INHIBITION OF ALPHA-SYNUCLEIN TOXICITY

• US 20100273776A1
• Filed: 03/29/2007
• Published: 10/28/2010
• Est. Priority Date: 03/29/2006
• Status: Abandoned Application

• Current Assignee: FoldRx Pharmaceuticals, Inc. (Pfizer Inc.), Whitehead Institute for Biomedical Research
• Original Assignee: FoldRx Pharmaceuticals, Inc. (Pfizer Inc.), Whitehead Institute for Biomedical Research
• Inventors: Gupta, Sandeep, Fleming, James, Weigel, Charlotte, Outeiro, Tiago, Bulawa, Christine Ellen, Ripka, Amy, Lindquist, Susan L., Liang, Feng, Labaudinière, Richard
• Application Number:
  US12/294,893
• Publication Number:
  US 20100273776A1
• Time in Patent Office: Days
• US Class Current: 514/215
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Compounds and compositions are provided for treatment or amelioration of one or more symptoms of α-synuclein toxicity, α-synuclein mediated diseases or diseases in which α-synuclein fibrils are a symptom or cause of the disease.

Claims

1. A method of treating or ameliorating a disorder characterized by α

-synuclein toxicity or α

-synuclein fibril formation, comprising administering to a subject or contacting a cell with a compound of Formula I;

2. The method of claim 1, wherein the method is inhibiting or preventing α

-synuclein toxicity and/or fibril formation, inhibiting or preventing α

-synuclein fibril growth, and/or causing disassembly, disruption, and/or disaggregation of α

-synuclein fibrils and α

-synuclein-associated protein deposits, comprising administering to a mammal or contacting a cell with the compound of Formula I^o;

3. The method of claim 1, wherein substituents for Y are selected from the group consisting of halo, pseudohalo, alkyl, cycloalkyl, aryl, aralkyl, NO₂, alkoxy, aryloxy, arylalkyoxy, CF₃, OCF₃, CN, NR⁵R⁶, NR⁵COR⁶, (CH₂)_nOR⁶, SR⁶, CO₂H, CO₂R⁶, CONR⁶R⁵, COR⁶, and SO₂NR⁵R⁶.

4. The method of claim 1, wherein n is 1.

5. The method of claim 1, wherein each X is N.

6. The method of claim 1, wherein R³ is selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, aryl, and aralkyl.

7. The method of claim 1, wherein R² is selected from the group consisting of hydrogen, halo, or substituted or unsubstituted aryl, heteroaryl, aralkyl, and aralkenyl.

8. The method of claim 1, wherein R¹ and Z are each independently selected from the group consisting of hydrogen, or substituted or unsubstituted alkyl, arylcarbonyl, aralkylcarbonyl, haloarylcarbonyl, arylsulfonyl, aralkylsulfonyl, and haloarylsulfonyl.

9. The method of claim 1, wherein R¹ is H and Z is H.

10. The method of claim 1, wherein R¹ is methyl and Z is H.

11. The method of claim 1, wherein R⁴ is H.

12. The method of claim 1, wherein R⁴ is NH₂.

13. The method of claim 1, wherein the compound is selected from the compounds set forth in FIG. 1a.

14. The method of claim 2, wherein the method is treating or ameliorating one or more symptoms of a synuclein disease or synucleinopathy in a mammal, comprising administering to the mammal a compound of Formula I^o.

15. The method of claim 13, wherein the synuclein disease or synucleinopathy is Parkinson'"'"'s disease, familial Parkinson'"'"'s disease, Lewy body disease, the Lewy body variant of Alzheimer'"'"'s disease, dementia with Lewy bodies, multiple system atrophy, and the Parkinsonism-dementia complex of Guam.

16. The method of claim 13, wherein the synuclein disease or synucleinopathy is associated with α

-synuclein toxicity.

17. The method of claim 1, wherein the compound is represented by Formula Ib:

18. The method of claim 1, wherein the compound is represented by Formula Ic:

19. The method of claim 17, wherein R¹ is H.

20. The method of claim 17, wherein:

R² is H, halo, CN, NO₂, NH₂, or C₁-C₁₀ alkyl optionally substituted with 1-3 independent halo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵;

COOR⁵, NO₂, CN, C(O)R⁵, OC(O)NR⁵R⁵, or C(O)NR⁵R⁵.

