Novel phosphorus-containing prodrugs

Abstract

Novel cyclic phosphoramidate prodrugs of drugs of formula I their use in delivery of drugs to the liver, their use in enhancing oral bioavailability, and their method of preparation are described.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6 , P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       2 - 57 . (canceled)  
   
   
       58 . A method of enhancing oral bioavailability of a parent drug by administering to an animal a prodrug of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —R 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4− , or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       59 - 69 . (canceled)  
   
   
       70 . A method of delivering a biologically active drug to an animal for a sustained period using compounds of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       71 - 74 . (canceled)  
   
   
       75 . A method of delivering a biologically active drug to an animal with greater selectivity for the liver using compounds of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       76 - 83 . (canceled)  
   
   
       84 . A method of increasing the therapeutic index of a drug by administering to an animal compounds of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 2 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       85 - 88 . (canceled)  
   
   
       89 . A method of bypassing kinase resistance by administering to an animal compounds of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, beteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, 7, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       90 - 96 . (canceled)  
   
   
       97 . A method of treating cancer expressing a P450 enzyme, by administering to an animal a compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       98 - 111 . (canceled)  
   
   
       112 . A method of treating viral infections by administering to an animal a compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       113 - 125 . (canceled)  
   
   
       126 . A method of treating tumor cells expressing a P450 enzyme comprising administering a cyclophosphamide analog selected from the group consisting of  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 66  is selected from the group consisting of —H, lower 2-haloalkyl, and lower alkyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 R″ is lower 2-haloalkyl;  
 R′″ is selected from the group consisting of H, lower alkyl, and R″;  
 each Y is independently selected from the group consisting of —O—, —NR 66 — with the proviso that at least one Y is —NR 66 —;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       127 - 149 . (canceled)  
   
   
       150 . A method of making a prodrug of a compound drug having a —PO 3   2−  or —P(O)(NHR 6 )O −  moiety comprising, 
 a) transforming said phosph(on)ate into a compound of formula I:                          wherein:    V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or    together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or    together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;    together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;    together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;    together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;    Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;    p is an integer 2 or 3;    with the provisos that:    a) V, Z, W, W′ are not all —H; and    b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;    R 2  is selected from the group consisting of R 3  and —H;    R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;    R 6  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;    R 12  is selected from the group consisting of —H, and lower acyl;    each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is NR 6 —;    M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4− , or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;    with the provisos that:    1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and    2) R 6  is not lower alkylhalide;    and pharmaceutically acceptable prodrugs and salts thereof.    
   
   
       151 - 157 . (canceled)  
   
   
       158 . The method of making a prodrug of formula I:  
     
       
         
         
             
             
         
       
     
     comprising converting a hydroxyl or an amino to a phosphate or phosphoramidate, respectively, by reaction with L′-P(O)(—YCH(V)CH(Z)-CW(W′)Y—) 
 wherein L′ is a leaving group selected from the group consisting of —NR 2   2 , aryloxy, and halogen;  
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —.  
 
   
   
       159 - 160 . (canceled)  
   
   
       161 . A compound,  
       R 1   2 N—P—(—YCH(V)CH(Z)-CW(W′)Y—)  
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 q is an integer 1 or 2;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 each R′ is independently selected from the group consisting of alkyl, aryl, and aralkyl or together R 1  and R 1  form a cyclic group, optionally containing a heteroatom;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is selected from the group consisting of —O— and NR 6 — with the proviso that at least one Y is —NR 6 —.  
 with the proviso that R 1  is not methyl.  
 
   
   
       162 . A compound R 1   2 N—P(O)(—YCH(V)CH(Z)-CW(W′)Y—) wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or    together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or    together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;    together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;    together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;    together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;    Z is selected from the group consisting of CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;    p is an integer 2 or 3;    q is an integer 1 or 2;    with the provisos that:    a) V, Z, W, W′ are not all —H; and    b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;    each R 1  is independently selected from the group consisting of alkyl, aryl, and aralkyl;    or together R 1  and R 1  form a cyclic group, optionally containing a heteroatom;    with the proviso that both R 1  groups are not benzyl or ethyl at the same time; and    R 2  is selected from the group consisting of R 3  and —H;    R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;    R 6  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;    R 12  is selected from the group consisting of —H, and lower acyl;    each Y is selected from the group consisting of —O— and —NR 6 — with the proviso that at least one Y is —NR 6 —.    
   
   
       163 . A method of delivering a compound to hepatocytes wherein said compound has a moiety selected from the group consisting of phosph(on)ate comprising: 
 a) converting said compound to a prodrug of formula I:                          wherein:    V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or    together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or    together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;    together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;    together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;    together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;    Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;    p is an integer 2 or 3;    with the provisos that:    a) V, 7, W, W′ are not all —H; and    b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;    R 2  is selected from the group consisting of R 3  and —H;    R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;    R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;    R 12  is selected from the group consisting of —H, and lower acyl;    each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;    M is selected from the group that attached to PO 3   2− , P 2 O 6   3− , P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;    with the provisos that:    1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and    2) R 6  is not lower alkylhalide;    and pharmaceutically acceptable prodrugs and salts thereof.    
   
   
       164 . A method of enhancing the pharmacodynamic half-life of a parent drug by administering to an animal a prodrug of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or  
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;  
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;  
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 Z is selected from the group consisting of —CHR 2 OH, —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 12 , and —(CH 2 ) p —SR 12 ;  
 p is an integer 2 or 3;  
 with the provisos that:  
 a) V, Z, W, W′ are not all —H; and  
 b) when Z is —R 2 , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;  
 R 2  is selected from the group consisting of R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 R 6  is selected from the group consisting of —H, and lower alkyl, acyloxyalkyl, alkoxycarbonyloxy alkyl and lower acyl;  
 R 12  is selected from the group consisting of —H, and lower acyl;  
 each Y is independently selected from the group consisting of —O—, —NR 6 — with the proviso that at least one Y is —NR 6 —;  
 M is selected from the group that attached to PO 3   2− , P 2 O 6   3− ), P 3 O 9   4−  or P(O)(NHR 6 )O −  is a biologically active agent, but is not an FBPase inhibitor, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;  
 with the provisos that:  
 1) M is not —NH(lower alkyl), —N(lower alkyl) 2 , —NH(lower alkylhalide), —N(lower alkylhalide) 2 , or —N(lower alkyl)(lower alkylhalide); and  
 2) R 6  is not lower alkylhalide;  
 and pharmaceutically acceptable prodrugs and salts thereof.  
 
   
   
       165 . (canceled)