxymethyl;  
 R 14  is independently H, halogen, OH, CH 3 , CH 2 OH, C 3 -C 12  acyloxymethyl, or C 2 -C 12  acyloxy;  
 R 25  is CH 2 , CHF or O;  
 R 26  is CH or S, provided that when R 25  is CH, R 26  is not S;  
 R 27  is H, OH, halogen, N 3 , C 1 -C 4  alkyl, C 1 -C 4  alkoxy or when, R 26  is S, R 27  is absent;  
 R 27a  is H, OH, halogen, N 3 , C 1 -C 4  alkyl, C 1 -C 4  alkoxy;  
 R 28 =R 27a  and is independently chosen;  
 R 29  is O, S, CH 2 , CHF, CF 2 ;  
 R 32 is O;  
 m1=m2=m3=m4 is an integer having a value from 0 to 4 wherein each is independently chosen;  
 the carbon atom designated C# has linked substituents that are in the R, S or RS configuration; and  
 B is a heterocyclic base.  
 
     
     
         2 . A compound of the formula Ib  
       
         
           
           
               
               
           
         
       
       and stereoisomers and salts of such compounds wherein 
 X 1  is O or S;  
 L 1  is an amino acid, a polypeptide residue, a substituted or unsubstituted amine, an oxyester or a thio ester; and  
 the carbon atom designated # has linked substituents that are in the R, S or RS configuration, provided that L 1  is not a C 1 —C 4  alkyl ester or, when when B is cytosin—1—yl, then L 1 is not OCH 2 C(O)NR 5a   2 , OCH 2 C(O)OR 5a , OCH 2 OC(O)R 5a , OCH(R 5a )OC(O)R 5a (R, S or RS stereochemistry), OCH 2 C(R 5a ) 2 CH 2 OH, OCH 2 OR 5a , OR 5a , NHR 5a or NR 5a   2  wherein R 5a is C 1 -C 20  alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by substituents independently selected from the group consisting of hydroxy and halogen, and provided that when X 1  is O and B is adenine, cytosine, guanine, thymine, uracil, 2,6- diamino purine, hypoxanthine, or Z 2 ; wherein Z 2  is  
                     
 Q is independently chosen from H, Cl, NHR X , NR X   2 , NHC(O)R X , N(C(O)R X ) 2 , OH or NCHN(R X ) 2 , then L 1  is not OR Y , NH 2 , NHR X , or N(R X ) 2  where R Y  represents a physiologically hydrolyzable ester group selected from the group consisting of CH 2 C(O)N(R X ) 2 , CH 2 C(O)OR X , CH 2 OC(O)R X , CH(R X )OC(O)R X , CH 2 C(R X ) 2 CH 2 OH, or CH 2 OR X ; R Y  may also be R X  provided that R Y  and R X  are not simultaneously alkyl;  
 R X  represents C 1 -C 20  alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by substituents independently selected from the group consisting of hydroxy, oxygen, nitrogen and halogen.  
 
     
     
         3 . The compound of    claim 2    wherein L 1  is NHR 40  or OR 31  wherein 
 R 40  is C 1-20  alkyl;  
 R 31  is 2,3-dihydro—6-hydroxyindene; sesamol; catechol monoester; —CH 2 (O)—N(R 7 ) 2  wherein each R 7  the same or different; CH 2 —S(O)(R 7 ); CH 2 —S(O) 2 (R 7 ); OCH 2 —CH(OC(O)CH 2 R 7 )—CH 2 (OC(O)CH 2 R 7 ); cholesteryl; a monosaccharide; a disaccharide; an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate; glycerol; an α-D-βdiglyceride; trimethoxybenzyl; triethoxybenzyl; 2-alkyl pyridinyl (C 1-4  alkyl);  
                     
 C 3 -C 6  aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, OH, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 -C 12  alkenyl or C 2 -C 12  alkynyl; or  
 C 1 -C 4  alkylene C 3 -C 6  aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, OH, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 -Cl 2  alkenyl or C 2 -C 12  alkynyl.  
 
     
     
         4 . The compound of    claim 3    wherein B is  
       
         
           
           
               
               
           
         
       
       wherein R 15  is H, OH, F, Cl, Br, I, OR 16 , SH, SR 16 , NH 2 , or NHR 17 ; 
 R 16  is C 1 -C 6  alkyl  
 R 17  is C 1 -C 6  alkyl;  
 R 18  is N, CF, CCl, CBr, CI, CRI 9  or CSR 19 , COR 19 ;  
 R 19  is H, C 1 -C 9  alkyl, C 2 -C 9  alkenyl, C 2 -C 9  alkynyl or C 7 -C 9  aryl—alkyl unsubstituted or substituted by OH, O, N, F, Cl, Br or I;  
 R 20  is N or CH;  
 R 21  is N, CH, CCN, CCF3, CC═CH or CC(O)NH 2 ;  
 R 22  is H, OH, NH 2 , SH, SCH 3 , SCH 2 CH 3 , SCH 2 CCH, SCH 2 CHCH 2 , SC 3 H 7 , NH(CH 3 ), N(CH 3 ) 2 , NH(CH 2 CH 3 ), N(CH 2 CH 3 ) 2 , NH(CH 2 CCH), NH(CH 2 CHCH 2 ), NH(C 3 H 7 ) or halogen;  
 R 23  is H, OH, F, Cl, Br, I, SCH 3 , SCH 2 CH 3 , SCH 2 CCH, SCH 2 CHCH 2 , SC 3 H 7 , OR 16 , NH 2 , or NHR 17 ; and  
 R 24 is O, S or Se.  
 
