Phosphonate inhibitors of HCV

1. A compound having a structure according to Formula I, Formula II, Formula III or Formula IV:

or a pharmaceutically acceptable salt, solvate, and/or ester thereof, wherein:

L 1 is —O—, —S—, or —N(R 11 )—;

L 2 is —C(R 10 ) 2 —;

each R 3a is CH 2 R 9 , alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;

each R 3b is CH 2 R 9 , alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl wherein R 9 is not H;

each R 3c is CH 2 R 9 , alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl wherein R 9 is not H, OH, or F;

each R 3d is H, CH 2 R 9 , alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;

each R 4 is independently H, CH 2 R 9 , alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;

each R 5 and R 6 is independently H, N(R a ) 2 , N 3 , CN, NO 2 , SR a , halogen, CH 2 R 9 , alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; or R 5 and R 6 taken together are ═O, ═NR b , or ═CR c R d ; or R 5 and R 6 taken together with the carbon atom to which they are attached form a 3-7 membered heterocyclic ring wherein one carbon atom in the heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —;

each R a is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;

each R b is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or OR a ;

each R c and R d are independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or halo;

each R 7 is independently H, CH 2 R 9 , alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;

each R 8 is independently H, CH 2 R 9 , halo, alkyl, substituted alkyl, haloalkyl, —CN, —N 3 , alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;

each R 9 is independently H, OH, halo, N 3 , CN, N(R a ) 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, wherein one or more of the non-adjacent carbon atoms in the alkyl or substituted alkyl is optionally replaced with —O—, —S— or —NR a —;

each R 10 is independently H, alkoxy, alkyl, or halo;

each R 11 is independently H, alkyl, aryl, or substituted aryl;

B 1 is a nucleobase selected from

each R 13 is independently OH or NH 2 ;

R 14 is H or CH 3 ;

R 15 is H, amino, or halo;

R 16 is H, halo, OR 17a , N(R 20 )(R 21 ), N(R 28 )N(R 28 )S(O) 2 R 28 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, S(O) m R 28 , or S(O) 2 NR 17a R 17b , NR 17a R 17b , N 3 , NO, NO 2 , formyl, cyano, —C(O)NR 17a R 17b , C(S)NR 17a R 17b , or —C(O)OR 17a ;

each R 17a and R 17b are independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkanoyl;

R 20 is H or OR 17a ;

R 21 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, optionally substituted aryl, cycloalkyl, or arylalkyl; or

R 20 and R 21 together with the nitrogen to which they are attached form an optionally substituted 3-7 membered heterocyclic ring wherein one carbon atom of the heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —;

E 2 is >N, >C—R 25 or >C—R 30 ;

D, E, and F x are each independently >N or >C—R 25 ;

each R 25 is independently H, cyano, nitro, azido, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkenyl, optionally substituted (C 1 -C 6 )alkynyl, —NHCONH 2 , C(O)NR 26 R 27 , C(S)NR 26 R 27 , C(O)OR 28 , hydroxy, OR 28 , S(O) m R 28 , S(O) m NR 26 R 27 , —NR 26 R 27 , halo, 1,3-oxazol-2-yl, 1,3-oxazol-5-yl, 1,3-thiazol-2-yl, imidazol-2-yl, 2-oxo-[1,3]dithiol-4-yl, furan-2-yl, or 2H-[1,2,3]triazol-4-yl;

each R 26 and R 27 is independently H, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkenyl, optionally substituted (C 1 -C 6 )alkynyl, optionally substituted (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, optionally substituted heterocycle, hydroxy, optionally substituted (C 1 -C 6 )alkoxy; or R 26 and R 27 together with the nitrogen to which they are attached form an optionally substituted 3-7 membered heterocyclic ring wherein one carbon atom of the heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —;

each R 28 is independently H, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkenyl, optionally substituted (C 1 -C 6 )alkynyl, optionally substituted (C 3 -C 8 )cycloalkyl, aryl, heteroaryl or heterocycle;

