INHIBITORS OF HISTONE DEACETYLASE

BACKGROUND OF THE INVENTION

Field of the Invention

[0001] This invention relates to compounds for the inhibition of histone deacetylase.

Description of Related Art

[0002] In eukaryotic cells, nuclear DNA associates with histones to form a compact complex called chromatin. The histones constitute a family of basic proteins which are generally highly conserved across eukaryotic species. The core histones, termed H2A, H2B, H3, and H4, associate to form a protein core. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin. [0003] Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HATl). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure. Indeed, Taunton et al, Science, 111: 408-411 (1996), teaches that access of transcription factors to chromatin templates is enhanced by histone hyperacetylation. Taunton et al. further teaches that an enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome. [0004] Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). The molecular cloning of gene sequences encoding proteins with HDAC activity has established the existence of a set of discrete HDAC enzyme isoforms. Grozinger et al., Proc. Natl. Acad. ScL USA, 96:4868-4873 (1999), teaches that HDACs may be divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hdl-like proteins. Grozinger et al. also teaches that the human HDAC-I, HDAC-2, and HDAC-3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC- 4, HDAC-5, and HDAC-6, which are members of the second class of HDACs. Kao et al., Gene & Development 14:55-66 (2000), discloses an additional member of this second class, called HDAC-7. More recently, Hu, E. et al. J. Bio. Chem. 275: 15254-13264 (2000) disclosed another member of the first class of histone deacetylases, HDAC-8. Zhou et al., Proc. Natl. Acad. ScL U.S.A., 98: 10572-10577 (2001) teaches the cloning and

characterization of a new histone deacetylase, HDAC-9. Kao et al, J. Biol. Chem., 277:187- 93 (2002) teaches the isolation and characterization of mammalian HDAClO, a novel histone deacetylase. Gao et al, J. Biol. Chem. (In press) teaches the cloning and functional characterization of HDACIl, a novel member of the human histone deacetylase family. Shore, Proc. Natl. Acad. Sci. U.S.A. 97: 14030-2 (2000) discloses another class of deacetylase activity, the Sir2 protein family. It has been unclear what roles these individual HDAC enzymes play.

[0005] Studies utilizing known HDAC inhibitors have established a link between acetylation and gene expression. Numerous studies have examined the relationship between HDAC and gene expression. Taunton et al., Science 272:408-411 (1996), discloses a human HDAC that is related to a yeast transcriptional regulator. Cress et al., J. Cell. Phys. 184:1-16 (2000), discloses that, in the context of human cancer, the role of HDAC is as a corepressor of transcription. Ng et al., TIBS 25: March (2000), discloses HDAC as a pervasive feature of transcriptional repressor systems. Magnaghi-Jaulin et al., Prog. Cell Cycle Res. 4:41-47 (2000), discloses HDAC as a transcriptional co-regulator important for cell cycle progression. [0006] Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998), discloses that HDAC activity is inhibited by trichostatin A (TSA), a natural product isolated from Streptomyces hygroscopicus, which has been shown to inhibit histone deacetylase activity and arrest cell cycle progression in cells in the Gl and G2 phases (Yoshida et al., J. Biol. Chem. 265: 17174-17179, 1990; Yoshida et al, Exp. Cell Res. Ill: 122-131, 1988), and by a synthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida and Beppu, Exper. Cell Res., Ill: 122-131 (1988), teaches that TSA causes arrest of rat fibroblasts at the Gi and G ₂ phases of the cell cycle, implicating HDAC in cell cycle regulation. Indeed, Finnin et al. , Nature, 401: 188-193 (1999), teaches that TSA and SAHA inhibit cell growth, induce terminal differentiation, and prevent the formation of tumors in mice. Suzuki et al, U.S. Pat. No. 6,174,905, EP 0847992 and JP 258863/96, disclose benzamide derivatives that induce cell differentiation and inhibit HDAC. Delorme et al, WO 01/38322 and WO 2001/070675, disclose additional compounds that serve as HDAC inhibitors. Other inhibitors of histone deacetylase activity, including trapoxin, depudecin, FR901228 (Fujisawa Pharmaceuticals), and butyrate, have been found to similarly inhibit cell cycle progression in cells (Taunton et al, Science 272: 408-411, 1996; Kijima ef al, J. Biol. Chem. 268(30):22429-22435, 1993; Kwon et al, Proc. Natl. Acad. Sci. USA 95(7):3356-61, 1998).

