Indian Patents
Title of Invention

HISTONE DEACETYLASE INHIBITORS
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 example. The present invention also provides methods for preparing compounds of the invention and intermediates thereto.
Full Text Histone Deacetylase Inhibitors
Related Applications
[0001] The present invention claims priority under 35 U.S.C. § 119(e) to U.S. provisional
patent application, USSN 60/773,172, filed February 14, 2006, which is incorporated herein
by reference.
Background of the Invention
[0002] The identification of small organic molecules that affect specific biological
functions is an endeavor that impacts both biology and medicine. Such molecules are useful
as therapeutic agents and as probes of biological function. In but one example from the
emerging field of chemical genetics, in which small molecules can be used to alter the
function of biological molecules to which they bind, these molecules have been useful at
elucidating signal transduction pathways by acting as chemical protein knockouts, thereby
causing a loss of protein function (Schreiber et al, J. Am. Chem. Soc, 1990,112, 5583;
Mitchison, Chem. and Biol., 1994,1,3). Additionally, due to the interaction of these small
molecules with particular biological targets and their ability to affect specific biological
function, they may also serve as candidates for the development of therapeutics. One
important class of small molecules, natural products, which are small molecules obtained
from nature, clearly have played an important role in the development of biology and
medicine, serving as pharmaceutical leads, drugs (Newman et al., Nat. Prod. Rep. 2000,17,
215-234), and powerful reagents for studying cell biology (Schreiber, S.L. Chem. and Eng.
News 1992 (October 26), 22-32).
[0003] Because it is difficult to predict which small molecules will interact with a
biological target, and it is oftent difficult to obtain and synthesize efficiently small molecules
found in nature, intense efforts have been directed towards the generation of large numbers,
or libraries, of small organic compounds, often "natural product-like" libraries. These
libraries can then be linked to sensitive screens for a particular biological target of interest to
identify the active molecules.
[0004] One biological target of recent interest is histone deacetylase (see, for example, a
discussion of the use of inhibitors of histone deacetylases for the treatment of cancer: Marks
et al. Nature Reviews Cancer 2001,1,194; Johnstone et al. Nature Reviews Drug Discovery
2002, /, 287). Post-translational modification of proteins through acetylarion and

deacetylation of lysine residues has a critical role in regulating their cellular functions.
HDACs are zinc hydrolases that modulate gene expression through deacetylation of the N-
acetyl-lysine residues of histone proteins and other transcriptional regulators (Hassig et al.
Curr. Opin. Chem. Biol 1997,1, 300-308). HDACs participate in cellular pathways that
control cell shape and differentiation, and an HDAC inhibitor has been shown effective in
treating an otherwise recalcitrant cancer (Warrell et al. J. Nail. Cancer Inst. 1998, 90, 1621 -
1625). Eleven human HDACs, which use Zn as a cofactor, have been characterized (Taunton
et al. Science 1996, 272, 408-411; Yang et al J. Biol. Chem. 1997,272, 28001-28007;
Grozinger et al. Proc. Natl. Acad Sd. U.S.A. 1999,96,4868-4873; Kao et al. Genes Dev.
2000,14, 55-66; Hu et al. J. Biol. Chem. 2000, 275, 15254-15264;; Zhou et al. Proc. Natl.
Acad. Set U.S.A. 2001,98, 10572-10577; Venter et al. Science 2001, 291,1304-1351).
These members fall into three related classes (class I, II, and ID). An additional seven
HDACs have been identified which use NAD as a confactor. To date, no small molecules are
known that selectively target either the two classes or individual members of this family ((for
example ortholog-selective HDAC inhibitors have been reported: (a) Meinke et al. J. Med.
Chem. 2000,14, 4919-4922; (b) Meinke, et al. Curr. Med Chem. 2001, 8, 211-235).
Summary of the Invention
[0005] The present invention provides novel histone deacetylase inhibitors and methods
of preparing and using these compounds. The inventive HDAC inhibitors comprise an
esterase-senshive ester linakge, thereby when the compound is exposed to an esterase such as
in the bloodstream the compound is inactivated. The compounds are particularly useful in
the treatment of skin disorders such as cutaneous T-cell lymphoma, neurofibromatosis,
psoriasis, hair loss, dermatitis, baldness, and skin pigmentation. The inventive compound is
adminitered topically to the skin of the patient where it is clinically active. Once the
compound is absoRBed into the body, it is quickly inactivated by esterases which cleave the
compound into two or more biologically inactive fragments. Thus, allowing for high local
concentrations (e.g., in the skin) and reduced systemic toxicity. In certain embodiments, the
compound is fully cleaved upon exposure to serum in less than 5 min., preferably less than 1
mm.
[0006] The present invention provides novel compounds of general formula (I),


and pharmaceutical compositions thereof, as described generally and in subclasses herein,
which compounds are useful as inhibitors of histone deacetylases or other deacetylases, and
thus are useful for the treatment of proliferative diseases. The inventive compounds are
additionally useful as tools to probe biological function. In certain embodiments, the
compounds of the ivention are particularly useful in the treatment of skin disorders. The ester
linkage is susceptible to esterase cleavage, particularly esterases found in the blood.
Therefore, these compounds may be administered topically to treat skin disorders, such as
cutaneous T-cell lymphoma, psoriasis, hair loss, dermatitis, etc., without the risk of systemic
effects. Once the compound enters the bloodstream it is quickly degraded by serum
esterases. Preferably, the compound is degraded into non-toxic, biologically inactive by products.
[0007] In another aspect, the present invention provides methods for inhibiting histone
deacetylase activity or other deacetylase activity in a patient or a biological sample,
comprising administering to said patient, or contacting said biological sample with an
effective inhibitory amount of a compound of the invention. In certain embodiments, the
compounds specifically inhibit a particular HDAC (e.g., HDAC1, HDAC2, HDAC3,
HDAC4, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11) or
class of HDACs (e.g., Class I, IE, or HE). In certain embodiments, the compounds specifically
inhibit HDAC6. In still another aspect, the present invention provides methods for treating
skin disorders involving histone deacetylase activity, comprising administering to a subject in
need thereof a therapeutically effective amount of a compound of the invention. The
compounds may be administered by any method known in the art. In certain embodiments,
the compounds are administered topically (e.g., in a cream, lotion, ointment, spray, gel,
powder, etc.). In certain embodiments, the compound is administered to skin. In other
certain embodiments, the compound is administered to hair. The compounds may also be
administered intravenously or orally. The invention also provides pharmaceutical
compositions of the compounds wherein the compound is combined with a pharmaceutically
acceptable excipient.
[0008] In yet another aspect, the present invention provides methods for preparing
compounds of the invention and intermediates thereof.
Definitions
[0009] Certain compounds of the present invention, and definitions of specific functional
groups are also described in more detail below. For purposes of 1his invention, the chemical

elements are identified in accordance with the Periodic Table of the Elements, CAS version,
Handbook of Chemistry and Physics, 75th Ed., inside cover, and Specific functional groups
are generally defined as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity, are described in Organic
Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of
which are incorporated herein by reference. Furthermore, it will be appreciated by one of
ordinary skill in the art that the synthetic methods, as described herein, utilize a variety of
protecting groups. By the term "protecting group," has used herein, it is meant that a
particular functional moiety, e.g., C, O, S, or N, is temporarily blocked so that a reaction can
be carried out selectively at another reactive site in a multifunctional compound. In preferred
embodiments, a protecting group reacts selectively in good yield to give a protected substrate
that is stable to the projected reactions; the protecting group must be selectively removed in
good yield by readily available, preferably nontoxic reagents that do not attack the other
functional groups; the protecting group forms an easily separable derivative (more preferably
without the generation of new stereogenic centers); and the protecting group has a minimum
of additional functionality to avoid further sites of reaction. As detailed herein, oxygen,
sulfur, nitrogen and caRBon protecting groups may be utilized. Exemplary protecting groups
are detailed herein, however, it will be appreciated that the present invention is not intended
to be limited to these protecting groups; rather, a variety of additional equivalent protecting
groups can be readily identified using the above criteria and utilized in the method of the
present invention. Additionally, a variety of protecting groups ares described in Protective
Groups in Organic Synthesis, Third Ed. Greene, T.W. and Wuts, P.G., Eds., John Wiley &
Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
Furthermore, a variety of caRBon protecting groups are described in Myers, A.; Rung, D. W.;
Zhong, B.; Movassaghi, M.; Kwon, S. J. Am Chem. Soc. 1999,121, 8401-8402, the entire
contents of which are hereby incorporated by reference.
[0010] It will be appreciated that the compounds, as described herein, may be substituted
with any number of substituents or functional moieties. In general, the term "substituted"
whether preceded by the term "optionally" or not, and substituents contained in formulas of
this invention, refer to the replacement of hydrogen radicals in a given structure with the
radical of a specified substituent. When more than one position in any given structure may
be substituted with more than one substituent selected from a specified group, the substituent
may be either the same or different at every position. .As used herein, the term "substituted"
is contemplated to include all permissible substituents of organic compounds. In a broad

aspect, the permissible substituents include acyclic and cyclic, branched and unbranched,
caRBocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
For purposes of this invention, heteroatoms such as nitrogen may liave hydrogen substituents
and/or any permissible substituents of organic compounds described herein which satisfy the
valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any
manner by the permissible substituents of organic compounds. Combinations of substituents
and variables envisioned by this invention are preferably those that result in the formation of
stable compounds useful in the treatment, for example of proliferative disorders, including,
but not limited to cancer. The term "stable", as used herein, preferably refers to compounds
which possess stability sufficient to allow manufacture and which maintain the integrity of
the compound for a sufficient period of time to be detected and preferably for a sufficient
period of time to be useful for the purposes detailed herein.
[0011] The term "acyl", as used herein, refers to a caRBonyl-containing functionality, e.g.,
-C(=O)R' wherein R is an aliphatic, alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
(aliphatic)aryl, (heteroaliphatic)aryl, heteroaliphatic(aryl) or heteroaliphatic(heteroaryl)
moiety, whereby each of the aliphatic, heteroaliphatic, aryl, or heteroaryl moieties is
substituted or unsubstituted, or is a substituted (e.g., hydrogen or aliphatic, heteroaliphatic,
aryl, or heteroaryl moieties) oxygen or nitrogen containing functionality (e.g., forming a
caRBoxylic acid, ester, or amide functionality).
[0012] The term "aliphatic", as used herein, includes both saturated and unsaturated,
straight chain (i.e., unbranched) or branched aliphatic hydrocaRBons, which are optionally
substituted with one or more functional groups. As will be appreciated by one of ordinary
skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl,
alkynyl moieties. Thus, as used herein, the term "alkyl" includes straight and branched alkyl
groups. An analogous convention applies to other generic terms such as "alkenyl", "alkynyl"
and the like. Furthermore, as used herein, the terms "alkyl", "alkenyl", "alkynyl" and the like
encompass both substituted and unsubstitated groups. In certain embodiments, as used
herein, "lower alkyl" is used to indicate those alkyl groups (substituted, unsubstituted,
branched or unbranched) having 1-6 caRBon atoms.
[0013] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the
invention contain 1-20 aliphatic caRBon atoms. In certain other embodiments, the alkyl,
alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic caRBon atoms.
In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention
contain 1-8 aliphatic caRBon atoms. In still other embodiments, the alkyl, alkenyl, and

alkynyl groups employed in the invention contain 1-6 aliphatic caRBon atoms. In yet other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4
caRBon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example,
methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-peniyl, sec-
pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear
one or more substituents. Alkenyl groups include, but are not limited to, for example,
ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like. Representative alkynyl
groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the
like.
[0014] The term "alicyclic", as used herein, refers to compounds which combine the
properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or
polycyclic aliphatic hydrocaRBons and bridged cycloalkyl compounds, which are optionally
substituted with one or more functional groups. As will be appreciated by one of ordinary
skill in the art, "alicyclic" is intended herein to include, but is not limited to, cycloalkyl,
cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more
functional groups. Illustrative alicyclic groups thus include, but are not limited to, for
example, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, -CB2-cycloburyl, cyclopentyl, -CH2-
cyclopentyl-n, cyclohexyl, -CH2-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl,
noRBoRByl moieties and the like, which again, may bear one or more substituents.
[0015] The term "alkoxy" (or "alkyloxy"), or "thioalkyl" as used herein refers to an alkyl
group, as previously defined, attached to the parent molecular moiety through an oxygen
atom or through a sulfur atom. In certain embodiments, the alkyl group contains 1-20
aliphatic caRBon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic
caRBon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in
the invention contain 1-8 aliphatic caRBon atoms. In still other embodiments, the alkyl group
contains 1-6 aliphatic caRBon atoms. In yet other embodiments, the alkyl group contains 1-4
aliphatic caRBon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy,
propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of
thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-
butylthio, and the like.
[0016] The term "alkylamino" refers to a group having the structure -NHR'wherein R' Is
alkyl, as defined herein. The term "aminoalkyl" refers to a group having the structure
NH2R'-, wherein R' is alkyl, as defined herein. In certain embodiments, the alkyl group
contains 1-20 aliphatic caRBon atoms. In certain other embodiments, the alkyl group contains

1-10 aliphatic caRBon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the invention contain 1-8 aliphatic caRBon atoms. In still other
embodiments, the alkyl group contains 1-6 aliphatic caRBon atoms. In yet other
embodiments, the alkyl group contains 1-4 aliphatic caRBon atoms. Examples of alkylamino
include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
[0017] Some examples of substituents of the above-described aliphatic (and other)
moieties of compounds of the invention include, but are not limited to aliphatic;
heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;
heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO2; -
CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)RX; -
CO2(RX); -CON(RX)2; -0C(O)RX; -OCO2RX; -OCONCRX)2 -N(RX)2; -S(O)2RX; -NRX(CO)RX
wherein each occurrence of RX independently includes, but is not limited to, aliphatic,
alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein
any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above
and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic,
and wherein any of the aryl or heteroaryl substituents described above and herein may be
substituted or unsubstituted. Additional examples of generally applicable substituents are
illustrated by the specific embodiments shown in the Examples that are described herein.
[0018] In general, the term "aromatic moiety", as used herein, refers to a stable mono- or
polycyclic, unsaturated moiety having preferably 3-14 caRBon atoms, each of which may be
substituted or unsubstituted. In certain embodiments, the term "aromatic moiety" refers to a
planar ring having p-oRBitals perpendicular to the plane of the ring at each ring atom and
satisfying the Huckel rale where the number of pi electrons in the ling is (4n+2) wherein n is
an integer. A mono- or polycyclic, unsaturated moiety that does not satisfy one or all of these
criteria for aromaticity is defined herein as "non-aromatic", and is encompassed by the term
"alicyclic".
[0019] In general, the term "heteroaromatic moiety", as used herein, refers to a stable
mono- or polycyclic, unsaturated moiety having preferably 3-14 caRBon atoms, each of which
may be substituted or unsubstituted; and comprising at least one heteroatom selected from O,
S and N within the ring (i.e., in place of a ring caRBon atom). In certain embodiments, the
term "heteroaromatic moiety" refers to a planar ring comprising at least on heteroatom,
having p-oRBitals perpendicular to the plane of the ring at each ring atom, and satisfying the
Huckel rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer.