     
     
         5 . The compound of    claim 4    wherein B is cytosin-1-yl, 6-azacytosin-1-yl, 5-fluorocytosin-1-yl, adenin-9-yl, guanin-9-yl or 2, 6-diaminopurin-9-yl.  
     
     
         6 . The compound of    claim 4    wherein R 31  is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-ethoxy-5-hydroxyphenyl, 2-ethoxy-4-hydroxyphenyl 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2-(haloalkyl)-phenyl, 3-(haloalkyl)phenyl, 4-(haloalkyl)-phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-ethoxyphenyl, 3ethoxyphenyl, 4-ethoxyphenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl, or 2-haloalkylbenzyl, 3-haloalkylbenzyl or 4-haloalkylbenzyl.  
     
     
         7 . The compound of    claim 2    of the formula IIa  
       
         
           
           
               
               
           
         
       
       wherein 
 n is 1, 2, 3, 4 or 5, wherein for n>1, each —C(R 2 )(R 3 ) is the same or different;  
 n1 is an integer;  
 R 1  is H or C 1 -C 9  alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR 4  and halogen, C 3 -C 6  aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR 4  and halogen or C 3 -C 9  aryl-alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR 4  and halogen;  
 R 2 =R 1  and is independently chosen;  
 R 3  is C(O)—OR 4 , amino, C 1 -C 3  alkylamino, C 1 -C 3  alkyldiamino, C 1 -C 6  alkenylamino, hydroxy, thiol, C 1 -C 3  alkoxy, C 1 -C 3  alkthiol, (CH 2 ) n COOR 4 , C 1 -C 6  alkyl which is unsubstituted or substituted with OH, halogen, SH, NH 2 , phenyl, hydroxyphenyl or C 7 -C 10  alkoxyphenyl; C 2 -C 6  alkenyl which is unsubstituted or substituted with OH, halogen, SH, NH 2 , phenyl, hydroxyphenyl or C 7 -C 10  alkoxyphenyl; C 6 -C 12  aryl which is unsubstituted or substituted with OH, halogen, SH, NH 2 , phenyl, hydroxyphenyl or C 7 -C 10  alkoxyphenyl; and  
 R 4  is H provided that n1 greater than 1, or is C 3 -C 9  alkyl which is substituted by substituents independently selected from the group consisting of OH, O, N and halogen, C 3 -C 6  aryl which is substituted by substituents independently selected from the group consisting of OH, O, N and halogen or C 3 -C 9  aryl-alkyl which is substituted by substituents independently selected from the group consisting of OH, O, N and halogen.  
 
     
     
         8 . The compound of    claim 7    wherein 
 n and n1 are 1;  
 R 1  is H, methyl, phenyl or benzyl;  
 R 2  is H;  
 R 3  is H, CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CHCH 3 —CH 2 —H 3 , —CH 2 -C 6 H 5 , —CH 2 —CH 2 —S—CH 3 , —CH 2 OH, —CH(OH)CH 3 , —CH 2 —SH, —CH 2 —C 6 H 4 OH, —CH 2 —CO—NH 2  —CH 2 —CH 2  —CO—NH 2 , —CH 2 —COOH, —CH 2 —CH 2 —COOH, —(CH 2 ) 4 —NH 2  —(CH 2 ) 3 —NHC(NH 2 )—NH 2 , 1-guanidinoprop—3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl or ethoxyphenyl; and  
 R 4  is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl, benzyl, 1-pyridyl, 3-pyridyl, 1-pyrimidinyl, pivaloyloxymethyl, N-ethylmorpholino, N-2-propylmorpholino, methoxyethyl, 4-N-methylpiperidyl, 3-N-methylpiperidyl, 2-, 3-, or 4-N,N-dimethylaminophenyl, 2-, 3-, or 4-N,N-diethylaminophenyl or 1-ethylpiperazinyl.  
 
     
     
         9 . The compound of    claim 8    wherein B is cytosin-1-yl, 6-azacytosin-1-yl, adenin-9-yl, guanin-9-yl or 2, 6-diaminopurin-9-yl, and X 1  is O.  
     
     
         10 . The compound of    claim 1    of the formula Id  
       
         
           
           
               
               
           
         
       
       .  
     
     
         11 . The compound of    claim 10    wherein L 1  is of the formula III  
       
         
           
           
               
               
           
         
       
       wherein 
 n is 1, 2, 3, 4 or 5, wherein for n>1, each —C(R 2 )(R 3 ) is the same or different;  
 n1 is an integer;  
 R 1  is H or C 1 -C 9  alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR 4  and halogen, C 3 -C 6  aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR 4  and halogen or C 3 -C 9  aryl-alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N, COOR 4  and halogen;  
 R 2 =R 1  and is independently chosen;  
 R 3  is C(O)—OR 4 , amino, C 1 -C 3  alkylamino, C 1 -C 3  alkyldiamino, C 1 -C 6  alkenylamino, hydroxy, thiol, C 1  -C 3  alkoxy, C 1 -C 3  alkthiol, (CH 2 ) n COOR 4 , C 1 -C 6  alkyl which is unsubstituted or substituted with OH, halogen, SH, NH 2 , phenyl, hydroxyphenyl or C 7  -C 10  alkoxyphenyl; C 2 -C 6  alkenyl which is unsubstituted or substituted with OH, halogen, SH, NH 2 , phenyl, hydroxyphenyl or C 7 -C 10  alkoxyphenyl; C 6 -C 12  aryl which is unsubstituted—or substituted with OH, halogen, SH, NH 2 , phenyl, hydroxyphenyl or C 7  -C 10  alkoxyphenyl; and  
 R 4  is H provided that n1 greater than 1, or is C 3 -C 9  alkyl which is substituted by substituents independently selected from the group consisting of OH, O, N and halogen, C 3 -C 6  aryl which is substituted by substituents independently selected from the group consisting of OH, O, N and halogen or C 3 -C 9  aryl-alkyl which is substituted by substituents independently selected from the group consisting of OH, O, N and halogen;  
 L 2  is OR, SR or is the same as L 1  wherein, 
 R is H,  
 C 3 -C 24  acyloxyalkyl,  
 C 6 C 24  acyloxyarylalkyl,  
 C 3 -C 24  acyloxyalkoxyalkyl,  
 C 3 -C 24  acyloxyhaloalkyl,  
 C 1 -C 20  alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (F, Cl, Br, I),  
 C 3 -C 20  aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen, or  
 C 4 C 20  aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen.  
 