[0007] Research in the past decade has uncovered a new classification of inherited neurodegenerative diseases, the polyglutamine (polyQ) expansion diseases. In each, the

underlying mutation is an expansion of a CAG trinucleotide repeat that encodes polyQ in the respective disease protein. All are progressive, ultimately fatal disorders that typically begin in adulthood and progress over 10 to 30 years. The clinical features and pattern of neuronal degeneration differ among the diseases, yet increasing evidence suggests that polyQ diseases share important pathogenic features. In particular, abnormal protein conformations promoted by polyQ expansion seem to be central to pathogenesis. This class of PolyQ expansion neurodegenerative disease are Huntington's Disease (HD), Dentatorubralpallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and five spinocerebellar ataxias (SCAl, SCA2, SCA3/MJD (Machado- Joseph Disease), SCA6 and SCA7). [0008] It is known that certain HDAC inhibitors, for example SAHA, CBHA and pryoxiamide can cross the blood brain barrier at sufficient amounts to significantly inhibit HDAC activity causing the accumulation of acetylated histones in the brain (WO 03/032921). This discovery therefore provides for the use of HDAC inhibitors for inhibiting HDAC in the brain, for the treatment of polyglutamine (polyQ) expansion diseases. [0009] The art provides data that HDAC inhibitors are promising novel therapeutics for polyglutamine expansion diseases. Other data support a therapeutic benefit of HDAC inhibitors for Huntington's disease. Sadri-Vakili and Cha (Nature Clinical Practice Neurology, 2006, 2(6):330-338), and references cited therein, for example, review the current state of knowledge regarding the status of histones in Huntington's Disease and teach that recent studies have shown a therapeutic role for hisone deacetylase inhibitors in a number of Huntington's Disease models. In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polygluatmine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease (Steffan et al., 2001, Nautre 413: 739-743). Similar findings were observed with sodium butyrate and TSA (Zhao et al., 2005, J. Expt. Biol., 208:697-705). Gardian et al. (2005, J. Biol. Chem., 280:556-563) showed that phenylbutyrate is capable of improving survival and attenuating brain atrophy in the N171- 82Q transgenic mouse model of Huntington' s Disease. In the R6/2 model of Huntington' s Disease, sodium butyrate extended survival, improved motor deficits and delayed neuropathological sequelae (Ferrante et al., 2003, J. Neurosci., 23:9418-9427). In that same model, suberoylanilide hydroxamic acid (SAHA) was also active in improving the motor impairment (Hockly, 2003, Proc. Natl. Acad.Sci. USA, 100:2041-0246). Ying et al. (2005, J. Biol. Chem., 281: 12580-12586) showed that sodium butyrate improved life span and motor deficits in a mouse model for DRPLA. Bates et al. (2006, The Journal of Neuroscience, 26(10):2830-2838) reported that in Caenorhabditis elegans expressing a human huntingtin

fragment with an expanded polyglutamine tract (Htn-Q150), knockdown of C. elegans hda-3 suppressed Htn-Q150 toxicity. Neuronal expression of hda-3 restored Htn-Q150 toxicity and suggested that C. elegans HDAC3 acts within neurons to promote degeneration in response to Htn-Q150.

[0010] Cinnamic hydroxamates are known as HDAC pan inhibitors. WO2006/097460 discloses piperidine-linked hydroxamates. However, the compounds in this publication are not described as selective HDAC-8 inhibitors.

[0011] These findings suggest that inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation and that HDAC inhibitors have great therapeutic potential in the treatment of polyglutamine (polyQ) expansion diseases, such as Huntington's Disease. It would be highly desirable to have novel and isoform-selective inhibitors of histone deacetylase.

SUMMARY OF THE INVENTION

[0012] The present invention provides compounds for the inhibition of histone deacetylase. We have now found that optionally substituted 2-heterocyclylidene-N- hydroxyacetamide or optionally substituted 2-cyclylidene-N-hydroxyacetamide are not only well tolerated but cause increase in HDAC inhibition activity and selectivity against histone deacetylase- 8.

[0013] In a first aspect, the present invention provides compounds having the Formula

(I),

[0014] and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, in which A and Y are as defined below.

