Trisubstituted nitrogen modulators of tyrosine phosphatases

• US 20060135773A1
• Filed: 06/17/2005
• Published: 06/22/2006
• Est. Priority Date: 06/17/2004
• Status: Abandoned Application

• Current Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.), Cengent Therapeutics, Inc. (Long-E International, Inc.)
• Original Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.)
• Inventors: Yalamoori, Venkatachalapathi V., Tsai, Chung Ying, Wang, Jing, Shenderovich, Mark, Wu, Feiyue, Semple, Joseph E., Nutt, Ruth F., Mylvaganam, Shankari, Rideout, Darryl, Loweth, Colin J.
• Application Number:
  US11/156,230
• Publication Number:
  US 20060135773A1
• Time in Patent Office: Days
• US Class Current: 546/22
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 311/16 : having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/18 : to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07C 311/19 : to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 311/29 : having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/51 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 317/32 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07D 207/337 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07F 9/3882 : Arylalkanephosphonic acids C07F9/3839 takes precedence
• CPC Class Codes: C07F 9/4056 : Esters of arylalkanephosphonic acids C07F9/4025 takes precedence
• CPC Class Codes: C07F 9/4075 : Esters with hydroxyalkyl compounds
• CPC Class Codes: C07F 9/4426 : Amides of arylalkanephosphonic acids
• CPC Class Codes: C07F 9/4465 : of aliphatic amines
• CPC Class Codes: C07F 9/59 : Hydrogenated pyridine rings
• CPC Class Codes: C07F 9/6524 : having four or more nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C07F 9/65517 : condensed with carbocyclic rings or carbocyclic ring systems

Abstract

Compounds, compositions and methods are provided for modulating the activity of protein tyrosine phosphatases, including PTP-1B. In one embodiment, the compounds are N,N-dibenzylarylsulfonamides.

Claims

1. A compound that has the formula I:

or a pharmaceutically acceptable derivative thereof, wherein;

L₁, L₂ and L₃ are independently selected from;

N—

C single bond (i.e. G₁, G₂, or G₃ are directly bonded to N by a single bond), alkylene, alkenylene, alkynylene, cycloalkylene, oxocycloalkylene, amidocycloalkylene, heterocyclylene, heteroarylene, C═

O, sulfonyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, amido, carboxamido, alkylamido, alkylcarboxamido, and alkoxyoxo; and

where each of the above substituents are unsubstituted or substituted with one or more substituents, in one embodiment, one, two, or three substituents, each independently selected from D¹, where D¹ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, amido, cyano, cyanoalkenyl, amidoalkyl, amidoalkenyl, and oxo;

G₁, G₂, and G₃ are independently selected from;

(i) alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl, alkarylalkyl, alkenylaryl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, amido, alkylamino, alkylaminoaryl, arylamino, aminoalkyl, aminoaryl, alkoxy, alkoxyaryl, aryloxy, alkylamido, alkylcarboxamido, arylcarboxamido, alkoxyoxo, biaryl, alkoxyoxoaryl, amidocycloalkyl, carboxyalkylaryl, carboxyaryl, carboxyamidoaryl, carboxamido, cyanoalkyl, cyanoalkenyl, cyanobiaryl, cycloalkyl, cycloalkyloxo, cycloalkylaminoaryl, haloalkyl, haloalkylaryl, haloaryl, heterocyclyl, heteroaryl, hydroxyalkylaryl, and sulfonyl; and

(ii) G₁ and G₂ can be linked together to form a cycloalkyl, oxocycloalkyl, cycloalkyloxo, amidocycloalkyl, cycloalkylamido, alkenylaryl, amidoalkenylaryl, and the following groups,

where J₁, J₂, J₃, and J₄ are selected from H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, amido, cyano, cyanoalkenyl, amidoalkyl, amidoalkenyl, oxo, and CH═

C(CN)C(O)NH; and

where each of the above substituents are unsubstituted or substituted with one or more substituents, in one embodiment, one, two, or three substituents, each independently selected from M¹, where M¹ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkoxyoxo, alkylthia, amino, amido, arylamino, aryloxy, alkylamino, alkylsulfonyl, alkylcarboxyalkylphosphonato, arylcarboxamido, carboxy, carboxyoxo, carboxyalkyl, carboxyalkyloxa, carboxyalkenyl, carboxyamido, carboxyhydroxyalkyl, cycloalkyl, amido, cyano, cyanoalkenyl, cyanoaryl, amidoalkyl, amidoalkenyl, halo, haloalkyl, haloalkylsulfonyl, heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, hydroxy, hydroxyalkyl, hydroxyamino, hydroxyimino, heteroarylalkyloxa, nitro, phosphonato, phosphonatoalkyl, and phosphonatohaloalkyl.

