Heteroaromatic compounds containing a phosphonate group that are inhibitors of fructose-1,6-bisphosphatase

A method of treating a disease or condition responsive to inhibition of gluconeogenesis or responsive to lowered blood glucose levels in an animal which comprises administering to an animal suffering from a disease or condition responsive to inhibition of gluconeogenesis or responsive to lowered blood glucose levels a pharmaceutically effective amount of a FBPase inhibitor of formula (I):

• wherein R5 is selected from the group consisting of:
• wherein:
• each G is independently selected from the group consisting of C, N, O, S and Se, and wherein no more than one G is O, S, or Se;
• each G′ is independently selected from the group consisting of C and N and wherein no more than two G′ groups are N;
• A is selected from the group consisting of —H, —NR4, -CONR42, —CO2R3, halo, —S(O)R3—SO2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH2OH, —CH2NR42, —CH2CN, —CN, —C(S)NH2, —OR3, —SR3, —N3, —NHC(S)NR42, —NHAc, and nothing;
• each B and D are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R11, —C(O)SR3, —SO2R11, —S(O)R3, —CN, —NR92, —OR3, —SR3, perhaloalkyl, halo, —NO2, and nothing, all except —H, —CN, perhaloalkyl, —NO2, and halo are substituted or unsubstituted;
• E is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C(O)OR3, —CONR42, —CN, —NR92, —NO2, —OR3, —SR3, perhaloalkyl, halo, and nothing, all except —H, —CN, perhaloalkyl, and halo are substituted or unsubstituted;
• J is selected from the group consisting of —H and nothing;
• X is a substituted or unsubstituted linking group that links R5 to the phosphorus atom via 2-4 atoms, wherein 0-1 atoms are heteroatoms selected from N, O, and S and the remaining atoms are carbon, except that if X is urea or carbamate there are 2 heteroatoms, measured by the shortest path between R5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein there is no N in the linking group unless it is connected directly to a carbonyl or in the ring of a heterocycle;
• and wherein X is not a 2 carbon atom -alkyl- or -alkenyl group;
• with the proviso that X is not substituted with —COOR2, —SO3R1, or —PO3R12;
• Y is independently selected from the group consisting of —O—, and —NR6—;
• when Y is —O—, then R1 attached to —O— is independently selected from the group consisting of —H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, substituted or unsubstituted-alkylaryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—OC(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alkyl-S—C(O)R3, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,
• when Y is —NR6—, then R1 attached to —NR6— is independently selected from the group consisting of —H, —[C(R2)2]q—COOR3, —C(R4)2COOR3, —[C(R2)2]q—C(O)SR3, and —cycloalkylene-COOR3;
• or when either Y is independently selected from —O— and —NR6—, then together R1 and R1 are R1 are -alkyl-S—S-alkyl- to form a cyclic group, or together R1 and R1 are
• wherein
• V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
• together V and W are connected via an additional 3 carbon atoms to form a substituted or unsubstituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
• 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, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR2, and —(CH2)p—SR2;
• p is an integer 2 or 3;
• q is an integer 1 or 2;
• with the provisos that:
• a) V, Z, W, W′ are not all —H;
• and
• b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
• R2 is selected from the group consisting of R1 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
• each R4 is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
• R6 is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• each R9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl, group;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• and with the provisos that:
• 1) when G′ is N, then the respective A, B, D, or E is nothing;
• 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or nothing;
• 3) when R5 is a six-membered ring, then X is not any 2 atom linker, a substituted or unsubstituted -alkyl-, a substituted or unsubstituted -alkenyl-, a substituted or unsubstituted -alkyloxy-, or a substituted or unsubstituted -alkylthio-;
• 4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
• 5) R1 is not unsubstituted C1-C10 alkyl;
• 6) when X is not an -aryl- group, then R5is not substituted with two or more aryl groups;
• or pharmaceutically acceptable prodrugs or salts thereof.