21. The method of claim 20, wherein R² is H, F, Cl, Br, CF₃, CCl₃, CN, NO₂, NH₂, or C₁-C₆ alkyl.

22. The method of claim 20, wherein R² is aryl, heteroaryl, aralkyl, or heteroaralkyl, each substituted with:

H, halo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵;

COOR⁵, NO₂, CN, C(O)R⁵, OC(O)NR⁵R⁵, or C(O)NR⁵R⁵;

or

aryl, C₁-C₁₀ alkyl, or C₂-C₁₀ alkenyl each optionally substituted with 1-3 independent aryl, halo, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵;

COOR⁵, NO₂, CN, C(O)R⁵, OC(O)NR⁵R⁵, or C(O)NR⁵R⁵.

23. The method of claim 22, wherein the optionally substituted aryl, heteroaryl, aralkyl, or heteroaralkyl groups in R² are selected from phenyl, napthyl, benzyl, phenylethylene, napthylmethylene, phenoxymethylene, napthyloxymethylene, pyridylmethylene, benzofurylmethylene, dihydrobenzofurylmethylene, benzodioxolmethylene, indanylmethylene, furyl, thienyl, pyridyl, benzothienyl, and benzofuryl.

24. The method of claim 22, wherein the optional substituents for the aryl, heteroaryl, aralkyl, or heteroaralkyl groups in R² are:

H, F, Cl, Br, OH, C₁-C₆ alkoxy, amino, C₁-C₆ alkylamino, COOH, COO—

C₁-C₆ alkyl, NO₂, CN, or C(O)—

C₁-C₆ alkyl;

or

C₁-C₆ alkyl, C₂-C₆ alkenyl, or aryl optionally substituted with phenyl, F, Cl, Br, C₁-C₆ alkoxy, COOH, COO—

C₁-C₆ alkyl, NO₂, or CN.

25. The method of claim 22, wherein R³ is H;

C₁-C₁₀ alkyl or C₂-C₁₀ alkenyl each optionally substituted with 1-3 halo, CF₃, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵;

COOR⁵, NO₂, CN, C(O)R⁵, OC(O)NR⁵R⁵, C(O)NR⁵R⁵;

C₃-C₁₀ cycloalkyl;

or C₂-C₁₀ alkynyl.

26. The method of claim 25, wherein R³ is:

H, C₁-C₈ alkyl optionally substituted with 1-3 halo, OR⁵, NR⁵R⁵, COOR⁵, C(O)R⁵, C(O)NR⁵R⁵, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

or

cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, or cyclohexylmethyl.

27. The method of claim 20, wherein R³ is aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or heterocyclyalkyl, each substituted with:

H, alkyl, halo, OR⁵, OC(O)R⁵, NR⁵R⁵;

COOR⁵, NO₂, CN, C(O)R⁵, OC(O)NR⁵R⁵, or C(O)NR⁵R⁵;

or

optionally substituted aryl, heteroaryl, or heterocyclyl.

28. The method of claim 27, wherein the aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or heterocyclyalkyl groups represented by R³ are selected from benzyl, pyridyl, pyridylmethylene, furyl, thienyl, tetrahydrofuryl, or tetrahydrothienyl.

29. The method of claim 28, wherein substituents for the aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or heterocyclyalkyl groups represented by R³ are:

H, F, Cl, Br, SR⁵, OR⁵, NR⁵R⁵;

COOR⁵, NO₂, CN, C(O)R⁵;

or

C₁-C₆ alkyl, C₂-C₆ alkenyl, or aryl optionally substituted with phenyl, F, Cl, Br, SR⁵, OR⁵, COOR⁵, NO₂, or CN.

30. The method of claims 20, wherein R⁴ is independently aryl;

heteroaryl;

C₁-C₁₀ alkyl or C₂-C₁₀ alkenyl, each optionally substituted with 1-3 independent aryl, R⁷, or heteroaryl;

C₂-C₁₀ alkynyl;

halo;

haloalkyl;

CF₃;

SR⁵;

OR⁵;

OC(O)R⁵;

NR⁵R⁵;

NR⁵R⁶;

COOR⁵;

NO₂;

CN;

C(O)R⁵;

C(O)C(O)R⁵;

C(O)NR⁵R⁵;

S(O)_mR⁵;

S(O)_mNR⁵R⁵;

NR⁵C(O)NR⁵R⁵;

NR⁵C(O)C(O)R⁵;

NR⁵C(O)R⁵;

NR⁵(COOR⁵);

NR⁵C(O)R⁸;

NR⁵S(O)_mNR⁵R⁵;

NR⁵S(O)_mR⁵;

NR⁵S(O)_mR⁸;

NR⁵C(O)C(O)NR⁵R⁵;

or NR⁵C(O)C(O)NR⁵R⁶.