 
     
     
         12 . The compound of    claim 11    wherein 
 n and n1 are 1;  
 R is N-ethylmorpholino, pivaloyloxymethyl, phenyl, benzyl, isopropyl, t-butyl, ethyl, isopropyl, butyl, adamantoyloxymethyl, 3-methoxyphenyl, 2-carboethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2-ethoxyphenyl, 3-dimethylaminophenyl, 4-trifluoromethylbenzyl, 2-ethylsalicyl, O-CH 2 O—C(O)—CloH 15,  -C 6 H 4 —CH 2 —N(CH 3 ) 2 , —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CH 2 —CF 3 , CH 2 —CCl 3 , R 5 , NHR 6  or N(R 6 ) 2    
 wherein, 
 R 5  is CH 2 C(O)N(R 6 ) 2 , CH 2 C(O)OR 6 , CH 2 OC(O)R 6 , CH(R 6 )OC(O)R 6 , CH 2 C(R 6 ) 2 CH 2 OH, or CH 2 OR 6 , and  
 R 6  is C 1 -C 20  alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (1 to 5 halogen atoms), C 6 -C 20  aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (1 to 5 halogen atoms) or C 7 -C 20  aryl-alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (1 to 5 halogen atoms);  
 
 R 1  is H, methyl, ethyl, isopropyl, phenyl or benzyl;  
 R 2  is H;  
 R 3  is H, (H 3 , CH(CH 3 ) 2 , —CH 2 —CH(CH 3 ) 2 , CHCH 3 -CH 2 , CH 2 —C 6 H 5 , CH 2 CH 2 —SCH 3 , CH 2 OH, CH(OH)<IH, —CH 2 -SH, —CH 2 —C 6 H 4 OH, —CH 2 —CO—NH 2 , —CH 2 —CH 2 —CO—NH 2 , —CH 2 COOH, —CH 2 —CH 2 —COOH, —(CH 2 ) 4 —NH 2 , —(CH 2 ) 3 —NH—C(NH 2 )—NH 2, 1 -guanidinoprop—3-yl, benzyl, 4-hydroxybenzyl, imidazol4-yl, indol—3-yl, methoxyphenyl or ethoxyphenyl; and  
 R 4  is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl, benzyl, 1-pyridyl, 3-pyridyl, 1-pyrimidinyl, pivaloyloxymethyl, N-ethylmorpholino, N-2-propylmorpholino, methoxyethyl, 4-N-methylpiperidyl, 3-N-methylpiperidyl, 2-, 3-, and 4-N,N-dimethylaminophenyl and 2-, 3-, and 4-N,N-diethylaminophenyl or 1-ethylpiperazinyl.  
 
     
     
         13 . The compound of    claim 12    wherein Z is CHR 7 -R 11 —(CH 2 ) m1 —C(R 8 )((CH 2 ) m2 (R 9 ))—(CH 2 ) m3 -R 10 —(CH 2 ) m4 —,  
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of    claim 13    wherein 
 Z is —CH 2 —O—CH 2 CH 2 —, —CH 2 —CH 2 CH(CH 2 OH)—, —CH 2 —O—CH 2 —CH(CH 2 F)—, CH 2 O—CH 2 CH(CH 3 )—, CH 2 OH 2 CH(CH═CH 2 )— or —CH 2 —O—CH 2 —CH(CH 2 N 3 )—, or is of formula IV or V  
                     
 wherein  
 R 25  and R 29  are O;  
 R 26  is CH;  
 R 27  and R 28  are H; and  
 B is adenin-9-yl, 1-deazaadenin-9-yl, 3-deazaadenin-9-yl, 7-deaza—8-azaadenin-9-yl, 8-azaadenin-9-yl, guanin-9-yl, 2, 6-diaminopurin-9-yl, 2-aminopurin-9-yl, thymin-1-yl, cytosin-1-yl, 5-fluorocytosin-1-yl, 6-azacytosin—1-yl, 5-methylcytosin-1-yl, 5-bromovinyluracil-1-yl, 5-fluorouracil-1-yl or 5-trifluoromethyluracil—1 -yl.  
 
     
     
         15 . The compound of    claim 1    of the formula Ic  
       
         
           
           
               
               
           
         
       
       .  
     