[0015] In a second aspect, the invention provides a composition comprising a compound according to the first aspect and a pharmaceutically acceptable carrier. [0016] In a third aspect, the invention provides a method of inhibiting histone deacetylase, the method comprising contacting the histone deacetylase or a cell containing histone deacetylase, with a histone deacetylase inhibiting amount of a compound according to the first aspect or a composition according to second aspect.

[0017] The foregoing merely summarizes various aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. The issued patents, applications, and references that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of inconsistencies, the present disclosure will prevail.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention provides compounds that are useful as inhibitors of histone deacetylase.

[0019] In one aspect, the invention provides certain compounds of the Formula (I)

[0020] and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof wherein groups A and Y are defined herein.

[0021] In particular, the compounds in this invention are useful to inhibit HDAC-8. [0022] In a second aspect, the invention provides a composition comprising a compound according to the first aspect and a pharmaceutically acceptable carrier. [0023] In the third aspect, the invention provides a method of inhibiting histone deacetylase. In particular, the methods in this invention are useful to inhibit HDAC-8. In one embodiment, the method comprises contacting the histone deacetylase with a histone deacetylase inhibiting amount of a compound according to the first aspect or a preferred embodiment thereof. In a further embodiment of the third aspect, the method comprises contacting the histone deacetylase with a histone deacetylase inhibiting amount of a composition according to the second aspect. In yet another embodiment, the method comprises inhibiting histone deacetylase in a cell comprising contacting the cell with a histone deacetylase inhibiting amount of compound according to the first aspect or a preferred embodiment thereof. In still another embodiment, the method comprises inhibiting histone deacetylase in a cell comprising contacting the cell with a histone deacetylase inhibiting amount of a composition according to the second aspect.

[0024] In a particularly preferred embodiment of the third aspect, compounds according to the first aspect are able to cross the blood brain barrier and inhibit a histone deacetylase in a cell thereacross. In a preferred embodiment, the cell is a cell of the central nervous system, more preferably a brain cell, more preferably a cortical cell.

[0025] In another aspect, the present invention provides a method of inhibiting HDAC in the brain of an individual. The method comprises administering to the individual a HDAC inhibiting amount of a histone deacetylase inhibitor according to the present invention, or a composition thereof.

[0026] In another aspect, the present invention provides a method of treating a polyglutamine (polyQ) expansion disease, comprising administering to an individual in need of treatment a therapeutically effective amount of a compound according to the present invention, or a composition thereof.

[0027] In certain preferred embodiments, the disease is selected from the group consisting of Huntington's Disease (HD), Dentatorubralpallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and five spinocerebellar ataxias (SCAl, SCA2,

SCA3/MJD (Machado- Joseph Disease), SCA6 and SCA7).

[0028] In a preferred embodiment, the disease is Huntington's Disease.

[0029] In preferred embodiments, the individual is a mammal, preferably a primate, more preferably a human.

[0030] For purposes of the present invention, the following definitions will be used

(unless expressly stated otherwise).

[0031] The terms "treating", "treatment", or the like, as used herein covers the treatment of a disease-state in an animal and includes at least one of: (i) preventing the disease-state from occurring, in particular, when such animal is predisposed to the disease-state but has not yet developed symptoms of having it; (ii) inhibiting the disease- state, i.e., partially or completely arresting its development; (iii) relieving the disease-state, i.e., causing regression of symptoms of the disease-state, or ameliorating a symptom of the disease; and (iv) reversal or regression of the disease-state, preferably eliminating or curing of the disease. In a preferred embodiment the terms "treating", "treatment", or the like, covers the treatment of a disease-state in an animal and includes at least one of (ii), (iii) and (iv) above. In a preferred embodiment of the present invention the animal is a mammal, preferably a primate, more preferably a human. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction

and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.

[0032] As used herein, the terms "histone deacetylase" and "HDAC" are intended to refer to any one of a family of enzymes that remove acetyl groups from a protein, such as for example, the ε-amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term "histone" is meant to refer to any histone protein, including Hl, H2A, H2B, H3, H4, and H5, from any species. Preferred histone deacetylases include class I and class II enzymes. Other preferred histone deacetylases include class III enzymes. Preferably the histone deacetylase is a human HDAC, including, but not limited to, HDAC-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10 and HDAC-I l. In some other preferred embodiments, the histone deacetylase is derived from a protozoal or fungal source.