31. The method of claim 30, wherein R⁴ is

H;

OR⁵;

OC(O)R⁵;

NR⁵R⁵;

COOR⁵;

NO₂;

CN;

C(O)R⁵;

C(O)C(O)R⁵;

or C(O)NR⁵R⁵;

or

C₁-C₁₀ alkyl optionally substituted with 1-3 halo, OR⁵, OC(O)R⁵, NR⁵R⁵;

COOR⁵, NO₂, CN, C(O)R⁵, OC(O)NR⁵R⁵, or C(O)NR⁵R⁵.

32. The method of claim 31, wherein R⁴ is

H, CF₃, CCl₃, amino, C₁-C₆ alkoxy, COOH, COO—

C₁-C₆ alkyl, OC(O)—

C₁-C₆ alkyl, phenoxy, or alkylphenoxy;

or

C₁-C₆ alkyl optionally substituted with amino, COOH, COO—

C₁-C₆ alkyl or OC(O)—

C₁-C₆ alkyl, or 1 or 2 C₁-C₆ alkoxy.

33. The method of claim 31, wherein R⁴ is an optionally substituted aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein the optional substituents are halo, CF₃, SR⁵, OR⁵, OC(O)R⁵, NR⁵R⁵;

COOR⁵, NO₂, CN, C(O)R⁵, OC(O)NR⁵R⁵, C(O)NR⁵R⁵, N(R⁵)C(O)R⁵, N(R⁵)(COOR⁵), or S(O)_mNR⁵R⁵.

34. The method of claim 33, wherein the aryl, aralkyl, heteroaryl, and heteroaralkyl groups represented by R⁴ are selected from phenyl, benzyl, pyridyl, pyridylmethylene, furyl, furylmethylene, thienyl, thienylmethylene, pyrazolyl, and pyrazolylmethylene.

35. The method of claim 33, wherein the optional substituents for the aryl, aralkyl, heteroaryl, or heteroaralkyl groups represented by R⁴ are:

F, Cl, OH, amino, NO₂, C₁-C₆ alkoxy, C₁-C₆ alkyl, phenoxy, or alkylphenoxy;

or

phenyl, imidazolyl, or morpholino optionally substituted with F, Cl, amino, NO₂, C₁-C₆ alkoxy, or C₁-C₆ alkyl.

36. The method of claim 1, wherein the compound is selected from the compounds in FIGS. 1a, 1b, 1c, 1d, 1e, or 1f.

37. A composition comprising a compound of Formula I as set forth in claim 1 or a compound as set forth in FIGS. 1a, 1b, 1c, 1d, 1e, or 1f, or a pharmaceutically acceptable salt or derivative thereof, and one or more of donepezil hydrochloride (Aracept), rivastigmine tartrate (Exelon), tacrine hydrochloride (Cognex) or galantamine hydrobromide (Reminyl).

38. The composition of claim 37, wherein the compound is represented by Formula I^o or is a compound as set forth in FIG. 1a or 1f, or a pharmaceutically acceptable salt or derivative thereof, and one or more of the following:

donepezil hydrochloride (Aracept), rivastigmine tartrate (Exelon), tacrine hydrochloride (Cognex) and galantamine hydrobromide (Reminyl).

39. A method of inhibiting or preventing α

-synuclein toxicity and/or fibril formation, inhibiting or preventing α

-synuclein fibril growth, and/or causing disassembly, disruption, and/or disaggregation of α

-synuclein fibrils and α

-synuclein-associated protein deposits, comprising administering to a mammal or contacting a cell with the composition of claim 37.

40. The method of claim 39, wherein the method is inhibiting or preventing α

-synuclein toxicity and/or fibril formation, inhibiting or preventing α

-synuclein fibril growth, and/or causing disassembly, disruption, and/or disaggregation of α

-synuclein fibrils and α

-synuclein-associated protein deposits, comprising administering to a mammal or contacting a cell with the composition of claim 38, wherein the compound of the composition is represented by Formula I^o or is a compound as set forth in FIGS. 1a and 1f, or a pharmaceutically acceptable salt or derivative thereof.