     
         16 . The compound of    claim 15    of the formula IIc  
       
         
           
           
               
               
           
         
       
       wherein L 2  is OR, SR or  
       
         
           
           
               
               
           
         
       
       wherein 
 R is H, 
 C 3 -C 24  acyloxyalkyl,  
 C 6 -C 24  acyloxyarylalkyl,  
 C 3 -C 24  acyloxyalkoxyalkyl,  
 C 3 -C 24  acyloxyhaloalkyl,  
 C 1 -C 20  alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (F, Cl, Br, I),  
 C 3 -C 20  aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen, or  
 C 4 -C 20  aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen; and  
 
 R 1  is O—C 6 H 4 —CH 2 —N(CH 3 ) 2 , OR 5 , NHR 6  or N(R 6 ) 2  wherein R 5  is CH 2 C(O)N(R 6 ) 2 , CH 2 C(O)OR 6 , CH 2 OC(O)R 6 , CH(R 6 )OC(O)R 6 , CH 2 C(R 6 ) 2 CH 2 OH, or CH 2 OR 6 , and wherein R 6  is C 1 -C 20  alkyl, C 6 C 20  aryl or C 7 -C 20  aryl-alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen.  
 
     
     
         17 . A compound of the formula (OR 31 ) 2 P(O)—Z 1 —B or (OR)(OR 31 )P(O)—Z 1 —B, wherein; 
 B is a heterocyclic base;  
 Z 1  is selected from the group consisting of —CH 2 —O—CH 2 —CH 2 —, —CH 2  —C#H(CH 2 OH)CH 2 —, —CH 2 —O#H(CH 3 )—CH 2 —, —CH 2 —O—C#H(CH 2 F)—CH 2 —, H 2 —O—C#H(CH═CH 2 )—CH 2 — and CH 2 —O—C#H(CH 2 N 3 )—CH 2 —;  
 R is H, 
 C 3 -C 24  1-acyloxy-1-alkyl,  
 C 6 -C 24  1-acyloxy-1-aryl-1-alkyl,  
 C 3 -C 24  1-acyloxy-2-alkoxy-1-alkyl,  
 C 3 -C 24  1-acyloxy-2-halo-1-alkyl,  
 C 1 -C 20  alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (F, Cl, Br, I),  
 C 3 -C 20  aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, cyano, nitro, OH, O, N and halogen, or  
 C 4 -C 20  aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, cyano, nitro, OH, O, N and halogen;  
 
 R 31  is 2,3-dihydro-6-hydroxyindene; sesamol; catechol monoester; —CH 2 —C(O)—N(R 7 ) 2  wherein each R 7  is hydrogen or C 1-4  alkyl and is the same or different; CH 2 —S(O)(R 7 ); CH 2 —S(O) 2 (R 7 ); OH 2 CH(OC(O)CH 2 R 7 )—CH 2 (OC(O)CH 2 R 7 ); cholesteryl; a monosaccharide; a disaccharide; an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate; glycerol; an α-D-β-diglyceride; trimethoxybenzyl; triethoxybenzyl; 2-alkyl pyridinyl (C 1-4  alkyl);  
                     
 C 3 -C 6  aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, OH, C 1 -C 12  haloalkyl, C 1 C 12  alkyl, C 2 -C 12  alkenyl or C 2 -C 12  alkynyl; or C 1 -C 4  alkylene—C 3 C 6  aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, Cl—C 12  alkoxy, cyano, nitro, OH, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 C 2  alkenyl or C 2 -C 12  alkynyl, provided that when Z 1  is CH 2 —OCH 2 —CH 2 — and B is adenin-9-yl, both R 31  are not 4-nitrobenzyl or 4-trifluoromethyl—benzyl, and provided that when Z 1  is —CH 2 -O—CH 2 —CH 2 —, CH 2 -O—C#H(CH 2 OH)—CH 2 —, —CH 2 —O—C#H(CH 3 )—CH 2 —, CH 2 —O—C#H(CH 2 F)—CH 2 — or —CH 2 O—C#H(CH═CH 2 )CH 2 — and B is adenine, cytosine, guanine, thymine, uracil, 2,6-diamino purine, hypoxanthine, or Z 2 ; wherein Z 2  is  
                     
 Q is independently chosen from H, Cl, NHR X , NR X   2 , NHC(O)R X , N(C(O)R X ) 2 , OH or NCHN(R X ) 2 , then L 1  is not ORY, NH 2 , NHR X , or N(R X ) 2  where R Y  represents a physiologically hydrolyzable ester group selected from the group consisting of CH 2 C(O)N(R X ) 2 , CH 2 C(O)OR X , CH 2 OC(O)R X , CH(R X )OC(O)R X , CH 2 C(R X ) 2 CH 2 OH, or CH 2 OR X ; R Y  may also be R X  provided that R Y  and R X are not simultaneously alkyl;  
 R X represents C 1 C 20  alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by substituents independently selected from the group consisting of hydroxy, oxygen, nitrogen and halogen.  
 
     
     
         18 . The compound of    claim 17    wherein R 31  is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-ethoxv-5-hydroxyphenyl, 2-ethoxy-4-hydroxyphenyl 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2-(haloalkyl)-phenyl, 3-(haloalkyl)phenyl, 4-(haloalkyl)-phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-ethoxyphenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl, or 2-haloalkylbenzyl, 3-haloalkylbenzyl or 4-haloalkylbenzyl.  
     
     
         19 . The compound of    claim 18    wherein B is cytosin-1-yl, 6-azacytosin-1-yl, 5-fluorocytosin-1-yl, adenin-9-yl, guanin-9-yl or 2, 6-diaminopurin-9-yl.  
     
