# US 6,294,672 B1 · Indole and azaindole inhibitors of Fructose-1,6-biphosphatase

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 6,294,672 B1
- Document ID: US6294672B1
- Status: Granted
- Kind: B1
- Application number: 09/479,384
- Filed: 2000-01-05
- Granted: 2001-09-25
- Earliest claimed: 1997-03-07
- Assignees: Metabasis Therapeutics, Inc.
- Inventors: K. Raja Reddy; Gerard R. Scarlato; Qun Dang; Mark D. Erion; Srinivas Rao Kasibhatla; M. Rami Reddy
- Web page: https://patentgrep.com/patent/US6294672B1

## CPC

- C07F 9/5728: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07F 9/65586: {at least one of the hetero rings does not contain nitrogen as ring hetero atom}
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention is directed towards novel azaindole compounds which bind to the AMP site and are potent FBPase inhibitors. The present invention also is directed towards the clinical use of the novel FBPase inhibitors as a method of treatment or prevention of diseases responsive to lowered blood glucose levels.

## Claims

### Claim 1

A compound of formula 1:
wherein:
A, E, and L are selected from the group consisting of —NR82, —NO2, —H, —OR7, —SR7, —C(O)NR42, halo, —COR11, —SO2R3, guanidine, amidine, —NHSO2R5, —SO2NR42, —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J 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 Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X is selected from the group consisting of alkylamino, alkyl(hydroxy), alkyl(carboxyl), alkyl(phosphonate), alkyl, alkenyl, alkynyl, alkyl(sulfonate), aryl, heteroaryl, carbonylalkyl, 1,1-dihaloalkyl, aminocarbonylamino, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alkylaminocarbonyl, alkylcarbonylamino, alicyclic, aralkyl, and alkylaryl, all optionally substituted; or together with Y forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted; or together with X forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
R1 is independently selected from the group consisting of —H, alkyl, aryl, alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, 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, or together R1 and R1 are -alkyl-S—S-alkyl to form a cyclic group, or together R1 and R1 are
wherein
V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9; or
together V and Z are connected to form a cyclic group containing 3-5 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
together V and W are connected to form a cyclic group containing 3 carbon atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
with the provisos that:
a) V, Z, W are not all —H; and
b) when Z is —R2, then at least one of V and W is not —H or —R9;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R6 is independently selected from the group consisting of —H, and lower alkyl;
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 said R8 groups form a bidentate alkyl;
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic;
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, —OH, —NH2 and —OR3; or
pharmaceutically acceptable prodrugs or salts thereof;
with the provisos that:
a) R is not lower alkyl of 1-4 carbon atoms;
b) X is not alkylamine and alkylaminoalkyl substituted with phosphonic esters or acids;
c) A, L, E, J, Y, and X together may only form 0-2 cyclic groups; and
d) X is not aryl and alkylaryl linked 1,4 through a 6-membered aromatic ring.

### Claim 2 (depends on 1)

The compounds of claim 1 wherein X is not substituted with a phosphonic acid or ester.

### Claim 3 (depends on 1)

The compounds of claim 1 wherein when X is alkyl and alkene, then A is —N(R8)2, and Y is not —H.

### Claim 4 (depends on 1)

The compounds of claim 1 wherein A, L and E are independently selected from the group consisting of —NR82, —H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and lower alkyl.

### Claim 5 (depends on 1)

The compounds of claim 1 wherein J is selected from the group consisting of —H, halogen, lower alkyl, lower hydroxyalkyl, —NR82, lower R82N-alkyl, lower haloalkyl, lower alkenyl, alicyclic, and aryl.

### Claim 6 (depends on 1)

The compounds of claim 1 wherein Y is selected from the group consisting of —H, aralkyl, aryl, alicyclic, and alkyl, all except —H may be optionally substituted.

### Claim 7 (depends on 1)

The compounds of claim 1 wherein X is selected from the group consisting of alkyl, alkynyl, alkoxyalkyl, alkylthio, aryl, heteroaryl, alkylaminocarbonyl, alkylcarbonylamino, 1,1-dihaloalkyl, carbonylalkyl, alkyl(OH), and alkyl(sulfonate).

### Claim 8 (depends on 7)

The compounds of claim 7 wherein X is selected from the group consisting of heteroaryl, alkylaminocarbonyl, and alkoxyalkyl.

### Claim 9 (depends on 1)

The compounds of claim 1 wherein each R1 is independently selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, —C(R2)2OC(O)R3, and —H.

### Claim 10 (depends on 1)

The compounds of claim 1 wherein R is H.

### Claim 11 (depends on 1)

The compounds of claim 1 wherein at least one R is aryl, or —C(R2)2-aryl.