41. The method of claim 40, wherein the method is treating or ameliorating the symptoms of a synuclein disease or synucleinopathy, comprising administering to a mammal the composition of claim 37 or 38.

42. The method of claim 41, wherein the synuclein disease or synucleinopathy is Parkinson'"'"'s disease, familial Parkinson'"'"'s disease, Lewy body disease, the Lewy body variant of Alzheimer'"'"'s disease, dementia with Lewy bodies, multiple system atrophy, or the Parkinsonism-dementia complex of Guam.

43. The method of claim 41, wherein the synuclein disease or synucleinopathy is associated with α

-synuclein toxicity.

44. The method of claim 2, wherein the method is treating or ameliorating one or more symptoms of α

-synuclein toxicity in a mammal, comprising administering to the mammal a compound of Formula I^o.

45-51. -51. (canceled)

52. A compound represented by structural formula I:

53. The compound of claim 52, wherein:

when R¹ and Z are H, then;

R² is 5-NO₂-fur-2-yl, or phenyl optionally substituted with a single 4-Cl, 4-CH₃, or 4-OCH₃; and

R³ is unsubstituted phenyl, cyclohexyl, or acyclic C₁-C₄ alkyl; and

the compound is in the form of a free base;

then R⁴ is not H, unsubstituted C₁-C₄ alkyl, or phenyl optionally substituted with 4-Cl or 4-CH₃;

R² is CN or CH₂CN; and

R³ is CH₃, or phenyl optionally substituted with 4-NO₂;

then R⁴ is not CO₂-alkyl or CCl₃;

R³ is cyclopentyl, and R⁴ is unsubstituted 4-pyridyl, then R² is not CF₃;

CN, Br, Cl, or NO₂;

R³ is cyclopentyl, and R⁴ is optionally substituted 4-pyridyl, then R² is not C₁-C₄ alkyl optionally substituted with F;

R³ is unsubstituted C₁-C₄ alkyl, cyclopentyl, or phenyl, and R⁴ is unsubstituted pyridyl, then R² is not unsubstituted CH₃, benzyl, or CH₂-pyrid-4-yl, and then R² is not H when the compound is in the form of a free base;

R² is H or unsubstituted C₁-C₂ alkyl, benzyl, or CH₂-pyridyl; and

R⁴ is unsubstituted 4-pyridyl, then R³ is not a lone pair, C₁-C₄ alkyl optionally substituted with CO₂-alkyl, dialkylamino, or cyclopentyl;

benzyl optionally substituted with Cl, CN, or CH₃;

unsubstituted cyclobutyl, cyclopentyl, 3-tetrahydrofuryl, or 2-bicyclo[2.2.1]heptyl; and

then R³ is not H when the compound is in the form of a free base;

R³ is H, a lone pair, cyclopentyl, 3-(5-ethyl-5H-[1,2,4]triazino[5,6-b]indolyl);

unsubstituted benzyl;

C₁-C₄ alkyl optionally substituted with OCH₃;

phenyl optionally substituted with Cl, 3-NO₂, 4-NO₂, or 4-Me;

or ribofuranose; and

R⁴ is 2-furyl optionally substituted with 5-NO₂;

5-NH₂-pyrazol-4-yl optionally substituted with methyl or optionally chlorinated phenyl;

phenyl optionally substituted with imidazolyl, 4-Cl, 4-OH, or 4-NO₂;

C₁-C₄ alkyl optionally substituted with F or acetate;

or unsubstituted benzyl;

then R² is not unsubstituted C₁-C₂ alkyl, and when the compound is in the form of a free base, then R² is not H;

R³ is H or a lone pair, and R⁴ is phenyl optionally substituted with OH, NH₂, NO₂, NHC(O)NHPhSO₂F, NHC(O)PhSO₂F;

fur-2-yl with an optional 5-NO₂ group, 3-NH₂-pyrazol-4-yl;

C₁-C₄ alkyl optionally substituted with F or CO₂-alkyl;

or unsubstituted pyridyl or benzyl;

then R² is not CN, and R² is not H when the compound is in the form of a free base; and

when R³ is tert-butyl;

R⁴ is H;

R¹ and Z are both H or acetyl, or R¹ is H and Z is acetyl, optionally substituted SO₂-phenyl, or substituted benzoyl;

then R² is not H or Br;

phenyl optionally 3 or 4-substituted with OCH₃, phenoxy or benzyloxy, or substituted only with a single Cl, 4-CF₃, 4-F, 4-C₁-C₄ alkyl, or 4-phenyl;

benzyl optionally substituted with Cl, F, or CH₃;

unsubstituted naphthyl, CH₂-naphthyl, or OCH₂-naphthyl;

or unsubstituted thien-2-yl or benzothien-2-yl.

