Novel bisamidate phosphonate prodrugs

A method of treating diabetes, by administering to an animal in need thereof a pharmaceutically effective amount of a compound of formula (I):

• 74
• wherein R5 is selected from the group consisting of:
• 75
• wherein:
• each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
• 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, —OR2, —SR2, —N3, —NHC(S)NR42, —NHAc, and null;
• each B and D are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R1l, —C(O)SR3, —SO2R11, —S(O)R3, —CN, —NR92, —OR3, —SR3, perhaloalkyl, halo, —NO2, and null, all except —H, —CN, perhaloalkyl, —NO2, and halo are optionally substituted;
• 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 null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;
• J is selected from the group consisting of —H and null;
• X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 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 X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted;
• with the proviso that X is not substituted with —COOR2, —SO3H, or —PO3R22;
• n is an integer from 1 to 3;
• 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;
• 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;
• each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
• each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —N17, —NR2OR19 and —SR17;
• R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R16 is selected from the group consisting of —(CR12R13)n—C(O)—R14, —H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
• each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
• and with the proviso that:
• 1) when G′ is N, then the respective A, B, D, or E is null;
• 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or null;
• 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
• and pharmaceutically acceptable salts thereof.

A method of inhibiting fructose-1,6-bisphosphatase in an animal in need thereof comprising the administration of a pharmaceutically effective amount of a compound of formula (I):

• 76
• wherein R5 is selected from the group consisting of:
• 77
• wherein:
• each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
• 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, —OR2, —SR2, —N3, —NHC(S)NR42, —NHAc, and null;
• 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, —SO2R3, —S(O)R3, —CN, —NR92, —OR3, —SR3, perhaloalkyl, halo, —NO2, and null, all except —H, —CN, perhaloalkyl, —NO2, and halo are optionally substituted;
• 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 null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;
• J is selected from the group consisting of —H and null;
• X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 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 X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted;
• with the proviso that X is not substituted with —COOR2, —SO3H, or —PO3R22;
• n is an integer from 1 to 3;
• 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;
• 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;
• each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
• each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17;
• R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R16 is selected from the group consisting of —(CR12R13)n—C(O)—R14, —H, lower alkyl lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
• each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
• and with the proviso that:
• 1) when G′ is N, then the respective A, B, D, or E is null;
• 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or null;
• 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
• and pharmaceutically acceptable salts thereof.

A method of lowering blood glucose, by administering to an animal in need thereof a pharmaceutically effective amount of compound of Formula (I):

• 78
• wherein R5 is selected from the group consisting of:
• 79
• wherein:
• each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
• 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, —OR2, —SR2, —N3, —NHC(S)NR42, —NHAc, and null;
• 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 null, all except —H, —CN, perhaloalkyl, —NO2, and halo are optionally substituted;
• 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 null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;
• J is selected from the group consisting of —H and null;
• X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 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 X is selected from the group consisting of —alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted;
• with the proviso that X is not substituted with —COOR2, —SO3H, or -PO3R22;
• n is an integer from 1 to 3;
• 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;
• 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;
• each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
• each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17;
• R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R16 is selected from the group consisting of —(CR12R13)n—C(O)—R14, —H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
• each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
• and with the proviso that:
• 1) when G′ is N, then the respective A, B, D, or E is null;
• 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or null;
• 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
• and pharmaceutically acceptable salts thereof.

A method of treating glycogen storage diseases, by administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I):

• 80
• wherein R5 is selected from the group consisting of:
• 81
• wherein:
• each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
• 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, —OR2, —SR2, —N3, —NHC(S)NR42, —NHAc, and null;
• 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 null, all except —H, —CN, perhaloalkyl, —NO2, and halo are optionally substituted;
• 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 null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;
• J is selected from the group consisting of —H and null;
• X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 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 X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted;
• with the proviso that X is not substituted with —COOR2, —SO3H, or —PO3R22;
• n is an integer from 1 to 3;
• 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 R4is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
• 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;
• each R12 and R3is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
• each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17;
• R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R16 is selected from the group consisting of —(CR12R13)n—C(O)—R14, —H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
• each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
• and with the proviso that:
• 1) when G′ is N, then the respective A, B, D, or E is null;
• 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or null;
• 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
• and pharmaceutically acceptable salts thereof.