R 30 is —C≡CR 31 , —CH═CHR 32 , formyl, —CH═NNHR 33 , —CH═N(OR 33 ), —CH(OR 34 ), or —B(OR 33 );

R 31 is H, tri(C 1 -C 6 )alkylsilyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted heteroaryl, optionally substituted aryl, carboxy, or (C 1 -C 6 )alkoxycarbonyl;

R 32 is hydrogen or (C 1 -C 6 )alkoxy;

R 33 is H or (C 1 -C 6 )alkyl;

R 34 is (C 1 -C 6 )alkyl;

m is 0, 1, or 2;

wherein each aryl or heteroaryl of R 26 , R 27 , R 28 and R 31 is independently optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, NR 35 R 36 , —C(═O)NR 35 R 36 , cyano, halo, hydroxy, nitro, carboxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkoxy, guanidino, trifluoromethoxy, mercapto, S(O) m R 38 , S(O) m NR 35 R 36 or trifluoromethyl;

R 35 and R 36 are each independently H, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl;

R 38 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl;

B 2 is a nucleobase selected from

E 1 is >N or >C—R 25 ;

E 2 , R 16 , E, F x , and D are defined as for B 1 ;

R 40 is H, NR 4a R 4b , NHC(O)R 4b , (C 1 -C 6 )alkylNR 4a R 4b , NHNH 2 , cyano, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl(C 1 -C 6 )alkyl, heterocycle(C 1 -C 6 )alkyl, halo, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, hydroxy, or mercapto;

R 41 is H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heterocycle, aryl, aryl(C 1 -C 6 )alkyl;

each R 42 is independently H, hydroxy, mercapto, cyano, —SNR 4c R 4d , —C(NH)NR 4c R 4d , —C(═NH)NHOH, —C(NH)NHOR 4c , —C(═NH)NHNR 4c R 4d , NHCOR 4c , SR 4c , OR 4c , SOR 4c , SO 2 R 4c , —C(O)NR 4c R 4d , —C(S)NR 4c R 4d , or R 4c ;

R 43 is H, hydroxy, NR 4c R 4d , NHC(O)NR 4c , NHNHR 4c , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heterocycle, aryl, aryl(C 1 -C 6 )alkyl, halo, C(O)OR 4c , C(O)NR 4c R 4d , or absent when Y is N;

R 4a and R 4b are each independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heterocycle, or aryl;

R 4c , and R 4d are each independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heterocycle, or aryl;

X, Y, and W are each independently N, C, CR 4c , S or P;

each R 44 and R 45 is independently H, hydroxy, mercapto, cyano, —SNR 4c R 4d , —C(NH)NR 4c R 4d , —C(═NH)NHOH, —C(NH)NHOR 4c , —C(═NH)NHNR 4c R 4d , NHCOR 4c , SR 4c , OR 4c , SOR 4c , SO 2 R 4c , —C(O)NR 4c R 4d , —C(S)NR 4c R 4d , or R 4c ;

R 46 , and R 47 together with the atoms to which they are attached form a heterocyclic ring;

U is S or O;

wherein each aryl or heterocycle of R 40 , R 41 , R 42 , R 43 , R 4a , R 4b , R 4c , R 4d , R 44 and R 45 is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, cyano, halo, hydroxy, nitro, carboxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkoxy, trifluoromethoxy, mercapto, or trifluoromethyl;

R 50 is NR 5a R 5b , ONR 5a R 5b , NR 5a NR 5a R 5b , SR 5b , OR 5b , H, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, or aryl;

R 51 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or aryl;

R 55 is NR 5a R 5b , ONR 5a R 5b , NR 5a NR 5a R 5b , SR 5b , OR 5b , H, halo, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl;

R 56 is H, halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl;