54. The compound of claim 52, wherein:

when R¹ and Z are H, then;

R² is nitrofuryl, or phenyl optionally substituted with halo, alkyl, or alkoxy; and

R³ is unsubstituted alkyl, cycloalkyl, or phenyl;

then R⁴ is not H, unsubstituted alkyl, or phenyl optionally substituted with Cl or alkyl;

R² is CN or CH₂CN; and

R³ is alkyl, or phenyl optionally substituted with NO₂;

then R⁴ is not CO₂-alkyl or CCl₃;

R³ is cycloalkyl, and R⁴ is optionally substituted pyridyl, then R² is not CF₃;

CN, Br, Cl, or NO₂, or alkyl optionally substituted with F;

R³ is unsubstituted alkyl, cycloalkyl, or phenyl, and R⁴ is unsubstituted pyridyl, then R² is not H or unsubstituted alkyl, benzyl, or CH₂-pyridyl;

R² is H or unsubstituted alkyl, benzyl, or CH₂-pyridyl; and

R⁴ is unsubstituted pyridyl, then R³ is not H, a lone pair, alkyl optionally substituted with CO₂-alkyl, dialkylamino, or cycloalkyl;

benzyl optionally substituted with Cl, CN, or alkyl;

unsubstituted cycloalkyl, bicycloalkyl, or tetrahydrofuryl;

R² is H or unsubstituted alkyl, and R³ is H, a lone pair, cycloalkyl, a tricyclic heteroaryl substituted with alkyl;

unsubstituted benzyl;

C₁-C₄ alkyl optionally substituted with OCH₃;

phenyl optionally substituted with Cl, NO₂, or Me;

or ribofuranose;

then R⁴ is not furyl optionally substituted with NO₂;

NH₂-pyrazolyl optionally substituted with methyl or optionally chlorinated phenyl;

phenyl optionally substituted with imidazolyl, Cl, OH, or NO₂;

C₁-C₄ alkyl optionally substituted with F or acetate;

or unsubstituted benzyl; and

R³ is H or a lone pair, and R² is H or CN, then R⁴ is not phenyl optionally substituted with OH, NH₂, NO₂, NHC(O)NHPhSO₂F, NHC(O)PhSO₂F;

furyl optionally substituted with NO₂, NH₂-pyrazolyl;

C₁-C₄ alkyl optionally substituted with F or CO₂-alkyl;

or unsubstituted pyridyl or benzyl; and

when R¹ and Z are both H or acetyl, or R¹ is H and Z is acetyl, SO₂-phenyl, or optionally substituted benzoyl, R³ is tert-butyl, and R⁴ is H, then R² is not H or Br;

phenyl optionally substituted with Cl, CF₃, F, C₁-C₄ alkyl, phenyl, or OCH₃, phenoxy or benzyloxy;

benzyl optionally substituted with Cl, F, or CH₃;

unsubstituted naphthyl, CH₂-naphthyl, or OCH₂-naphthyl;

or unsubstituted thienyl or benzothienyl.

55. The compound of claim 52, wherein:

when R¹ and Z are H, then;

R² is nitrofuryl or optionally substituted phenyl; and

R³ is unsubstituted alkyl, cycloalkyl, or phenyl;

then R⁴ is not H, unsubstituted alkyl, or optionally substituted phenyl;

R² is CN or CH₂CN; and

R³ is alkyl, or phenyl optionally substituted with NO₂;

then R⁴ is not CO₂-alkyl or CCl₃;

R³ is unsubstituted alkyl, cycloalkyl, or phenyl, and R⁴ is optionally substituted pyridyl, then R² is not H oCF₃;

CN, Br, Cl, NO₂, alkyl, haloalkyl, benzyl, or CH₂-pyridyl;

