Antiviral phosphonate analogs

1. A conjugate of the following formula:

or a pharmaceutically acceptable salt or solvate thereof;

wherein:

B is selected from adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O 6 -methylguanine, N 6 -methyladenine, O 4 -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and pyrazolo[3,4-d]pyrimidine;

X is selected from O, C(R y ) 2 , OC(R y ) 2 , NR and S;

Z is independently selected from H, OH, OR, NR 2 , CN, NO 2 , SH, SR, F, Cl, Br, and I;

Y 1 is independently O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ;

Y 2 of the moiety

is independently CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;

Y 2 of the moiety

is independently O, CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;

M2 is 0, 1 or 2;

R y is independently H, F, Cl, Br, I, OH, —C(═Y 1 )R, —C(═Y 1 )OR, —C(═Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC(═Y 1 )R, —OC(═Y 1 )OR, —OC(═Y 1 )(N(R) 2 ), —SC(═Y 1 )R, —SC(═Y 1 )OR, —SC(═Y 1 )(N(R) 2 ), —N(R)C(═Y 1 )R, N(R)C(═Y 1 )OR, or —N(R)C(═Y 1 )N(R) 2 , amino (—NH 2 ), ammonium (—NH 3 + ), alkylamino, dialkylamino, trialkylammonium, C 1 -C 8 alkyl, C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, alkylsulfone (—SO 2 R), arylsulfone (—SO 2 Ar), arylsulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO 2 NR 2 ), alkylsulfoxide (—SOR), ester (—C(═O)OR), amido (—C(═O)NR 2 ), 5-7 membered ring lactam, 5-7 membered ring lactone, nitrite (—CN), azido (—N 3 ), nitro (—NO 2 ), C 1 -C 8 alkoxy (—OR), C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 1 -C 8 alkenyl, C 1 -C 8 substituted alkenyl, C 1 -C 8 alkynyl, C 1 -C 8 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocycle, C 2 -C 20 substituted heterocycle, polyethyleneoxy, or W 3 ; or when taken together, R y forms a carbocyclic ring of 3 to 7 carbon atoms;

R x is independently R y , a protecting group, or the formula:

wherein:

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

R is C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 1 -C 8 alkenyl, C 1 -C 8 substituted alkenyl, C 1 -C 8 alkynyl, C 1 -C 8 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocycle, C 2 -C 20 substituted heterocycle, or a protecting group; and

W 3 is W 4 or W 5 , where W 4 is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ; and W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.

2. The conjugate of claim 1 wherein C 1 -C 8 substituted alkyl, C 1 -C 8 substituted alkenyl, C 1 -C 8 substituted alkynyl, C 6 -C 20 substituted aryl, and C 2 -C 20 substituted heterocycle are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 3 -C 12 carbocycle, C 6 -C 20 aryl, C 2 -C 20 heterocycle, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.

3. The conjugate of claim 1 wherein protecting group is selected from a carboxyl ester, a carboxamide, an aryl ether, an alkyl ether, a trialkylsilyl ether, a sulfonic acid ester, a carbonate, and a carbamate.

4. The conjugate of claim 1 wherein W 5 is selected from the structures:

5. The conjugate of claim 1 wherein X is O and each R y is H.

6. The conjugate of claim 1 wherein the conjugate is a resolved enantiomer having the structure:

7. The conjugate of claim 1 wherein the conjugate is a resolved enantiomer having the structure:

8. The conjugate of claim 1 having the structure:

9. The conjugate of claim 1 having the structure:

10. The conjugate of claim 1 having the structure:

11. The conjugate of claim 1 having the structure:

12. The conjugate of claim 1 having the structure:

wherein R 2 is H or C 1 -C 8 alkyl.

13. The conjugate of claim 1 having the structure:

14. The conjugate of claim 13 wherein Z is H.

15. The conjugate of claim 13 wherein B is adenine.

16. The conjugate of claim 13 having the structure:

wherein Y 2c is O, N(R y ) or S.

17. The conjugate of claim 16 having the structure:

18. The conjugate of claim 17 wherein Y 2c is O.

19. The conjugate of claim 17 wherein Y 2c is N(CH 3 ).

20. The conjugate of claim 1 wherein substituted triazole has the structure:

21. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a conjugate as described in claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

22. A method for promoting an anti-viral effect in vitro or in vivo comprising contacting a sample in need of such treatment with a a conjugate as described in claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

23. A method of inhibiting a viral infection in an animal, comprising administering an effective amount of a conjugate as described in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to the animal.