[0020] It will also be appreciated that aromatic and heteroaromatic moieties, as defined
herein may be attached via an alkyl or heteroalkyl moiety and thus also include -
(a]kyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -
(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the plirases "aromatic or
heteroaromatic moieties" and "aromatic, heteroaromatic, -(alkyl)airomatic, -
(heteroalkyl)aromatic, -(heteroalkyl)heteroarornatic, and -(heteroalkyl)heteroaromatic" are
interchangeable. Substitueuts include, but are not limited to, any of the previously mentioned
substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as
disclosed herein, resulting in the formation of a stable compound.
[0021] The term "aryl", as used herein, does not differ significantly from the common
meaning of the term in the art, and refers to an unsaturated cyclic moiety comprising at least
one aromatic ring. In certain embodiments, "aryl" refers to a mono- or bicyclic caRBocyclic
ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl,
tetrahydronaphthyl, indanyl, indenyl and the like.
[0022] The term "heteroaryl", as used herein, does not differ significantly from the
common meaning of the term in the art, and refers to a cyclic aromatic radical having from
five to ten ring atoms of which one ring atom is selected from S, C) and N; zero, one or two
ring atoms are additional heteroatoms independently selected from S, O and N; and the
remaining ring atoms are caRBon, the radical being joined to the rest of the molecule via any
of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,
quinolinyl, isoquinolinyl, and the like.
[0023] It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl
groups) can be unsubstituted or substituted, wherein substitution includes replacement of one
or more of the hydrogen atoms thereon independently with any one or more of the following
moieties including, but not limited to: aliphatic; alicyclic; heteroaliphatic; heterocyclic;
aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl;
heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; F; Cl; Br, I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -
CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)RX; -CO2(RX); -CON(RX)2; -OC(O)RX;
-OCO2RX; -OCON(RX)2; -N(RX)2; -S(O)RX; -S(O)2RX; -NRX(CO)RX wherein each occurrence
of RX independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,
heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic,

heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and
herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated,
and wherein any of the aromatic, heteroaromatic, aryl, heteroaryl, -(alkyl)aryl or -
(alkyl)heteroaryl substituents described above and herein may be substituted or unsubstituted.
Additionally, it will be appreciated, that any two adjacent groups taken together may
represent a 4, 5, 6, or 7-membered substituted or unsubstituted alicyclic or heterocyclic
moiety. Additional examples of generally applicable substituents are illustrated by the
specific embodiments shown in the Examples that are described herein.
[0024] The term "cycloalkyl", as used herein, refers specifically to groups having three to
seven, preferably three to ten caRBon atoms. Suitable cycloalkyls include, but are not limited
to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the
case of aliphatic, alicyclic, heteroaliphatic or heterocyclic moieties, may optionally be
substituted with substituents including, but not limited to aliphatic; alicyclic; heteroaliphatic;
heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;
alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;
alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br, I; -OH; -NO2; -CN; -CF3; -
CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)RX; -CO2(RX); -
CON(RX)2; -OC(0)RX; -OCO2RX; -OCON(RX)2; -NCRX)2; -S(O)2R,:; -NRX(CO)RX wherein
each occurrence of RX independently includes, but is not limited to, aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteioaryl, alkylaryl,
alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic,
alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described
above and herein may be substituted or unsubstituted, branched or unbranched, saturated or
usaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted. Additional examples of
generally applicable substituents are illustrated by the specific embodiments shown in the
Examples that are described herein.
[0025] The term "heteroaliphatic", as used herein, refers to aliphatic moieties in which
one or more caRBon atoms in the main chain have been substituted with a heteroatom. Thus,
a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen,
sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of caRBon atoms. Heteroaliphatic
moieties may be linear or branched, and saturated o runsaturated. In certain embodiments,
heteroaliphatic moieties are substituted by independent replacement of one or more of the
hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic;

alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl;
alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; atylihio;
heteroalkylthio; heteroarylthio; F; Cl; Br, I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -
CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)RX; -CO2(RX); -CON(RX)2; -OC(O)RX;
-OC02RX; -OCON(RX)2; -N(RX)2; -S(O)2RX; -NRX(CO)RX wherein each occurrence of RX
independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,
aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or
heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic,
alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or
unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the
aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be
substituted or unsubstituted. Additional examples of generally applicable substituents are
illustrated by the specific embodiments shown in the Examples that are described herein.
[0026] The term "heterocycloalkyl", "heteroeycle" or "heterocyclic", as used herein,
refers to compounds which combine the properties of heteroaliphatic and cyclic compounds
and include, but are not limited to, saturated and unsaturated mono- or polycyclic cyclic ring
systems having 5-16 atoms wherein at least one ring atom is aheteroatom selected from O, S
and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), wherein
the ring systems are optionally substituted with one or more functional groups, as defined
herein. In certain embodiments, the term "heterocycloalkyl", "heterocycle" or "heterocyclic"
refers to a non-aromatic 5-, 6-, or 7- membered ring or a polycyclic group wherein at least
one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur
heteroatoms may be optionally be oxidized), including, but not limited to, a bi- or tri-cyclic
group, comprising fused six-membered rings having between one and three heteroatoms
independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring
has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds and each 7-
membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be
optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv)
any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative
heterocycles include, but are not limited to, heterocycles such as furanyl, thiofuranyl,
pyranyl, pyrrolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
imidazolidiayl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl,
dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl,
thiadiazolyl, oxadiazolyl, morpholinyl, thiazoiyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,

dithiazolyl, dithiazolidinyl, tetrahydrofuryl, and benzofused derivatives thereo£ In certain
embodiments, a "substituted heterocycle, or heterocycloalkyl or heterocyclic" group is
utilized and as used herein, refers to a heterocycle, or heterocycloalkyl or heterocyclic group,
as defined above, substituted by the independent replacement of one, two or three of the
hydrogen atoms thereon with but are not limited to aliphatic; alicyclic; heteroaliphatic;
heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;
alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy, heteroalkoxy; heteroaryloxy;
alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; - OH; -NO2; -CN; -CF3; -
CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)RX; -CO2(RX); -
CON(RX)2; -OC(O)RX; -OCO2RX; -OCONCRX)2; -N(R)2; -S(O)2RX; -NR,(CO)RX wherein
each occurrence of RX independently includes, but is not limited to, aliphatic, alicyclic,
heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl,
alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic,
alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described
above and herein may be substituted or unsubstituted, branched or unbranched, saturated or
unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substitutents
described above and herein may be substituted or unsubstituted. Additional examples or
generally applicable substituents are illustrated by the specific embodiments shown in the
Examples, which are described herein.
[0027) Additionally, it will be appreciated that any of the alicyclic or heterocyclic
moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto.
Additional examples of generally applicable substituents are illustrated by the specific
embodiments shown in the Examples that are described herein.The terms "halo" and
"halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and
iodine.
[0028] The terms "halo" and "halogen" as used herein refer to an atom selected from
fluorine, chlorine, bromine, and iodine.
[0029] The term "haloalkyl" denotes an alkyl group, as defined above, having one, two,
or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl,
bromoethyl, trifluoromethyl, and the like.
[0030] The term "ammo", as used herein, refers to a primary (-NH2), secondary (-NHRX),
tertiary (-NRXRy) or quaternary (-NlRXRyRz) amine, where RX, Ry and Rz are independently
an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as
defined herein. Examples of amino groups include, but are not limited to, methylamino,

dimethylamino, ethylamino, diethylamino, diethylaminocaRBonyl, methylethylamino, iso-
propylamino, piperidino, trimethylamino, and propylamino.
[0031] The term "alkylidene", as used herein, refers to a substituted or unsubstituted,
linear or branched saturated divalent radical consisting solely of caRBon and hydrogen atoms,
having from one to n caRBon atoms, having a free valence "-" at both ends of the radical.
[0032] The term "alkenylidene", as used herein, refers to a substituted or unsubstituted,
linear or branched unsaturated divalent radical consisting solely of caRBon and hydrogen
atoms, having from two to n caRBon atoms, having a free valence "-" at both ends of the
radical, and wherein the unsaturation is present only as double bonds and wherein a double
bond can exist between the first caRBon of the chain and the rest of the molecule.
[0033] The term "alkynylidene", as used herein, refers to a substituted or unsubstituted,
linear or branched unsaturated divalent radical consisting solely of caRBon and hydrogen
atoms, having from two to n caRBon atoms, having a free valence "-" at both ends of the
radical, and wherein the unsaturation is present only as triple bonds and wherein a triple bond
can exist between the first caRBon of the chain and the rest of the molecule.
[0034] Unless otherwise indicated, as used herein, the terms "alkyl", "alkenyl",
"alkynyl", "heteroalkyl", "heteroalkenyl", "heteroalkynyl", "alkylidene", alkenylidene", -
(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)heieroaryl, and the like
encompass substituted and unsubstituted, and linear and branched groups. Similarly, the
terms "aliphatic", "heteroaliphatic", and the like encompass substituted and unsubstituted,
saturated and unsaturated, and linear and branched groups. Similarly, the terms "cycloalkyl",
"heterocycle", "heterocyclic", and the like encompass substituted and unsubstituted, and
saturated and unsaturated groups. Additionally, the terms "cycloaJkenyl", "cycloalkynyl",
"heterocycloalkenyl", "heterocycloalkynyl", "aromatic", "heteroaromatic, "aryl",
"heteroaryl" and the like encompass both substituted and unsubstituted groups.
[0035] The phrase, "pharmaceuticaJly acceptable derivative", as used herein, denotes any
pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other
adduct or derivative which, upon administration to a patient, is capable of providing (directly
or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is
a derivative of a compound, usually with significantly reduced pharmacological activity,
which contains an additional moiety, which is susceptible to removal in vivo yielding the
parent molecule as the pharmacologically active species. An example of a pro-drug is an
ester, which is cleaved in vivo to yield a compound of interest Pro-drugs of a variety of

compounds, and materials and methods for derivatizing the parent compounds to create the
pro-drugs, are known and may be adapted to the present invention. Pharmaceutically
acceptable derivatives also include "reverse pro-drugs." Reverse pro-drugs, rather than being
activated, are inactivated upon absorption. For example, as discussed herein, many of the
ester-containing compounds of the invention are biologically active but are inactivated upon
exposure to certain physiological environments such as a blood, lymph, serum, extracellular
fluid, etc. which contain esterase activity. The biological activity of reverse pro-drugs and
pro-drugs may also be altered by appending a functionality onto the compound, which may
be catalyzed by an enzyme. Also, included are oxidation and reduction reactions, including
en2yme-cata!yzed oxidation and reduction reactions. Certain exemplary pharmaceutical
compositions and pharmaceutically acceptable derivatives will be discussed in more detail
herein below.
[0036] The term "linker," as used herein, refers to a chemical moiety utilized to attach
one part of a compound of interest to another part of the compound. Exemplary linkers are
described herein.
[0037] Unless indicated otherwise, the terms defined below have the following meanings:
[0038] "Compound": The term "compound" or "chemical compound" as used herein can
include organometallic compounds, organic compounds, metals, transitional metal
complexes, and small molecules. In certain preferred embodiments, polynucleotides are
excluded from the definition of compounds. In other preferred embodiments,
polynucleotides and peptides are excluded from the definition of compounds. In a
particularly preferred embodiment, the term compounds refers to small molecules (e.g.,
preferably, non-peptidic and non-oligomeric) and excludes peptides, polynucleotides,
transition metal complexes, metals, and organometallic compounds.
[0039] "Small Molecule": As used herein, the term "small molecule" refers to a non-
peptidic, non-oligomeric organic compound either synthesized in the laboratory or found in
nature. Small molecules, as used herein, can refer to compounds that are "natural product-
like", however, the term "small molecule" is not limited to "natural product-like"
compounds. Rather, a small molecule is typically characterized in that it contains several
caRBon-caRBon bonds, and has a molecular weight of less than 2000 g/mol, preferably less
than 1500 g/mol, although this characterization is not intended to be limiting for the purposes
of the present invention. Examples of "small molecules" that occur in nature include, but are
not limited to, taxol, dynemicin, and rapamycin. Examples of "small molecules" mat are
synthesized in the laboratory include, but are not limited to, compounds described in Tan et