R 57 and R 58 are each independently -L-R 5c ;

each L is independently a direct bond, —N(R 5a )—, O or S;

each R 5a and R 5b is independently H, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl;

each R 5c is NR 5a R 5b , H, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl;

wherein each (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl of R 50 , R 51 , R 55 , R 56 , R 57 , R 58 , R 5a , R 5b and R 5c is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, cyano, halo, hydroxy, nitro, carboxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkoxy, trifluoromethoxy, mercapto, or trifluoromethyl;

R 60 , R 61 , and R 62 are each independently H, halo, NR 6b R 6c , hydroxyamino, NR 6b NR 6b R 6c , N 3 , NO, NO 2 , formyl, cyano, —C(O)NR 6b R 6c , —C(S)NR 6b R 6c , —C(O)OR 6b , R 6b , OR 6b or SR 6b ;

R 6b , and R 6c are each independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, (C 1 -C 6 )alkanoyl, or aryl(C 1 -C 6 )alkyl;

wherein each (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or aryl of R 6b and R 6c is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, cyano, halo, hydroxy, nitro, carboxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkoxy, trifluoromethoxy, mercapto, or trifluoromethyl;

X 5 , X 6 , and X 7 are each independently N, CH, or C—R 7a ;

R 70 and R 7a are each independently H, halo, NR 7b R 7c , hydroxyamino, NR 7b NR 7b R 7c , N 3 , NO, NO 2 , formyl, cyano, —C(O)NR 7b R 7c , —C(S)NR 7b R 7c , —C(O)OR 7b , R 7b , OR 7b , or SR 7b ;

R 7b , and R 7c are each independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, (C 1 -C 6 )alkanoyl, or aryl(C 1 -C 6 )alkyl;

A 80 , B 80 , and Y 80 are each independently H, halo, OR 80 , S(O) n R 80 , NR 80 R 81 , cyano, trifluoromethyl, C(W 80 )OR 80 , C(W 80 )SR 80 , C(W 80 )NR 80 R 81 , nitro, azido, carbocyclic, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, aryl(C 1 -C 6 )alkyl, or heterocycle; or A 80 and B 80 taken together with the carbon atoms to which they are attached from a 4-7 membered carbocyclic or heterocyclic ring;

W 80 is O, S, NR 80 ;

n is 0, 1, or 2;

Z 80 is O, S, NR 80 , or CR 80 R 81 ;

each V 80 is independently N or CR 80 ;

each R 80 and R 81 is independently H, carbocycle, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halo, (C 1 -C 6 )alkoxy, amino, methylamino, dimethylamino, cyano, (C 1 -C 6 )alkanoyl, aryl, aryl(C 1 -C 6 )alkyl, an amino acid residue or heterocycle; or R 80 and R 81 taken together with the atom(s) to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring;

X 9 is CR 90a or N;

X 10 is O, S, or NR 91a ;

R 90 and R 91 are each independently H, halo, hydroxy, (C 1 -C 6 )alkoxy, NR 90b R 91b , aryl, heterocycle; (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, aryl(C 1 -C 6 )alkyl, S(O) m R 90b , S(O) m (aryl), or S(O) m NR 90b R 91b ;

R 90a is H, halo, methyl, azido, or amino;

R 91a is H, (C 1 -C 6 )alkyl or (C 1 -C 6 ) alkanoyl;

R 90b and R 91b are each independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, aryl(C 1 -C 6 )alkyl, aryl, (C 1 -C 6 ) alkanoyl, or aryl-C(O)—;

wherein each (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, aryl(C 1 -C 6 )alkyl, aryl, (C 1 -C 6 ) alkanoyl, aryl-C(O)— and heterocycle of R 90 , R 91 , R 91a , R 90b and R 91b are optionally substituted with one to four halo, hydroxy, amino, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy;

each Z 1 is independently N, C—R 9a , O, S, NR 9b , >C═O, >C═S, >C═NR 9b , >S═O, >S(O) 2 or CH—R 9a ; provided that if a Z 1 participates in an optional bond represented by a dotted line in the formula, then that Z 1 is N or C—R 9a ; and provided that if a Z 1 does not participate in an optional bond represented by a dotted line in the formula, then that Z 1 is O, S, NR 9b , >C═O, >C═S, >C═NR 9b , >S═O, >S(O) 2 or CH—R 9a ;