2. The compound of claim 1, wherein:

L₁, L₂ and L₃ are independently selected from;

N—

C single bond (i.e. G1, G2, or G3 are directly bonded to N by a single bond), (CRR1)_m, CF₂, CF₂CF₂, C(═

O), C(═

O)C(═

O), C(═

O)(CRR1)_m, (CRR1)_mC(═

O)(CRR1)_m, C(═

O)O(CRR1)_m, (CRR1)_mC(═

O)O, N(R), —

C(═

O)N(R)N(R1), N(R)SO₂N(R1), C(═

O)N(R), N(R)C(═

O)N(R1), O, OC(═

O)N(R), P(═

O)(OR), P(═

O)(NR), P(═

S)(OR), P(═

S)(NR), SO₂, S(═

O)_n(CRR1)_m, (CRR1)_mS(═

O)_n(CRR1)_m, where m=0-6 and n=0-2, S(═

O)(═

NR), S(═

NR)(═

NR1), SO₂NR, wherein R and R1 are independently selected from hydrogen, C1-C6 alkyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, —

OC(R2R3)OC(═

O)R4, —

OC(R2R3)OC(═

O)OR4, where R2, R3 and R4 are independently selected from H, C₁-C₇ alkyl, R2, R3 and R4 can be combined to form a 5-7-membered ring, C2-C6 alkenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, C2-C6 alkynyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, C3-C8 cycloalkyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, C6-C14 aryl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, C10-C20 linked biaryl and heterobiaryl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, C7-C16 aralkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃,

C5-C14 monocyclic-heteroaryl and bicyclic-heteroaryl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, and C5-C14 heteroaralkyl which is optionally substituted on the alkyl chain and on the ring with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, R and R1 can be joined together to form an alicyclic or heterocyclic ring;

R and R1 are independently and optionally substituted with 1 to 3 substituents Y₁, Y₂, and Y₃.

3. The compound of claim 1, wherein:

L₁, L₂ and L₃ are independently selected from;

N—

C single bond (i.e. G₁, G₂, or G₃ are directly bonded to N by a single bond), alkylene, alkenylene, alkynylene, cycloalkylene, oxocycloalkylene, amidocycloalkylene, heterocyclylene, heteroarylene, C═

O, sulfonyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, amido, carboxamido, alkylamido, alkylcarboxamido, and alkoxyoxo;

where each of the above substituents are unsubstituted or substituted with one or more substituents, in one embodiment, one, two, or three substituents, each independently selected from D¹, where D¹ is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, amido, cyano, cyanoalkenyl, amidoalkyl, amidoalkenyl, and oxo.

4. The compound of claim 1, wherein:

L₁, L₂ and L₃ are independently selected from;

N—

C single bond, C1-C5 alkylene, C1-C5 alkenylene, C1-C5 alkynylene, C3-C15 cycloalkylene, C3-C15 amidocycloalkylene, C3-C15 heterocyclylene, C3-C15 heteroarylene, oxo, sulfonyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, amido, carboxamido, alkylamido, alkylcarboxamido, and alkoxyoxo;

where each of the above substituents are unsubstituted or substituted with one or more substituents, in one embodiment, one, two, or three substituents, each independently selected from D¹, where D¹ is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, amido, cyano, cyanoalkenyl, amidoalkyl, amidoalkenyl, and oxo.

5. The compound of claim 1, wherein:

L₁, L₂ and L₃ are independently selected from;

N—

C single bond, C1-C5 alkylene, C1-C5 alkenylene, C1-C5 alkynylene, C3-C15 cycloalkylene, C3-C15 amidocycloalkylene, C3-C15 heterocyclylene, C3-C15 heteroarylene, oxo, sulfonyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, amido, carboxamido, alkylamido, alkylcarboxamido, and alkoxyoxo.

6. The compound of claim 1, wherein:

L₁, L₂ and L₃ are independently selected from;

N—

C single bond, —

CH₂, —

C(═

O), —

CH₂CH₂, —

SO₂, —

S(═

O)₂CH₂, —

S(═

O)₂CH₂CH₂, —

C(═

O)NHCH₂, —

C(═

O)OCH₂, and —

S(═

O)₂CH═

CH,

7. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently N—

C single bond.

8. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

CH₂.

9. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

CH₂CH₂.

10. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

C(═

O)NHCH₂.

11. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

C(═

O).

12. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

C(═

O)OCH₂.

13. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

SO₂.

14. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

S(═

O)₂CH₂.

15. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

S(═

O)₂CH₂CH₂.

16. The compound of claim 1, wherein:

L₁, L₂ or L₃ is independently —

S(═

O)₂CH═

CH.

17. The compound of claim 1, wherein:

G₁, G₂ and G₃ are independently selected from;

H, C1-6 alkyl and which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, C2-C6 alkenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, C2-C6 alkynyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃;

C3-C8 cycloalkyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃;

C6-C14 aryl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃;

C7-C16 aralkyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃;

C5-C14 heteroaryl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃, and C5-C14 heteroaralkyl, which is optionally substituted on the ring and the alkyl chain with 1 to 3 substituents selected from the group consisting of Y₁, Y₂, and Y₃; and

Y₁, Y₂, and Y₃ are selected from R, (CRR1)_nOR, OH, (CRR1)_nNRR1, C(═

NR)NRR1, C(═

NOR)NRR1, halogen (F, Cl, Br, I), cyano, nitro, CF₃, CF₂CF₃, CH₂CF₃, CH(CF₃)₂, C(OH)(CF₃)₂, OCHCl₂, OCF₃, OCF₂H, OCF₂CF₃, OCH₂CF₃, (CRR1)_nOC(═

