Novel Phosphorus-Containing Thyromimetics

Abstract

The present invention relates to compounds of phosphonic acid-containing T3 mimetics and monoesters thereof, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndrome x and diabetes.

1 - 77 . (canceled) 
   
   
       78 . A compound of Formula VIII: 
     
       
         
         
             
             
         
       
     
     wherein:
 G is selected from the group consisting of —O—, —S—, —Se—, —S(═O)—, —S(═O) 2 —, —Se—, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —CH(C 1 -C 4  alkyl)-, —CH(C 1 -C 4  alkoxy)-, —C(═CH 2 )—, —NH—, and —N(C 1 -C 4  alkyl)-, or CH 2  linked to any of the preceding groups; 
 or G is R 50 -R 51  wherein; 
 R 50 -R 51  together are —C(R 52 )═C(R 52 )— or alternatively R 50  and R 51  are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50  and R 51  is —CH(R 53 )—, and when one of R 50  and R 51  is O or S, then R 53  is R 54 ; 
 R 54  is hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; 
 R 53  is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and 
 R 52  is selected from hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 
 T is selected from the group consisting of (CR a   2 ) k —, —CR b ═CR b —(CR a   2 ) n —, (CR a   2 ) n —CR b ═CR b —, (CR a   2 )—CR b ═CR b —(CR a   2 )—, —O(CR b   2 )(CR a   2 ) n —, —S(CR b   2 )(CR a   2 ) n —, —N(R c )(CR b   2 )(CR a   2 ) n —, —N(R b )C(O)(CR a   2 ) n —, —(CR a   2 ) m C(R b )(NR b R c )—, —C(O)(CR a   2 ) m —, (CR a   2 ) m C(O)—, —(CR b   2 )—O—(CR b   2 )—(CR a   2 ) p —, —(CR b   2 )—S—(CR b   2 )—(CR a   2 ) p —, —(CR b   2 )—N(R c )—(CR b   2 )—(CR a   2 ) p —, —(CR a   2 ) p —(CR b   2 )—O—(CR b   2 )—, (CR a   2 ) p —(CR b   2 )—S—(CR b   2 )—, —(CR a   2 ) p —(CR b   2 )—N(R c )—(CR b   2 )— and —(CH 2 ) p C(O)N(R b )C(R a   2 )—; 
 k is an integer from 0-4; 
 m is an integer from 0-3; 
 n is an integer from 0-2; 
 p is an integer from 0-1; 
 Each R a  is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4  alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4  alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4  alkyl, —NR b R c , optionally substituted —C 2 -C 4  alkenyl, and optionally substituted —C 2 -C 4  alkynyl; with the proviso that when one R a  is attached to C through an O, S, or N atom, then the other R a  attached to the same Cis a hydrogen, or attached via a carbon atom; 
 Each R b  is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4  alkyl; 
 Each R c  is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4  alkyl, optionally substituted —C(O)—C 1 -C 4  alkyl, and —C(O)H; 
 R 1 , R 2 , R 6 , and R 7  are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted —S—C 1 -C 3  alkyl, optionally substituted —C 2 -C 4  alkenyl, optionally substituted —C 2 -C 4  alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3  alkyl, and cyano; with the proviso that at least one of R 1  and R 2  is not hydrogen; 
 R 8  and R 9  are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted —S—C 1 -C 3  alkyl, optionally substituted —C 2 -C 4  alkenyl, optionally substituted —C 2 -C 4  alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted-O—C 1 -C 3  alkyl, hydroxy, —(CR a   2 )aryl, —(CR a   2 )cycloalkyl, 
 
     —(CR a   2 )heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano;
 or R 6  and T are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3  and R 5  are attached, including 0 to 2 heteroatoms independently selected from —NR i —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; and X is attached to this ring by a direct bond to a ring carbon, or by —(CR a   2 )— or —C(O)— bonded to a ring carbon or a ring nitrogen; 
 R i  is selected from the group consisting of hydrogen, —C(O)C 1 -C 4  alkyl, —C 1 -C 4  alkyl, and —C 1 -C 4 -aryl; or 
 R 1  and R 7  are taken together along with the carbons to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 1  and R 7  are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; 
 t is an integer from 3-6; 
 r and s are integers from 0-5; 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —OCF 3 , cyano, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR a   2 ) m aryl, optionally substituted —(CR a   2 ) m cycloalkyl, optionally substituted —(CR a   2 ) m heterocycloalkyl, C(R b )═C(R b )-aryl, —C(R b )═C(R b )-cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ; 
 Each R d  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, optionally substituted 
 
     —(CR b   2 ) n heterocycloalkyl, and —C(O)NR f R g ;
 Each R e  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR a   2 ) n aryl, optionally substituted —(CR a   2 ) n cycloalkyl, and optionally substituted —(CR a   2 ) n heterocycloalkyl; 
 R f  and R g  are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, and optionally substituted —(CR b   2 ) n heterocycloalkyl, or R f  and R g  may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4  alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ; 
 Each R h  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, and optionally substituted —(CR b   2 ) n heterocycloalkyl; or 
 R 3  and R 8  are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3  and R 8  are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or 
 R 8  and G are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring comprising —CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═; 
 R 5  is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6  alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or 
 R 3  and R 5  are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3  and R 5  are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; 
 X is P(O)(YR 11 )(Y′R 11 ); 
 Y and Y′ are each independently selected from the group consisting of —O—, and —NR v —; 
 when Y and Y′ are both —O—, R 11  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z   2 , 
 
     —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy;
 when Y and Y′ are both —NR v —, then R 11  attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —C(O)OR y , —C(R x ) 2 C(O)OR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-C(O)OR y ; 
 when Y is —O— and Y′ is NR v , then R 11  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z   2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; and R 11  attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —COOR y , —C(R x ) 2 COOR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-COOR y ; or 
 when Y and Y′ are independently selected from —O— and —NR v —, then R 11  and R 11  together form a cyclic group comprising -alkyl-S—S-alkyl-, or together R 11  and R 11  are the group: 
 
     
       
         
         
             
             