al,, ("Stereoselective Synthesis of over Two Million Compounds Having Structural Features
Both Reminiscent of Natural Products and Compatible with Miniaturized Cell-Based Assays"
J. Am. Chem. Soc. 120:8565, 1998; incorporated herein by reference). In certain other
preferred embodiments, natural-product-like small molecules are utilized.
[0040] "Natural Product-Like Compound": As used herein, the term "natural product-
like compound" refers to compounds that are similar to complex natural products which
nature has selected through evolution. Typically, these compounds contain one or more
stereocenters, a high density and diversity of functionality, and a diverse selection of atoms
within one structure. In this context, diversity of functionality can. be defined as varying the
topology, charge, size, hydrophilicity, hydrophobicity, and reactivity to name a few, of the
functional groups present in the compounds. The term, "high density of functionality", as
used herein, can preferably be used to define any molecule that contains preferably three or
more latent or active divers ifiable functional moieties. These structural characteristics may
additionally render the inventive compounds functionally reminiscent of complex natural
products, in that they may interact specifically with a particular biological receptor, and thus
may also be functionally natural product-like.
[0041] "Metal chelator": As used herein, the term "metal chelator" refers to any
molecule or moiety that is is capable of forming a complex (i.e., "chelates") with a metal ion.
In certain exemplary embodiments, a metal chelator refers to to any molecule or moiety that
"binds" to a metal ion, in solution, making it unavailable for use in chemical/enzymatic
reactions. In certain embodiments, the solution comprises aqueous environments under
physiological conditions. Examples of metal ions include, but are not limited to, Ca2+, Fe3+,
Zn2+, Na+, etc. In certain embodiments, the metal chelator binds Zr,n2+. In certain
embodiments, molecules of moieties that precipitate metal ions are not considered to be metal
chelators.
[0042] As used herein the term "biological sample" includes, without limitation, cell
cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or
extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts
thereof. For example, the term "biological sample" refers to any solid or fluid sample
obtained from, excreted by or secreted by any living organism, including single-celled micro-
organisms (such as bacteria and yeasts) and multicellutar organisms (such as plants and
animals, for instance a vertebrate or a mammal, and in particular a. healthy or apparently
healthy human subject or a human patient affected by a condition or disease to be diagnosed
or investigated). The biological sample can be in any form, including a solid material such as

a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a
biological fluid. The biological fluid may be obtained from any site (e.g., blood, saliva (or a
mouth wash containing buccal cells), tears, plasma, serum, urine, bile, cerebrospinal fluid,
amniotic fluid, peritoneal fluid, andpleural fluid, or cells therefrom, aqueous or vitreous
humor, or any bodily secretion), atransudate, an exudate {e.g. fluid obtained from an abscess
or any other site of infection or inflammation), or fluid obtained from a joint (e.g. a normal
joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout or septic
arthritis). The biological sample can be obtained from any organ or tissue (including a biopsy
or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or
medium conditioned by any cell, tissue or organ. Biological samples may also include
sections of tissues such as frozen sections taken for histological purposes. Biological samples
also include mixtures of biological molecules including proteins, lipids, caRBohydrates and
nucleic acids generated by partial or complete fractionation of cell or tissue homogenates.
Although the sample is preferably taken from a human subject, biological samples may be
from any animal, plant, bacteria, virus, yeast, etc. The term animal, as used herein, refers to
humans as well as non-human animals, at any stage of development, including, for example,
mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live
tissue samples are considered to be pluralities of animals. In certain exemplary embodiments,
the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog,
a cat, a sheep, cattle, a primate, or a pig). An animal may be a transgenic animal or a human
clone. If desired, the biological sample may be subjected to preliminary processing,
including preliminary separation techniques.
Brief Description of the Drawing
[0043] Figure 1 includes a table of esterases found in human and mouse plasma.
[0044] Figure 2 shows the design of a reverse pro-drug version of SAHA—SAHP.
[0045] Figure 3 illustrates the stability of SAHA (with an amide) in PBS.
[0046] Figure 4 illustrates the stability of SAHA in serum.
[0047] Figure 5 shows the stability of SAHP (ester instead of amdie) in PBS.
[0048] Figure 6 shows the degradation of SAHP in serum. In less than 15 minutes,
SAHP is completely degraded.
[0049] Figure 7 shows a more detailed study of the degradation of SAHP in serum. In
less than 2 minutes, SAHP is completely degraded into phenol and the corresponding
caRBoxylic acid.

[0050] Figure 8 shows the degradation of SAHP by human serum under various
conditions.
[0051] Figure 9 shows the degradation of SAHP by recombinant paraoxonase.
[0052] Figure 10 shows the degradation of SAHP in RPMI media with 10% FBS.
[0053] Figure 11 shows the effect of SAHA v. SAHP on lysine acetylation.
[0054] Figure 12 shows the stability of SAHP in an olive oil/acetone formulation for
murine model.
[0055] Figure 13 is an exemplary synthetic scheme for preparing SAHP.
[0056] Figure 14. Interleukin-7 is a growth factor for T-cell development, in particular
the gamma-delta subset Transgenic mice overexpressing IL-7 in keratinocytes were
developed by the laboratories of Thomas Kupper and Benjamin Rich, using a tissue-specific
keratin-14 promoter element These mice have been reported to develop a characteristic
lymphoproliferative skin disease grossly and histologically similar to human cutaneous T-cell
lymphoma (CTCL). Transformed lymphocytes derived from involved skin were passaged ex
vivo and injected into syngeneic (non-transgenic) mice. After fourteen days, these mice
develop a homogeneous lymphoproliferative disease. Two cohorts of five mice were
included in a prospective study of topical, daily suberoyl hydroxamic acid phenyl ester
(SAHP, also known as SHAPE) versus vehicle control. After fourteen days of therapy, mice
were sacrificed and the treated region was dissected for histopathologic examination. In
SHAPE-treated mice, hematoxylin-eosin staining demonstrates a marked reduction in
lymphomatous infiltration within the treated window. Vehicle control mice failed to
demonstrate a cytotoxic response.
[0057] Figure 15 shows the pharmacodynamic effect of SAHP treatment as assessed
using immunohistochemical staining for acetylated histones compared to vehicle treated
controls. In SAHP-treated mice, AcH3K18 staining demonstrates hyperacetylated histone
staining at the margin of compound treatment, with absent nuclear staining in the region of
drag response. Vehicle control mice failed to demonstrate an increase in histone
hyperacetylation.
Detailed Description of the Invention
[0058] As discussed above, there remains a need for the development of novel histone
deacetylase inhibitors. The present invention provides novel compounds of general formula
(I), and methods for the synthesis thereof, which compounds are useful as inhibitors of
histone deacetylases, and thus are useful for the treatment of proliferative diseases,

particularly proliferative or other disorders associated with the skin and/or hair. In particular,
the inventive compounds comprise an ester linkage. The ester linkage is preferably sensitive
to esterase cleavage; therefore, when the compound is contacted •with an esterase it is
deactivated.
Compounds of the Invention
[0059] As discussed above, the present invention provides a novel class of compounds
useful for the treatment of cancer and other proliferative conditions related thereto. In certain
embodiments, the compounds of the present invention are useful as inhibitors of histone
deacetylases and thus are useful as anticancer agents, and thus may be useful in the treatment
of cancer, by effecting tumor cell death or inhibiting the growth of tumor cells. In certain
exemplary embodiments, the inventive anticancer agents are useful in the treatment of
cancers and other proliferative disorders, including, but not limited to breast cancer, cervical
cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-
Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer,
to name a few. In certain embodiments, the inventive anticancer zigents are active against
leukemia cells and melanoma cells, and thus are useful for the treatment of Ieukemias (e.g.,
myeloid, lymphocytic, myelocytic and lymphoblastic Ieukemias) ;ind malignant melanomas.
In certain embodiments, the inventive compouns are active against cutaneous T-cell
rymphoma. Additionally, as described above and in the exemplification, the inventive
compounds may also be useful in the treatment of protozoal infections. In certain exemplary
embodiments, the compounds of the invention are useful for disorders resulting from histone
deacetylation activity. In certain embodiments, the compounds ars useful for skin disorders.
Examplary skin disorders that may be treated using the inventive compounds include
cutaneous T-cell lymphoma (CTCL), skin cancers (e.g., squamous cell carcinoma, basal cell
carcinoma, malignant melanoma, etc.), psoriasis, hair loss, dermatitis, neurofibromatosis,
disorders asscoiated with skin hyperpigmentation, etc.
[0060] Compounds of this invention comprise those, as set foith above and described
herein, and are illustrated in part by the various classes, subgenera and species disclosed
elsewhere herein.
[0061] In general, the present invention provides compounds having the general structure
(1):

and phannaceutically acceptable salts and derivatives thereof;
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.
[0062] In certain embodiments, A comprises a metal chelating functional group. For
example, A comprises a Zn2+ chelating group. In certain embodiments, A comprises a
functional group selected group consisting of:

and phannaceutically acceptable salts and derivatives thereof;
wherein
A comprises a functional group that inhibits histone deacetylase;
L is a linker moiety; and
Ax 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.
[0062] In certain embodiments, A comprises a metal chelating functional group. For
example, A comprises a Zn2+ chelating group. In certain embodiments, A comprises a
functional group selected group consisting of:



SH).
[0063] In certain embodiments, Ar is arylaliphatic. In other embodiments, Ar is
heteroarylaliphatic. In certain embodiments, Ar is a substituted or unsubstituted aryl moiety.
In certain embodiments, Ar is a monocylic, substituted or unsubstituted aryl moiety,
preferably a five- or six-membered aryl moiety. In other embodiments, Ar is a bicyclic,
substituted or unsubstituted aryl moiety. In still other embodiments, Ar is a tricyclic,
substituted or unsubstituted aryl moiety. In certain embodiments, Ar is a susbstituted or
unsubstituted phenyl moiety. In certain embodiments, Ar is an unsubstituted phenyl moiety.
In other embodiments, Ar is a substituted phenyl moiety. In certain embodiments, Ar is a
monosubstituted phenyl moiety. In certain particular embodiments, Ar is an ortho-substituted
Ar moiety. In certain particular embodiments, Ar is an meta-substituted Ar moiety. In
certain particular embodiments, Ar is an para-substituted Ar moiety. In certain embodiments,
Ar is a disubstituted phenyl moiety. In certain embodiments, Ar is a trisubstituted phenyl
moiety. In certain embodiments, Ar is a tetrasubstituted phenyl moiety. In certain
embodiments, Ar is a substituted or unsubstituted cyclic or heterocyclic.
[0064] In certain embodiments, Ar is a substituted or unsubstituted heteroaryl moiety. In
certain embodiments, Ar is a monocylic, substituted or unsubstituted heteroaryl moiety,
preferably a five- or six-membered heteroaryl moiety. In other embodiments, Ar is a
bicyclic, substituted or unsubstituted heteroaryl moiety. In still other embodiments, Ar is a
tricyclic, substituted or unsubstituted heteroaryl moiety. In certain embodiments, Ar

comprises N, S, or O. In certain embodiments, Ar comprises at least one N. In certain
embodiments, Ar comprises at least two N.
[0065] In certain embodiments, Ar is:

wherein
n is an integer between 1 and 5, inclusive; preferably, between 1 and 3, inclusive;
more preferably, 1 or 2;
R1 is 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; -ORA; -C(=O)RA; -CO2KA, -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)2; ; -NHRA; -NHC(O)RA; or-C(RA)3; wherein each occurrence of RA is independently
a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkyhhio; arylthio; amino, alkylamino,
dialkylamino, heteroaryloxy; or heteroarylthio moiety. In certain embodiments, Ar is

C6 alkyl. In certain embodiments, R1 is -ORA, wherein RA is hydrogen or C1-C6 alkyl. In
certain particular embodiments, R1 is -OMe. In certain embodiments, R1 is branched or
unbranched acyl. In certain embodiments, R1 is -O(=O)0RA. In certain embodiments, R1 is
-C(=O)ORA, wherein RA is hydrogen or C1-C6 alkyl. In certain embodiments, R1 is -
C(=O)NH2,. In certain embodiments, R, is -NHC(-O)RA. In certain embodiments, R1 is -
N'HC(-O)RA, wherein RA is hydrogen or Ci-C6 alkyl. In certain embodiments, R1 is halogen.
In certain embodiments, R1 is C1-C6 alkyl.
[0066] In certain particular embodiments, Ar is a substituted phenyl moiety of formula:


wherein
n is an integer between 1 and 4, inclusive; preferably, between 1 and 3, inclusive;
more preferably, 1 or 2;
R1 is 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
unbranchod hcteroaryl: -ORA; CY-O)RA, -CO2RA, -CN; -SCN; -SKA; -SORA; -SO2RA; NO,;
-N(RA)2; ; -NHRA; -NHC(O)RA; or -C(RA)3; wherein each occurrence of RA 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; alylthio; amino, alkylamino,
dialkylamino, heteroaryloxy; or heteroaiylthio moiety.
[0068] In certain embodiments, Ar is chosen from one of the following:

Any of the above bicyclic ring system may be substituted with up to seven R1 susbstituents as
defined above.
[0069] In certain embodiments, L is a substituted or unsubstituted, cyclic or acyclic,
branched or unbranched aliphatic moiety; a substituted or unsubstitnted, cyclic or acyclic,
branched or unbranched heteroaliphatic moiety; a substituted or unsubstituted aryl moiety; a
substituted or unsubstituted heteroaryl moiety. In certain embodiments, L is a substituted or
unsubstituted, cyclic or acyclic, branched or unbranched aliphatic moiety. In certain

embodiments, L is C1-C20 alkylidene, preferably C1 to C12 alkylidene, more preferably C4-C7
alkylidene. In certain embodiments, L is C1-C20 alkenylidene, preferably C1 to C12
alkenylidene, more preferably C4-C7 alkenylidene. In certain embodiments, L is C1-C20
alkynylidene, preferably C1 to C12 alkynylidene, more preferably C4-C7 allcynylidene. In
certein embodiments, L is a a substituted or tinsubstituted, cyclic or acyclic, branched or
unbranched heteroaliphatic moiety. In certain embodiments, L comprises a cyclic ring
system, wherein the rings may be aryl, heteroaryl, non-aromatic caRBocyclic, or non-aromatic
heterocyclic. In still other embodiments, L comprises a substituted or unsubstituted
heteroaryl moiety. In certain particular embodiments, L comprises a phenyl ring. In certain
embodiments, L comprises multiple phenyl rings (e.g., one, two, three, or four phenyl rings).