     
         20 . A compound of the formula (L 1 ) 2 P(O)—Z—B 1  or  
       
         
           
           
               
               
           
         
       
       wherein 
 substituents linked to the carbon atom designated # are in the R, S or RS configuration;  
 L 1  is independently an amino acid, a polypeptide, an oxyester, a thioester or a substituted or unsubstituted amine;  
 B 1  is a protected heterocyclic base; and  
 Z—B 1  is  
                     
 wherein  
 R 27  is H, OH, halogen, N 3 , C 1 -C 4  alkyl, C 1 -C 4  alkoxy or when, R 26  is S, R 27  is absent;  
 R 28  is H, OH, halogen, N 3 , C 1 -C 4  alkyl or C 1 -C 4  alkoxy;  
 R 29  is O, S, CH 2 , CHF or CF 2 ;  
 R 33  is H, OH, TBSO, halogen, cyano, CH 2 N 3 , C 1 -C 4  alkyl, C 1 -C 4  alkoxy, CH 2 OH or azido; and  
 R 34  is H, CH 2 CN or CF 3 , with the proviso that, for structure XXX, when R 25  is O or CH 2  and R 29  CH 2  or 0, L 1  is not H or C 1 -C 6  alkyl, provided that for compounds of structure  
                     
 when B 1  is  
                     
 wherein Q is independently chosen from H, Cl, NHR X , NR X   2 , NHC(O)R X , N(C(O)R X ) 2 , OH or NCHN(R X ) 2 , then L 1  is not ORY, NH 2 , NHR X , or N(R X ) 2  where R Y  represents a physiologically hydrolyzable ester group selected from the group consisting of CH 2 C(O)N(R X ) 2 , CH 2 C(O)OR X , CH 2 OC(O)R X , CH(R X )OC(O)R X , CH 2 C(R X ) 2 CH 2 OH, or CH 2 OR X ; R Y  may also be R X provided that R Y  and R X are not simultaneously alkyl;  
 R X represents C 1 -C 20  alkyv, aryl or aryl-alkyl which may be substituted or unsubstituted by substituents independently selected from the group consisting of hydroxy, oxygen, nitrogen and halogen;  
 provided that when R 25  is O, R 29  is CH 2 , R 26  is CH, R 27  is OH, R 28  is H or F, and B is adenine, thymine, guanine, cytosine or protected adenine, protected guanine or protected cytosine, both L 1  are not H, methyl or phenyl.  
 
     
     
         21 . The compound of    claim 20    wherein B 1  is  
       
         
           
           
               
               
           
         
         wherein  
         R 18  is N, CF, CCl, CBr, CI, CR 19  or CSR 19 , COR 19 ;  
         R 20  is N or CH;  
         R 21  is N, CH, CCN, CCF 3 , CC≡CH or CC(O)NH 2 ;  
         R 22A  is R 39  or R 22  provided that R 22  is not NH 2 ;  
         R 22  is H, OH, NH 2 , SH, SCH 3 , SCH 2 CH 3 , SCH 2 CCH, SCH 2 CHCH 2 , SC 3 H 7 , NH(CH 3 ), N(CH 3 ) 2 , NH(CH 2 CH 3 ), N(CH 2 CH 3 ) 2 , NH(CH 2 CCH), NH(CH 2 CHCH 2 ), NH(C 3 H 7 ) or halogen (F, Cl, Br or I);  
         R 23A  is R 39  or R 23  provided that R 23  is not NH 2 ;  
         R 23  is H, OH, F, Cl, Br, I, SCH 3 , SCH 2 CH 3 , SCH 2 CCH, SCH 2 CHCH 2 , SC 3 H 7 , R 16 , NH 2 , or NHR 17 ;  
         R 24  is O, S or Se; and  
         R 39  is NHR 40 , NHC(O)R 36  or NCR 41 N(R 38 ) 2  wherein, R 36  is C 1 -C 19  alkyl, C 1 - C 19  alkenyl, C 3 -C 10  aryl, adamantoyl, alkylanyl, or C 3 -C 10  aryl substituted with 1 or 2 atoms or groups selected from halogen, methyl, ethyl, methoxy, ethoxy, hydroxy and cyano;  
         R 38  is C 1 -C 10  alkyl, or both R 38  together are 1-morpholino, 1-piperidine or 1-pyrrolidine;  
         R 40  is C 1-20  alkyl; and  
         R 41  is hydrogen or CH 3 .  
       
     
     
         22 . The compound of    claim 21    wherein L 1  is R or R 31  wherein R is 
 C 3 -C 24  1-acyloxy-1-alkyl,  
 C 6 -C 24  1-acyloxy-1-aryl-1-alkyl,  
 C 3 -C 24  1-acyloxy-2-alkoxy-1-alkyl,  
 C 3 C 24  1-acyloxy-2-halol- alkyl,  
 C 1 -C 20  alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (F, Cl, Br, I),  
 C 3 -C 20  aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloaikyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,  
 C 4 -C 20  aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,  
 C 3 C 6  aryl substituted by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C 1 -C 12  alkoxy, cyano, nitro, hvdroxy, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2  -C 12  alkenyl or C 2 -C 12  alkynyl, or  
 C 1 -C 4  alkylene-C 3 -C 6  aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C 1 -C 12  alkoxy, cyano, nitro, hydroxy, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 -C 12  alkenyl or C 2 -C 12  alkynyl; and  
 R 31  is 2,3-dihydro-6-hydroxyindene; sesamol; catechol monoester; —CH 2 —C(O)—N(R 7 ) 2  wherein each R 7  the same or different; —CH 2 —S(O)(R 7 ); —CH 2 —S(O) 2 (R 7 ); —O—CH 2 CH(OC(O)CH 2 R 7 )—CH 2 (OC(O)CH 2 R 7 ); cholesteryl; a monosaccharide; a disaccharide; an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate; glycerol; an α-D-β-diglyceride; trimethoxybenzyl; triethoxybenzyl; 2-alkyl pyridinyl (C 1-4  alkyl);  
                     
 C 3 -C 6  aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, OH, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 c 12  alkenyl or C 2 -C 12  alkynyl; or C 1 -C 4  alkyleneC 3 -C 6  aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, OH, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 -C 12  alkenyl or C 2 -C 12  alkynyl.  
 