R² is H or unsubstituted alkyl, benzyl, or CH₂-pyridyl; and

R⁴ is unsubstituted pyridyl, then R³ is not H, a lone pair, optionally substituted alkyl, dialkylamino, or cycloalkyl;

optionally substituted benzyl;

cycloalkyl, bicycloalkyl, or tetrahydrofuryl;

R² is H or alkyl, and R³ is H, a lone pair, cycloalkyl, a tricyclic heteroaryl substituted with alkyl;

benzyl;

alkyl, alkoxyalkyl;

optionally substituted phenyl;

or ribofuranose;

then R⁴ is not optionally substituted furyl, NH₂-pyrazolyl, phenyl, alkyl or benzyl;

R³ is H or a lone pair, and R² is H or CN, then R⁴ is not an optionally substituted phenyl;

furyl, pyrazolyl;

alkyl, pyridyl or benzyl; and

when R¹ and Z are both H or acetyl, or R¹ is H and Z is acetyl, SO₂-phenyl, or optionally substituted benzoyl, R³ is tert-butyl, and R⁴ is H, then R² is not H or Br;

optionally substituted phenyl, phenoxy, benzyloxy, benzyl, naphthyl, CH₂-naphthyl, OCH₂-naphthyl, thienyl or benzothienyl.

56. The compound of claim 52, wherein:

when R¹ and Z are H, then;

R² is nitrofuryl or optionally substituted phenyl; and

R³ is alkyl, cycloalkyl, or phenyl;

then R⁴ is not H, alkyl, or optionally substituted phenyl;

R² is CN or CH₂CN; and

R³ is alkyl or optionally substituted phenyl;

then R⁴ is not CO₂-alkyl or CCl₃;

R³ is unsubstituted alkyl, cycloalkyl, or phenyl, and R⁴ is optionally substituted pyridyl, then R² is not H, CN, Br, C₁, NO₂, alkyl, haloalkyl, benzyl, or CH₂-pyridyl;

R² is H or unsubstituted alkyl, benzyl, or CH₂-pyridyl; and

R⁴ is unsubstituted pyridyl, then R³ is not H, a lone pair, dialkylamino, or optionally substituted alkyl, cycloalkyl, bicycloalkyl, benzyl, or tetrahydrofuryl;

R² is H or alkyl, and R³ is H, a lone pair, cycloalkyl, a substituted tricyclic heteroaryl, benzyl, alkyl, alkoxyalkyl;

optionally substituted phenyl;

or a sugar;

then R⁴ is not optionally substituted furyl, pyrazolyl, phenyl, alkyl or benzyl;

R³ is H or a lone pair, and R² is H or CN, then R⁴ is not an optionally substituted phenyl, furyl, pyrazolyl, alkyl, pyridyl or benzyl; and

when R¹ and Z are both H or acetyl, or R¹ is H and Z is acetyl, SO₂-phenyl, or optionally substituted benzoyl, R³ is tert-butyl, and R⁴ is H, then R² is not H or Br;

optionally substituted phenyl, phenoxy, benzyloxy, benzyl, naphthyl, CH₂-naphthyl, OCH₂-naphthyl, thienyl or benzothienyl.

57. The compound of claim 52, wherein the compound is represented by the following structural formula:

58. The compound of claim 52, wherein R¹ and Z are independently H, C₁-C₆ alkyl, C(O)—

C₁-C₆ alkyl, C(O)-aryl, S(O)_m—

C₁-C₆ alkyl or S(O)_m-aryl, wherein each C₁-C₆ alkyl and aryl represented in R¹ and Z is optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, or halo.

59. The compound of claim 52, wherein Z is H and R¹ is C₁-C₆ alkyl, C(O)—

C₁-C₆ alkyl;

or C(O)-phenyl or S(O)₂-phenyl optionally substituted with C₁-C₆ alkyl, F, or Cl.

60. The compound of claim 52, wherein R¹ and Z are each H.

61. The compound of claim 52, wherein the compound is represented by one of structural formulas:

62. The compound of claim 52, wherein R² is phenyl, napthyl, benzofuryl, benzothienyl, furyl, or thienyl, each optionally substituted with:

halo, CN, amino, alkylamino, C₁-C₆ hydroxyalkyl, S—

C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, COOH, COO—

C₁-C₆ alkyl, C(O)—

C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

or

optionally halogenated aryl, aralkyl, O-aryl, or O-aralkyl.