1 and 4, inclusive; preferably, between 1 and 3, inclusive; more preferably, 1 or 2; and R1 is
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; -ORA; -C(=O)RA; -CO2RA; -CN; -SCN; -SRA -SORA; -SO2RA; -NO2;
-N(RA)2;; -NHRA; -NKC(O)RA; or -C(RA)3; wherein each occurrence of RA 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 heteroarythio moiety. Incertain embodiments, L is

[0072] In certain embodiments, L is an unbranched, unsubstituted, acyclic alkyl chain. In
certain embodiments, L is .In other embodiments, L is
. In certain other embodiments, L is


[0074] In certain embodiments, L is an unbranched, unsubstituted, acyclic heteroaliphatic
chain. In certain particular embodiments, L is , wherein n is an integer
between 0 and 10, inclusive; preferably, between 0 and 5, inclusive; and m is an integer
between 0 and 10, inclusive; preferably, between 0 and 5, inclusive. In certain particular
embodiments, L is herein n is an integer between 0 and 10, inclusive;
preferably, between 0 and 5, inclusive; and m is an integer between 0 and 10, inclusive;
preferably, between 0 and 5, inclusive. In certain particular embodiments, L is
, wherein n is an integer between 0 and 10, inclusive; preferably, between 0
and 5, inclusive; m is an integer between 0 and 10, inclusive; preferably, between 0 and 5,
inclusive; and R' is hydrogen, C1-C6 aliphatic, heteroaliphatic, aryl, heteroaryl, or acyl. In
certain particular embodiments, L i herein n is an integer between 0 and
10, inclusive; preferably, between 0 and 5, inclusive; and m is an integer between 0 and 10,
inclusive; preferably, between 0 and 5, inclusive.
[00751 IN certain embodiments of the invention, compounds of formula (I) have the
following structure as shown in formula (la):

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

AT is defined as above. In certain embodiments, n is 5. In other embodiments, n is 6.
In still other embodiments, n is 7.
[0076] In certain embodiments of the invention, compounds of formula (I) have the
following structure as shown in formula (1b):
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;
m is an integer between 1 and 5, inclusive; preferably, m is 1, 2, or 3; 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; -ORA; -C(O)RA; -CO2RA; -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)2; -NHC(O)RA; or -C(RA)3; wherein each occurrence of RA 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. In certain embodiments, R1 is
hydrogen, halogen, hydroxy, amino, alkylamino, dialkylamino, nitroso, acyl, or C1-C6 alkyl.
In certain embodiments, R1 is aryl. In certain embodiments, R1 is a multicyclic aryl moiety.
In other embodiments, R1 is heteroaryl. In certain embodiments, R1 is caRBocyclic. In other
embodiments, R1 is heterocyclic. In certain embodiments R1 comprises a 1,3-dioxane ring
optionally substituted. In certain embodiments, n is 5. In other embodiments, n is 6. In still
other embodiments, n is 7. In certain embodiments, m is 0. In other embodiments, m is 1. In
still other embodiments, m is 2.
[0077] In certain embodiments of the invention, compounds of formula (I) are of the
formula (1c):


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 beteroaryl; -ORA; -C(=O)RA; -CO2RA; -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)2; -NHC(O)RA; or -C(RA)3; wherein each occurrence of RA 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. In certain embodiments, R1 is
hydrogen, halogen, hydroxy, amino, alkylamino, dialkylamino, nitroso, acyl, or C1-C6 alkyl
In certain embodiments, R1 is aryl. In other embodiments, R1 is heteroaryl. In certain
embodiments, R1 is caRBocyclic. In other embodiments, R1 is heterocyclic. In certain
embodiments, n is 5. In other embodiments, n is 6. In still other embodiments, n is 7.
[0078] In certain embodiments of the invention, compounds of formula (1) are of the
formula (Id):

wherein
n is an integer between 1 and 5, inclusive; preferably, between 1 and 3; more
preferably, 1 or 2; and
R1 is hydrogen; halogen; cyclic or acyclic, substituted or uosubstituted, 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; -ORA; -C(=O)RA; -CO2RA; -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)2.; -NHC(O)RA; or -C(RA}A; wherein each occurrence of RA 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,

dialkylainino, heteroaryloxy; or heteroaryltbio moiety. In certain embodiments, R1 is
hydrogen, halogen, hydroxy, amino, alkylamino, dialkylamino, nitroso, acyl, or C1-C6 alkyl.
In certain embodiments, R1 is aryl. In other embodiments, R1 is heteroaryl. In certain
embodiments, R1 is caRBocyclic. In other embodiments, R1 is heterocyclic. In certain
embodiments, n is 1. In other embodiments, n is 2.
[0079] In certain embodiments of the invention, compounds of formula (I) are of the
formula (Ie):

wherein R1 is defined as above.
[0080] In certain embodiments of the invention, compounds of formula (I) have the
following stereochemistry and structure as shown in formula (If):

wherein A, L and Ar are defined as above; and
n is an integer between 0 and 10, inclusive; preferably, between 0 and 5, inclusive;
even more preferably, 0,1,2, or 3. In certain embodiments, Ar is phenyl.
[0081] In certain embodiments, compounds of formula (I) are of the formula (Ig):
wherein
A and L are defined as above;
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

unsubstirued, branched or unbranched aryl; substituted or unsubstituted, branched or
unbranched heteroaryl; -ORB; -C(=O)RB; -CO2RB; -CN; -SCN; -S'RB; -SORB; -SO2RB; -NO2;
-N(RB)2; -NHC(O)RB; or -C(RB)3; wherein each occurrence of RB 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; aiylthio; 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; -ORc; -C(=O)RC; -CO2Rc; -CN; -SCN; -SRc; -SORc; -SO2Rc; -NO2;
-N(Rc)2; -NHC(O)Rc; or -C(Rc)3-: wherein each occurrence of Rc 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.
[0082] In certain embodiments, R2 is hydrogen. In other embodiments, R2 is hydroxyl or
a protected hydroxyl group. In certain embodiments, R2 is alkoxy. In yet other
embodiments, R2 is a lower alkyl, alkenyl, or alkynyl group. In certain embodiments, R2 is -
CH2-X(RB)n, wherein X is O, S, N, or C, preferably O, S, or N; and n is 1, 2, or 3. In certain
embodiments, R2 is-CH2-ORB. In other embodiments, R2 is-CH2-SRB- In yet other
embodiments, R2 is -CH2-RB- In other embodiments, R2 is -CH2--N(RB)2. In still other
embodiments, R2 is -CH2NHRB- In certain embodiments of the invention, RB is one of:



wherein m and p are each independently integers from 0 to 3; q1 is an integer from 1
to 6; R2C is hydrogen, lower alkyl or a nitrogen protecting group; and each occurrence of R2B
is independently hydrogen, halogen, -CN, or WRW1 wherein W is O, S, NRW2, -C(=O), -
S(=O), -SO2, -C(=O)O-, -OC(=O), -C(=O)NRW2, -NRw2C(=O); wherein each occurrence of
RW1 and Rw2 is independently hydrogen, a protecting group, a prodrug moiety or an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, or, when W is NRw2, RW1 and
R 2, 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. In certain
embodiments of the invention, RB is one of the structures:

xx
wherein m is an integer from 1 to 4; R2C is hydrogen, lower alkyl or a nitrogen protecting
group; and each occurrence of R2B is independently hydrogen, halogen, -CN, or WRW1
wherein W is O, S, NRw2, -C(=O), -S(=O), -SO2, -C(=O)O-, -OC(=O), -C(=O)NRW2, -
NRW2C(=O); wherein each occurrence of Rm and RW2 is independently hydrogen, a
protecting group, a prodrug moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NRw2, Rw1 and Rw2, taken together with the nitrogen atom
to which they are attached, form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R28, 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.
[0083] In certain embodiments, -X(RB)n has one of the structures:




[0085] In certain embodiments, K3 is substituted or unsubsututed aryl. in certain
embodiments, R3 is substituted or unsubstituted phenyl. In certain particular embodiments,R3
is monosubstituted phenyl. In certain embodiments, R3 is para-substituted phenyl. In certain
embodiments, wherein R3' is hydrogen, a protecting group, a
solid support unit, an alkyl, acyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, -



n is an. integer between 0 and 10, inclusive; preferably, between 1 and 6, inclusive;
more preferably, between 1 and 3, inclusive; and even more preferably, 0,1,2, or 3;
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; -ORB; -C(=O)Rs; -CO2RB; -CN; -SCN; -SRB; -SORB; -SO2RB; -NO2;
-NCRB)2; -NHC(O)RB; or -C(RB)3; wherein each occurrence of RB is independently a
hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylfbio; arylthio; amino, alkylamino,
dialkylamino, heteroaryloxy; or heteroarylihio 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; -ORc; -C(=O)Rc; -CO2Rc; -CN; -SCN; -SRc; -SORc; -SO2Rc; -NO2;
-NCRc)2; -NHC(0)Rc; or -C(Rc)3; wherein each occurrence of Rc 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.
[0088] In certain embodiments, R2 is hydrogen. In other embodiments, R2 is hydroxyl or
a protected hydroxyl group. In certain embodiments, R2 is alkoxy. In yet other
embodiments, R2 is a lower alkyl, alkenyl, or alkynyl group. In certain embodiments, R2 is -
CH2-X(RB)D, wherein X is O, S, N, or C, preferably O, S, or N; and n is 1, 2, or 3. In certain
embodiments, R2 is -CH2-ORB. In other embodiments, R2 is -CH2-SRB. In yet other
embodiments, R2 is -CH2-RB- In other embodiments, R2 is -CH2-N(RB)2- In still other
embodiments, R2 is —CH2-NHRB. In certain embodiments of the invention, RB is one of:



wherein m and p are each independently integers from 0 to 3; q1 is an integer from 1
to 6; R2C is hydrogen, lower alkyl or a nitrogen protecting group; and each occurrence of R2B
is independently hydrogen, halogen, -CN, or WRW1 wherein W is O, S, NRW2, -C(=O), -
S(=O), -SO2, -C(=O)O-, -OC(=O), -C(=O)NRW2, -NRw2C(=O); wherein each occurrence of

R and R is independently hydrogen, a protecting group, a prodrug moiety or an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, or, when W is NRW2, RW1 and
RW2, 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. In certain
embodiments of the invention, RB is one of the structures:

wherein m is an integer from 1 to 4; R2C is hydrogen, lower alkyl or a nitrogen protecting
group; and each occurrence of R23 is independently hydrogen, halogen, -CN, or WRW1
wherein W is O, S, NRW2, -C(=O), -S(=O), -SO2, -C(=O)0-, -OC(=O), -C(=O)NRW2, -
NRW2C(=O); wherein each occurrence of RW1 andRw2 is independently hydrogen, a
protecting group, a prodrug moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NRw2, RW1 and Rw2, taken together with the nitrogen atom
to which they are attached, form a heterocyclic or heteroaryl moierty; 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.
[0089] In certain embodiments, -X(RB)n has one of the structures:




[0091] In certain emDocuments, K3 IS substitued or unsuostitutea aryl. in certain
embodiments, R3 is substituted or unsubstituted phenyi. In certain particular embodiments,R3
is monosubstituted phenyi. In certain embodiments, R3 is para-substituted phenyi. In certain
embodiments, wherein R3' is hydrogen, a protecting group, a
solid support unit, an alkyl, acyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, -



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; -ORB; -C(=O)RB; -CO2RB; -CN; -SCN; -SRB; -SORB; -SO2RB; -NO2;
-N(RB)2; -NHC(O)RB; or -C(RB)3; wherein each occurrence of RB 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; -ORc; -C(=O)Rc; -CO2Rc; -CN; -SCN; -SRc; -SORc; -SO2Rc; -NO2;
-N(Rc)2; -NHC(O)Rc; or -C(Rc)3; wherein each occurrence of Re 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.
[0094} In certain embodiments, R2 is hydrogen. In other embodiments, R2 is hydroxyl or
a protected hydroxyl group. In certain embodiments, R2 is alkoxy. In yet other
embodiments, R2 is a lower alkyl, alkenyl, or alkynyl group. In certain embodiments, R2 is -
CH2-X(RB)n,, wherein X is O, S, N, or C, preferably O, S, or N; and n is 1,2, or 3. In certain
embodiments, R2 is -CH2-ORB. In other embodiments, R2 is -CH2-SRB. In yet other
embodiments, R2 is -CH2-RB. In other embodiments, R2 is -CH2-NCRB)2 In still other
embodiments, R2 is -CH2-NHRB. In certain embodiments of the invention, RB is one of:



wherein m and p are each independently integers from 0 to 3; q1 is an integer from 1
to 6; R2C is hydrogen, lower alkyl or a nitrogen protecting group; and each occurrence of R2B
is independently hydrogen, halogen, -CN, or WRW1 wherein W is 0, S, NRW2, -C(=0), -
S(=0), -S02, -C(=0)0-, -0C(=0), -C(=O)Rw2, -NRW2C(=O): wherein each occurrence of
R"l and Rw2 is independently hydrogen, a protecting group, a prodrug moiety or an alkyl,
cycloaliyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, or, when W is NRw2, Rw1 and
RW2, 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. In certain
embodiments of the invention, Rs is one of the structures:

wherein m is an integer from 1 to 4; R2C is hydrogen, lower alkyl or a nitrogen protecting
group; and each occurrence of R23 is independently hydrogen, halogen, -CN, or WRW1
wherein W is O, S, NRW2, -C(=O), -S(=O), -SO2, -C(=O)O-, -OC(=O), -C(=O)NRW2, -
NR.W2C(=O); wherein each occurrence of RW1 and RW2 is independently hydrogen, a
protecting group, a prodrug moiety or an alkyl, cyeloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NRW2, Rw1 and Rw2, taken togeiher with the nitrogen atom
to which they are attached, form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R28, 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.
[0095] In certain embodiments, -X(RB)N has one of the structures:




[0097] In certain embodiments, R3 is substituted or unsubstituted aryl. In certain
embodiments, R3 is substituted or unsubstituted phenyl. In certain particular embodiments, R3
is monosubstituted phenyl. In certain embodiments, R3 is para-substituted phenyl. In certain
embodiments wherein R3' is hydrogen, a protecting group, a
solid support unit, an alkyl, acyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, -



wherein
R2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or
uubranched 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; -ORB; -C(=O)RB; -CO2RB; -CN; -SCN; -SRB; -SORB; -SO2RS; -NO2;
-N(RB)2; -NHC(O)RB; or -C(RB)3; wherein each occurrence of RB 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; -ORc; -C(=O)Rc; -CO2Rc; -CN; -SCN; -SRc; -SORc; -SO2Rc; -NO2;
-N(Rc)2; -NHC(O)Rc; or -C(Rc)3; wherein each occurrence of Re 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.
[00100] In certain embodiments, R2 is hydrogen. In other embodiments, R2 is hydroxyl or
a protected hydroxyl group. In certain embodiments, R2 is alkoxy. In yet other
embodiments, R2 is a lower alkyl, alkenyl, or alkynyl group. In cesrtain embodiments, R2 is -
CH2-X(RB)n, wherein X is O, S, N, or C, preferably O, S, orN; and n is 1,2, or 3. In certain
embodiments, R2 is -CH2-ORB. In other embodiments, R2 is -CH2-SRB. In yet other
embodiments, R2 is -CH2-RB. In other embodiments, R2 is -CH2-N(RB)2. In still other
embodiments, R2 is -CH2-NER.B. In certain embodiments of the invention, RB is one of:



wherein m and p are each independently integers from 0 to 3; q1 is an integer from 1
to 6; R2c is hydrogen, lower alkyl or a nitrogen protecting group; and each occurrence of R2B
is independently hydrogen, halogen, -CN, or WRW1 wherein W is O, S, NRW2, -C(=O), -
S(=O), -SO2, -C(=O)O-, -OC(=O), -C(=O)NRw2, -NRw2C(=O); wherein each occurrence of

Rw1 and Rw2 is independently hydrogen, a protecting group, a prodrug moiety or an alkyl,
cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, or, when W is NRW2, RW1 and
Rw2 , 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. In certain
embodiments of Hie invention, RB is one of the structures:

wherein m is an integer from 1 to 4; R2C is hydrogen, lower alkyl or a nitrogen protecting
group; and each occurrence of R28 is independently hydrogen, halogen, -CN, or WRW1
wherein W is 0, S, NRW2 -C(=0), -S(=O), -S02, -C(=O)O-, -0C(=0), -C(=0)NRW2, -
NRw2(=O); wherein each occurrence of RW1 and RW2 is independently hydrogen, a
protecting group, a prodrug moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or
heteroaryl moiety, or, when W is NRw2, RW1 and Rw2, taken together with the nitrogen atom
to which they are attached, form a heterocyclic or heteroaryl moiety; or any two adjacent
occurrences of R23, 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.
[00101J In certain embodiments, -X(RB)n has one of the structures:




[00103] In certain embodiments, R3 is substituted or unsubstituted aryl. In certain
embodiments, R3 is substituted or unsubstituted phenyl. In certain particular embodiments.R3
is monosubstituted phenyl. In certain embodiments, R3 is para-substituted phenyl. In certain
embodiment wherein R3' is hydrogen, a protecting group, a
solid support unit, an alkyl, acyl, cycioalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, -

(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or-(heteroalkyl)heteroaryl moiety. In
certain embodiments In other embodiments, R3 is substituted
or unsubstituted heteroaryl.
[00104] Another class of compounds of special interest includes those compounds of the
invention as described above and in certain subclasses herein, wherein R3 is a substituted
phenyl moiety and the compounds have the formula (II):

wherein
L, A, X, and RB are defined as above;
n is an integer between 0 and 5, inclusive; preferably, between, 1 and 3; more
preferably, 2; and
Z is hydrogen, -(CH2)qOR2, -(CH2)qSRz, -(CH2),N(RZ)2, -C(=O)RZ, -q=O)N(Rz)2, or
an alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -
(heteroalkyl)heteroaryl moiety, wherein q is CM-, and wherein each occurrence of Rz is
independently hydrogen, a protecting group, a solid support unit, or an alkyl, acyl, cycloalkyl,
heteroalkyl, heterocyclic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl,
or -(heteroalkyl)heteroaryl moiety. In certain embodiments, Rz is hydrogen. In other
embodiments, Rz is C1-C6 alkyl. In certain embodiments, Rz is an oxygen-protecting group.
[00105] Another class of compounds includes those compounds of formula (E), wherein Z
is -CH2ORZ, and the compounds have the general structure (1m):


wherein
R.B, R , X, L, n, and A are defined generally above and in classes and subclasses
herein. In certain embodiments, X is S. In other embodiments, X is O.
[00106] Yet another class of compounds of particular interest includes those compounds of
formula (ft), wherein X is S and the compounds have the general structure (In):
wherein
RB, X, L, n, and A are defined as above; and
Rz is as defined generally above and in classes and subclasses herein.
[00107] Yet another class of compounds of special interest includes those compounds of
formula (E), wherein X is -NR2A and the compounds have the general structure (Io):

wherein
RB, RZ, X, L, n, and A are defined generally above and in classes and subclasses
herein.
[00108] Yet another class of compounds of special interest includes those compounds of
formula (EL), wherein X is O and the compounds have the general structure (Ip):

wherein
RB, RZ, X, L, n, and A are defined generally above and in classes and subclasses
herein.
[00109] Exemplary compounds of the invention are shown:


[00110] Some of the foregoing compounds can comprise one or more asymmetric center-,
and this can exist in varous isomeric forms. e.g streoisomers and/diastereomers, This,
inventive compounds and pharmaceutical compositions thereof may be in the form of an
individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture

of stereoisomers. In certain embodiments, the compounds of the invention axe enantiopure
compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are
provided.
[00111] Furthermore, certain compounds, as described herein may have one or more
double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The
invention additionally encompasses the compounds as individual isomers substantially free of
other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of
stereoisomers. In addition to the above-mentioned compounds per se, this invention also
encompasses pharmaceutically acceptable derivatives of these compounds and compositions
comprising one or more compounds of the invention and one or more pharmaceutically
acceptable excipients or additives.
[00112] Compounds of the invention may be prepared by crystallization of the compound
under different conditions and may exist as one or a combination of polymorphs of the
compound forming part of this invention. For example, different polymorphs may be
identified and/or prepared using different solvents, or different mixtures of solvents for
recrystallization; by performing crystallizations at different temperatures; or by using various
modes of cooling, ranging from very fast to very slow cooling during crystallizations.
Polymorphs may also be obtained by heating or melting the compound followed by gradual
or fast cooling. The presence of polymorphs may be determined by solid probe NMR
spectroscopy, JR. spectroscopy, differential scanning calorimetry, powder X-ray
difrractogram and/or other techniques. Thus, the present invention encompasses inventive
compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs,
their pharmaceutically acceptable salts their pharmaceutically iicceptable solvates and
pharmaceutically acceptable compositions containing them.
Synthetic Overview
[00113] The synthesis of the various monomeric compounds used to prepare the dimeric,
multimeric, and polymeric compounds of the invention are known in the art These published
syntheses may be utilized to prepare the compounds of the invention. Exemplary synthesic
methods for preparing compounds of the invention are described in US 6,960,685; US
6,897,220; US 6,541,661; US 6,512,123; US 6,495,719; US 2006/0020131; US 2004/087631;
US 2004/127522; US 2004/0072849; US 2003/0187027; WO 2005/018578; WO
2005/007091; WO 2005/007091; WO 2005/018578; WO 2004/046104; WO 2002/89782;

each of which is incorporated herein by reference. In many cases, an amide moiety is
changed to an ester moiety to prepare the inventive compounds.
[00114] An exemplary synthetic scheme for preparing SAHP is showin in Figure 13.
Those of skill in the art will realize that based on this teaching and those in the art as
referenced above one could prepare any of the esterase-sensitive compounds of the invention.
[00115] In yet another aspect of the invention, methods for producing intermediates useful
for the preparation of certain compounds of the invention are provided.
[00116] In one aspect of the invention, a method for the synthesis of the core structure of
certain compounds is provided, one 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 tike structure R3CH(OMe>2 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;
R is hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic,
heterocyclic, aromatic or heteroaromatic moiety;
X is -O-, -C(R2A)-, -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
Rz is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic
moiety and is optionally attached to a solid support.
[00117] In certain exemplary embodiments, the epoxy alcohol has the structure:
[0C


[00119] In certain embodiments, R3 has the following structure:

and the method described above generates the structure:

[00120] In another aspect of the invention, a method for the synthesis of the core structure
of certain compounds of the invention is provided, one 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 R1 is hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic,
aromatic or heteroaromatic moiety;
R2 is hydrogea, 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 WRW1 wherein W is O,
S, NRW2, -C(=O), -S(=O), -SO2, -C(=0)O, -OC(=O), -C(=O)NRW2, -NRW2C(=O); wherein
each occurrence of RW1 and RW2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, or, when
W is NR'1'2, RW1 and RW2, 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
Rz is an aliphatic, alicyclic, heteroaliphatic, heterocyclic;, aromatic or heteroaromatic
moiety and is optionally attached to a solid support.
[00121] In certain exemplary embodiments, the epoxy alcohol has the structure:
+



[00123] In certain embodiments, the methods described above are carried out in solution
phase. In certain other embodiments, the methods described above are carried out on a solid
phase. In certain embodiments, the synthetic method is amenable to high-throughput
techniques or to technqiues commonly used in combinatorial chemistry.
Pharmaceutical Compositions
[00124] As discussed above, the present invention provides novel compounds having
antitumor and antiproliferative activity, and thus the inventive compounds are useful for the
treatment of cancer (e.g., cutaneous T-cell lymphoma). Benign proliferative diseases may
also be treated using the inventive compounds. The compounds are also useful in the
treatment of other diseases or condition that benefit from inhibtion of deacetylation activity
(e.g. HDAC inhibition). In certain embodiments, the compounds are useful in the treatment
of baldness based on the discovery that HDAC inhibition( particularly, HDAC6 inhibition)
blocks androgen signaling vis hsp90. HDAC inhibition has also been shown to inhibit
estrogen signaling. In certain embodiments, the compounds are useful in blocking the
hyperpigmentation of skin by HDAC inhibition.
[00125] Accordingly, in another aspect of the present invention, pharmaceutical
compositions are provided, which comprise any one of the compounds described herein (or a
prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative
thereof), and optionally comprise a pharmaceutically acceptable carrier. In certain
embodiments, these compositions optionally further comprise one or more additional
therapeutic agents. Alternatively, a compound of this invention may be administered to a
patient in need thereof in combination with the administration of one or more other
therapeutic agents. For example, additional therapeutic agents for conjoint administration or
inclusion in a pharmaceutical composition with a compound of this invention may be an
approved chemotherapeutic agent, or it may be any one of a number of agents undergoing
approval in the Food and Drug Administration that ultimately obtain approval for the
treatment of hair loss, skin hyperpigmentation, protozoal infections, and/or any disorder
associated with cellular hyperproliferation. In certain other embodiments, the additional
therapeutic agent is an anticancer agent, as discussed in more detail herein. In certain other
embodiments, the compositions of the invention are useful for the treatment of protozoal
infections.
[00126] It will also be appreciated that certain of the compounds of present invention can
exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable

derivative thereof. According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of
such esters, or a pro-drug or other adduct or derivative of a compound of this invention which
upon administration to a patient in need is capable of providing, directly or indirectly, a
compound as otherwise described herein, or a metabolite or residue thereof.
[00127] As used herein, the term "pharmaceutically acceptable salt" refers to those salts
which are, within the scope of sound medical judgment, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically
acceptable salts of amines, caRBoxylic acids, and other types of compounds, are well known
in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in
detail in J. Pharmaceutical Sciences, 66: 1-19(1977), incorporated herein by reference. The
salts can be prepared in situ during the final isolation and purification of the compounds of
the invention, or separately by reacting a free base or free acid function with a suitable
reagent, as described generally below. For example, a free base function can be reacted with a
suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety,
suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali
metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or
magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are
salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic
acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic
acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by
using other methods used in the art such as ion exchange. Other pharmaceutically acceptable
salts include adipate, alginate, ascoRBate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,
gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, pahnitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate,
sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium, lithium, potassium,
calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using