A method of inhibiting a fructose-1,6-bisphosphatase in an animal in need thereof which comprises the administration of a pharmaceutically effective amount of a compound of formula (X):

• 92
• wherein:
• G″ is selected from the group consisting of —O— and —S—;
• A2 is selected from the group consisting of —H, —NR42, —NHAc, —OR2, —SR2, —C(O)NR42, halo, —COR11, —CN, perhaloalkyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• L2, E , and J are selected from the group consisting of —NR42, —NHAc, —NO2, —H, —OR2, —SR2, —C(O)NR42, halo, —COR11, —SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkyloxyalkyl, —SCN, —NHSO2R3, —SO2NR42, —CN, —S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C6 alkyl(OH), C1-C6 alkyl(SH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
• X2 is selected from the group consisting of —CR22—, —CF2—, —CR22—O—, —CR22—S—, —C(O)—O—, —C(O)—S—, —C(S)—O—, —CH2—C(O)—O— and —CR22—NR20—, and wherein in the atom attached to the phosphorus is a carbon atom;
• with the proviso that X2 is not substituted with —COOR2, —SO3H, or —PO3R22;
• n is an integer from 1 to 3;
• 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;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
• each R is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17
• R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R16 is selected from the group consisting of —(CR2R3)n—C(O)—R14, —H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• each R7is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
• each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
• R20 is selected from the group consisting of lower alkyl, —H, and —COR2;
• and
• pharmaceutically acceptable salts thereof.

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

• 93
• wherein:
• G″ is selected from the group consisting of —O— and —S—;
• A2 is selected from the group consisting of —H, —NR42, —NHAc, —OR2, —SR2, —C(O)NR42, halo, —COR11, —CN, perhaloalkyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
• L2, E2, and J2 are selected from the group consisting of —NR42, —NHAc, —NO2, —H, —OR2, —SR2, —C(O)NR42, halo, —COR11, —SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkyloxyalkyl, —SCN, —NHSO2R3, —SO2NR3, —CN, —S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C6 alkyl(OH), C1-C6 alkyl(SH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
• X2 is selected from the group consisting of —CR22—, —CF2—, —CR22—O—, —CR22—S—, —C(O)—O—, —C(O)—S—, —C(S)—O—, —CH2—C(O)—O— and —CR22—NR20—, and wherein in the atom attached to the phosphorus is a carbon atom;
• with the proviso that X2 is not substituted with —COOR2, —SO3H, or —PO3R22;
• n is an integer from 1 to 3;
• 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;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
• each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17;
• R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R17 is selected from the group consisting of —(CR2R13)—C(O)—R14, —H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
• each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
• R20 is selected from the group consisting of lower alkyl, —H, and —COR2;
• and
• pharmaceutically acceptable salts thereof.

A method of treating an animal for diabetes, comprising administering to said animal a therapeutically effective amount of a compound of formula XI:

• 99
• wherein:
• A3, E3, and L3 are selected from the group consisting of —NR82, —NO2, —H, —OR7, —SR7, —C(O)NR42, halo, —COR11, —SO2R3, guanidine, amidine, —NHSO2R3, —SO2NR42, —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A3 and L3 form a cyclic group, or together L3 and E3 form a cyclic group, or together E3 and J3 form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
• J3 is selected from the group consisting of —NR82, —NO2, —H, —OR7, —SR7, —C(O)NR42, halo, —C(O)R11, —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl;
• alicyclic, aryl, and aralkyl, or together with Y3 forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
• X3 is selected from the group consisting of —alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted;
• with the proviso that X3 is not substituted with —COOR2, —SO3H, or —PO3R22;
• Y3 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—R11, —CONHR3, NR22, and —OR3, all except H are optionally substituted;
• n is an integer from 1 to 3;
• 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;
• R7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R10;
• R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together they form a bidentate alkyl;
• 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;
• R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
• R11 is selected from the group consisting of alkyl, aryl, —NR22, and —OR2;
• each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
• each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17;
• R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R16 is selected from the group consisting of —(CR12R13)n—C(O)—R14, —H lower alkyl lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
• R18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
• each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
• and pharmaceutically acceptable salts thereof.