Antiviral phosphonate compounds and methods therefor

A prodrug of a nucleotide analog having a structure according to Formula 3 or Formula 4,

• wherein Z1 and Z2 are independently H, alkyl, halogen, OR5, SR5, NR5R6, CO-alkyl, CO-aryl, or CO-alkoxyalkyl, and wherein W is H, OR5, SR5, NR5R6, NH(NR5R6), N(alkyl)(NR5R6), CN, C(O)NR5R6, C(NH)NR5R6, or halogen;
• wherein V is hydrogen, halogen, OR5, SR5, NR5R6, NH(NR5R6), N(alkyl)(NR5R6), CN, C(O)NR5R6, or C(NH)NR5R6, and wherein Y is H, alkyl, halogen, OR5, SR5, NR5R6, CO-alkyl, CO-aryl, or CO-alkoxyalkyl;
• X is a covalent bond between the C4′-atom of the sugar and the carbon atom in the phosphonate group, O, CH2, CHR5, CHHalogen, or C(Halogen)2;
• D is CH2 CHHalogen, or C (Halogen)2;
• R1′, R2′, R3′, and R4′ are independently H or alkyl, with the proviso that at least one of R1′, R2′, R3′, and R4′ is alkyl:
• R3 and R4 are independently H, phosphate, acyl, or alkyl;
• R5 and R6 are independently H, alkyl, or acyl;
• R1 and R2 together are
• wherein:
• X1, W1, and W2 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 X1 and X2 are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorous;
• or
• together X1 and X2 are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorous;
• or
• together X1 and W1 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 carbon atoms that is three atoms from an O attached to the phosphorous;
• or
• together X2 and W1 are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and X1 must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• or
• together W1 and W2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and X1 must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• wherein
• X2 is selected from the group consisting of —CHR12OH, —CHR12OC(O)R13, —CHR12OC(S)R13, —CHR12OC(S)OR13, —CHR12OC(O)SR13, —CHR12OCO2R13, —OR12, SR12, —CHR12N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR122)OH, —CH(C≡CR12)OH, —R12, —NR122, —OCOR13, —OCO2R13, —SCOR13, —SCO,R2R13, —NHCOR12, —NHCO2R13, —CH2NHaryl, —(CH2)p—OR14, and —(CH2)p—SR14;
• p is 2 or 3;
• R12 is selected from the group consisting of R13 and —H;
• R13 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
• and
• R14 is selected from the group consisting of —H and lower acyl.