     
     
         23 . The compound of    claim 21    wherein L 1  is ethyiglycine or N-methylglycine.  
     
     
         24 . A compound of the formula (OR 35 )(OR 35 )P(O)—Z—B, wherein; 
 B is a heterocyclic base;  
 R 35  is independently R or R 31 , wherein R is independently 
 H,  
 C 3 C 24  1-acyloxy-1-alkyl,  
 C 6 C 24  1-acyloxy-1-aryl-1-alkyl,  
 C 3 C 24  1-acyloxy- 2-alkoxy-1-alkyl,  
 C 3 C 24  1-acyloxy- 2-halo-1-alkyl,  
 
 C 1 -C 20  aikyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (F, Cl, Br, I),  
 C 3 -C 20  aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,  
 C 4 -C 20  aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,  
 C 3 -C 6  aryl substituted by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C 1 -C 12  alkoxy, cyano, nitro, hydroxy, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 -C 12  alkenyl or C 2 -C 12  alkynyl, or  
 C 1 -C 4  alkylene-C 3 -C 6  aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C 1 -C 12  alkoxy, cyano, nitro, hydroxy, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 -C 2  alkenyl or C 2 -C 12  alkynyl;  
 R 31  is 2,3-dihydro-6-hydroxyindene; sesamol; catechol monoester; —CH 2 (O)—N(R 7 ) 2  wherein each R 7  the same or different; —CH 2 —S(O)(R 7 ); CH 2 —S(O) 2 (R 7 ); OCH 2 CH(OC(O)CH 2 R 7 )—CH 2 (OC(O)CH 2 R 7 ); cholesteryl; a monosaccharide; a disaccharide; an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate; glycerol; an α-D-β-diglyceride; trimethoxybenzyl; triethoxybenzyl; 2-alkyl pyridinyl (C 1-4  alkyl);  
                     
 C 3 -C 6  aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, OH, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 -C 12  alkenyl or C 2 -C 12  alkynyl; or  
 C 1 -C 4  alkylene C 3 -C 6  aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, OH, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl, C 2 -C 12  alkenyl or C 2 -C 12  alkynyl;  
 Z—B is selected from the group consisting of  
                     
 wherein  
 substituents linked to the carbon atom designated # are in the R, S or RS configuration,  
 R 25  is CH 2 , CHF or O;  
 R 26  is CH or S, provided that when R 25  is CH, R 26  is not S;  
 R 27  is H, OH, halogen, N 3 , C 14  alkyl, C 1 -C 4  alkoxy or when, R 26  is S, R 27  is absent;  
 R 28  is H, OH, halogen, N 3 , C 1 C 4  alkyl or C 1 -C 4  alkoxy;  
 R 29  is 0, 5, CH 2 , CHF or CF 2 ;  
 R 33  is H, OH, TBSO, halogen, cyano, CH 2 N 3 , C 1 -C 4  alkyl, C 14  alkoxy, CH 2 OH or azido; and  
 R 34  is H, CH 2 CN or CF 3 , with the proviso that, for structure XXX, when R 25  is O or CH 2  and R 29  CH 2  or O, R 35  is not H or Cj 6  alkyl; and  
 provided that when R 25  is CH 2 , R 29  is CH 2 , R 26  is CH, R 27  is H, R 28  is H, and B is adenine, R 35  are not both H or C 3 H 7 ; and  
 provided that when R 25  is O, R 29  is CH 2 , R 26  is S, R 28  is H, and B is cytosine or protected cytosine, R 35  are not both H or ethyl; and  
 provided that when R 25  is CH 2 , R 29  is O, R 26  is CH, R 27  is H, R 28  is H, and B is adenine, guanine, hypoxanthine, cytosine, uracil or thymine, R 35  are not both H or C 3 H 7 ; and  
 provided that when R 25  is O, R 29  is CH 2 , R 26  is CH, R 27  is N 3 , R 28  is H, and B is thyrnine, R 35  is not H or phenyl; and  
 provided that when R 25  is CH 2 , R 29  is O, R 26  is CH, R 27  is H, R 28  is H, and B is thyrnine, R 35  is not H or C 16  alkyl; and  
 provided that when R 25  is O, R 29  is CH 2 , R 26  is CH, R 27  is OH, R 28  is H or F, and B is adenine, thymine, guanine, cytosine or protected adenine, protected guanine or protected cytosine, both R 35  are not H, methyl or phenyl; and  
 provided that when R 25  is O, R 29  is O, R 26  is CH, R 27  is H, OH or C 1 C 4  F alkyl, R 28  is H, OH or C 1 -C 4  alkyl, and B is xanthine, substituted xanthine, guanine, substituted guanine, purine, substituted purine, cytosine, substituted cytosine, thymine, uracil, substituted uracil, adenine or substituted adenine, R 35  is not H or C 1 -C 6  alkyl.  
 