[0033] The terms "histone deacetylase inhibitor" and "inhibitor of histone deacetylase" are intended to mean a compound having a structure as defined herein, which is capable of interacting with a histone deacetylase and inhibiting its enzymatic activity. [0034] The term "inhibiting histone deacetylase enzymatic activity" is intended to mean reducing the ability of a histone deacetylase to remove an acetyl group from a protein, such as a histone. The concentration of inhibitor which reduces the activity of a histone deacetylase to 50% of that of the uninhibited enzyme is determined as the IC ₅₀ value. In some preferred embodiments, such reduction of histone deacetylase activity is at least 50%, more preferably at least about 75%, and still more preferably at least about 905. In other preferred embodiments, histone deacetylase activity is reduced by at least 95% and more preferably by at least 99%.

[0035] Preferably, such inhibition is specific, i.e., the histone deacetylase inhibitor reduces the ability of a histone deacetylase to remove an acetyl group from a protein, such as a histone, at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect. Preferably, the concentration of the inhibitor required for histone deacetylase inhibitory activity is at least 2-fold lower, more preferably at least 5 -fold lower, even more preferably at least 10-fold lower, and most preferably at least 20-fold lower than the concentration required to produce an unrelated biological effect.

[0036] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances

clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH ₃ -CH ₂ -), in certain circumstances a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH ₂ -CH ₂ -), which is equivalent to the term "alkylene." (Similarly, in circumstances in which a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene). All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A) _a -B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-. [0037] For simplicity, reference to a "C _n -C _1n " heterocyclyl or "C _n -C _1n " heteroaryl means a heterocyclyl or heteroaryl having from "n" to "m" annular atoms, where "n" and "m" are integers. Thus, for example, a Cs-Ce-heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (C ₅ ) and piperidinyl (C ₆ ); C ₆ -heteroaryl includes, for example, pyridyl and pyrimidyl.

[0038] The term "hydrocarbyl" refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A "Co" hydrocarbyl is used to refer to a covalent bond. Thus, "Co-C ₃ -hydrocarbyl" includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.

[0039] The term "alkyl" is intended to mean a straight or branched chain aliphatic group having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably _1-6 carbon atoms. Other preferred alkyl groups have from 2 to 12 carbon atoms, preferably 2-8 carbon atoms and more preferably 2-6 carbon atoms. Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl, pentyl, and hexyl. A "Co" alkyl (as in "Co-C ₃ -alkyl") is a covalent bond.

[0040] The term "alkenyl" is intended to mean an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms. Preferred alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl. [0041] The term "alkynyl" is intended to mean an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0042] The terms "alkylene," "alkenylene," or "alkynylene" as used herein are intended to mean an alkyl, alkenyl, or alkynyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Preferred alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Preferred alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Preferred alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

[0043] The term "cycloalkyl" is intended to mean a saturated or unsaturated mono-, bi, tri- or poly-cyclic hydrocarbon group having about 3 to 15 carbons, preferably having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons. In certain preferred embodiments, the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group. Preferred cycloalkyl groups include, without limitation, cyclopenten-2-enone, cyclopenten-2- enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. [0044] In certain preferred embodiments, the cycloalkyl group is a bridged cycloalkyl group, preferably a C ₅ -C ₁₀ bridged bicyclic group. In certain preferred embodiments, the bridged cycloalkyl group is a C ₅ bridged bicyclic group. In certain preferred embodiments, the bridged cycloalkyl group is a C ₆ bridged bicyclic group. In certain preferred embodiments, the bridged cycloalkyl group is a C ₇ bridged bicyclic group. In certain preferred embodiments, the bridged cycloalkyl group is a Cs bridged bicyclic group. In certain preferred embodiments, the bridged cycloalkyl group is a C ₉ bridged bicyclic. In certain preferred embodiments, the bridged cycloalkyl group has a bridge of 0, 1, 2 or 3 carbon atoms. A bridge of 0 carbon atoms is a bond, and equates to a cycloalkyl group fused to another ring structure. In certain preferred embodiments, the bridged cycloalkyl group has a bridge of 0, 1 or 3 carbon atoms. In certain preferred embodiments, the bridged cycloalkyl group has a bridge of 1 or 3 carbon atoms. In certain preferred embodiments, the bridged cycloalkyl group has a bridge of 1 carbon atom. In certain preferred embodiments, the bridged cycloalkyl group has a bridge of 2 carbon atoms. In certain preferred embodiments, the bridged cycloalkyl group has a bridge of 3 carbon atoms. If a bridged cycloalkyl group is described as "optionally substituted", it is intended to be optionally substituted on any position, including the bridge. The bridged cycloalkyl group is not limited to any particular stereochemistry.