         
       
     
     wherein:
 V, W, and W′ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or 
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, 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, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and said cyclic group is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus; or 
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon substituted by hydrogen 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 a Y attached to the phosphorus; or 
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or 
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 Z is selected from the group consisting of —CHR z OH, —CHR z OC(O)R y , —CHR z OC(S)R y , —CHR z OC(S)OR y , —CHR z OC(O)SR y , —CHR z OCO 2 R y , —OR z , —SR z , —CHR z N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR z   2 )OH, —CH(C≡CR z )OH, -R z , —NR z   2 , —OCOR y , —OCO 2 R y , —SCOR y , —SCO 2 R y , —NHCOR z , —NHCO 2 R y , —CH 2 NHaryl, —(CH 2 ) q —OR z , and —(CH 2 ) q —SR z ; 
 q is an integer 2 or 3; 
 Each R z  is selected from the group consisting of R y  and —H; 
 Each R y  is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; 
 Each R x  is independently selected from the group consisting of —H, and alkyl, or together R x  and R x  form a cycloalkyl group; 
 Each R v  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; 
 with the provisos that: 
 a) when G is —O—, —S—, —Se—, —S(═O)—, —S(═O) 2 —, —CH 2 —, —C(O)—, —NH— and, T is —(CH 2 ) 0-4 — or —C(O)NH(CR b   2 )—, R 1  and R 2  are independently chosen from the group consisting of hydrogen, halogen, —C 1 -C 4  alkyl, R 8  and R 9  are each independently selected from hydrogen, halogen and C 1-4 alkyl, R 6  and R 7  are each independently selected from hydrogen, halogen O—C 1-3 alkyl, hydroxy, cyano and C 1-4 alkyl, R 3  is —C(O)NR 25 R 26 , —CH 2 —NR 25 R 26 , —NR 25 OC(O)R 26 , —OR 27 , R 28 , or 
 
     
       
         
         
             
             
         
       
     
     R 4  is hydrogen, halogen, cyano or alkyl, and R 5  is —OH, R 25  and R 26  are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl, R 27  is aryl, heteroaryl, alkyl, aralkyl, or heteroaralkyl, R 28  is aryl, heteroaryl, or cycloalkyl, R 29  is hydrogen, aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl, then X is not —P(O)(OH) 2 , or —P(O)(O-lower alkyl) 2 ;
 b) when G is —O—, —S—, —Se—, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CF 2 —, —C(O)—, —NH— and, T is —C(O)NH(CR b   2 )—, R 1  and R 2  are independently halogen, cyano, —C 1 -C 4  alkyl, R 8  and R 9  are each independently selected from hydrogen, halogen and C 1-4 alkyl, R 6  and R 7  are each independently selected from hydrogen, halogen O—C 1-3 alkyl, hydroxy, cyano and C 1-4 alkyl, R 3  is halogen, —C 1 -C 6  alkyl, —C 2 -C 6  alkynyl, —C 4 -C 7  cycloalkenyl, —C 3 -C 7  cycloalkoxy, —S(═O) 2 (NR 14 R 15 ), —N(R 16 )S(═O) 2 R 17 , —SR 17 , —S(═O)R 17 , 
 
     —S(═O) 2 R 17 , —C(O)R 16 , or —CR 18 (OR 16 )R 19 , R 4  is halogen, cyano or alkyl, and R 5  is —OH, optionally substituted —OC 1 -C 6  alkyl, aroyl or alkanoyl, R 14 , R 15 , R 16 , R 18  and R 19  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, R 17  is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, or R 14  and R 15  may be joined so as to comprise a chain of 3 to 6 methylene groups to form a ring of 4 to 7-membered in size, then X is not —P(O)(OH) 2  or —P(O)(O-lower alkyl) 2 ;
 c) when G is O and T is —(CH 2 ) k —, R 1  and R 2  are independently halogen, alkyl of 1 to 3 carbons, R 3  is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4  is hydrogen, R 5  is OH, R 6 , R 7 , R 8  and R 9  are hydrogen, then X is not phosphonic acid or a lower alkyl ester thereof; 
 d) when G is O, T is —(CH 2 ) 1-3 — or —(CH 2 ) 1-2 —CH(R aa ), R aa  is —OH, —NH 2 , —NH(C 1-4 alkyl), —NH(C 2-4 alkenyl), or —NH(C 2-4 alkynyl), R 4 , R 6 , R 7 , R 8  and R 9  are hydrogen, R 1  and R 2  are independently selected from halogen, C 1  alkyl substituted with 1, 2, or 3 hydrogen, fluorine, or a bioisosteric equivalent, C 1-4  alkyl and CF 3 , and R 3  and R 5  are taken together along with the carbon atoms to which they are attached to form a five member heterocyclic ring of formula -A-C(R bb )═B— wherein A, attached where the R 5  group is attached, is selected from —O—, —S—, and —NR h —, B is selected from —CH—, and —N—, R bb  is selected from C 6-10 aryl, C 5-9 heteroaryl, or C 1-4 alkyl, then X is not phosphonic acid, phosphamic acid, or a lower alkyl ester or acyloxyalkyl ester thereof; 
 e) when G is O, R 4 , R 6 , R 7 , R 8  and R 9  are hydrogen, R 3  is selected from hydrogen, halogen, cyano, C 6-10 aryl, C 5-10 heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 2 -alkenyl, C 2-10 alkynyl, and R 5  is —NHC(O)R e , NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ) or —NHC(O)NH(R h ), then X is not phosphonic acid or phosphamic acid or a lower alkyl ester thereof; 
 f) when G is —CH 2 —O—, wherein the oxygen atom is attached to the ring bearing the T group, R6 and R7 are hydrogen, T is —(CH 2 ) 1-2 CH(R cc ), R cc  is —OH, —SH, —NH 2 , or —NH(C 1-4 ), R 1  and R 2  are each independently selected from chlorine, bromine, C 1-4  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl, then X is not phosphonic acid or phosphamic acid or a lower alkyl ester thereof; 
 g) when G is O, T is —(CR a   2 ) 0-4 —, R 4 , R 6 , R 7  and R 8  are hydrogen, R 5  is hydroxy, methoxy, or —NHC(O)R e , R 3  is hydrogen, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, or C 5-8 cycloalkylalkyl, R 1  and R 2  are each independently selected from hydrogen, halogen, C 1-4 alkyl, or C 3-6 cycloalkyl, and R 9  is C 1-4 alkyl, CH 2 aryl, C(O)aryl, or C(O)alkyl, then X is not phosphonic acid or a lower alkyl ester thereof; 
 h) V, Z, W, W′ are not all —H; and 
 i) when Z is -R z , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; 
 and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs. 
 