O)NRR1, (CRR1)_nNHC(═

O)C(═

O)OR, (CRR1)_nNHC(═

O)NRSO₂(Me, CF₃), (CRR1)_nNHSO₂(Me, CF₃), (CRR1)_nNHSO₂NRR1, NHSO₂NRC(═

O)(Me, CF₃), (CRR1)_nNHC(═

O)R, (CRR1)_nNHC(═

O)NRR1, C(═

O)OH, (CRR1)_nC(═

O)OH, C(═

O)OR, C(═

O)O(CRR1)OC(═

O)R, C(═

O)O(CRR1)OC(═

O)OR, C(═

O)R, —

(CRR1)_nC(═

O)R, (CF₂)_nC(═

O)R, (CFR)_nC(═

O)R, tetrazolyl (Tzl), (CRR1)_nTzl, (CF₂)_nTzl, (CFR)_nTzl, (CRR1)_nC(═

O)OR, (CRR1)_nC(═

O)NH₂, (CRR1)_nC(═

O)NRR1, (CRR1)_nC(═

O)C(═

O)OR, (CRR1)_nCH(OR)C(═

O)OR, (CF₂)_nC(═

O)OH, (CF₂)_nC(═

O)OR, (CF₂)_nC(═

O)NH₂, (CF₂)_nC(═

O)NRR1, (CRR1)_nC(═

O)C(═

O)OR, (CRR1)_nCH(OR)C(═

O)OR, C(R)═

C(R1), C(═

O)OR, C(R)═

C(R1)-Tzl, (CRR1)_nP(═

O)(OH)₂, (CRR1)_nP(═

O)(OR)(OR1), P(═

O)(OR)[(OCRR1)OC(═

O)R], P(═

O)(OR)[(OCRR1)OC(═

O)OR], P(═

O)[(OCRR1)OC(═

O)R)][(OCRR1)OC(═

O)R], P(═

O)[(OCRR1)OC(═

O)OR)][(OCRR1)OC(═

O)OR], (CRR1)_nP(═

O)(Me)(OR), (CRR1)_nP(═

O)(CF₃)(OR), (CF₂)_nP(═

O)(OR)(OR1), (CF₂)_nP(═

O)(Me)(OR), (CF₂)_nP(═

O)(CF₃)(OR), (CFR)_qP(═

O)(OR)(OR1), CR═

CR—

P(═

O)(OR)(OR1), CR═

CR—

P(═

O)(Me)(OR), CC—

P(═

O)(OR)(OR1), (C═

O)P(═

O)(OR)(OR1), (C═

O)P(═

O)(Me)(OR), (C═

O)P(═

O)(CF₃)(OR), (CROR1)_nP(═

O)(OR)(OR1), (CROR1)_nP(═

O)(Me)(OR), (CROR1)_nP(═

O)(CF₃)(OR), O(CRR1)_nC(═

O)OR, O(CF₂)_nC(═

O)OR, OCH[C(═

O)OR]₂, O(CRR1)_nCH[C(═

O)OR]₂, OCF[C(═

O)OR]₂, O(CRR1)_nC(═

O)C(═

O)OR, O(CF₂)_nC(═

O)C(═

O)OR, O(CRR1)_nTzl, O(CF₂)_nTzl, OCH(Tzl)₂, O(CF₂)_nP(═

O)(OR)(OR1), O(CF₂)_nP(═

O)(Me)(OR), O(CF₂)_nP(═

O)(CF₃)(OR), O(CFR)_nP(═

O)(OR)(OR1), O(CFR)_nP(═

O)(Me)(OR), O(CFR)_nP(═

O)(CF₃)(OR), (CRR1)_nP(═

O)(OR)(OR1), O(CRR1)_nP(═

O)(Me)(OR), O(CRR1)_nP(═

O)(CF₃)(OR), OCF[P(═

O)(Me)(OR)]₂, SO₃H, —

(CRR1)_nSO₃H, S(O)_nR, SCF₃, SCHF₂, SO₂CF₃, SO₂Ph, (CRR1)_nS(O)_nR, (CRR1)_nS(O)₂CF₃, (CRR1)_nSO₂NRR1, (CRR1)_nSO₂NRC(═

O)(Me, CF₃), (CF₂)_nSO₃H, (CFR)_nSO₃H, (CF₂)_nSO₂NRR1, wherein n=0-2, and R and R1 are as defined above;

Y₁, Y₂ and/or Y₃ may also be selected together to be (CRR1)_2-6 and substituted variants thereof, —

O[C(R2)(R3)]_rO—

or —

O[C(R2)(R3)]_r+1—

, wherein r is an integer from 1 to 4 and R2 and R3 are independently selected from the group consisting of hydrogen, C1-C12 alkyl, C6-14 aryl, C5-C14 heteroaryl, C7-C15 aralkyl, and C5-C14 heteroarylalkyl.

18. The compound of claim 1, wherein:

G₁, G₂, and G₃ are independently selected from;

alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl, alkarylalkyl, alkenylaryl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, amido, alkylamino, alkylaminoaryl, arylamino, aminoalkyl, aminoaryl, alkoxy, alkoxyaryl, aryloxy, alkylamido, alkylcarboxamido, arylcarboxamido, alkoxyoxo, biaryl, alkoxyoxoaryl, amidocycloalkyl, carboxyalkylaryl, carboxyaryl, carboxyamidoaryl, carboxamido, cyanoalkyl, cyanoalkenyl, cyanobiaryl, cycloalkyl, cycloalkyloxo, cycloalkylaminoaryl, haloalkyl, haloalkylaryl, haloaryl, heterocyclyl, heteroaryl, hydroxyalkylaryl, and sulfonyl;

where each of the above substituents are unsubstituted or substituted with one or more substituents, in one embodiment, one, two, or three substituents, each independently selected from M¹, where M¹ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkoxyoxo, alkylthia, amino, amido, arylamino, aryloxy, alkylamino, alkylsulfonyl, alkylcarboxyalkylphosphonato, arylcarboxamido, carboxy, carboxyoxo, carboxyalkyl, carboxyalkyloxa, carboxyalkenyl, carboxyamido, carboxyhydroxyalkyl, cycloalkyl, amido, cyano, cyanoalkenyl, cyanoaryl, amidoalkyl, amidoalkenyl, halo, haloalkyl, haloalkylsulfonyl, heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, hydroxy, hydroxyalkyl, hydroxyamino, hydroxyimino, heteroarylalkyloxa, nitro, phosphonato, phosphonatoalkyl, and phosphonatohaloalkyl.

19. The compound of claim 1, wherein:

G₁ and G₂ can be linked together to form a cycloalkyl, oxocycloalkyl, cycloalkyloxo, amidocycloalkyl, cycloalkylamido, alkenylaryl, amidoalkenylaryl, and the following groups,

where J₁, J₂, J₃, and J₄ are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, amido, cyano, cyanoalkenyl, amidoalkyl, amidoalkenyl, oxo, and CH═

C(CN)C(O)N.

20. The compound of claim 1, wherein:

G₁ and G₂ can be linked together to form the following groups,

21. The compound of claim 1, wherein:

G₁ and G₂ can be linked together to form

22. The compound of claim 1, wherein:

G₁ and G₂ can be linked together to form.