X 8 is O, S, SO, SO 2 , Se, SeO, SeO 2 or NR 9b ;

each W 6 is C, CH, or N; wherein if a W 6 participates in an optional bond represented by a dotted line in the formula, then that W 6 is C; and if a W 6 does not participate in an optional bond represented by a dotted line in the formula, then that W 6 is CH, or N;

each R 9a is independently H, halo, NR 9c R 9d , hydroxyamino, NR 9c NR 9c R 9d , N 3 , cyano, C(O)NR 9c R 9d , —C(S)NR 9c R 9d , —C(S)NR 9c R 9d , —C(═NH)OR 9c , R 9c , OR 9c , or SR 9c ;

each R 9b is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, (C 1 -C 6 )alkanoyl, or aryl(C 1 -C 6 )alkyl;

R 9c and R 9d are each independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, (C 1 -C 6 )alkanoyl, or aryl(C 1 -C 6 )alkyl;

Y 3 ═Y 4 is —N═N—, —CH═N—, —N═CR 8a —, or —CH═CR 8a —;

each R 8a is independently H, halo, or (C 1 -C 6 )alkyl;

B 3 is a nucleobase selected from

W 1 and W 2 are each independently a group of the formula:

wherein:

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

each Y 2 is independently a bond, 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;

each 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; or

when taken together, two R x are optionally substituted C 2 -C 4 alkylene thereby forming a phosphorous-containing heterocycle;

each R y is independently H, F, Cl, Br, I, OH, R, —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, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, alkylsulfone (—SO 2 R), sulfonamide (—SO 2 NR 2 ), alkylsulfoxide (—SOR), ester (—C(═O)OR), amido (—C(═O)NR 2 ), nitrile (—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 2 -C 8 alkenyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 substituted alkynyl, a protecting group, or W 3 ; or when taken together, two R y on the same carbon atom forms a carbocyclic ring of 3 to 7 carbon atoms;

each R is independently H, halogen, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 2 -C 8 alkenyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 alkynyl, C 2 -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;

W 3 is W 4 or W 5 ;

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. A compound according to claim 1 wherein

of Formula I, Formula II, Formula III, or Formula IV is

3. A compound according to claim 2 wherein each Y 2 is independently —O— or —N(R)—.

4. A compound according to claim 1 wherein

of Formula I, Formula II, Formula III, or Formula IV is

wherein W 5 is phenyl or substituted phenyl, and each Y 2 is independently —O—, —N(R)— or —S—.

5. A compound according to claim 1 wherein

of Formula I, Formula II, Formula III, or Formula IV is

wherein W 5 is a carbocycle.

6. A compound according to claim 1 wherein

of Formula I, Formula II, Formula III, or Formula IV is

wherein W 5 is phenyl or phenyl substituted with 0 to 3 R y and Y 2 is —O— or —N(R)—.

7. A compound according to claim 1 wherein

of Formula I, Formula II, Formula III, or Formula IV is

8. A compound according to claim 1 wherein

of Formula I, Formula II, Formula III, or Formula IV is

wherein Y 1 is O or S and each Y 2 is —O— or —N(R)—.

9. A compound according to claim 1 wherein

of Formula I, Formula II, Formula III, or Formula IV is

wherein each R is independently C 1 -C 8 alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.

10. A compound of claim 1 according to Formula I.

11. A compound according to claim 10 wherein the nucleobase is

each R 10 is H, L 1 is O, and each R a is H.

12. A compound according to claim 11 wherein R 13 is NH 2 and R 15 is H or R 13 is OH and R 15 is NH 2 .

13. A compound according to claim 12 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

14. A compound according to claim 10 wherein the nucleobase is

each R 10 is H, L 1 is O, and each R a is H.