   
   
       79 . The compound of  claim 78 , having Formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 G is selected from the group consisting of —O—, —S—, —Se—, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C 1 -C 4  alkyl)-, or CH 2  linked to any of the preceding groups; 
 or G is R 50 -R 51  wherein; 
 R 50 -R 51  together are —C(R 52 )═C(R 52 )— or alternatively R 50  and R 51  are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50  and R 51  is —CH(R 53 )—, and when one of R 50  and R 51  is O or S, then R 53  is R 54 ; 
 R 54  is hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; 
 R 53  is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and 
 R 52  is selected from hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 
 T is selected from the group consisting of —(CR a   2 ) k —, —CR b ═CR b —(CR a   2 ) n —, —(CR a   2 ) n —CR b ═CR b —, —(CR a   2 )—CR b ═CR b —(CR a   2 )—, O(CR b   2 )(CR a   2 ) n —, —S(CR b   2 )(CR a   2 ) n —, —N(R c )(CR b   2 )(CR a   2 ) n —, —N(R b )C(O)(CR a   2 ) n —, —(CR a   2 ) m C(R b )(NR b R c )—, —C(O)(CR a   2 ) m —, —(CR a   2 ) m C(O)—, —(CR b   2 )—O—(CR b   2 )—(CR a   2 ) m —, —(CR b   2 )—S—(CR b   2 )—(CR a   2 ) p —, —(CR b   2 )—N(R c )—(CR b   2 )—(CR a   2 ) p —(CR a   2 ) p —(CR b   2 )—O—(CR b   2 )—, (CR a   2 ) p —(CR b   2 )—S—(CR b   2 )_—(CR a   2 ) p —(CR b   2 )—N(R)—(CR 2 )— and —(CH 2 ) p C(O)N(R b )C(R a   2 )—; 
 k is an integer from 0-4; 
 m is an integer from 0-3; 
 n is an integer from 0-2; 
 p is an integer from 0-1; 
 Each R a  is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4  alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4  alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4  alkyl, —NR b R c , optionally substituted —C 2 -C 4  alkenyl, and optionally substituted —C 2 -C 4  alkynyl; with the proviso that when one R a  is attached to C through an O, S, or N atom, then the other R a  attached to the same Cis a hydrogen, or attached via a carbon atom; 
 Each R b  is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4  alkyl; 
 Each R c  is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted —C(O)—C 1 -C 4  alkyl, and —C(O)H; 
 R 1  and R 2  are each independently selected from the group consisting of halogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted —S—C 1 -C 3  alkyl, optionally substituted —C 2 -C 4  alkenyl, optionally substituted —C 2 -C 4  alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3  alkyl, and cyano; 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR a   2 ) n aryl, optionally substituted —(CR a   2 ) m cycloalkyl, optionally substituted (CR a   2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )-cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR a   2 ) n (CR b   2 )NR f R g , —OR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R c , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ; 
 Each R d  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, optionally substituted 
 
     —(CR b   2 ) n heterocycloalkyl, and —C(O)NR f R g ;
 Each R e  is optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR a   2 ) n aryl, optionally substituted —(CR a   2 ) n cycloalkyl, and optionally substituted —(CR a   2 ) n heterocycloalkyl; 
 R f  and R g  are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, and optionally substituted —(CR b   2 ) n heterocycloalkyl, or R f  and R g  may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup selected from the group of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4  alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ; 
 Each R h  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, and optionally substituted —(CR b   2 ) n heterocycloalkyl; 
 R 5  is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6  alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or 
 R 3  and R 5  are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3  and R 5  are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; 
 X is P(O)(YR 11 )(Y′R 11 ); 
 Y and Y′ are each independently selected from the group consisting of —O—, and NR v —; 
 when Y and Y′ are both —O—, R 11  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z   2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; and 
 when Y and Y′ are both —NR v —, then R 11  attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —C(O)OR y , —C(R x ) 2 C(O)OR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-C(O)OR y ; and 
 when Y is —O— and Y′ is NR v , then R 11  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z   2 , 
 
     —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; and R 11  attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —COOR y , —C(R x ) 2 COOR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-COOR y ;
 or when Y and Y′ are independently selected from —O— and —NR v —, then R 11  and R 11  together form a cyclic group comprising -alkyl-S—S-alkyl-, or R 11  and R 11  together are the group: 
 
     
       
         
         
             
             
         
       
     
     wherein:
 V, W, and W′ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; 
 or together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or 
 or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and said cyclic group is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus; 
 or together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon substituted by hydrogen 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 a Y attached to the phosphorus; 
 or together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein O 2  atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 Z is selected from the group consisting of —CHR z OH, —CHR z OC(O)R y , —CHR z OC(S)R y , —CHR z OC(S)OR y , —CHR z OC(O)SR y , —CHR z OCO 2 R y , —OR z , —SR z , —CHR z N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR z   2 )OH, —CH(C≡CR z )OH, -R z , —NR z   2 , —OCOR y , —OCO 2 R y , —SCOR y , —SCO 2 R y , —NHCOR z , —NHCO 2 R y , —CH 2 NHaryl, —(CH 2 ) q —OR z , and —(CH 2 ) q —SR z ; 
 q is an integer 2 or 3; 
 Each R z  is selected from the group consisting of R y  and —H; 
 Each R y  is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; 
 Each R x  is independently selected from the group consisting of —H, and alkyl, or together R x  and R x  form a cycloalkyl group; 
 Each R v  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; 
 with the provisos that: 
 a) when G is —O—, —S—, —Se—, —S(═O)—, —S(═O) 2 —, —CH 2 —, —C(O)—, —NH— and, T is —(CH 2 ) 04 — or —C(O)NH(CR b   2 )—, R 1  and R 2  are independently chosen from the group consisting of hydrogen, halogen, —C 1 -C 4  alkyl, R 3  is C(O)NR 25 R 26 , —CH 2 —NR 25 R 26 , —NR 25 —C(O)R 26 , —OR 27 , R 28 , or 
 