[0045] The term "heteroalkyl" is intended to mean a saturated or unsaturated, straight or branched chain aliphatic group, wherein one or more carbon atoms in the chain are

independently replaced by a heteroatom selected from the group consisting of O, S(O) _0-2 , N and N(R ³³ ).

[0046] The term "aryl" is intended to mean a mono-, bi-, tri- or polycyclic C ₆ -Ci ₄ aromatic moiety, preferably comprising one to three aromatic rings. Preferably, the aryl group is a C ₆ -Ci _O aryl group, more preferably a C ₆ aryl group. Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0047] The terms "aralkyl" or "arylalkyl" is intended to mean a group comprising an aryl group covalently linked to an alkyl group. If an aralkyl group is described as "optionally substituted", it is intended that either or both of the aryl and alkyl moieties may independently be optionally substituted or unsubstituted. Preferably, the aralkyl group is (C ₁ - C ₆ )alk(C ₆ -Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as "arylalkyl" this term, and terms related thereto, is intended to indicate the order of groups in a compound as "aryl - alkyl". Similarly, "alkyl-aryl" is intended to indicate the order of the groups in a compound as "alkyl-aryl". [0048] The terms "heterocyclyl", "heterocyclic" or "heterocycle" are intended to mean a group which is a mono-, bi-, or polycyclic structure having from about 3 to about 14 atoms, wherein one or more atoms are independently selected from the group consisting of N, O, and S. The ring structure may be saturated, unsaturated or partially unsaturated. In certain preferred embodiments, the heterocyclic group is non-aromatic. In a bicyclic or polycyclic structure, one or more rings may be aromatic; for example one ring of a bicyclic heterocycle or one or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9,10-dihydro anthracene. Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certain preferred embodiments, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular O or S atom is adjacent to another O or S atom.

[0049] In certain preferred embodiments, the heterocyclic group is a bridged heterocyclic group, preferably a C ₆ -Ci _O bridged bicyclic group, wherein one or more carbon atoms are independently replaced by a heteroatom selected from the group consisting of N, O and S. In certain preferred embodiments, the bridged heterocyclic group is a C ₆ bridged bicyclic group. In certain preferred embodiments, the bridged heterocyclic group is a C ₇ bridged bicyclic group. In certain preferred embodiments, the bridged heterocyclic group is a Cs bridged

bicyclic group. In certain preferred embodiments, the bridged heterocyclic group is a C ₉ bridged bicyclic. In certain preferred embodiments, the bridged heterocyclic group has a bridge of 0, 1, 2 or 3 carbon atoms. In certain preferred embodiments, the bridged heterocyclic group has a bridge of 0, 1 or 3 carbon atoms. A bridge of 0 carbon atoms is a bond, and equates to a heterocyclic group fused to another ring structure. In certain preferred embodiments, the bridged heterocyclic group has a bridge of 1 or 3 carbon atoms. In certain preferred embodiments, the bridged heterocyclic group has a bridge of 1 carbon atom. In certain preferred embodiments, the bridged heterocyclic group has a bridge of 2 carbon atoms. In certain preferred embodiments, the bridged heterocyclic group has a bridge of 3 carbon atoms. If a bridged heterocyclic group is described as "optionally substituted", it is intended to be optionally substituted on any position, including the bridge. The bridged heterocyclic group is not limited to any particular stereochemistry.

[0050] In certain preferred embodiments, the heterocyclic group is a heteroaryl group. As used herein, the term "heteroaryl" is intended to mean a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, between one or more heteroatoms independently selected from the group consisting of N, O, and S. For example, a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl. Preferred heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.

[0051] The terms "arylene," "heteroarylene," or "heterocyclylene" are intended to mean an aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. [0052] Preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,

1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H- pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl), thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5- triazolyl, 1,3,4-triazolyl), and xanthenyl.

[0053] Aromatic polycycles include, but are not limited to, bicyclic and tricyclic fused ring systems, including for example naphthyl.

[0054] Non-aromatic polycycles include, but are not limited to, bicyclic and tricyclic fused ring systems where each ring can be 4-9 membered and each ring can contain zero, 1 or more double and/or triple bonds. Suitable examples of non-aromatic polycycles include, but are not limited to, decalinyl, octahydroindenyl, perhydrobenzocycloheptenyl and perhydrobenzo- \f\ - azulenyl .