### Claim 12 (depends on 1)

The compounds of claim 1 wherein together R1 and R1 are
V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9; or
together V and Z are connected to form a cyclic group containing 3-5 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
together V and W are connected to form a cyclic group containing 3 carbon atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
with the provisos that:
a) V, Z, W are not all —H; and
b) when Z is —R2, then at least one of V and W is not —H or —R9;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; and
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic.

### Claim 13 (depends on 12)

The compounds of claim 12 wherein V and W both form a 6-membered carbocyclic ring substituted with 0-4 groups, selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, and alkoxy; and Z is —R2.

### Claim 14 (depends on 12)

The compounds of claim 12 wherein V and W are hydrogen; and Z is selected from the group consisting of hydrogen, hydroxyalkyl, acyloxyalkyl, alkyloxyalkyl, and alkoxycarbonyloxy.

### Claim 15 (depends on 12)

The compounds of claim 12 wherein V and W are independently selected from the group consisting of hydrogen, optionally substituted aryl, and optionally substituted heteroaryl, with the proviso that at least one of V and W is optionally substituted aryl or optionally substituted heteroaryl.

### Claim 16 (depends on 1)

The compounds of claim 1 wherein
A, L and E are independently selected from the group consisting of —NR82, —H, hydroxy, halogen, lower alkoxy, lower alkyl, and lower perhaloalkyl;
X is selected from the group consisting of aryl, heteroaryl, alkoxyalkyl, alkyl, alkylthio, 1,1-dihaloalkyl, carbonylalkyl, alkyl(hydroxy), alkyl(sulfonate), alkylaminocarbonyl, and alkylcarbonylamino;
and each R4 and R7 is independently selected from the group consisting of —H and lower alkyl.

### Claim 17 (depends on 16)

The compounds of claim 16 wherein A, L, and E are independently selected from the group consisting of —H, lower alkyl, halogen, and —NR82;
J is selected from the group consisting of —H, halogen, haloalkyl, hydroxyalkyl, —R82 N-alkyl, lower alkyl, lower aryl, heterocyclic and alicyclic, or together with Y forms a cyclic group; and
X is selected from the group consisting of heteroaryl, alkylaminocarbonyl, 1,1-dihaloalkyl, and alkoxyalkyl.

### Claim 18 (depends on 17)

The compounds of claim 17 wherein A is selected from the group consisting of —H, —NH2, —F, and —CH3;
L is selected from the group consisting of —H, —F, —OCH3, and —CH3;
E is selected from the group consisting of —H, and —Cl;
J is selected from the group consisting of —H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, C1-C5 R82 N-alkyl C1-C5 alicyclic, and C1-C5 alkyl;
X is —CH2OCH2—, 2,5-furanyl; and
Y is lower alkyl.

### Claim 19

A method of treating an animal for diabetes mellitus, comprising
administering to said animal a therapeutically effective amount of a compound of formula (1):
wherein:
A, E, and L are selected from the group consisting of —NR82, —NO2, —H, —OR7, —SR7, —C(O)NR42, halo, —COR11, —SO2R3, guanidine, amidine, —NHSO2R5, —SO2NR42, —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J 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 Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X is selected from the group consisting of alkylamino, alkyl(hydroxy), alkyl(carboxyl), alkyl(phosphonate), alkyl, alkenyl, alkynyl, alkyl(sulfonate), aryl, heteroaryl, carbonylalkyl, 1,1-dihaloalkyl, aminocarbonylamino, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alkylaminocarbonyl, alkylcarbonylamino, alicyclic, aralkyl, and alkylaryl, all optionally substituted; or together with Y forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted; or together with X forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
R1 is independently selected from the group consisting of —H, alkyl, aryl, alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, 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, or together R1 and R1 are -alkyl-S—S-alkyl to form a cyclic group, or together R1 and R1 are
wherein
V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9; or
together V and Z are connected to form a cyclic group containing 3-5 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
together V and W are connected to form a cyclic group containing 3 carbon atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
with the provisos that:
a) V, Z, W are not all —H; and
b) when Z is —R2, then at least one of V and W is not —H or —R9;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R6 is independently selected from the group consisting of —H, and lower alkyl;
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 said R8 groups form a bidentate alkyl;
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic;
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, —OH, —NH2 and —OR3; or
pharmaceutically acceptable prodrugs or salts thereof.