15. A compound according to claim 14 wherein R 14 is H and R 13 is NH 2 or OH.

16. A compound according to claim 15 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

17. A compound according to claim 10 wherein the nucleobase is

each R 10 is H, L 1 is O, and each R a is H.

18. A compound according to claim 17 wherein each E and D is >N and F x is >C—R 25 .

19. A compound according to claim 18 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

20. A compound according to claim 10 wherein the nucleobase is

each R 10 is H, L 1 is O, and each R a is H.

21. A compound of claim 1 according to Formula II.

22. A compound according to claim 21 wherein the nucleobase is

each R 10 is H, L 1 is O, and each R a is H.

23. A compound according to claim 22 wherein each E 2 , E, and D is >N and each E 1 and F x is independently >C—R 25 .

24. A compound according to claim 23 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

25. A compound according to claim 22 wherein each E 1 , E 2 , E, and D is >N and F x is >C—R 25 .

26. A compound according to claim 25 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

27. A compound according to claim 22 wherein each E 1 , E, and D is >N and each E 2 and F x is independently >C—R 25 .

28. A compound according to claim 27 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

29. A compound according to claim 22 wherein each E and D is >N, each E 1 and F x is independently >C—R 25 , and E 2 is >C—R 30 .

30. A compound according to claim 29 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

31. A compound according to claim 21 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

32. A compound according to claim 21 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

33. A compound according to claim 21 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

34. A compound according to claim 33 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

35. A compound according to claim 21 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

36. A compound according to claim 35 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

37. A compound according to claim 21 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

38. A compound according to claim 21 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

39. A compound according to claim 38 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

40. A compound according to claim 21 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

41. A compound according to claim 21 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

42. A compound according to claim 41 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

43. A compound of claim 1 according to Formula III.

44. A compound according to claim 43 wherein the nucleobase is

each R 10 is H, L 1 is O, and each R a is H.

45. A compound according to claim 44 wherein each E 2 , E, and D is >N and each E 1 and F x is independently >C—R 25 .

46. A compound according to claim 45 wherein each R 5 and R 6 is H.

47. A compound according to claim 45 wherein R 5 and R 6 taken together are ═CR c R d .

48. A compound according to claim 45 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

49. A compound according to claim 44 wherein each E 1 , E 2 , E, and D is >N and F x is >C—R 25 .

50. A compound according to claim 49 wherein each R 5 and R 6 is H.

51. A compound according to claim 49 wherein R 5 and R 6 taken together are ═CR c R d .

52. A compound according to claim 49 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

53. A compound according to claim 44 wherein each E 1 , E, and D is >N and each E 2 and F x is independently >C—R 25 .

54. A compound according to claim 53 wherein each R 5 and R 6 is H.

55. A compound according to claim 53 wherein R 5 and R 6 taken together are ═CR c R d .

56. A compound according to claim 53 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

57. A compound according to claim 44 wherein each E and D is >N, each E 1 and F x is independently >C—R 25 , and E 2 is >C—R 30 .

58. A compound according to claim 57 wherein each R 5 and R 6 is H.

59. A compound according to claim 57 wherein R 5 and R 6 taken together are ═CR c R d .

60. A compound according to claim 57 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

61. A compound according to claim 43 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

62. A compound according to claim 43 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

63. A compound according to claim 43 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

64. A compound according to claim 63 wherein each R 5 and R 6 is H.

65. A compound according to claim 63 wherein R 5 and R 6 taken together are ═CR c R d .

66. A compound according to claim 63 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

67. A compound according to claim 43 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

68. A compound according to claim 67 wherein each R 5 and R 6 is H.

69. A compound according to claim 67 wherein R 5 and R 6 taken together are ═CR c R d .

70. A compound according to claim 67 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

71. A compound according to claim 43 wherein the nucleobase is

wherein each R10 is H, L 1 is O, and each R a is H.