23. The compound of claim 1, wherein:

G₁ and G₂ can be linked together to form

24. The compound of claim 1, wherein:

G₁, G₂, and G₃ are independently selected from, —

CH(E¹)₂, —

CH═

CH(E¹), —

CH(E¹)CH₂(E¹), —

CH═

C(E¹)C(O)NHE¹,

where E¹ at each instance is independently selected from —

CN, —

OCH₃, —

COOH, Cl, F, Br, CH₃,

25. The compound of claim 1, wherein:

G₁, G₂, and G₃ are independently selected from, CH₃, C(═

O)CH₃, CH(CH₃)CH₃,

26. The compound of claim 1, wherein:

G₁ and/or G₂ and/or G₃ is

27. The compound of claim 1, wherein:

G₁ and/or G₂ and/or G₃ is

28. The compound of claim 1, wherein the compound is:

29. A prodrug of a compound of claim 1.

30. The prodrug of claim 29, wherein the prodrug is a mono- or di-ester of a phosphonic acid or an ester of a carboxylic acid, and has the formula —

CH(H/Me)OC(═

O)OiPr, —

(CH(H/Me)OC(═

O)tBu, or ROCH₂CHR′

CH₂—

, where R is C_14-20-n-alkyl and R′

is H, OH or OMe.

31. A prodrug of a compound of claim 28.

32. The prodrug of claim 31, wherein the prodrug is a mono- or di-ester of a phosphonic acid or an ester of a carboxylic acid, and has the formula —

CH(H/Me)OC(═

O)OiPr, —

(CH(H/Me)OC(═

O)tBu, or ROCH₂CHR′

CH₂—

, where R is C_14-20-n-alkyl and R′

is H, OH or OMe.

33. The prodrug claim 29 that is a mono- or bis-amidate prodrug, a mono- or di-lipid ester prodrug, a mono- or di-alpha-acyloxyalkyl ester or amide prodrug, a cytochrome P450 3A activated prodrug, a cyclic diester prodrug, a cyclic monoester monoamide prodrug, a cyclic diamide prodrug, or a carbohydrate prodrug.

34. The prodrug claim 31 that is a mono- or bis-amidate prodrug, a mono- or di-lipid ester prodrug, a mono- or di-alpha-acyloxyalkyl ester or amide prodrug, a cytochrome P450 3A activated prodrug, a cyclic diester prodrug, a cyclic monoester monoamide prodrug, a cyclic diamide prodrug, or a carbohydrate prodrug.

35. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

36. The pharmaceutical composition of claim 35 that is formulated for single dosage administration.

37. A pharmaceutical composition, comprising a prodrug of claim 29 and a pharmaceutically acceptable carrier.

38. The pharmaceutical composition of claim 37 that is formulated for single dosage administration.

39. A method of treatment or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by tyrosine phosphatase activity or in which tyrosine phosphatase activity is implicated, comprising administering a compound of claim 1 or a pharmaceutically acceptable derivative thereof.

40. The method of any of claim 39, wherein the disease or disorder is selected from metabolic disorders, autoimmune disease, and oncologic disease.

41. The method of claim 39, wherein the autoimmune disease is selected from glomeralonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves'"'"' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn'"'"'s disease, psoriasis and graft vs. host disease.

42. A method of treating or ameliorating one or more symptoms of an oncologic disease, comprising administering a compound of claim 1 or a pharmaceutically acceptable derivative thereof.

43. A method of treating or ameliorating one or more symptoms of cancer, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the disease is a solid tumor.

45. The method of claim 43, wherein the cancer is resistant to cytotoxic agents.

46. The method of claim 44, wherein the cancer is breast cancer, stomach cancer, cancer of the ovaries, cancer of the colon, lung cancer, brain cancer, cancer of the larynx, cancer of the lymphatic system, cancer of the genito-urinary tract including the bladder and the prostate, bone cancer and cancer of the pancreas.

47. A method of cancer chemotherapy, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof.

48. The method of claim 40, wherein the metabolic disorder is selected from diabetes mellitus and diabetes insipidus.

49. The method of claim 40, wherein the diabetes is selected from type 1 diabetes and type 2 diabetes.

50. A method for inhibiting tyrosine phosphatase activity, comprising contacting the tyrosine phosphatase with a compound of claim 1 or a pharmaceutically acceptable derivative thereof.

51. The method of claim 50, wherein the tyrosine phophatase is PTP-1B.