     
       
         
         
             
             
         
       
     
     R 4  is hydrogen, halogen, cyano or alkyl, and R 5  is —OH, R 25  and R 26  are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl, R 27  is aryl, heteroaryl, alkyl, aralkyl, or heteroaralkyl, R 28  is aryl, heteroaryl, or cycloalkyl, R 29  is hydrogen, aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl, then X is not —P(O)(OH) 2 , or —P(O)(O-lower alkyl) 2 ;
 b) when G is —O—, —S—, —Se—, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CF 2 —, —C(O)—, —NH— and, T is —C(O)NH(CR b   2 )—, R 1  and R 2  are independently halogen, cyano, —C 1 -C 4  alkyl, R 3  is halogen, —C 1 -C 6  alkyl, —C 2 -C 6  alkynyl, —C 4 -C 7  cycloalkenyl, —C 3 -C 7  cycloalkoxy, —S(═O) 2 (NR 14 R 15 ), —N(R 16 )S(═O) 2 R 17 , —SR 17 , —S(═O)R 17 , —S(═O) 2 R 17 , —C(O)R 16 , or —CR 18 (OR 16 )R 19 , R 4  is halogen, cyano or alkyl, and R 5  is —OH, optionally substituted —OC 1 -C 6  alkyl, aroyl or alkanoyl, R 14 , R 15 , R 16 , R 18  and R 19  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, or R 14  and R 15  may be joined so as to comprise a chain of 3 to 6 methylene groups to form a ring of 4 to 7-membered in size, R 17  is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, then X is not —P(O)(OH) 2  or —P(O)(O-lower alkyl) 2 ; 
 c) when G is O and T is —(CH 2 ) k —, R 1  and R 2  are independently halogen, alkyl of 1 to 3 carbons, R 3  is alkyl of 1 to 4 carbons or cycloalkyl of 3 to 7 carbons, R 4  is hydrogen, R 5  is OH, then X is not phosphonic acid or a lower alkyl ester thereof; 
 d) when G is O, T is —(CH 2 ) 1-3 — or —(CH 2 ) 1-2 —CH(R aa ), R aa  is —OH, —NH 2 , —NH(C 1-4 alkyl), —NH(C 2-4 alkenyl), or —NH(C 2-4 alkynyl), R 4  is hydrogen, R 1  and R 2  are independently selected from halogen, C 1  alkyl substituted with 1, 2, or 3 hydrogen, fluorine, or a bioisosteric equivalent, C 1-4  alkyl and CF 3 , and R 3  and R 5  are taken together along with the carbon atoms to which they are attached to form a five member heterocyclic ring of formula -A-C(R bb )═B— wherein A, attached where the R 5  group is attached, is selected from —O—, —S—, and —NR h —, B is selected from —CH—, and —N—, R bb  is selected from C 6-10 aryl, C 5-9 heteroaryl, or C 1-4 alkyl, then X is not phosphonic acid, phosphamic acid, or a lower alkyl ester or acyloxyalkyl ester thereof; 
 e) when G is O, R 4  is hydrogen, R 3  is selected from hydrogen, halogen, cyano, C 6-10 aryl, C 5-10 heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, and R 5  is —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ) or —NHC(O)NH(R h ), T is —(CH 2 ) 1-2 —, —CH═CH—, —O(CH 2 ) 1-2 —, or —NH(CH 2 ) 1-2 —, then X is not phosphonic acid or phosphamic acid or a lower alkyl ester thereof; 
 f) when G is —CH 2 —O—, wherein the oxygen atom is attached to the ring bearing the T group, T is —(CH 2 ) 1-2 CH(R cc ), R cc  is —OH, —SH, —NH 2 , or —NH(Cl 4 ), R 1  and R 2  are each independently selected from chlorine, bromine, C 1-4  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl, then X is not phosphonic acid or phosphamic acid or a lower alkyl ester thereof; 
 g) V, Z, W, W′ are not all —H; and 
 h) when Z is -R z , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; 
 and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs. 
 
   
   
       80 . A compound of Formula III: 
     
       
         
         
             
             
         
       
     
     wherein:
 G is selected from the group consisting of —O—, —S—, —Se—, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C 1 -C 4  alkyl)-, or CH 2  linked to any of the preceding groups; 
 or G is R 50 -R 51  wherein;
 R 50 -R 51  together are —C(R 52 )═C(R 2 )— or alternatively R 50  and R 51  are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50  and R 51  is CH(R 53 )—, and when one of R 50  and R 51  is O or S, then R 53  is R 54 ; 
 
 R 54  is hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; 
 R 53  is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and 
 R 52  is selected from hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 
 T is selected from the group consisting of (CR a   2 ) k —, —CR b ═CR b —(CR a   2 )—CR a   2 ) n CR b ═CR b —, —(CR a   2 )—CR b ═CR b —(CR a   2 )—, —O(CR b   2 )(CR a   2 ) n —, —S(CR b   2 )(CR a   2 ) n —, —N(R c )(CR b   2 )(CR a   2 ) n —, —N(R b )C(O)(CR a   2 ) n , (CR a   2 ) m C(R b )(NR b R c )—, —C(O)(CR a   2 ) m , —(CR a   2 ) m C(O)—, —(CR b   2 )—O—(CR b   2 )—(CR a   2 ) p —, —(CR b   2 )—S—(CR b   2 )—(CR a   2 ) p —, —(CR b   2 )—N(R c )—(CR b   2 )—(CR a   2 ) p —, —(CR a   2 ) p —(CR b   2 )—O—(CR b   2 )—, —(CR a   2 ) p —(CR b   2 )—S—(CR b   2 )—, —(CR a   2 ) p —(CR b   2 )—N(R e )—(CR 2 )— and —(CH 2 ) p C(O)N(R b )C(R a   2 )—; 
 k is an integer from 0-4; 
 m is an integer from 0-3; 
 n is an integer from 0-2; 
 p is an integer from 0-1; 
 Each R a  is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4  alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4  alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4  alkyl, —NR b R c , optionally substituted —C 2 -C 4  alkenyl, and optionally substituted —C 2 -C 4  alkynyl; with the proviso that when one R a  is attached to C through an O, S, or N atom, then the other R a  attached to the same Cis a hydrogen, or attached via a carbon atom; 
 Each R b  is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4  alkyl; 
 Each R c  is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4  alkyl, optionally substituted —C(O)—C 1 -C 4  alkyl, and —C(O)H; 
 R 1  and R 2  are each independently selected from the group consisting of halogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted —S—C 1 -C 3  alkyl, optionally substituted —C 2 -C 4  alkenyl, optionally substituted —C 2 -C 4  alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3  alkyl, and cyano; 
 R 8  is selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted —S—C 1 -C 3  alkyl, optionally substituted —C 2 -C 4  alkenyl, optionally substituted —C 2 -C 4  alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3  alkyl, hydroxy, —(CR a   2 )aryl, —(CR a   2 )cycloalkyl, 
 