72. A compound according to claim 43 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

73. A compound according to claim 72 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

74. A compound according to claim 50 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

75. A compound according to claim 43 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

76. A compound according to claim 75 wherein each R 5 and R 6 is H.

77. A compound according to claim 75 wherein R 5 and R 6 taken together are ═CR c R d .

78. A compound according to claim 75 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

79. A compound of claim 1 according to Formula IV.

80. A compound according to claim 79 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

81. A compound according to claim 80 wherein each E and D is >N and F x is >C—R 25 .

82. A compound according to claim 81 wherein each R 5 and R 6 is H.

83. A compound according to claim 81 wherein R 5 and R 6 taken together are ═CR c R d .

84. A compound according to claim 81 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

85. A compound according to claim 79 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

86. A compound according to claim 79 wherein the nucleobase is

wherein each R 10 is H, L 1 is O, and each R a is H.

87. A compound according to claim 86 wherein each R 5 and R 6 is H.

88. A compound according to claim 86 wherein R 5 and R 6 taken together are ═CR c R d .

89. A compound according to claim 86 wherein each W 1 and W 2 is independently Y 2 —R x wherein each Y 2 is independently —O— or —N(R)— and R x is not H.

90. A compound selected from the group consisting of:

or pharmaceutically acceptable salts, solvates, and/or esters thereof.

91. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and a pharmaceutically acceptable carrier or excipient.

92. The pharmaceutical composition of claim 91 , further comprising at least one additional therapeutic agent.

93. The pharmaceutical composition of claim 92 , wherein said at least one additional therapeutic agent is selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.

94. The pharmaceutical composition of claim 93 , wherein said interferon is selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha, feron, reaferon, intermax alpha, rIFN-beta, infergen+actimmune, IFN-omega with DUROS, and albuferon; said ribavirin analog is selected from the group consisting of rebetol, copegus, and viramidine (taribavirin); said NS5b polymerase inhibitor is selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, and XTL-2125; said NS3 protease inhibitor is selected from the group consisting of SCH-503034 (SCH-7), VX-950, and BILN-2065; said alpha-glucosidase 1 inhibitor is selected from the group consisting of MX-3253 (celgosivir) and UT-231B; said hepatoprotectant is selected from the group consisting of IDN-6556, ME 3738, and LB-84451; and said non-nucleoside inhibitor of HCV is selected from the group consisting of benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives; and 17) other drugs for treating HCV, e.g., zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17, KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and NIM811.

95. A combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof; and

b) a second pharmaceutical composition comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.

96. A method of inhibiting HCV polymerase, comprising:

contacting a cell infected with HCV with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or ester thereof, whereby HCV polymerase is inhibited.

97. The method of claim 96 , further comprising contacting said cell infected with HCV with at least one additional therapeutic agent.

98. The method of claim 97 , wherein said at least one additional therapeutic agent is selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.

99. A method of treating HCV in a patient, comprising:

administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

100. The method of claim 99 , further comprising:

administering at least one additional therapeutic agent.

101. The method of claim 100 , wherein said at least one additional therapeutic agent is selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.

102. The method of claim 101 , wherein said interferon is selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha, feron, reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS, and albuferon; said ribavirin analog is selected from the group consisting of rebetol, copegus, and viramidine (taribavirin); said NS5b polymerase inhibitor is selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, and XTL-2125; said NS3 protease inhibitor is selected from the group consisting of SCH-503034 (SCH-7), VX-950, and BILN-2065; said alpha-glucosidase 1 inhibitor is selected from the group consisting of MX-3253 (celgosivir) and UT-231B; said hepatoprotectant is selected from the group consisting of IDN-6556, ME 3738, and LB-84451; and said non-nucleoside inhibitor of HCV is selected from the group consisting of benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives; and 17) other drugs for treating HCV, e.g., zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17, KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and NIM811.

103. The use of a compound of claim 1 for the manufacture of a medicament for treating infection by HCV in a patient.

104. A compound as described in Table 6 or Table 7.

105. A new compound, substantially as described herein.

106. A new pharmaceutical composition or use for the preparation of a medicament, substantially as described herein.

107. A compound of claim 1 as a therapeutic substance.