### Claim 20

A method of lowering blood glucose levels in an animal in need thereof, comprising administering to said animal a pharmaceutically acceptable amount of a compound of formula (1):
wherein:
A, E, and L are selected from the group consisting of —NR82, —NO2, —H, —OR7, —SR7, —C(O)NR42, halo, —COR11, —SO2R3, guanidine, amidine, —NHSO2R5, —SO2NR42, —CN, sulfoxide perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J 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 Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X is selected from the group consisting of alkylamino, alkyl(hydroxy), alkyl(carboxyl), alkyl(phosphonate), alkyl, alkenyl, alkynyl, alkyl(sulfonate), aryl, heteroaryl, carbonylalkyl, 1,1-dihaloalkyl, aminocarbonylamino, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alkylaminocarbonyl, alkylcarbonylamino, alicyclic, aralkyl, and alkylaryl, all optionally substituted; or together with Y forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted; or together with X forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
R1 is independently selected from the group consisting of —H, alkyl, aryl, alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, 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, or together R1 and R1 are -alkyl-S—S-alkyl to form a cyclic group, or together R1 and R1 are
wherein
V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9; or
together V and Z are connected to form a cyclic group containing 3-5 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
together V and W are connected to form a cyclic group containing 3 carbon atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
with the provisos that:
a) V, Z, W are not all —H; and
b) when Z is —R2, then at least one of V and W is not —H or —R9;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R6 is independently selected from the group consisting of —H, and lower alkyl;
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 said R8 groups form a bidentate alkyl;
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic;
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, —OH, —NH2 and —OR3; or
pharmaceutically acceptable prodrugs or salts thereof.

### Claim 21

A method of inhibiting FBPase at the AMP site in patients in need thereof, comprising administering to said patients a compound of formula (1):
wherein:
A, E, and L are selected from the group consisting of —NR82, —NO2, —H, —OR7, —SR7, —C(O)NR42, halo, —COR10, —SO2R3, guanidine, amidine, —NHSO2R5, —SO2NR42, —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J is selected from the group consisting of —NR82, —NO2, —H, —OR7, —SR7, —C(O)NR42, halo, —C(O)R10, —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl, or together with Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X is selected from the group consisting of alkylamino, alkyl(hydroxy), alkyl(carboxyl), alkyl(phosphonate), alkyl, alkenyl, alkynyl, alkyl(sulfonate), aryl, heteroaryl, carbonylalkyl, 1,1-dihaloalkyl, aminocarbonylamino, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alkylaminocarbonyl, alkylcarbonylamino, alicyclic, aralkyl, and alkylaryl, all optionally substituted; or together with Y forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted; or together with X forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
R1 is independently selected from the group consisting of —H, alkyl, aryl, alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, 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, or together R1 and R1 are -alkyl-S—S-alkyl to form a cyclic group, or together R1 and R1 are
wherein
V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9; or
together V and Z are connected to form a cyclic group containing 3-5 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
together V and W are connected to form a cyclic group containing 3 carbon atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
with the provisos that:
a) V, Z, W are not all —H; and
b) when Z is —R2, then at least one of V and W is not —H or —R9;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R6 is independently selected from the group consisting of —H, and lower alkyl;
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 said R8 groups form a bidentate alkyl;
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic;
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, —OH, —NH2 and —OR3; or
pharmaceutically acceptable prodrugs or salts thereof.

### Claim 22

A method of inhibiting gluconeogenesis in an animal in need thereof, comprising administering to said animal an FBPase inhibitory amount of a compound of formula (1):
wherein:
A, E, and L are selected from the group consisting of —NR2, —NO2, —H, —OR7, —SR7, —C(O)NR42, halo, —COR11, —SO2R3, guanidine, amidine, —NHSO2R5, —SO2NR42, —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J 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 Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X is selected from the group consisting of alkylamino, alkyl(hydroxy), alkyl(carboxyl), alkyl(phosphonate), alkyl, alkenyl, alkynyl, alkyl(sulfonate), aryl, heteroaryl, carbonylalkyl, 1,1-dihaloalkyl, aminocarbonylamino, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alkylaminocarbonyl, alkylcarbonylamino, alicyclic, aralkyl, and alkylaryl, all optionally substituted; or together with Y forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted; or together with X forms a cyclic group including aryl, cyclic alkyl, and heterocyclic;
R1 is independently selected from the group consisting of —H, alkyl, aryl, alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, 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, or together R1 and R1 are -alkyl-S—S-alkyl to form a cyclic group, or together R1 and R1 are
wherein
V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9; or
together V and Z are connected to form a cyclic group containing 3-5 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
together V and W are connected to form a cyclic group containing 3 carbon atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(C═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
with the provisos that:
a) V, Z, W are not all —H; and
b) when Z is —R2, then at least one of V and W is not —H or —R9;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R6 is independently selected from the group consisting of —H, and lower alkyl;
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 said R8 groups form a bidentate alkyl;
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic;
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, —OH, —NH2 and —OR3; or
pharmaceutically acceptable prodrugs or salts thereof.