     
     
         25 . The compound of    claim 24    wherein R 35  is independently phenyl, benzyl, adamantoyl oxymethyl, pivaloyloxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-ethoxy-5-hydroxyphenyl, 2-ethoxy-4-hydroxyphenyl 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2-(haloalkyl)—phenyl, 3-(haloalkyl)phenyl, 4-(haloalkyl)-phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-ethoxyphenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl, or 2-haloalkylbenzyl, 3-haloalkylbenzyl or 4-haloalkylbenzyl.  
     
     
         26 . The compound of    claim 25    wherein BI is N 4 -benzoylcytosin-1-yl, N 4 -(6-aminohexyl)cytosin-1-yl, N 4 -(10-aminodecyl)cytosin-1-yl, N 4 -( 14-aminolauryl)cytosin-1-yl.  
     
     
         27 . The compound of    claim 1    where L 1  or L 2  is an immunogenic peptide or protein.  
     
     
         28 . An antibody capable of binding specifically to a compound of    claim 27   .  
     
     
         29 . A compound of    claim 2    for oral administeration of an antivirally-effective dose to a subject.  
     
     
         30 . The compound of    claim 29    wherein the compound is enriched or resolved at the phosphate atom chiral center.  
     
     
         31 . A compound of    claim 20    having the structure  
       
         
           
           
               
               
           
         
         for oral administeration of antivirally-effective dose to a subject.  
       
     
     
         32 . The compound of    claim 31    wherein the compound is enriched or resolved at the phosphate atom chiral center.  
     
     
         33 . A compound of formula L, wherein the compound is labeled with a detectable moiety selected from the group of an enzyme, radioisotope, stable free radical, fluorophor, and a chemiluminescent group.  
     
     
         34 . A compound of the formula (R 31 O) 2 P(O)—CH 2 OH or (R 31 O) 2 P(OSi(CH 3 ) 3 ) wherein 
 R 31  is trimethoxybenzyl; triethoxybenzyl; 2-alkyl pyridinyl (C 1-4  alkyl);  
                     
 wherein R 7  is hydrogen or C 1-4  alkyl; or C 3 -C 6  aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, Cl 12  haloalkyl, C 1 -C 12  alkyl or C 2 -12 alkynyl, provided that for compound (R 31 O) 2 P(O)H 2 —OH, R 31  is not phenyl.  
 
     
     
         35 . A method to synthesize a compound of structure (R 31 O) 2 P(O)—CH 2 —OH comprising silylating a compound of structure (R 31 O) 2 P(O)H with about 1 equivalent of bis(trimethylsilyl)trifluoroacetamide, drying the resulting compound and reacting the resulting compound with paraformaidehyde containing catalytic amounts of a lewis acid, wherein R 31  is trimethoxybenzyl; triethoxybenzyl; 2-alkyl pyridinyl (C 1-4  alkyl);  
       
         
           
           
               
               
           
         
       
       wherein R 7  is hydrogen or C 1-4  alkyl; 
 C 3 C 6  aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C 1 C 12  alkoxy, cyano, nitro, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl or C2-12 alkynyl.  
 
     
     
         36 . A method to synthesize a compound of structure  
       
         
           
           
               
               
           
         
       
       by reacting a compound of structure  
       
         
           
           
               
               
           
         
         with iodine and (R 31 O) 2 P(O)—CH 2 OH at high temperature, wherein B2 is a heterocyclic base or a protected heterocyclic base; R 31  is trimethoxybenzyl; triethoxybenzyl; 2-alkyl pyridinyl (C 1-4  alkyl);  
         
           
             
             
                 
                 
             
           
         
         wherein R 7  is hydrogen or C 1-4  alkyl;  
         C 3 C 6  aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C 1 -C 12  alkoxy, cyano, nitro, C 1 -C 12  haloalkyl, C 1 -C 12  alkyl or C 2 -12 alkynyl; and R 44  is iodine or fluorine.  
       
     
     
         37 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       and stereoisomers and salts of such compounds wherein 
 B is a purine or pyrimidine base;  
 R 35  is R or R 31 ;  
 R is 2-alkoxyphenyl, 3-alkoxyphenyl, 4-alkoxyphenyl (C 1 -C 12  alkyl), 2-halophenyl, 3-halophenyl, 4-halophenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl, 4-haloalkylphenyl (1-5 halogens, C 1 C 12  alkyl), carboalkoxyphenyl (C 1-4  alkyl), 2-haloalkylbenzyl, 3-haloalkylbenzyl, 4-haloalkylbenzyl (1 to 5 halogen atoms, C 1 -C 12  alkyl), alkylsalicylphenyl (C 1 -C 4  alkyl), alkoxy ethyl (C 1 -C 6  alkyl), aryloxy ethyl (C 6 -C 9  aryl optionally substituted by OH, NH 2 , halo, C 1-4  alkyl or C 1-4  alkyl substituted by OH or by 1 to 3 halo atoms), 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-imidazolyl, 4-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 2-thiazolyl, 4-thiazolyi, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trichloromethylphenyl, 3-trichloromethylphenyl, 4-trichloromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4arboethoxyphenyl (—C 6 H 4 —C(O)—OC 2 H 5 ), 2,3-dicarboethoxyphenyl, 2,4-dicarboethoxyphenyl, 2,5-dicarboethoxyphenyl, 2,6-dicarboethoxyphenyl, 3,4-dicarboethoxyphenyl, 3,5-dicarboethoxyphenyl, 1-pyridinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl (C 5 H 4 N), 2-nitrophenyl, 3-nitrophenyl 4-nitrophenyl, 4-trifluoromethylbenzyl, 2-ethylsalicylphenyl, 3-ethylsalicylphenyl, 4ethylsalicylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 1,8-dihydroxy-naphthyl (—O—C 10 H 6 —OH or —O—C 10 H 6 —), 2,2′-dihydroxybiphenyl (—O—C 6 H 4 —C 6 H 4 —), methoxy ethyl (CH 2 CH 2 H 3 ), phenoxymethyl, phenoxy ethyl, —C 6 H 4 -CH 2 —N(CH 3 )2 or N-ethylmorpholino —(CH 2 ) 2 —N[(CH 2 ) 2 (CH 2 ) 2 ]O);  
 R 31  is 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, —CH 2 -C(O)—N(R 7 ) 2  wherein each R 7  is the same or different, CH 2 —S(O)(R 7 ), CH 2 —S(O ) 2 (R 7 ), O CH 2  CH(OC(O)CH 2 R 7 )H 2 (OC(O)CH 2 R 7 ), cholesteryl, enolpyruvate, glycerol, an α-D-p—diglyceride, trimethoxybenzyl, triethoxybenzyl or 2-alkyl pyridinyl (C 1-4  alkyl);  
 R 7  is H or C 1 -C 4  alkyl; and  
 the carbon atom designated # has linked substituents that are in the R, S or RS configuration.  
 