A method of treating diabetes, by administering to a patient in need thereof a pharmaceutically effective amount of an FBPase inhibitor of Formula I:

• wherein R5 is selected from the group consisting of:
• wherein:
• each G is independently selected from the group consisting of C, N, O, S and Se, and wherein no more than one G is O, S, or Se;
• each G′ is independently selected from the group consisting of C and N and wherein no more than two G′ groups are N;
• A is selected from the group consisting of —H, —NR42, —CONR42, —CO2R3, halo, —S(O)R3, —SO2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH2OH, —CH2NR42 —CH2CN, —CN, —C(S)NH2, —OR3, —SR3, —N3, —NHC(S)NR42, —NHAc, and nothing;
• each B and D are independently selected from the group consisting of —H, alky, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R11, —C(O)SR3, —SO2R11, —S(O)R3, —CN, —NR92, —OR3, —SR3, perhaloalkyl, halo, —NO2, and nothing, all except —H, —CN, perhaloalkyl, —NO2, and halo are substituted or unsubstituted;
• E is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C(O)OR3, —CONR42, —CN, —NR92, —NO2, —OR3, —SR3, perhaloalkyl, halo, and nothing, all except —H, —CN, perhaloalkyl, and halo are substituted or unsubstituted;
• J is selected from the group consisting of —H and nothing;
• X is a substituted or unsubstituted linking group that links R5 to the phosphorus atom via 2-4 atoms, wherein 0-1 atoms are heteroatoms selected from N, O, and S and the remaining atoms are carbon, except that if X is urea or carbamate there are 2 heteroatoms, measured by the shortest path between R5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein there is no N in the linking group unless it is connected directly to a carbonyl or in the ring of a heterocycle;
• and wherein X is not a 2 carbon atom -alkyl- or -alkenyl- group;
• with the proviso that X is not substituted with —COOR2, —SO3R1, or —PO3R12;
• Y is independently selected from the group consisting of —O—, and —NR6—;
• when Y is —O—, then R1 attached to —O— is independently selected from the group consisting of —H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, substituted or unsubstituted-alkylaryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—C(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alkyl-S—C(O)R3, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,
• when Y is —NR6—, then R1 attached to —NR6 is independently selected from the group consisting of —H, —[C(R2)2]q, —COOR3, —C(R4)2COOR3, —[C(R2)2]q—C(O)SR3, and -cycloalkylene-COOR3;
• or when either Y is independently selected from —O— and —NR6, then together R1 and R1 are -alkyl-S—S-alkyl- to form a cyclic group, or together R1 and R1 are
• wherein
• V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
• together V and W are connected via an additional 3 carbon atoms to form a substituted or unsubstituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
• 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, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR2, and —(CH2)p—SR2;
• p is an integer 2 or 3;
• q is an integer 1 or 2;
• with the provisos that:
• a) V, Z, W, W′ are not all —H;
• and
• b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl aralkyl, or alicyclic;
• R2 is selected from the group consisting of R3and —H;
• R3 is selected from the group consisting of alky, aryl, alicyclic, and aralkyl;
• each R4 is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
• R6 is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• each R9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• and with the provisos that:
• 1) when G′ is N, then the respective A, B, D, or E is nothing;
• 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or nothing;
• 3) when R5 is a six-membered ring, then X is not any 2 atom linker, a substituted or unsubstituted -alkyl-, a substituted or unsubstituted -alkenyl-, a substituted or unsubstituted -alkyloxy-, or a substituted or unsubstituted -alkylthio-;
• 4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
• 5) R1 is not unsubstituted C1-C10 alkyl;
• 6) when X is not an -aryl- group, then R5 is not substituted with two or more aryl groups;
• or pharmaceutically acceptable prodrugs or salts thereof.