63. The compound of claim 62, wherein R² is phenyl, napthyl, benzofuryl, benzothienyl, furyl, thienyl, fluoronapthyl, benzyloxyphenyl, (chlorobenzyl)oxyphenyl, hydroxymethylphenyl, cyclohexylphenyl, chorophenyl, cyanophenyl, carboxyl phenyl, alkyl carboxyl phenyl, alkanoyl phenyl, alkylamino phenyl, trifluoromethoxyphenyl, alkoxyphenyl, phenoxyphenyl, biphenyl, or alkyl-S-phenyl.

64. The compound of claim 63, wherein R² is aralkyl, aralkenyl, or heteroaralkyl, each optionally substituted with halo, CN, amino, alkylamino, S—

C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, C₂-C₆ alkynyl, aryl, haloaryl, or heteroaryl.

65. The compound of claim 64, wherein R² is CH₂, CH(CH₃), CH═

CH, or CH₂CH₂, each substituted with phenyl, naphthyl, tetrahydronaphthyl, pyridyl, indanyl, benzofuryl, benzodioxolyl, dihydrobenzofuranyl, or tetrahydronaphthyl, wherein each phenyl, napthyl, tetrahydronaphthyl, pyridyl, indanyl, benzofuryl, benzodioxolyl, dihydrobenzofuranyl, or tetrahydronaphthyl in R² is optionally substituted with one or two substituents selected from the group consisting of F, Cl, CF₃;

C₁-C₆ alkyl, C₁-C₆ alkoxy, acetylenyl, CN, alkylamino, and phenyl.

66. The compound of claim 64, wherein R² is CH(CH₃)-phenyl, CH═

CH-phenyl, CH₂CH₂-phenyl, CH₂-naphthyl, CH₂—

(methylnaphthyl), CH₂—

(fluoronaphthyl), CH₂-pyridyl, CH₂-indanyl, CH₂-benzofuryl, CH₂-benzodioxolyl, CH₂-dihydrobenzofuranyl, CH₂-tetrahydronaphthyl, dichlorobenzyl, (chloro,trifluoromethyl)benzyl, (fluoro,trifluoromethyl)benzyl, (fluoro,chloro)benzyl, dimethylbenzyl, (methyl,fluoro)benzyl, dimethoxybenzyl, (acetylenyl)benzyl, cyanobenzyl, (dimethylamino)benzyl, methoxybenzyl, or phenylbenzyl.

67. The compound of claim 62, wherein R³ is optionally substituted aryl;

C₁-C₁₀ alkyl optionally substituted with aryl or C₃-C₁₀ cycloalkyl;

C₃-C₁₀ cycloalkyl;

C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl.

68. The compound of claim 67, wherein R³ is propenyl, propynyl, benzyl, cyclobutyl, cyclopropylmethyl, 2,2-dimethylpropyl, cyclohexyl, cyclopentyl, cyclopropyl, phenylethylene, ethyl, 2-propyl, methyl, phenyl, nitrophenyl, sec-butyl, or tert-butyl.

69. The compound of claim 64, wherein the compound is represented by the following structural formula:

70. The compound of claim 69, wherein R⁴ is pyridyl, C₁-C₆ alkoxy-C₁-C₆ alkyl, (C₁-C₆ alkyl)phenoxy-C₁-C₆ alkyl, C₁-C₆ alkyl, amino, or halophenyl.

71. The compound of claim 70, wherein R⁴ is pyridyl, CH(OCH₂CH₃)₂, tert-butyl-phenyoxymethylene, methyl, ethyl, amino, or chlorophenyl.

72. The compound of claim 64, wherein the compound is represented by the following structural formula:

73. The compound of claim 72, wherein R⁴ is pyridyl or C₁-C₆ alkyl.

74. The compound of claim 73, wherein R⁴ is pyridyl, methyl, or ethyl.

75. The compound of claim 52, wherein the compound is selected from the compounds in FIGS. 1a and 1b.

76. A compound, or a pharmaceutically acceptable salt or derivative thereof, having a structure as set forth in FIGS. 1a, 1b, and 1f.

77. The compound of claim 76 or a pharmaceutically acceptable salt or derivative thereof, having a structure set forth in FIG. 1a.

78. The compound of claim 76, wherein the compound is one of: