CA2642288A1 - Histone deacetylase inhibitors - Google Patents

Histone deacetylase inhibitors Download PDF

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CA2642288A1
CA2642288A1 CA002642288A CA2642288A CA2642288A1 CA 2642288 A1 CA2642288 A1 CA 2642288A1 CA 002642288 A CA002642288 A CA 002642288A CA 2642288 A CA2642288 A CA 2642288A CA 2642288 A1 CA2642288 A1 CA 2642288A1
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CA2642288C (en
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James Elliot Bradner
Ralph Mazitschek
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Harvard College
Dana Farber Cancer Institute Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

In recognition of the need to develop novel therapeutic agents, the present invention provides novel histone deacetylase inhibitors. These compounds include an ester bond making them sensitive to deactivation by esterases. Therefore, these compounds are particularly useful in the treatment of skin disorders. When the compounds reaches the bloodstream, an esterase or an enzyme with esterase activity cleaves the compound into biologically inactive fragments or fragments with greatly reduced activity Ideally these degradation products exhibit a short serum and/or systemic half-life and are eliminated rapidly. These compounds and pharmaceutical compositions thereof are particularly useful in treating cutaneous T-cell lymphoma, neurofibromatosis, psoriasis, hair loss, skin pigmentation, and dermatitis, for exmaple. The present invention also provides methods for preparing compounds of the invention and intermediates thereto.

Claims (102)

1. A compound of the formula (I), wherein A comprises a functional group that inhibits histone deacetylase;
L is a linker moiety; and Ar is a substituted or unsubstituted aryl or heteroaryl moiety; substituted or unsustituted, branched or unbranched arylaliphatic or heteroarylaliphatic moiety; a substituted or unsubstituted cyclic or heterocyclic moiety; substituted or unsustituted, branched or unbranched cyclicaliphatic or heterocyclicaliphatic moiety; and pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein A is a functional group that chelates Zn2+.
3. The compound of claim 1, wherein A is selected from the group consisting of:

4. The compound of claim 1, wherein A comprises .
5. The compound of claim 1, wherein A comprises .
6. The compound of claim 1, wherein A comprises .
7. The compound of any one of claims 1-6, wherein Ar is arylaliphatic.
8. The compound of any one of claims 1-6, wherein Ar is heteroarylaliphatic.
9. The compound of any one of claims 1-6, wherein Ar is substituted or unsubstituted aryl.
10. The compound of any one of claims 1-6, wherein Ar is a substituted phenyl moiety.
11. The compound of any one of claims 1-6, wherein Ar is chosen from one of the following:

12. The compound of any one of claims 1-6, wherein Ar is a substituted or unsubstituted heteroaryl moiety.
13. The compound of any one of claims 1-6, wherein Ar is chosen from one of the following:

14. The compound of any one of claims 1-13, wherein L is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic moiety; a substituted or unsubstituted, cyclic or acyclic, branched or unbranched heteroaliphatic moiety; a substituted or unsubstituted aryl moiety; a substituted or unsubstituted heteroaryl moiety.
15. The compound of any one of claims 1-13, wherein L is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic moiety.
16. The compound of any one of claims 1-13, wherein L is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched heteroaliphatic moiety.
17. The compound of any one of claims 1-13, wherein L is C1-C15 alkylidene.
18. The compound of any one of claims 1-13, wherein L is C1-C10 alkylidene.
19. The compound of any one of claims 1-13, wherein L is C2-C6 alkylidene.
20. The compound of any one of claims 1-13, wherein L is an unbranched, unsubstituted, acyclic alkyl chain.
21. The compound of any one of claims 1-13, wherein L is selected from one of the following:

22. The compound of any one of claims 1-13, wherein L is selected from one of the following:

23. The compound of any one of claims 1-13, wherein L is .
24. The compound of any one of claims 1-13 of the formula (Ia):

wherein n is an integer between 0 and 15.
25. The compound of any one of claims 1-13 of the formula (Ib):

wherein n is an integer between 0 and 15, inclusive;
m is an integer between 1 and 5, inclusive; and R1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR A; -C(=O)R A; -CO2R A; -CN; -SCN; -SR A; -SOR A; -SO2R A; NO2;
-N(R A)2; -NHC(O)R A; or -C(R A)3; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
26. The compound of claim 25, wherein n is an integer between 1 and 8, inclusive.
27. The compound of claim 25, wherein n is 5, 6 or 7.
28. The compound of claim 25, wherein n is 6.
29. The compound of any one of claims 25-28, wherein m is 1.
30. The compound of any one of claims 25-28, wherein m is 2.
31. The compound of any one of claims 25-28, wherein m is 3.
32. The compound of any one of claims 25-31, wherein R1 comprises a substituted or unsubstituted 1,3-dioxane ring.
33. The compoud of any one of claims 25-31, wherein R1 is halogen.
34. The compound of any one of claim 25-31, wherein R1 is -OR A.
35. The compound of any one of claims 25-31, wherein R1 is N(R A)2.
36. The compound of any one of claims 25-31, wehrein R1 is -NHR A.
37. The compound of any one of claims 25-31, wherein R1 is C1-C6 alkyl.
38. The compound of any one of claim 25-31, wherein R1 is substituted or unsubstituted acyl.
39. The compound of any one of claims 25-31, wherein R1 is -C(=O)OR A, wherein R A is hydrogen or C1-C6 alkyl.
40. The compound of any one of claims 25-31, wherein R1 is -C(=O)N(R A)2, wherein R A
is hydrogen or C1-C6 alkyl.
41. The compound of any one of claims 25-31, wherein R1 is -C(=O)NH2.
42. The compound of any one of claims 25-31, wherein R1 is -CHO.
43. The compound of any one of claims 25-3 1, wherein R1 is NHC(=O)R A, wherein R A
is C1-C6 alkyl.
44. The compound of claim 1 of formula (Ic):

wherein n is an integer between 0 and 15, inclusive; preferably, between 0 and 10, inclusive;
more preferably, between 1 and 8, inclusive; even more preferably, 4, 5, 6, 7, or 8; and R1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR A; -C(=O)R A; -CO2R A; -CN; -SCN; -SR A; -SOR A; -SO2R A; NO2;
-N(R A)2; -NHC(O)R A; or -C(R A)3; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
45. The compound of claim 1 of formula:

wherein n is an integer between 0 and 15, inclusive; preferably, between 0 and 10, inclusive;
more preferably, between 1 and 8, inclusive; even more preferably, 4, 5, 6, 7, or 8; and R1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR A; -C(=O)R A; -CO2R A; -CN; -SCN; -SR A; -SOR A; -SO2R A; NO2;
-N(R A)2; -NHC(O)R A; or -C(R A)3; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
46. The compound of claim 1 of formula:

wherein n is an integer between 0 and 15, inclusive; preferably, between 0 and 10, inclusive;
more preferably, between 1 and 8, inclusive; even more preferably, 4, 5, 6, 7, or 8; and R1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR A; -C(=O)R A; -CO2R A; -CN; -SCN; -SR A; -SOR A; -SO2R A; NO2;
-N(R A)2; -NHC(O)R A; or -C(R A)3; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
47. The compound of claim 1 of formula:

wherein n is an integer between 0 and 15, inclusive; preferably, between 0 and 10, inclusive;
more preferably, between 1 and 8, inclusive; even more preferably, 4, 5, 6, 7, or 8; and R1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR A; -C(=O)R A; -CO2R A; -CN; -SCN; -SR A; -SOR A; -SO2R A; NO2;
-N(R A)2; -NHC(O)R A; or -C(R A)3; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
48. The compound of claim 44, 45, 46, or 47, wherein n is an integer between 1 and 8, inclusive.
49. The compound of claim 44, 45, 46, or 47, wherein n is 5, 6 or 7.
50. The compound of claim 44, 45, 46, or 47, wherein n is 6.
51. The compound of claim 44, 45, 46, or 47, wherein R1 comprises a substituted or unsubstituted 1,3-dioxane ring.
52. The compoud of claim 44, 45, 46, or 47, wherein R1 is halogen.
53. The compound of claim 44, 45, 46, or 47, wherein R1 is -OR A.
54. The compound of claim 44, 45, 46, or 47, wherein R1 is N(R A)2.
55. The compound of claim 44, 45, 46, or 47, wehrein R1 is -NHR A.
56. The compound of claim 44, 45, 46, or 47, wherein R1 is C1-C6 alkyl.
57. The compound of claim 44, 45, 46, or 47, wherein R1 is substituted or unsubstituted acyl.
58. The compound of claim 44, 45, 46, or 47, wherein R1 is -C(=O)OR A, wherein R A is hydrogen or C1-C6 alkyl.
59. The compound of claim 44, 45, 46, or 47, wherein R1 is -C(=O)N(R A)2, wherein R A is hydrogen or C1-C6 alkyl.
60. The compound of claim 44, 45, 46, or 47, wherein R1 is -C(=O)NH2.
61. The compound of claim 44, 45, 46, or 47, wherein R1 is -CHO.
62. The compound of claim 44, 45, 46, or 47, wherein R1 is -NHC(=O)R A, wherein R A is C1-C6 alkyl.
63. The compound of claim 1 of formula (If):

wherein n is an integer between 1 and 6, inclusive.
64. The compound of claim 63, wherein Ar is substituted or unsubstituted phenyl.
65. The compound of claim 1 of formula (Ig):

wherein R2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR B; -C(=O)R B; -CO2R B; -CN; -SCN; -SR B; -SOR B; -SO2R B; NO2;
-N(R B)2; -NHC(O)R B; or -C(R B)3; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and R3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR C; -C(=O)R C; -CO2R C; -CN; -SCN; -SR C; -SOR C; -SO2R C; NO2, -N(R C)2; -NHC(O)R C; or -C(R C)3; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
66. The compound of claim 65, wherein R2 is -CH2-X(R B) n, wherein X is O, S, or N; and n is 1 or 2
67. The compound of claim 1 of formula (Ih):

wherein n is an integer between 1 and 6, inclusive;
R2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR B; -C(=O)R B; -CO2R B; -CN; -SCN; -SR B; -SOR B; -SO2R B; -NO2;
-N(R B)2; -NHC(O)R B; or -C(R B)3; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and R3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR C; -C(=O)R C; -CO2R C; -CN; -SCN; -SR C; -SOR C; -SO2R C; -NO2;

-N(R C)2; -NHC(O)R C; or -C(R C)3; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
68. The compound of claim 1 of formula (Ii):

wherein R2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR B; -C(=O)R B; -CO2R B; -CN; -SCN; -SR B; -SOR B; -SO2R B; NO2;
-N(R B)2; NHC(O)R B; or -C(R B)3; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and R3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR C; -C(=O)R C; -CO2R C; -CN; -SCN; -SR C; -SOR C; -SO2R C; -NO2;
-N(R C)2; -NHC(O)R C; or -C(R C)3; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;

an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
69. The compound of claim 1 of formula (Ij):

wherein R2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR B; -C(=O)R B; -CO2R B; -CN; -SCN; -SR B; -SOR B; -SO2R B; -NO2;
-N(R B)2; -NHC(O)R B; or -C(R B)3; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and R3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl;
substituted or unsubstitued, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; -OR C; -C(=0)R C; -CO2R C; -CN; -SCN; -SR C; -SOR C; -SO2R C; -NO2;
-N(R C)2; -NHC(O)R C; or -C(R C)3; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio;
amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety.
70. The compound of any one of claims 65, 66, 67, 68, or 69, wherein R2 is
71. The compound of claim 68 of formula (II):

wherein n is an integer between 0 and 5, inclusive; and Z is hydrogen, -(CH2) q OR Z, -(CH2) q SR Z, -(CH2) q N(R Z)2, -C(=O)R Z, -C(=O)N(R Z)2, or an alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety, wherein q is 0-4, and wherein each occurrence of R Z is independently hydrogen, a protecting group, a solid support unit, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl moiety.
72. The compound of claim 71 of formula:

73. A compound of claim 1 of formula:

74. A pharmaceutical composition comprising a compound of one of the claims 1-73 and a pharmaceutically acceptable excipient.
75. A method of inhibiting histone deacetylase, the method comprising steps of:
contacting a histone deacetylase with a compound of one of the claims 1-34.
76. The method of claim 75, wherein the histone deacetylase is purified.
77. The method of claim 75, wherein the histone deacetylase is in a cell.
78. The method of claim 75, 76, or 77, wherein the histone deacetylase is HDAC6.
79. A method of treating a subject with a proliferative disorder, the method comprising steps of:
administering a therapeutically effective amount of a compound of one of claims 1-34 to a subject.
80. The method of claim 79, wherein the subject is a mammal.
81. The method of claim 79, wherein the subject is human.
82. The method of claim 79, 80, or 81, wherein the proliferative disorder is cancer.
83. The method of claim 79, 80, or 81, wherein the proliferative disorder is an inflammatory disease.
84. The method of claim 79, 80, or 81, wherein the proliferative disorder is a proliferative disorder associated with the skin.
85. The method of claim 79, 80, or 81, wherein the proliferative disorder is cutaneous T-cell lymphoma.
86. The method of claim 79, 80, or 81, wherein the proliferative disorder is a skin cancer.
87. The method of claim 79, 80, or 81, wherein the proliferative disorder is a benign skin growth.
88. The method of claim 79, 80, or 81, wherein the proliferative disorder is psoriasis.
89. The method of claim 79, 80, or 81, wherein the proliferative disorder is a dermatitis.
90. The method of claim 79, 80, or 81, wherein the proliferative disorder is neurofibromatosis.
91. The method of any one of claims 79-90, wherein the step of administering comprises administering the compound topically.
92. The method of any one of claims 79-90, wherein the compound is cleaved by an esterase in vivo.
93. The method of claim 92, wherein the compound is cleaved by an esterase found in the bloodstream.
94. The method of any one of claims 79-90, wherein the compound is inactivated by an esterase in vivo.
95. The method of claim 94, wherein the compound is inactivated by an esterase found in the bloodstream.
96. A method of treating a subject with hair loss, the method comprising steps of:
administering a therapeutically effective amount of a compound of any one of claims 1-73 to a subject.
97. A method of treating a subject suffering from skin hyperpigmentation, the method comprising steps of:
administering a therapeutically effective amount of a compound of any one of claims 1-73 to a subject.
98. A method of administering a compound of any one of claims 1-73, the method comprising:
administering topically a compound of any one of claims 1-72 to a subject.
99. The method of claim 98, wherein the step of administering comprises administering the compound to the subject's skin.
100. The method of claim 98, wherein the step of administering comprises administering the compound to the subject's hair.
101. A method for synthesizing a compound of formula (III A), the method comprising steps of:
providing an epoxy alcohol having the structure:

reacting the epoxy alcohol with a reagent having the structure R2XH under suitable conditions to generate a diol having the core structure:

reacting the diol with a reagent having the structure R3CH(OMe)2 under suitable conditions to generate a compound of formula (IIIA):

wherein R1 is hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;

R2 is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
X is -O-, -C(R2A)2-, -S-, or NR2A-, wherein R2A is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
or wherein two or more occurrences of R2 and R2A, taken together, form an alicyclic or heterocyclic moiety, or an aryl or heteroaryl moiety;
R3 is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; and R Z is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety and is optionally attached to a solid support.
102. A method of synthesizing a compound of formula:
the method comprising steps of:
providing an epoxy alcohol having the structure:
reacting the epoxy alcohol with a reagent having the structure R2XH under suitable conditions to generate a diol having the core structure:
subjecting the diol to a reagent having the structure:

wherein R4C is a nitrogen protecting group, under suitable conditions to generate an amine having the structure:

reacting the amine with a reagent having the structure:
under suitable conditions to generate a scaffold having the core structure:
wherein R1 is hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
R2 is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
X is -O-, -C(R2A)2-, -S-, or -NR2A-, wherein R2A is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
or wherein two or more occurrences of R2 and R2A, taken together, form an alicyclic or heterocyclic moiety, or an aryl or heteroaryl moiety;
r is 0 or 1;
s is an integer from 2-5;

w is an integer from 0-4;
R4A comprises a metal chelator;
each occurrence of R4D is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, halogen, CN, NO2, or WR W1 wherein W is O, S, NR W2, -C(=O), -S(=O), -SO2, -C(=O)O-, -OC(=O), -C(=O)NR W2, -NR W2C(=O);
wherein each occurrence of R W1 and R W2 is independently hydrogen, a protecting group, a prodrug moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, or, when W is NR W2, R W1 and R W2, taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety; or any two adjacent occurrences of R2B, taken together with the atoms to which they are attached, form a substituted or unsubstituted, saturated or unsaturated alicyclic or heterocyclic moiety, or a substituted or unsubstituted aryl or heteroaryl moiety; and R Z is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety and is optionally attached to a solid support.
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