     —(CR a   2 )heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano;
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR a   2 ) m aryl, optionally substituted —(CR a   2 ) n cycloalkyl, optionally substituted —(CR a   2 ) m heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )_cycloalkyl, —C(R b )═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR a   2 ) n (CR b   2 )NR f R g , —OR d , —SR d , —S(═O)R e , —S(═O) 2 R e , —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ; 
 Each R d  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, optionally substituted —(CR b   2 ) n heterocycloalkyl, and —C(O)NR f R g ; 
 Each R e  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR a   2 ) n aryl, optionally substituted —(CR a   2 ) n cycloalkyl, and optionally substituted —(CR a   2 ) n heterocycloalkyl; 
 R f  and R g  are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, and optionally substituted —(CR b   2 ) n heterocycloalkyl, or R f  and R g  may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4  alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ; 
 Each R h  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, and optionally substituted —(CR b   2 ) n heterocycloalkyl; or 
 R 3  and R 8  are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3  and R 8  are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or 
 R 8  and G are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring comprising —CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═; 
 R 5  is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6  alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or 
 R 3  and R 5  are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3  and R 5  are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; 
 R 7  is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, —O—C 1 -C 4  alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, —CF 3 , —CHF 2 , —CH 2 F, cyano, —SH and —S-C 1 -C 4  alkyl; 
 X is P(O)(YR 11 )(Y′R 11 ); 
 Y and Y′ are each independently selected from the group consisting of —O—, and NR v —; 
 when Y and Y′ are both —O—, R 11  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z   2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; 
 when Y and Y′ are both —NR v —, then R 11  attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —C(O)OR y , —C(R x ) 2 C(O)OR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-C(O)OR y ; 
 when Y is —O— and Y 11  is NR v , then R 11  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, C(R z ) 2 OC(O)NR z   2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; and R 11  attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —COOR y , —C(R x ) 2 COOR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-COOR y ; 
 or when Y and Y′ are independently selected from —O— and —NR v —, then R 11  and R 11  together form a cyclic group comprising -alkyl-S—S-alkyl-, or together R 11  and R 11  are the group: 
 
     
       
         
         
             
             
         
       
     
     wherein:
 V, W, and W′ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or 
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, 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, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and said cyclic group is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus; or 
 together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon substituted by hydrogen 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 a Y attached to the phosphorus; or 
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 Z is selected from the group consisting of —CHR z OH, —CHR z OC(O)R y , —CHR z OC(S)R y , —CHR z OC(S)OR y , —CHR z OC(O)SR y , —CHR z OCO 2 R y , —OR z , —SR z , —CHR z N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR z   2 )OH, —CH(C≡CR z )OH, -R z , —NR z   2 , —OCOR y , —OCO 2 R y , —SCOR y , —SCO 2 R y , —NHCOR z , —NHCO 2 R y , —CH 2 NHaryl, —(CH 2 ) q —OR z , and —(CH 2 ) q —SR z ; 
 q is an integer 2 or 3; 
 Each R z  is selected from the group consisting of R y  and —H; 
 Each R y  is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; 
 Each R x  is independently selected from the group consisting of —H, and alkyl, or together R x  and R x  form a cycloalkyl group; 
 Each R v  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; 
 with the provisos that: 
 a) when G is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CH(OH)—, —C(O)— and —NR b —; T is -A-B- where A is selected from the group consisting of —NR b —, —O—, —CH 2 — and —S— and B is selected from the group consisting of a bond and substituted or unsubstituted C 1 -C 3  alkyl; R 3  is selected from the group consisting of halogen, trifluoromethyl, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy, substituted amide, sulfone, sulfonamide and C 3 -C 7  cycloalkyl, wherein said aryl, heteroaryl or cycloalkyl ring(s) are attached or fused to the aromatic; R 4  is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 1  and R 2  are each independently selected from the group consisting of halogen, and substituted or unsubstituted C 1 -C 4  alkyl; R 7  is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, —C 1 -C 4  alkyl, —O—C 1 -C 4  alkyl, —SH and —S—C 1 -C 4  alkyl; and R 5  is selected from the group consisting of hydroxyl, optionally substituted —OC 1 -C 6  alkyl, and —OC(O)R e ; then X is not —P(O)(OH) 2  or a lower alkyl ester or acyloxyalkyl ester thereof; 
 b) V, Z, W, W′ are not all —H; and 
 c) when Z is -R z , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; 
 and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs. 
 