A method of treating glycogen storage diseases, by administering to a patient in need thereof a pharmaceutically effective amount of an FBPase inhibitor of formula I:

• wherein R5 is selected from the group consisting of:
• wherein:
• each G is independently selected from the group consisting of C, N, O, S and Se, and wherein no more than one G is O, S, or Se;
• each G′ is independently selected from the group consisting of C and N and wherein no more than two G′ groups are N;
• A is selected from the group consisting of —H, —NR42, —CONR42, —CO2R3, halo, —S(O)R3, —SO2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH2OH, —CH2NR42, —CH2CN, —CN, —C(S)NH2, —OR3, —SR3, —N3, —NHC(S)NR42, —NHAc, and nothing;
• each B and D are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R11, —C(O)SR3, —SO2R11, —S(O)R3, —CN, —NR92, —OR3, —SR3, perhaloalkyl, halo, -NO2, and nothing, all except —H, —CN, perhaloalkyl, —NO2, and halo are substituted or unsubstituted;
• E is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C(O)OR3, —CONR42, —CN, —NR92, —NO2, —OR3, —SR3, perhaloalkyl, halo, and nothing, all except —H, —CN, perhaloalkyl, and halo are substituted or unsubstituted;
• J is selected from the group consisting of —H and nothing;
• X is a substituted or unsubstituted linking group that links R5 to the phosphorus atom via 2-4 atoms, wherein 0-1 atoms are heteroatoms selected from N, O, and S and the remaining atoms are carbon, except that if X is urea or carbamate there are 2 heteroatoms, measured by the shortest path between R5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein there is no N in the linking group unless it is connected directly to a carbonyl or in the ring of a heterocycle;
• and wherein X is not a 2 carbon atom -alkyl- or -alkenyl- group;
• with the proviso that X is not substituted with —COOR2, —SO3R1, or —PO3R12;
• Y is independently selected from the group consisting of —O—, and —NR6—;
• when Y is —O—, then R1 attached to —O— is independently selected from the group consisting of —H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, substituted or unsubstituted-alkylaryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—OC(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alkyl-S—C(O)R3, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,
• when Y is —NR6—, then R1 attached to —NR6— is independently selected from the group consisting of —H, —[C(R2)2]q—COOR3, —C(R4)2COOR3, —[C(R2)2]q—C(O)SR3, and -cycloalkylene-COOR3;
• or when either Y is independently selected from —O— and —NR6—, then together R1 and R1 are -alkyl-S—S-alkyl- to form a cyclic group, or together R1 and R1 are
• wherein
• V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
• together V and W are connected via an additional 3 carbon atoms to form a substituted or unsubstituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
• 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, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3—CH2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—R2, and —(CH2)p—SR2;
• p is an integer 2 or 3;
• q is an integer 1 or 2;
• with the provisos that:
• a) V, Z, W, W′ are not all —H;
• and
• b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl aralkyl, or alicyclic;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
• each R4 is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
• R6 is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• each R9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• and with the provisos that:
• 1) when G′ is N, then the respective A, B, D, or E is nothing;
• 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or nothing;
• 3) when R5 is a six-membered ring, then X is not any 2 atom linker, a substituted or unsubstituted -alkyl-, a substituted or unsubstituted-alkenyl-, a substituted or unsubstituted -alkyloxy-, or a substituted or unsubstituted -alkylthio-;
• 4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
• 5) R1 is not unsubstituted C1-C10 alkyl;
• 6) when X is not an -aryl- group, then R5 is not substituted with two or more aryl groups;
• or pharmaceutically acceptable prodrugs or salts thereof.

The compound of formula (X):

• wherein:
• G″ is selected from the group consisting of—O— and —S—;
• A2, L2, E2, and J2 are selected from the group consisting of —NR42, —NO2, —H, —OR2, —SR2, —C(O)NR42, halo, —COR11, —SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO2R9, —SO2NR42, —CN, —S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
• X2 is a substituted or unsubstituted linking group that links R5 to the phosphorus atom via 1-3 atoms, wherein 0-1 atoms are heteroatoms selected from N, O, and S and the remaining atoms are carbon, and wherein in the atom attached to the phosphorus is a carbon atom;
• with the proviso that X2 is not substituted with —COOR2, —SO3R1, or —PO3R12;
• Y is independently selected from the group consisting of—O—, and —NR6—;
• when Y is —O—, then R1 attached to —O— is independently selected from the group consisting of —H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, substituted or unsubstituted-alkylaryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—C(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alkyl-S—C(O)R, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,
• when Y is —NR6—, then R1 attached to —NR6— is independently selected from the group consisting of —H, —[C(R2)2]q—COOR3, —C(R4)2COOR3, —[C(R2)2]q—C(O)SR3, and -cycloalkylene-COOR3;
• or when either Y is independently selected from —O— and NR6—, then together R1 and R1 are -alkyl-S—S-alkyl- to form a cyclic group, or together R1 and R1 are
• wherein
• V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
• together V and W are connected via an additional 3 carbon atoms to form a substituted or unsubstituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
• 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, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3—CHR2OCO2R3—OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR 22)OH, —CH(C≡CR2)OH, —R2, —NR22—OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR2, and —(CH2)p—SR2;
• p is an integer 2 or 3;
• q is an integer 1 or 2;
• with the provisos that:
• a) V, Z, W, W′ are not all —H;
• and
• b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl aralkyl, or alicyclic;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
• each R4 is independently selected from the group consisting of —H, alkyl, or together R4 and R4 form a cyclic alkyl;
• R6 is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• each R9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• or pharmaceutically acceptable prodrugs or salts thereof.

A method of treating a disease or condition responsive to inhibition of gluconeogenesis or responsive to lowered blood glucose levels in an animal which comprises administering to an animal suffering from a disease or condition responsive to inhibition of gluconeogenesis or responsive to lowered blood glucose levels a pharmaceutically effective amount of a FBPase inhibitor of formula (X):

• wherein:
• G″ is selected from the group consisting of —O— and —S—;
• A2, L2, E2, and J2 are selected from the group consisting of —NR42, —NO2—H, —OR2, —SR2, —C(O)NR42, halo, —COR11, —SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO2R9, —SO2NR42, —CN, —S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
• X2 is a substituted or unsubstituted linking group that links R5 to the phosphorus atom via 1-3 atoms, wherein 0-1 atoms are heteroatoms selected from N, O, and S and the remaining atoms are carbon, and wherein in the atom attached to the phosphorus is a carbon atom;
• with the proviso that X2 is not substituted with —COOR2, —SO3R1, or —PO3R12;
• Y is independently selected from the group consisting of —O—, and —NR6—;
• when Y is —O—, then R1 attached to —O— is independently selected from the group consisting of —H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, substituted or unsubstituted-alkylaryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—C(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alkyl-S—C(O)R3, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,
• when Y is —NR6—, then R1 attached to —NR6— is independently selected from the group consisting of —H, —[C(R2)2]q—COOR3, —C(R4)2COOR3, —[C(R2)2]q—C(O)SR3, and -cycloalkylene-COOR3;
• or when either Y is independently selected from —O— and NR6, then together R1 and R1 are -alkyl-S—S-alkyl- to form a cyclic group, or together R1 and R1 are
• wherein
• V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
• together V and W are connected via an additional 3 carbon atoms to form a substituted or unsubstituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
• 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, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —COR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR2, and —(CH2)p—SR2;
• p is an integer 2 or 3;
• q is an integer 1 or 2;
• with the provisos that:
• a) V, Z, W, W′ are not all —H;
• and
• b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
• each R4 is independently selected from the group consisting of —H, alkyl, or together R4 and R4 form a cyclic alkyl;
• R6 is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• each R9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• or pharmaceutically acceptable prodrugs or salts thereof.

A method of treating diabetes, by administering to a patient in need thereof a pharmaceutically effective amount of an FBPase inhibitor of formula (X):

• wherein:
• G″ is selected from the group consisting of —O— and —S—.
• A2, L2, E2, and J2 are selected from the group consisting of—NR42, —NO2, —H, —OR2, —SR2, —C(O)NR42, halo, —COR11, —SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO2R9, —SO2NR42, —CN, —S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
• X2 is a substituted or unsubstituted linking group that links R5 to the phosphorus atom via 1-3 atoms, wherein 0-1 atoms are heteroatoms selected from N, O, and S and the remaining atoms are carbon, and wherein in the atom attached to the phosphorus is a carbon atom;
• with the proviso that X2 is not substituted with —COOR2, —SO3R1, or —PO3R12;
• Y is independently selected from the group consisting of —O—, and —NR6—;
• when Y is —O—, then R1 attached to —O— is independently selected from the group consisting of —H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, substituted or unsubstituted-alkylaryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—C(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, —alkyl-S—C(O)R3, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,
• when Y is —NR6—, then R1 attached to —NR6— is independently selected from the group consisting of —H, —[C(R2)2]q—COOR3, —C(R4)2COOR3, —[C(R2)2]q—C(O)SR3, and -cycloalkylene-COOR3;
• or when either Y is independently selected from —O— and —NR6—, then together R1 and R1 are -alkyl-S—S-alkyl- to form a cyclic group, or together R1 and R1 are
• wherein
• V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
• together V and W are connected via an additional 3 carbon atoms to form a substituted or unsubstituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
• 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, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3—CH2NHaryl, —(CH2)p—OR2, and —(CH2)p—SR2;
• p is an integer 2 or 3;
• q is an integer 1 or 2;
• with the provisos that:
• a) V, Z, W, W′ are not all —H;
• and
• b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
• each R4 is independently selected from the group consisting of —H, alkyl, or together R4 and R4 form a cyclic alkyl;
• R6 is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• each R9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• or
• pharmaceutically acceptable prodrugs or salts thereof.

A method of treating glycogen storage diseases, by administering to a patient in need thereof a pharmaceutically effective amount of an FBPase inhibitor of formula (X):

• wherein:
• G″ is selected from the group consisting of —O— and —S—;
• A2, L2, E2, and J2 are selected from the group consisting of —NR42, —NO2, —H, —OR2, —SR2, —C(O)NR42, halo, —COR11, —SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO2R9, —SO2NR42, —CN, —S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
• X2 is a substituted or unsubstituted linking group that links R5 to the phosphorus atom via 1-3 atoms, wherein 0-1 atoms are heteroatoms selected from N, O, and S and the remaining atoms are carbon, and wherein in the atom attached to the phosphorus is a carbon atom;
• with the proviso that X2 is not substituted with —COOR2, —SO3R1, or —PO3R12;
• Y is independently selected from the group consisting of —O—, and —NR6—;
• when Y is —O—, then R1 attached to —O— is independently selected from the group consisting of —H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, substituted or unsubstituted-alkylaryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—OC(O)—R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alkyl-S—C(O)R3, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,
• when Y is —NR6—, then R1 attached to —NR6— is independently selected from the group consisting of —H, —[C(R2)2]q—COOR3, —C(R4)2COOR3, —[C(R2)2]q—C(O)SR3, and -cycloalkylene-COOR3;
• or when either Y is independently selected from —O— and —NR6—, then together R1 and R1 are -alkyl-S—S-alkyl- to form a cyclic group, or together R1 and R1 are
• wherein
• V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus;
• or
• together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
• together V and W are connected via an additional 3 carbon atoms to form a substituted or unsubstituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
• 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, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
• Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —OR2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR2, and —(CH2)p—SR2;
• p is an integer 2 or 3;
• q is an integer 1 or 2;
• with the provisos that:
• a) V, Z, W, W′ are not all —H;
• and
• b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
• each R4 is independently selected from the group consisting of —H, alkyl, or together R4 and R4 form a cyclic alkyl;
• R6 is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• each R9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• or pharmaceutically acceptable prodrugs or salts thereof.