ccranterions such as halide, hydroxide, caRBoxylate, sulfate, phosphate, nitrate, loweralkyl
sulfonate and aryl sulfonate.
[00128] Additionally, as used herein, the term "pharmaceutically acceptable ester" refers
to esters that hydrolyze in vivo and include those that break down readily in the human body
to leave the parent compound or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic caRBoxylic acids, particularly
alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl
moeity advantageously has not more than 6 caRBon atoms. Examples of particular esters
include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
[00129] Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein
refers to those prodrugs of the compounds of the present invention which are, within the
scope of sound medical judgment, suitable for use in contact with the issues of humans and
lower animals with, undue toxicity, irritation, allergic response, and the like, commensurate
with a reasonable benefit/risk ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug"
refers to compounds that are rapidly transformed in vivo to yield the parent compound of the
above formula, for example by hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design,
American Pharmaceutical Association and Pergamon Press, 1987, both of which are
incorporated herein by reference.
[00130] As described above, the pharmaceutical compositions of the present invention
additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes
any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface
active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders,
lubricants and the like, as suited to the particular dosage form desired. Remington's
Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa.,
1980) discloses various carriers used in formulating pharmaceutical compositions and known
techniques for the preparation thereof. Except insofar as any conventional carrier medium is
incompatible with the compounds of the invention, such as by producing any undesirable
biological effect or otherwise interacting in a deleterious manner with any other
components) of the pharmaceutical composition, its use is contemplated to be within the
scope of this invention. Some examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose;

starches such, as corn starch and potato starch; cellulose and its derivatives such as sodium
caRBoxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt;
gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil,
cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as
propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as
magnesium hydroxide and aluminum hydroxide; aiginic acid; pyrogenfree water; isotonic
saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-
toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the composition, according to
the judgment of the formulator.
[00131] Liquid dosage forms for oral administration include, but are not limited to,
pharmaceutically acceptable emulsions, microemulsions, solution!?, suspensions, syrups and
elixirs. In addition to the active compounds, the liquid dosage forms may contain inert
diluents commonly used in the art such as, for example, water or other solvents, solubilizing
agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl caRBonate, ethyl acetate,
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,
oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils),
glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of soRBitan,
and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and
perfuming agents.
[00132] Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or
wetting agents and suspending agents. The sterile injectable preparation may also be a sterile
injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or
solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the
preparation of injectables.
[00133] The injectable formulations can be sterilized, for example, by filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid

compositions which can be dissolved or dispersed in sterile water or other sterile injectable
medium prior to use.
[00134] In order to prolong the effect of a drug, it is often desirable to slow the absorption
of the drug from subcutaneous or intramuscular injection. This may be accomplished by the
use of a liquid suspension or crystalline or amorphous material with poor water solubility.
The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may
depend upon crystal size and crystalline form. Alternatively, delayed absorption of a
parenterally administered drug form is accomplished by dissolving or suspending the drag in
an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the
drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio
of drug to polymer and the nature of the particular polymer employed, the rate of drug release
can be controlled. Examples of other biodegradable polymers include (poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drag in
liposomes or microemulsions which are compatible with body tissues.
[00135] Compositions for rectal or vaginal administration are preferably suppositories
which can be prepared by mixing the compounds of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which
are solid at ambient temperature but liquid at body temperature and therefore melt in the
rectum or vaginal cavity and release the active compound.
[00136] Solid dosage forms for oral administration include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound is mixed with at
least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol, and silicic acid, b) binders such as, for example, caRBoxymethylcelklose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d)
disintegrating agents such as agar-agar, calcium caRBonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium caRBonate, e) solution retarding agents such as paraffin, f)
absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as,
for example, cetyl alcohol and glycerol monostearate, h) absoRBents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets and pills, the dosage form may also comprise buffering agents.
[00137] Solid compositions of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high

molecular weight polyethylene glycols and the like. The solid dosage forms of tablets,
dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric
coatings and other coatings well known in the pharmaceutical formulating art They may
optionally contain opacifying agents and can also be of a composition that they release the
active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally,
in a delayed manner. Examples of embedding compositions that can be used include
polymeric substances and waxes. Solid compositions of a similar type may also be employed
as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar
as well as high molecular weight polethylene glycols and the like.
[00138] The active compounds can also be in micro-encapsulated form with one or more
excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings, release controlling
coatings and other coatings well known in the pharmaceutical formulating art In such solid
dosage forms the active compound may be admixed with at least one inert diluent such as
sucrose, lactose and starch. Such dosage forms may also comprise, as in normal practice,
additional substances other than inert diluents, e.g., tableting lubricants and other tableting
aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules,
tablets and pills, the dosage forms may also comprise buffering agents. They may optionally
contain opacifying agents and can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a
delayed manner. Examples of embedding compositions which can be used include polymeric
substances and waxes.
[00139] The present invention encompasses pharmaceutically acceptable topical
formulations of inventive compounds. The term "pharmaceutically acceptable topical
formulation", as used herein, means any formulation which is pharmaceutically acceptable
for intradermal administration of a compound of the invention by application of the
formulation to the epidermis. In certain embodiments of the invention, the topical
formulation comprises a carrier system. Pharmaceutically effective carriers include, but are
not limited to, solvents (eg., alcohols, poly alcohols, water), creams, lotions, ointments, oils,
plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g.,
liypotonic or buffered saline) or any other carrier known in the ait for topically administering
Pharmaceuticals. A more complete listing of art-known carriers is provided by reference
texts that are standard in the art, for example, Remington's Pharmaceutical Sciences, 16th
Edition, 1980 and 17th Edition, 1985, both published by Mack Publishing Company, Easton,

Pennsylvania, the disclosures of which are incorporated herein by reference in theix entireties.
In certain other embodiments, the topical formulations of the invention may comprise
excipients. Any pharmaceutically acceptable excipient known in the art may be used to
prepare the inventive pharmaceutically acceptable topical formulations. Examples of
excipients that can be included in the topical formulations of the invention include, but are
not limited to, preservatives, antioxidants, moisturizers, emollients, buffering agents,
solubilizing agents, other penetration agents, skin protectants, surfactants, and propellants,
and/or additional therapeutic agents used in combination to the inventive compound. Suitable
preservatives include, but are not limited to, alcohols, quaternary amines, organic acids,
parabens, and phenols. Suitable antioxidants include, but are not limited to, ascoRBic acid and
its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols,
and chelating agents like EDTA and citric acid. Suitable moisturizers include, but are not
limited to, glycerine, soRBitol, polyethylene glycols, urea, and propylene glycol. Suitable
buffering agents for use with the invention include, but are not limited to, citric, hydrochloric,
and lactic acid buffers. Suitable solubilizing agents include, but are not limited to, quaternary
ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysoRBates. Suitable
skin protectants that can be used in the topical formulations of the invention include, but are
not limited to, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.
[00140] In certain embodiments, the pharmaceutically acceptable topical formulations of
the invention comprise at least a compound of the invention and a penetration enhancing
agent. The choice of topical formulation will depend or several factors, including the
condition to be treated, the physicochemical characteristics of the inventive compound and
other excipients present, their stability in the formulation, available manufacturing
equipment, and costs constraints. As used herein the term "penetration enhancing agent"
means an agent capable of transporting a pharmacologically active compound through the
stratum corneum and into the epidermis or dermis, preferably, with little or no systemic
absorption. A wide variety of compounds have been evaluated as to their effectiveness in
enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous
Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CB.C Press, Inc., Boca Raton,
Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and
Buyuktiinkin et ai, Chemical Means of Transdermal Drug Permeation Enhancement in
Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pf ister W. R., Yum S. I.
(Eds.), tnterpharm Press Inc., Buffalo Grove, 111. (1997). In certain exemplary embodiments,
penetration agents for use with the invention include, but are not limited to, triglycerides

(e.g., soybean oil), aloe compositions (e.g., aloe-vera gel), ethyl alcohol, isopropyl alcohol,
octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol '100, propylene glycol, N-
decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol
monooleate, and propylene glycol monooleate), and N-methyl pyrrolidone.
[00141] In certain embodiments, the compositions may be in the form of ointments, pastes,
creams, lotions, gels, powders, solutions, sprays, inhalants or patches. In certain exemplary
embodiments, formulations of the compositions according to the invention are creams, which
may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid,
oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred.
Creams of the invention may also contain a non-ionic surfactant, for example, polyoxy-40-
stearate. In certain embodiments, the active component is admixed under sterile conditions
with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be
required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being
within the scope of this invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing controlled delivery of a
compound to the body. Such dosage forms are made by dissolving or dispensing the
compound in the proper medium. As discussed above, penetration enhancing agents can also
be used to increase the flux of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the compound in a polymer
matrix or gel.
[00142] It will also be appreciated that the compounds and pharmaceutical compositions
of the present invention can be formulated and employed in combination therapies, that is, the
compounds and pharmaceutical compositions can be formulated with or administered
concurrently with, prior to, or subsequent to, one or more other desired therapeutics or
medical procedures. The particular combination of therapies (therapeutics or procedures) to
employ in a combination regimen will take into account compatibility of the desired
therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also
be appreciated that the therapies employed may achieve a desired effect for the same disorder
(for example, an inventive compound may be administered concurrently with another
immunotnodulatory agent, anticancer agent or agent useful for the treatment of psoriasis), or
they may achieve different effects (e.g., control of any adverse effects).
[00143] For example, other therapies or anticancer agents that may be used in combination
with the inventive compounds of the present invention include surgery, radiotherapy (in but a

few examples, y-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton
therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy,
biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to
name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g.,
antiemetics), and other approved chemotherapeutic drugs, including, but not limited to,
alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan,
Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists
(6-Mercaptopurine, 5-Fhiorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine,
Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan),
antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine),
inorganic ions (Cisplatin, CaRBoplatin), enzymes (Asparaginase), and hormones (Tamoxifen,
Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion
of updated cancer therapies see, The Merck Manual, Seventeenth Ed, 1999, the entire
contents of which are hereby incorporated by reference. See also the National Cancer
Institute (CNI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA)
website for a list of the FDA approved oncology drugs
(www.fda.gov/cder/cancer/druglistframe).
[00144] In certain embodiments, the pharmaceutical compositions of the present invention
further comprise one or more additional therapeutically active ingredients (e.g.,
chemotherapeutic and/or palliative). For purposes of the invention, the term "palliative"
refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of
a therapeutic regimen, but is not curative. For example, palliative treatment encompasses
painkillers, antinausea medications and anti-sickness drugs. In addition, chemotherapy,
radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without
going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other
symptoms of cancer).
[00145] Additionally, the present invention provides pharmaceutically acceptable
derivatives of the inventive compounds, and methods of treating a subject using these
compounds, pharmaceutical compositions thereof, or either of these in combination with one
or more additional therapeutic agents.
[00146] It will also be appreciated that certain of the compounds of present invention can
exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable
derivative thereof. According to the present invention, a pharmaceutically acceptable

derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of
such esters, or a prodrug or other adduct or derivative of a compoxind of this invention which
upon administration to a patient in need is capable of providing, directly or indirectly, a
compound as otherwise described herein, or a metabolite or residue thereof.
Research Uses, Pharmaceutical Uses and Methods of Treatment
Research Uses
[00147] According to the present invention, the inventive compounds may be assayed in
any of the available assays known in the art for identifying compounds having antiprotozoal,
HDAC inhibitory, hair growth, androgen signalling inhibitory, estogen singaling inhibitory,
and/or antiproliferative activity. For example, the assay may be cellular or non-cellular, in
vivo or in vitro, high- or low-throughput format, etc.
[00148] Thus, in one aspect, compounds of this invention which are of particular interest
include those which:
• exhibit HDAC-inhibitory activity;
• exhibit HDAC Class I inhbitiory activity (e.g., HDAC1, HDAC2, HDAC3, HDAC8);
• exhibit HDAC Class II inhibitory activity (e.g., HDAC4, HDAC5, HDAC6, HDAC7,
HDAC9a, HDAC9b, HDRP/HDAC9c, HDAC10);
• exhibit the ability to inhibit HDAC1 (Genbank Accession No. NP_004955,
incorporated herein by reference);
• exhibit the ability to inhibit HDAC2 (Genbank Accession No. NP_001518,
incorporated herein by reference);
• exhibit the ability to inhibit HDAC3 (Genbank Accession No. 015739, incorporated
herein by reference);
• exhibit the ability to inhibit HDAC4 (Genbank Accession No. AAD29046,
incorporated herein by reference);

• exhibit the ability to inhibit HDAC5 (Genbank Accession No. NP_005465,
incorporated herein by reference);
• exhibit the ability to inhibit HDAC6 (Genbank Accession No. NP_006035,
incorporated herein by reference);
• exhibit the ability to inhibit HDAC7 (Genbank Accession No. AAP63491,
incorporated herein by reference);

• exhibit the ability to inhibit HDAC8 (Genbank Accession No. AAF73428,
NM_018486, AF245664, AF230097, each of which is incorporated herein by
reference);
• exhibit the ability to inhibit HDAC9 (Genbank Accession No. NMJ78425,
NM_178423, NMJ)58176, NM_014707, BC111735, NM. 058177, each of which is
incorporated herein by reference)
• exhibit the ability to inhibit HDAC10 (Genbank Accession No. NM_032019,
incorporated herein by reference)
• exhibit the ability to inhibit HDACl 1 (Genbank Accession No. BC009676,
incorporated herein by reference);