   
   
       81 . The compound of  claim 78  having Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 A is selected from the group consisting of —NR i —, —O—, and —S—; 
 B is selected from the group consisting of —CR b —, and —N—; 
 R i  is selected from the group consisting of hydrogen, —C(O)C 1 -C 4  alkyl, and —C 1 -C 4  alkyl; 
 R b  is selected from the group consisting of hydrogen and optionally substituted —C 1 -C 4  alkyl; 
 G is selected from the group consisting of —O—, —S—, —Se—, —S(═O)—, —S(═O) 2 —, —CH 2 —, —CF 2 —, —CHF—, —C(O)—, —CH(OH)—, —NH—, and —N(C 1 -C 4  alkyl)-, or CH 2  linked to any of the preceding groups; 
 or G is R 50 -R 51  wherein; 
 R 50 -R 51  together are -(R 52 )═C(R 52 )— or alternatively R 50  and R 51  are independently selected from O, S and —CH(R 53 )—, with the provisos that at least one R 50  and R 51  is —CH(R 53 )—, and when one of R 50  and R 51  is O or S, then R 53  is R 54 ; 
 R 54  is hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; 
 R 53  is selected from hydrogen, halogen, hydroxyl, mercapto, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and 
 R 52  is selected from hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; 
 D is selected from the group consisting of a bond, —(CR a   2 )—, and —C(O)—; 
 Each R a  is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 4  alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4  alkyl, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —S—C 1 -C 4  alkyl, —NR b R c , optionally substituted —C 2 -C 4  alkenyl, and optionally substituted —C 2 -C 4  alkynyl; with the proviso that when one R a  is attached to C through an O, S, or N atom, then the other R a  attached to the same Cis a hydrogen, or attached via a carbon atom; 
 R 1  and R 2  are each independently selected from the group consisting of halogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted —S—C 1 -C 3  alkyl, optionally substituted —C 2 -C 4  alkenyl, optionally substituted —C 2 -C 4  alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3  alkyl, and cyano; R 8  is selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted —S—C 1 -C 3  alkyl, optionally substituted —C 2 -C 4  alkenyl, optionally substituted —C 2 -C 4  alkynyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, optionally substituted —O—C 1 -C 3  alkyl, hydroxy, —(CR a   2 )aryl, —(CR a   2 )cycloalkyl, —(CR a   2 )heterocycloalkyl, —C(O)aryl, —C(O)cycloalkyl, —C(O)heterocycloalkyl, —C(O)alkyl and cyano; 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, cyano, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR a   2 ) m aryl, optionally substituted —(CR a   2 ) n cycloalkyl, optionally substituted —(CR a   2 ) n heterocycloalkyl, —C(R b )═C(R b )-aryl, —C(R b )═C(R b )_cycloalkyl, —C(kb)═C(R b )-heterocycloalkyl, —C≡C(aryl), —C≡C(cycloalkyl), —C≡C(heterocycloalkyl), —(CR 2 ) n (CR b   2 )NR f R g , —OR d , SR d , S(═O)R e , —S(═O) 2 R e —S(═O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(═O) 2 R e , —N(R b )S(═O) 2 NR f R g , and —NR f R g ; 
 Each R d  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, optionally substituted —(CR b   2 ) n heterocycloalkyl, and —C(O)NR f R g ; 
 Each R c  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR a   2 ) n aryl, optionally substituted —(CR a   2 ) n cycloalkyl, and optionally substituted —(CR a   2 ) n heterocycloalkyl; 
 R f  and R g  are each independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, and optionally substituted —(CR b   2 ) n heterocycloalkyl, or R f  and R g  may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup selected from the group consisting of O, NR c , and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —C 1 -C 4  alkyl, —OR b , oxo, cyano, —CF 3 , —CHF 2 , —CH 2 F, optionally substituted phenyl, and —C(O)OR h ; 
 Each R h  is selected from the group consisting of optionally substituted —C 1 -C 12  alkyl, optionally substituted —C 2 -C 12  alkenyl, optionally substituted —C 2 -C 12  alkynyl, optionally substituted —(CR b   2 ) n aryl, optionally substituted —(CR b   2 ) n cycloalkyl, and optionally substituted —(CR b   2 ) n heterocycloalkyl; or 
 R 3  and R 8  are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3  and R 8  are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; or 
 R 8  and G are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring comprising —CH═CH—CH═, —N═CH—CH═, —CH═N—CH═ or —CH═CH—N═; 
 R 5  is selected from the group consisting of —OH, optionally substituted —OC 1 -C 6  alkyl, —OC(O)R e , —OC(O)OR h , —NHC(O)OR h , —OC(O)NH(R h ), —F, —NHC(O)R e , —NHS(═O)R e , —NHS(═O) 2 R e , —NHC(═S)NH(R h ), and —NHC(O)NH(R h ); or 
 R 3  and R 5  are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R 3  and R 5  are attached, including 0 to 2 heteroatoms independently selected from —NR h —, —O—, and —S—, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; 
 X is P(O)YR 11 Y′R 11 ; 
 Y and Y′ are each independently selected from the group consisting of —O—, and —NR v —; 
 when Y and Y′ are both —O—, R 11  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, C(R z ) 2 OC(O)NR z   2 , 
 
     —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy;
 when Y and Y′ are both —NR v —, then R″ attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —C(O)OR y , —C(R x ) 2 C(O)OR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-C(O)OR y ; 
 when Y is —O— and Y′ is NR v , then R 11  attached to —O— is independently selected from the group consisting of —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —C(R z ) 2 OC(O)NR z   2 , —NR z —C(O)—R y , —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; and R 11  attached to —NR v — is independently selected from the group consisting of —H, —[C(R z ) 2 ] q —COOR y , —C(R x ) 2 COOR y , —[C(R z ) 2 ] q —C(O)SR y , and -cycloalkylene-COOR y ; 
 or when Y and Y′ are independently selected from —O— and —NR v —, then R 11  and R 11  together form a cyclic group comprising -alkyl-S—S-alkyl-, or together R 11  and R 11  are the group: 
 
     
       
         
         
             
             
         
       
     
     wherein:
 V, W, and W′ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; 
 or together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydrogen, hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or 
 or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and said cyclic group is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus; 
 or together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms or carbon substituted by hydrogen 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 a Y attached to the phosphorus; 
 or together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 or together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon or carbon substituted by hydrogen, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 Z is selected from the group consisting of —CHR z OH, —CHR z OC(O)R y , —CHR z OC(S)R y , —CHR z OC(S)OR y , —CHR z OC(O)SR y , —CHR z OCO 2 R y , —OR z , —SR z , —CHR z N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR z   2 )OH, —CH(C≡CR z )OH, -R z , —NR z   2 , —OCOR y , —OCO 2 R y , —SCOR y , —SCO 2 R y , —NHCOR z , —NHCO 2 R y , —CH 2 NHaryl, —(CH 2 ) q —OR z , and —(CH 2 ) q —SR z ; 
 q is an integer 2 or 3; 
 Each R z  is selected from the group consisting of R y  and —H; 
 Each R y  is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; 
 Each R x  is independently selected from the group consisting of —H, and alkyl, or together R x  and R x  form a cycloalkyl group; 
 Each R v  is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; 
 with the provisos that: 
 a) V, Z, W, W′ are not all —H; and 
 b) when Z is -R z , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl; 
 and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs. 
 