     
     
         38 . The compound of    claim 37    wherein R 35  is R.  
     
     
         39 . The compound of    claim 37    wherein R is 2-alkoxyphenyl , 3-alkoxyphenyl, 4-alkoxyphenyl (C 1 -C 12  alkyl), 2-halophenyl, 3-halophenyl, 4-halophenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl, 4-haloalkylphenyl (1-5 halogens, C 1 -C 12  alkyl), carboalkoxyphenyl (C 1 -C 4  alkyl), 2-haloalkylbenzyl, 3-haloalkylbenzyl, 4-haloalkylbenzyl (1 to 5 halogen atoms, C 1 -C 12  alkyl), alkylsalicylphenyl (C 1 -C 4  alkyl), alkoxy ethyl (C 1 -C 6  alkyl) or aryloxy ethyi (C 6 -C 9  aryl optionally substituted by OH, NH 2 , halo, C 1 -C 4  alkyl or C 1 C 4  alkyl substituted by OH or by 1 to 3 halo atoms).  
     
     
         40 . The compound of    claim 39    wherein B is cytosine, 5-fluorocytosine, 5-methylcytosine, adenine, guanine, 2,6-diaminopurine, 2-aminopurine, hypoxanthine or thymine.  
     
     
         41 . The compound of    claim 39    wherein R is alkylsalicylphenyl.  
     
     
         42 . The compound of    claim 41    wherein B is cytosine.  
     
     
         43 . The compound of    claim 37    wherein R is 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-imidazolyl, 4-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trichloromethylphenyl, 3-trichloromethylphenyl, 4-trichloromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl (—C 6 H 4 —C(O)—OC 2 H 5 ), 2,3-dicarboethoxyphenyl, 2,4-dicarboethoxyphenyl, 2,5-dicarboethoxyphenyl, 2,6-dicarboethoxyphenyi, 3,4-dicarboethoxyphenyl, 3,5-dicarboethoxyphenyi, 1-pyridinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl (C 5 H 4 N), 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-trifluoromethylbenzyl, 2-ethylsalicylphenyl, 3-ethylsalicylphenyl, 4-ethylsalicylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 1,8-dihydroxy-naphthyl (C 10 H 6 OH or O—C 10 H 6 -), 2,2′—dihydroxybiphenyl (—O—C 6 O—C 6 H 4 -), methoxy ethyl (CH 2 CH 2 OCH 3 ), phenoxymethyl, phenoxy ethyl, —C 6 H 4 -CH 2 -N(CH 3 )2 or N-ethylmorpholino (—(CH 2 ) 2 —N[(CH 2 ) 2 (CH 2 ) 2 ]O ).  
     
     
         44 . The compound of    claim 43    wherein B is cytosine, 5-fluorocytosine, 5-methylcytosine, adenine, guanine, 2,6-diaminopurine, 2-aminopurine, hypoxanthine or thymine.  
     
     
         45 . The compound of    claim 37    wherein B is cytosine, 5-fluorocytosine, 5-methylcytosine, adenine, guanine, 2,6-diaminopurine, 2-aminopurine, hypoxanthine or thymine.  
     
     
         46 . The use a of compound having the formula  
       
         
           
           
               
               
           
         
       
       and salts of such compounds wherein the carbon atom designated # has linked substituents that are in the R, S or RS configuration, B is cytosine and R 35  is alkylsalicylphenyl (C 1 -C 4  alkyl) in the preparation of a medicament for treating a viral infection by administering an antivirally-effective dose of the compound to an infected subject.  
     
     
         47 . The use of the compound in accordance with    claim 46    wherein the compound is enriched or resolved at the phosphate atom chiral center.  
     
     
         48 . The use of a compound of    claim 2    in the preparation of a medicament for treating a viral infection by administering an antivirally-effective dose of the compound to an infected subject.  
     
     
         49 . The use of the compound in accordance with    claim 48    wherein the compound is enriched or resolved at the phosphate atom chiral center.  
     
     
         50 . The use of a compound of    claim 20    having the structure  
       
         
           
           
               
               
           
         
       
       in the preparation of a medicament for treating a viral infection by administering an antivirally-effective dose of the compound to an infected subject.  
     
     
         51 . The use of the compound in accordance with    claim 50    wherein the compound is enriched or resolved at the phosphate atom chiral center.