• exhibit the ability to inhibit tubulin deacterylation (TDAC);
• exhibit the ability to modulate the glucose-sensitive subset of genes downstream of
Ure2p;
• exhibit cytotoxic or growth inhibitory effect on cancer cell lines maintained in vitro or
in animal studies using a scientifically acceptable cancer cell xenograft model; and/or
• exhibit a -therapeutic profile (e.g., optimum safety and curative effect) that is superior
to existing chemotherapeutic agents.
[00149] As detailed in the exemplification herein, in assays to determine the ability of
compounds to inhibit cancer cell growth certain inventive compounds may exhibit IC5o
values 50 M. In certain other embodiments, inventive compounds exhibit IC50 values certain other embodiments, inventive compounds exhibit IC50 values other embodiments, inventive compounds exhibit IC50 values embodiments, inventive compounds exhibit IC50 values embodiments, inventive compounds exhibit IC50 values inventive compounds exhibit IC+50 values compounds exhibit ICso values exhibit IC50 values certain embodiments, inventive compounds exhibit lC50 values embodiments, inventive compounds exhibit IC50 values embodiments, inventive compounds exhibit IC50 values embodiments, inventive compounds exhibit IC50 values
embodiments, inventive compounds exhibit IC50 values embodiments, inventive compounds exhibit IC50 values exemplary compounds exhibited IC50 values compounds exhibited IC50 values Phannaceutical Uses and Methods of Treatment
[00150] In general, methods of using the compounds of the present invention comprise
administering to a subject in need thereof a therapeutically effective amount of a compound
of the present invention. The compounds of the invention are generally inhibitors of
deacetyalse activity. As discussed above, the compounds of the invention are typically
inhibitors of histone deacetylases and, as such, are useful in the treatment of disorders
modulated by histone deacetylases. Other deacetylase such as tubulin deacetylases may also
be inhibited by the inventive compounds.
[00151] In certain embodiments, compounds of the invention are useful in the treatment of
proliferative diseases {e.g., cancer, benign neoplasms, inflammatory disease, autoimmune
diseases). In certain embodiments, given the esterase sensitive ester linkage in the
compounds of the invention, they are particularly useful in treating skin disorders modulated
by histone deacetyalses where systemic effects of the drug are to be avoided or at least
minimized. This feature of the inventive compounds may allow the use of compounds
normally too toxic for administration to a subject systemically. In certain embodiments,
these skin disorders are proliferative disorders. For example, the inventive compounds are
particularly useful in the treatment of skin cancer and benign skin tumors. In certain
embodiments, the compounds are useful in the treatment of cutaneous T-cell lymphoma. In
certain embodiments, the compounds are useful in the treatment of neurofibromatosis.
Accordingly, in yet another aspect, according to the methods of treatment of the present
invention, tumor cells are killed, or their growth is inhibited by contacting said tumor cells
with an inventive compound or composition, as described herein. In other embodiments, the
compounds are useful in treating inflammatory diseases of the skin such as psoriasis or
dermatitis. In other embodiments, the compounds are useful in the treatment or prevention of
hair loss. In certain embodiments, the compounds are useful in the treatment of diseases
associated with skin pigmentation. For example, the compounds may be used to prevent the
hyperpigmentation of skin.
[00152] Thus, in another aspect of the invention, methods for the treatment of cancer are
provided comprising administering a therapeutically effective amount of an inventive

compound, as described herein, to a subject in need thereof. In certain embodiments, a
method for the treatment of cancer is provided comprising administering atherapeutically
effective amount of an inventive compound, or a pharmaceutical composition comprising an
inventive compound to a subject in need thereof, in such amounts and for such time as is
necessary to achieve the desired result. Preferably, the inventive compounds is administered
topically. In certain embodiments of the present invention a "therapeutically effective
amount" of the inventive compound or pharmaceutical composition is that amount effective
for killing or inhibiting the growth of tumor cells. The compound!? and compositions,
according to the method of the present invention, may be administered using any amount and
any route of administration effective for killing or inhibiting the growth of tumor cells. Thus,
the expression "amount effective to kill or inhibit the growth of tumor cells," as used herein,
refers to a sufficient amount of agent to Mil or inhibit the growth of tumor cells. The exact
amount required will vary from subject to subject, depending on the species, age, and general
condition of the subject, the severity of the infection, the particular anticancer agent, its mode
of administration, and the like. In certain embodiments of the present invention a
"therapeutically effective amount" of the inventive compound or pharmaceutical composition
is that amount effective for inhibiting deacetylase activity (in particular, HDAC activity) in
skin cells. In certain embodiments of the present invention a "therapeutically effective
amount" of the inventive compound or pharmaceutical composition is that amount effective
to kill or inhibit the grwoth of skin cells.
[00153] In certain embodiments, the method involves the administration of a
therapeutically effective amount of the compound or a pharmaceutically acceptable derivative
thereof to a subject (including, but not limited to a human or animal) in need of it In certain
embodiments, the inventive compounds as useful for the treatment of cancer (including, but
not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal
cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung
cancer), melanoma and/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian
cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer,
kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal
cancer).
[00154] In certain embodiments, the inventive anticancer agents are useful in the treatment
of cancers and other proliferative disorders, including, but not limited to breast cancer,
cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple
myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and

gastric cancer, to name a few. In certain embodiments, the inventive anticancer agents are
active against leukemia cells and melanoma cells, and thus are useful for the treatment of
leukemias {e.g., myeloid, lymphocytic, myelocytic and lymphoblastic Ieukemias) and
malignant melanomas. In still other embodiments, the inventive anticancer agents are active
against solid tumors.
[00155] In certain embodiments, the inventive compounds also find use in the prevention
of restenosis of blood vessels subject to traumas such as angioplasry and stenting. For
example, it is contemplated that the compounds of the invention will be useful as a coating
for implanted medical devices, such as tubings, shunts, catheters, artificial implants, pins,
electrical implants such as pacemakers, and especially for arterial or venous stents, including
balloon-expandable stents. In certain embodiments inventive compounds may be bound to an
implantable medical device, or alternatively, may be passively adsoRBed to the surface of the
implantable device. In certain other embodiments, the inventive compounds may be
formulated to be contained within, or, adapted to release by a surgical or medical device or
implant, such as, for example, stents, sutures, indwelling catheters, prosthesis, and the like.
For example, drugs having antiproliferative and anti-inflammatory activities have been
evaluated as stent coatings, and have shown promise in preventing retenosis (See, for
example, Presbitero P. et al, "Drug eluting stents do they make the difference?", Minerva
Cardioangiol, 2002, 50(5):431-442; RuygrokP.N. et al, "Rapamycin in cardiovascular
medicine", Intern. Med. J., 2003, 33(3):103-109; and MaRX S.O. et al, "Bench to bedside: the
development of rapamycin and its application to stent restenosis", Circulation, 2001,
104(8):852-855, each of these references is incorporated herein by reference in its entirety).
Accordingly, without wishing to be bound to any particular theory, Applicant proposes that
inventive compounds having antiproliferative effects can be used as stent coatings and/or in
stent drug delivery devices, inter alia for the prevention of restenosis or reduction of
restenosis rate. Suitable coatings and the general preparation of coated implantable devices
are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically
biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane,
polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures
thereof. The coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to
impart controlled release characteristics in the composition. A variety of compositions and
methods related to stent coating and/or local stent drug delivery for preventing restenosis are
known in the art (see, for example, U.S. Patent Nos.: 6,517,889; 6,273,913; 6,258,121;

6,251,136; 6,248,127; 6,231,600; 6,203,551; 6,153,252; 6,071,305; 5,891,507; 5,837,313 and
published U.S. patent application No.: US2001/0027340, each of which is incorporated
herein by reference in its entirety). For example, stents may be coated with polymer-drug
conjugates by dipping the stent in polymer-drug solution or spraying the stent with such a
solution. In certain embodiment, suitable materials for the implantable device include
biocompatible and nontoxic materials, and may be chosen from the metals such as nickel-
titanium alloys, steel, or biocompatible polymers, hydrogels, polyurethanes, polyethylenes,
ethylenevinyl acetate copolymers, etc. In certain embodiments, the inventive compound is
coated onto a stent for insertion into an artery or vein following balloon angioplasty.
[00156] The compounds of this invention or pharmaceutically acceptable compositions
thereof may also be incorporated into compositions for coating implantable medical devices,
such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the
present invention, in another aspect, includes a composition for coating an implantable device
comprising a compound of the present invention as described generally above, and in classes
and subclasses herein, and a carrier suitable for coating said implantable device. In still
another aspect, the present invention includes an implantable device coated with a
composition comprising a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for coating said implantable
device.
[00157] Within other aspects of the present invention, methods are provided for expanding
the lumen of a body passageway, comprising inserting a stent into the passageway, the stent
having a generally tubular structure, the surface of the structure being coated with (or
otherwise adapted to release) an inventive compound or composition, such that the
passageway is expanded. In certain embodiments, the lumen of a body passageway is
expanded in order to eliminate a biliary, gastrointestinal, esophageal, tracheal/bronchial,
urethral and/or vascular obstruction.
[00158] Methods for eliminating biliary, gastrointestinal, esophageal, tracheal/bronchial,
urethral and/or vascular obstructions using stents are known in the art. The skilled
practitioner will know how to adapt these methods in practicing the present invention. For
example, guidance can be found in U.S. Patent Application Publication No.: 2003/0004209 in
paragraphs [0146]-[0155], which paragraphs are hereby incorporated herein by reference.
[00159] Another aspect of the invention relates to a method for inhibiting the growth of
multidrug resistant cells in a biological sample or a patient, which method comprises

administering to the patient, or contacting said biological sample with a compound of formula
I or a composition comprising said compound.
[00160] Additionally, the present invention provides pharmaceutically acceptable
derivatives of the inventive compounds, and methods of treating a subject using these
compounds, pharmaceutical compositions thereof, or either of these in combination with one
or more additional therapeutic agents.
[00161] Another aspect of the invention relates to a method of treating or lessening the
severity of a disease or condition associated with a proliferation disorder in a patient, said
method comprising a step of administering to said patient, a compound of formula I or a
composition comprising said compound.
[00162] It will be appreciated that the compounds and compositions, according to the
method of the present invention, may be administered using any amount and any route of
administration effective for the treatment of cancer and/or disorders associated with cell
hyperproliferation. For example, when using the inventive compounds for the treatment of
cancer, the expression "effective amount" as used herein, refers to a sufficient amount of
agent to inhibit cell proliferation, or refers to a sufficient amount to reduce the effects of
cancer. The exact amount required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of the diseases, the particular
anticancer agent, its mode of administration, and the like.
[00163] The compounds of the invention are preferably formulated in dosage unit form for
ease of administration and uniformity of dosage. The expression "dosage unit form" as used
herein refers to a physically discrete unit of therapeutic agent appropriate for the patient to be
treated. It will be understood, however, that the total daily usage of the compounds and
compositions of the present invention will be decided by the attending physician within the
scope of sound medical judgment. The specific therapeutically effective dose level for any
particular patient or organism will depend upon a variety of factors including the disorder
being treated and the severity of the disorder; the activity of the specific compound
employed; the specific composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of administration, and rate of excretion of
the specific compound employed; the duration of the treatment; drugs used in combination or
coincidental with the specific compound employed; and like factors well known in the
medical arts (see, for example, Goodman and Gilman's, "The Pharmacological Basis of
Therapeutics", Tenth Edition, A. Gilman, J.Hardman and L. Limblrd, eds., McGraw-Hill
Press, 155-173, 2001, which is incorporated herein by reference in its entirety).

[00164] Another aspect of the invention relates to a method for inhibiting histone
deacetylase activity in a biological sample or a patient, which method comprises
administering to the patient, or contacting said biological sample with an inventive compound
or a composition comprising said compound.
[00165] Furthermore, after formulation with an appropriate pharmaceutically acceptable
carrier in a desired dosage, the pharmaceutical compositions of this invention can be
administered to humans and other animals orally, rectally, parenterally, intracisternally,
intravaginally, intraperitoneally, topically (as by powders, ointments, creams or drops),
bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being
treated. In certain embodiments, the compounds of the invention may be administered at
dosage levels of about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25
mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or
more times a day, to obtain the desired therapeutic effect It will also be appreciated that
dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can
be administered to a subject. In certain embodiments, compounds are administered orally or
parenterally.
Treatment Kit
[00166] In other embodiments, the present invention relates to a kit for conveniently and
effectively carrying out the methods in accordance with the present invention. In general, the
pharmaceutical pack or kit comprises one or more containers filled with one or more of the
ingredients of the pharmaceutical compositions of the invention. Such kits are especially
suited for the topical delivery of the inventive compounds. Optionally associated with such
containers) can be a notice in the form prescribed by a governmental agency regulating the
manufacture, use or sale of pharmaceutical products, which notice reflects approval by the
agency of manufacture, use or sale for human administration.
Equivalents
[00167] The representative examples which follow are intended to help illustrate the
invention, and are not intended to, nor should they be construed to, limit the scope of the
invention. Indeed, various modifications of the invention and many farther embodiments
thereof, in addition to those shown and described herein, will become apparent to those
skilled in the art from the full contents of this document, including the examples which
follow and the references to the scientific and patent literature cited herein. It should further

be appreciated that, unless otherwise indicated, the entire contents of each of the references
cited herein are incorporated herein by reference to help illustrate 'the state of the art The
following examples contain important additional information, exemplification and guidance
which can be adapted to the practice of this invention in its various embodiments and the
equivalents thereof.
[00168] These and other aspects of the present invention will be further appreciated upon
consideration of the following Examples, which are intended to illustrate certain particular
embodiments of the invention but are not intended to limit its scope, as defined by the claims.
Examples
[00169] The compounds of this invention and their preparation can be understood further
by the examples that illustrate some of the processes by which these compounds are prepared
or used. Tt will be appreciated, however, that these examples do not limit the invention.
Variations of the invention, now known or further developed, are considered to fall within the
scope of the present invention as described herein and as hereinafter claimed.
General Description of Synthetic Methods
[00170] The various references cited herein provide helpful background information on
preparing compounds similar to the inventive compounds described herein or relevant
intermediates, as well as information on formulation, uses, and administration of such
compounds which may be of interest
[00171] Moreover, the practitioner is directed to the specific guidance and examples
provided in this document relating to various exemplary compounds and intermediates
thereof.
[00172] The compounds of this invention and their preparation can be understood further
by the examples that illustrate some of the processes by which these compounds are prepared
or used. It will be appreciated, however, that these examples do not limit the invention.
Variations of the invention, now known or further developed, are considered to fall within the
scope of the present invention as described herein and as hereinafter claimed.
[00173] According to the present invention, any available techniques can be used to make
or prepare the inventive compounds or compositions including them. For example, a variety
of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods
such as those discussed in detail below may be used. Alternatively or additionally, the