   
   
       82 . The compound of  claim 81  wherein D is selected from the group consisting of a bond and —CH 2 —. 
   
   
       83 . The compound of  claim 81  wherein A is selected from the group consisting of —NH—, —NMe-, —O—, and —S—. 
   
   
       84 . The compound of  claim 81  wherein B is selected from the group consisting of —CH—, —CMe-, and —N—. 
   
   
       85 . The compound of  claim 80  wherein R 7  is selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxyl, and —O—CH 3 . 
   
   
       86 . The compound of any one of  claims 78 - 81 , wherein G is selected from the group consisting of —O—, —CH 2 —, and R 50 -R 51 . 
   
   
       87 . The compound of any one of  claims 78 - 80  wherein T is selected from the group consisting of —(CR a   2 ) n —, —O(CR b   2 )(CR a   2 ) p —, —N(R c )(CR b   2 )(CR a   2 ) p —, —S(CR b   2 )(CR a   2 ) p —, —N(R b )C(O)—, and —CH 2 C(R b )(NR c R b )—. 
   
   
       88 . The compound of  claim 87  wherein T is —O(CR b   2 )(CR a   2 ) p — or —NH(CR b   2 )(CR a   2 ) p —. 
   
   
       89 . The compound of any one of  claims 78 - 81  wherein R 1  and R 2  are the same and are selected from the group consisting of halogen, —C 1 -C 4  alkyl, —CF 3 , and cyano. 
   
   
       90 . The compound of  claim 89  wherein R 1  and R 2  are both alkyl. 
   
   
       91 . The compound of any one of  claims 78 - 81  wherein R 1  and R 2  are different and are selected from the group consisting of halogen, —C 1 -C 4  alkyl, —CF 3 , and cyano. 
   
   
       92 . The compound of any one of  claims 78 - 81  wherein R 4  is selected from the group consisting of hydrogen, halogen, —C 1 -C 4  alkyl, cyano and CF 3 . 
   
   
       93 . The compound of  claim 92  wherein R 4  is hydrogen. 
   
   
       94 . The compound of  claim 78  wherein R 6  and R 7  are independently selected from the group consisting of hydrogen, halogen, —C 1 -C 4  alkyl, cyano and CF 3 . 
   
   
       95 . The compound of  claim 94  wherein R 6  and R 7  are independently hydrogen, halogen, or methyl. 
   
   
       96 . The compound of  claim 78  wherein R 8  and R 9  are independently selected from the group consisting of hydrogen, halogen, —C 1 -C 4  alkyl, —C 1 -C 4  alkylaryl, C(O)aryl, cyano and CF 3 . 
   
   
       97 . The compound of  claim 96  wherein R 8  and R 9  are independently hydrogen, halogen, methyl, benzyl, and benzoate. 
   
   
       98 . The compound of any one of  claims 80 - 81  wherein R 8  is independently selected from the group consisting of hydrogen, halogen, —C 1 -C 4  alkyl, —C 1 -C 4  alkylaryl, C(O)aryl, cyano and CF 3 . 
   
   
       99 . The compound of  claim 98  wherein R 8  is independently hydrogen, halogen, methyl, benzyl, and benzoate. 
   
   
       100 . The compound of any one of  claims 78 - 81  wherein R 5  is selected from the group consisting of —OH, —OC(O)R e , —OC(O)OR h , —NHS(O) 2 R e , and —NHC(O)R c . 
   
   
       101 . The compound of  claim 100  wherein R 5  is —OH. 
   
   
       102 . The compound of any one of  claims 78 - 81  wherein R 3  is selected from the group consisting of halogen, optionally substituted —C 1 -C 6  alkyl, —CF 3 , cyano, —C(O)NR f R g , optionally substituted —(CR a   2 ) n aryl, —SO 2 NR f R g , and —SO 2 R e . 
   
   
       103 . The compound of  claim 102  wherein R 3  is isopropyl, benzyl or 4-fluorobenzyl. 
   
   
       104 . The compound of any one of  claims 78 - 81  wherein X is selected from the group consisting of —PO 3 H 2 , —P(O)[—OCR z   2 OC(O)R y ] 2 , —P(O)[—OCR z   2 OC(O)OR y ] 2 , —P(O)[—N(H)CR z   2 C(O)OR y ] 2 , —P(O)[—N(H)CR z   2 C(O)OR y ][—OR 11 ], —P(O)[—OCH(V) CH 2 CH 2 O—], —P(O)(OH)(OR), —P(O)(OR e )(OR e ), —P(O) [—OCR z   2 OC(O)R y ](OR e ), —P(O) [—OCR z   2 OC(O)OR y ](OR e ), —P(O)[—N(H)CR z   2 C(O)OR y ](OR e ), and —P(O)(OH)(NH 2 ) wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl. 
   
   
       105 . The compound of any of  claims 78 - 81 , wherein X is selected from the group consisting of —PO 3 H 2 , —P(O)[—OCH 2 OC(O)-t-butyl] 2 , —P(O)[—OCH 2 OC(O)O-i-propyl] 2 , —P(O)[—N(H)CH(CH 3 )C(O)O CH 2 CH 3 ] 2 , —P(O)[—N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 , —P(O)[—N(H)CH (CH 3 )C(O)OCH 2 CH 3 ][3,4-methylenedioxyphenyl], —P(O)[—N(H)C (CH 3 ) 2 C(O)OCH 2 CH 3 ][3,4-methylenedioxyphenyl], —P(O) [—OCH (3-chlorophenyl)CH 2 CH 2 O—], —P(O)[—OCH(pyrid-4-yl)CH 2 CH 2 O—], —P(O)(OH)(OCH 3 ), —P(O)(OH)(OCH 2 CH 3 ), —P(O)[—OCH 2 OC(O)-t-butyl](OCH 3 ), —P(O)[—OCH 2 OC(O)O-i-propyl](OCH 3 ), —P(O)[—OCH (CH 3 )OC(O)-t-butyl](OCH 3 ), —P(O)[—OCH(CH 3 )OC(O)O-i-propyl](OCH 3 ), —P(O)[—N(H)CH(CH 3 )C(O)OCH 2 CH 3 ](OCH 3 ), —P(O)[—N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ](0CH 3 ), —P(O)[—N(H)CH 2 C(O)OCH 2 CH 3 ](CH 3 ) and —P(O)(OH)(NH 2 ). 
   
   
       106 . The compound of any one of  claims 78 - 81  wherein Y and Y′ are each independently selected from —O— and —NR v —; and together R 11  and R 11  are the group: 
     
       
         
         
             
             
         
       
     
   
   
       107 . The compound of  claim 106  wherein V is aryl. 
   
   
       108 . The compound of  claim 107  wherein Z is hydrogen, W is hydrogen, and W′ is hydrogen. 
   
   
       109 . The compound of  claim 106  wherein V is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl and 3,5-dichlorophenyl. 
   
   
       110 . The compound of  claim 109  wherein the relative stereochemistry between the V-group substituent and T on the ring is cis. 
   
   
       111 . The compound of  claim 110  wherein said cis ring has R stereochemistry at the carbon where the V-group is attached. 
   
   
       112 . The compound of  claim 111  wherein said cis ring has S stereochemistry at the carbon where the V-group is attached. 
   
   
       113 . A compound selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and monomethyl esters thereof, and pharmaceutically acceptable salts and prodrugs of the compounds and monomethyl esters thereof. 
   
   
       114 . A compound selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof. 
   
   
       115 . A compound of any one of  claims 78 - 81  wherein said compound is in the form of a co-crystal. 
   
   
       116 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one of  claims 78 - 81 . 
   
   
       117 . The pharmaceutical composition of  claim 116  wherein said pharmaceutical composition in a form selected from the group consisting of a controlled release composition, transdermal patch, tablet, hard capsule, and soft capsule. 
   
   
       118 . The pharmaceutical composition of  claim 116  wherein said pharmaceutical composition comprises a crystalline form of said compound. 
   
   
       119 . The pharmaceutical composition of  claim 116  wherein said pharmaceutical composition comprises a salt form of said compound. 
   
   
       120 . The pharmaceutical composition of  claim 116  wherein said pharmaceutical composition is administered orally in a unit dose of about 0.375 μg/kg to 3.75 mg/kg. 
   
   
       121 . The pharmaceutical composition of  claim 116  wherein said pharmaceutical composition is administered orally in a total daily dose of about 0.375 μg/kg/day to about 3.75 mg/kg/day, equivalent of the free acid. 
   
   
       122 . A method of preventing or treating a metabolic disease comprising administering to an animal a pharmaceutically effective amount of a phosphonic acid-containing compound of any one of  claims 78 - 81  and  113 - 114  or a pharmaceutically acceptable salt thereof, or prodrugs thereof or pharmaceutically acceptable salts of said prodrugs, wherein said phosphonic acid containing compound binds to a thyroid receptor. 
   
   
       123 . The method of  claim 122  wherein said phosphonic acid containing-compound binds to a thyroid receptor with a Ki of ≦1 μM. 
   
   
       124 . The method of  claim 123  wherein said thyroid receptor is TRα1. 
   
   
       125 . The method of  claim 123  wherein said thyroid receptor is TRβ1. 
   
   
       126 . The method of  claim 124  wherein said phosphonic acid-containing compound binds to a thyroid receptor with a Ki of ≦100 nM. 
   
   
       127 . The method of  claim 126  wherein said thyroid receptor is TRα1. 
   
   
       128 . The method of  claim 126  wherein said thyroid receptor is TRβ1. 
   
   
       129 . The method of  claim 122  wherein said metabolic disease is selected from the group consisting of obesity, hypercholesterolemia, hyperlipidemia, atherosclerosis, coronary heart disease, and hypertension. 
   
   
       130 . The method of  claim 122  wherein said metabolic disease is selected from the group consisting of obesity, hypercholesterolemia, and hyperlipidemia. 
   
   
       131 . The method of  claim 130  wherein said metabolic disease is hypercholesterolemia. 
   
   
       132 . The method of  claim 122  wherein said metabolic disease is fatty liver/steatosis, NAFLD, or NASH. 
   
   
       133 . The method of  claim 122  wherein said metabolic disease is selected from the group consisting of impaired glucose tolerance, diabetes, and metabolic syndrome X. 
   
   
       134 . The method of  claim 122 , wherein said phosphonic acid-containing compound activates said thyroid receptor. 
   
   
       135 . The method of  claim 134  wherein said thyroid receptor is TRα1. 
   
   
       136 . The method of  claim 134  wherein said thyroid receptor is TRα 1 . 
   
   
       137 . The method of  claim 122  wherein said phosphonic acid containing-compound increases mRNA expression of a gene selected from the group consisting of LDL receptor, ACC, FAS, spot-14, CPT-1, CYP7A, apo AI, and mGPDH. 
   
   
       138 . A method of activating a thyroid receptor in an animal by administering a phosphonic acid-containing-compound of any one of  claims 78 - 81  and  113 - 114  wherein said activation results in the 50% or greater increase in the mRNA expression of a gene selected from the group consisting of LDL receptor, ACC, FAS, spot-14, CPT-1, CYP7A, apo AI, and mGPDH. 
   
   
       139 . The method of  claim 138  wherein said phosphonic acid-containing-compound binds to a thyroid receptor with a Ki of ≦1 μM. 
   
   
       140 . The method of  claim 139  wherein said phosphonic acid-containing-compound binds to a thyroid receptor with a Ki of ≦100 nM.