inventive compounds may be prepared using any of a variety of solution phase synthetic
methods known in the art.
[00174] It will be appreciated as described below, that a variety of inventive compounds
can be synthesized according to the methods described herein. The starting materials and
reagents used in preparing these compounds are either available from commercial suppliers
such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St.
Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art
following procedures described in such references as Fieser and Fieser 1991, "Reagents for
Organic Synthesis", vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989
"Chemistry of CaRBon Compounds", vols. 1-5 and supps, Elsevier Science Publishers, 1989;
"Organic Reactions", vols 1-40, John Wiley and Sons, New York, NY, 1991; March 2001,
"Advanced Organic Chemistry", 5th ed. John Wiley and Sons, New York, NY; and Larock
1990, "Comprehensive Organic Transformations: A Guide to Functional Group
Preparations", 2nd ed. VCH Publishers. These schemes are merely illustrative of some
methods by which the compounds of this invention can be synthesized, and various
modifications to these schemes can be made and will be suggested to a person of ordinary
skill in the art having regard to this disclosure.
[00175] The starting materials, intermediates, and compounds of this invention may be
isolated and purified using conventional techniques, including filtration, distillation,
crystallization, chromatography, and the like. They may be characterized using conventional
methods, including physical constants and spectral data.
Synthesis of Exemplary Compounds
[00176] Unless otherwise indicated, starting materials are either commercially available or
readily accessibly through laboratory synthesis by anyone reasonably familiar with the art.
Described generally below, are procedures and general guidance for the synthesis of
compounds as described generally and in subclasses and species herein.


[00177] Described below is the synthesis of a SAHP, an ester-containing analog of S AHA
(as shown in Figure 12).
[00178] 3.86g (24.2mmol) O-benzylhydroxylamine hydrochloride and 13mL (75mmol)
diisopropylethylamine were dissolved in 100mL methylene chloride and cooled to 0 °C.
5.00g (24.2mmol) methyl 8-chloro-8-oxooctanoate were dissolved in lOmL methylene
chloride and slowly added to the reaction mixture. The reaction mixture was stirred for 1 h at
0 °C and warmed to room temperature. After stirring for additional 12 h, 300mL 0.5N HC1
were added. The organic layer was separated and washed with brine and sat. bicaRB. After
drying over sodium sulfate, the organic solvent was removed under reduced pressure and the
crude product was purified on silica (methylene chloride/ methanol 12:1, rf=0.7) to yield the
desired compound 1 as white solid (6.3g, 89%).
[00179] 6.3g (21.5mmol) methyl ester 1 were dissolved in 200mL methanol, followed by
the addition of 50mL 2N LIOH. The reaction mixture was heated to reflux for lh and cooled
to room temperature. After addition of 100mL IN HC1 and 200mL water, the reaction
mixture was extracted three times with 150mL ethyl acetate. The combined organic layers
were dried over sodium sulfate and the solvent was removed under reduced pressure to afford
the caRBoxylic acid 2 pure and in quantitative yields as white solid
[00180] 140mg caRBoxylic acid 2 (5mmol), 56.5mg phenol (6mmol) and 113mg
dicyclohexylcaRBodiimide (5.5mmol) are mixed followed by the addition of lOmL methylene
chloride and 30mg 4-Dimethylaminopyridine. The reaction mixture was stirred for 2h and
applied crude on a silica column followed by elution with haxanes/ethyl acetate (10-100%
ethyl acetate). The desired phenol ester 3 was obtained as a white solid in 87% yield
(155mg).
[00181] 80 mg phenol ester 3 (0.225mmol) are dissolved in methanol. A catalytical
amount of palladium on charcoal (10%) was as added and hydrogen was bubbled through the
reaction mixture. After lh hour no starting material was detectable by TLC. The reaction
mixture was filtered through Celite and the solvent was removed tinder reduced pressure to

yield the free hydroxamte SAHP as brownish solid in quantitative yields (59mg). The crude
product did not show any impurities as judged by LCMS and NMR.
Example 2: Biological Assay Procedures
[00182] Cell culture and Transfections. TAg-Jurkat cells were transfected by
electroporation with 5 u.g of FLAG-epitope-tagged pBJ5 constructs for expression of
recombinant proteins. Cells were harvested 48 h posttransfection.
[00183] HDAC assays. [3H]Acetate-incorporated Mstones were isolated from butyrate-
treated HeLa cells by hydroxyapatite chromatography (as described in Tong, et al. Nature
1997, 395, 917-921.) Immunoprecipitates were incubated with 1.4 g (10,000 dpm) histones
for 3 h at 37° C. HDAC activity was determined by scintillation counting of the ethyl
acetate-soluble [3H]acetic acid (as described in Taunton, et al, Science 1996,272,408-411).
Compounds were added in DMSO such that final assay concentrations were 1% DMSO.
IC50s were calculated using Prism 3.0 software. Curve fitting was done without constraints
using lie program's Sigmoidal-Dose Response parameters. All data points were acquired in
duplicate and IC50s are calculated from the composite results of at least two separate
experiments.
Example 3: In vivo activity
[00184] Although a variety of methods can be utilized, one exemplary method by which
the in vivo activity of the inventive compounds is determined is by subcutaneously
transplanting a desired tumor mass in mice. Drug treatment is then initiated when tumor
mass reaches approximately 100 mm3 after transplantation of the tumor mass. A suitable
composition, as described in more detail above, is then administered to the mice, preferably
in saline and also preferably administered once a day at doses of 5, 10 and 25 mg/kg,
although it will be appreciated that other doses can also be administered. Body weight and
tumor size are then measured daily and changes in percent ratio to initial values are plotted.
In cases where the transplanted tumor ulcerates, the weight loss exceeds 25-30% of control
weight loss, the tumor weight reaches 10% of the body weight of the cancer-bearing mouse,
or the cancer-bearing mouse is dying, the animal is sacrificed in accordance with guidelines
for animal welfare.
Example 4: Assays to identify potential antiprotozoal compounds by inhibition of
histone deacetylase

[00185] As detailed in US Patent Number 6,068,987, inhibitors of histone deacetylases
may also be useful as antiprotozoal agents. Described therein are assays for histone
deacetylase activity and inhibition and describe a variety of known protozoal diseases. The
entire contents of 6,068,987 are hereby incorporated by reference.

Claims
1. A compound of the formula (T),

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 orheterocyclic 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:



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



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:



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; -ORA; -C(=O)RA; -CO2RA; -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)2, -NHC(O)RA; or -C(RA)3; wherein each occurrence of RA 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 -ORA-
35. The compound of any one of claims 25-31, wherein R1 is -N(RA)2.
36. The compound of any one of claims 25-31, wehrein R1 is -NHRA.
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
3 9. The compound of any one of claims 25-31, wherein R1 is -C(=0)ORA, wherein RA is
hydrogen or C1-C6 alkyl.
40. The compound of any one of claims 25-31, wherein R1 is -C(=0)N(RA)2, wherein RA
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 25-31, wherein R1 is -NHC(=O)RA, wherein RA
is C1-C6 alkyl.


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; -ORA; -C(=O)RA; -CO2RA; -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)2; -NHC(O)RA; or -C(RA)3; wherein each occurrence of RA 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, allcylamino,
dialkylamino, heteroaryloxy; or heteroarylthio moiety.

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; -ORA; -C(=O)RA; -CO2RA; -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)2; -NHC(O)RA; or -C(RA)3; wherein each occurrence of RA 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; -ORA; -C(=O)RA; -CO2R.A.; -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)2: -NHC(O)RA; or -C(RA)3; wherein each occurrence of RA 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.

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; -ORA; -C(=O)RA; -CO2RA; -CN; -SCN; -SRA; -SORA; -SO2RA; -NO2;
-N(RA)i; -NHC(O)R,v; or -C(R.t^; wherein each occurrence of RA 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 -ORA-
54. The compound of claim 44, 45, 46, or 47, wherein R1 is -N(RA)2-
55. The compound of claim 44, 45, 46, or 47, wehrein R1 is -NHRA.
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)ORA, wherein RA is
hydrogen or C1-C6 alkyl.
59. The compound of claim 44, 45, 46, or 47, wherein R1 is -C(=O)N(RA)2, wherein RA is
hydrogen or C1-C6 alkyl.
60. The compound of claim '14, 45, 46, or 47, wherein R4 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)RA, wherein RA 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; -ORB; -C(=O)RB; -CO2RB; -CN; -SCN; -SRB; -SORB; -SO2RB; -NO2;
-N(RB)2; -NHC(O)RB; or -C(RB)3; wherein each occurrence of RB 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; -ORc; -C(=O)Rc; -CO2Rc; -CN; -SCN; -SRc; -SORc; -SO2Rc; -NO2;
-N(Rc)2; -NHC(O)Rc; or -C(Rc)3; wherein each occurrence of Re 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(RB)n, wherein X is O, S, or N; and
n is 1 or 2

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; -ORB; -C(=O)RB; -CO2RB; -CN; -SCN; -SRB; -SORB; -SO2RB; -NO2;
-N(RB)2; -NHC(O)RB; or -C(RB)3; wherein each occurrence of RB 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; -ORc; -C(=O)RC; -CO2Rc; -CN; -SCN; -SRC; -SORC; -SO2Rc; -NO2;

-N(Rc)2, -NHC(O)Rc; or -C(Rc)3; wherein each occurrence of Rc is independently a
hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;
an aryl moiety; aheteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino,
dialkylamino, heteroaryloxy; or heteroarylthio moiety.

wherein
R2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or
unbranched aliphatic; cych"c 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; -ORB; -C(=O)RB; -C02RB; -CN; -SCN; -SRB; -SORB; -SO2Ra; -NO2;
-N(RB)2; -NHC(O)RB; or -C(RB)3; wherein each occurrence of RB 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; -ORc; -C(=O)Rc; -CO2RC; -CN; -SCN; -SRC; -SORc; -SO2Rc; -NO2;
-N(Rc)2, -NHC(O)Rc:; or -C(Rc)3; wherein each occurrence of Rc is independently a
hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety;

an aryl moiety; a heteroatyl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino,
dialkylamino, heteroaryloxy; or heteroarylthio moiety.

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; -ORB; -C(=O)RB; -CO2RB; -CN; -SCN; -SRB; -SORB; -SO2RB; -NO2;
-N(RB)2; -NHC(O)RB; or - C(RB)3; wherein each occurrence of RB 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; -ORc; -C(=O)Rc; -CO2RC; -CN; -SCN; -SRc; -SORc; -SO2Rc; -NO2;
-N(Rc)2; -NHC(O)Rc; or -C(Rc)3; wherein each occurrence of Rc 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.


wnerein
a is an integer between 0 and 5, inclusive; and
Z is hydrogen, -(CH2)qORz -(CH2)qSRz, -(CH2)qN(Rz)2) -C(=O)RZ, -C(=0)N(Rz)2, or
an alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(a]kyl)heteroaryl, -(heteroalkyl)aryl, or -
(heteroalkyl)heteroaryl moiety, wherein q is 0-4, and wherein each occurrence of R2 is
independently hydrogen, a protecting group, a solid support unit, or an allcyl, cycloalkyl,
heteroalkyl, heterocyclic, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl,
or -(heteroalkyl)heteroaryl moiety.
72. The compound of claim 71 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 mamnral.
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, 30, 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 (IIIA), 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):

(III)
wherein R1 is hydrogen, or an aliphatic, alicyclic, heteroallphatic, heterocyclic,
aromatic or heteroaromatic moiety;

R2 is hydrogea, 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
Rz 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 Rl 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 R7 and R2A, taken together, form an alicyclic
or heterocyclic moiety, or an aryL or heteroaryl moiety;
r is Oor 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 WRW1 wherein W is O,
S, NRW25 -C(=O), -S(=O), -SO2, -C(=O)O-, -OC(=O), -C(=O)NRW2, -NRw2C(=O); wherein
each occurrence of RW1 and RW2 is independently hydrogen, a protecting group, a prodrug
moiety or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety, or, when
W is NRW2, RW1 and RW2, 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
Rz is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic
moiety and is optionally attached to a solid support.

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.

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Patent Number 270376
Indian Patent Application Number 3567/KOLNP/2008
PG Journal Number 51/2015
Publication Date 18-Dec-2015
Grant Date 16-Dec-2015
Date of Filing 01-Sep-2008
Name of Patentee DANA-FARBER CANCER INSTITUTE,INC.
Applicant Address 44 BINNEY STREET BOSTON, MA 02115 UNITED STATES OF AMERICA
Inventors:
# Inventor's Name Inventor's Address
1 MAZITSCHEK, RALPH 43 GLENWOOD ROAD, SOMERVILLE, MASSACHUSETTS 02145
2 BRADNER, JAMES, ELLIOT 129 FRANKLIN STREET, APT. 317, CAMBRIDGE, MASSACHUSETTS 02139
PCT International Classification Number C07C 309/00
PCT International Application Number PCT/US2007/062152
PCT International Filing date 2007-02-14
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/773172 2006-02-14 U.S.A.