[0055] Polyheteroaryl groups include bicyclic and tricyclic fused rings systems where each ring can independently be 5 or 6 membered and contain one or more heteroatom, for example, 1, 2, 3 or 4 heteroatoms, independently chosen from O, N and S such that the fused ring system is aromatic. Suitable examples of polyheteroaryl ring systems include quinolinyl, isoquinolinyl, pyridopyrazinyl, pyrrolopyridinyl, furopyridinyl, indole, benzofuranyl, benzothiofuranyl, benzindolyl, benzoxazolyl, pyrroloquinolinyl, and the like. [0056] Non-aromatic polyheterocyclic groups include but are not limited to bicyclic and tricyclic ring systems where each ring can be 4-9 membered, contain one or more heteratom, for example 1, 2, 3 or 4 heteratoms, independently chosen from O, N and S, and contain zero, or one or more C-C double or triple bonds. Suitable examples of non-aromatic polyheterocycles include but are not limited to, hexitol, cis-perhydro-cyclohepta[b]pyridinyl, decahydro-benzo[f][l,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octanyl, hexahydro-thieno[3,2- bjthiophenyl, perhydropyrrolo[3,2-b]pyrrolyl, perhydronaphthyridinyl, perhydrop-lH- dicyclopenta[b,e]pyranyl.

[0057] Mixed aryl and non-aryl polyheterocycle groups include but are not limited to bicyclic and tricyclic fused ring systems where each ring can be 4-9 membered, contain one

or more heteroatom independently chosen from O, N and S and at least one of the rings must be aromatic. Suitable examples of mixed aryl and non-aryl polyheteorcycles include 2,3- dihydroindolyl, 1 ,2,3 ,4-tetrahydroquinolinyl, 5,11 -dihydro- 10H-dibenz[b,e] [ 1 ,4]diazepinyl, 5H-dibenzo[b,e][l,4]diazepinyl, l,2-dihydropyrrolo[3,4-b][l,5]benzodiazepinyl, 1,5- dihydropyrido[2,3-b][l,4]diazepin-4-onyl, 1,2,3,4,6, ll-hexhydro-benzo[b]pyrido[2,3- e][l,4]diazepine-5-onyl, methylenedioxyphenyl, έώ-methylenedioxyphenyl, 1,2,3,4- tetrahydronaphthalenyl, dibenzosuberanyl dihydroanthracene and 9H-fluorenyl. [0058] The terms "aromatic polycycles," "non-aromatic polycycles," "mixed aryl and non-aryl polyheterocycle," "polyheteroaryl," or "non-aromatic polyheterocyclic," , as defined hereinabove, are intended to mean a polycyclic ring that is connected to one chemical group. [0059] As employed herein, and unless stated otherwise, when a moiety (e.g., alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Preferred substituents, which are themselves not further substituted (unless expressly stated otherwise) are:

(a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino,

(b) C ₁ -C ₅ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, Ci-Cs alkyl, Ci-Cs alkenyl, Ci-Cs alkoxy, Ci-Cs alkoxycarbonyl, aryloxycarbonyl, C ₂ -Cs acyl, C ₂ -Cs acylamino, Ci-Cs alkylthio, arylalkylthio, arylthio, Ci-Cs alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, Ci-Cs alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, Co-C ₆ N-alkyl carbamoyl, C ₂ -C ₁₅ N,N-dialkylcarbamoyl, C ₃ -C ₇ cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C ₃ -C ₇ heterocycle, C ₅ -C ₁₅ heteroaryl or any of these rings fused or spiro- fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; and

(c) -(CR ³² R ^33a ) _s -νR ³⁰ R ³¹ , wherein s is from 0 (in which case the nitrogen is directly bonded to the moiety that is substituted) to 6, R ³² and R ^33a are each independently hydrogen, halo, hydroxyl or Ci-C ₄ alkyl,and R and R are each independently

hydrogen, cyano, oxo, hydroxyl, -Ci-Cs alkyl, Ci-Cs heteroalkyl, Ci-Cs alkenyl, carboxamido, C ₁ -C ₃ alkyl-carboxamido, carboxamido-Ci-C ₃ alkyl, amidino, C ₂ - Cshydroxyalkyl, C ₁ -C ₃ alkylaryl, aryl-Ci-C ₃ alkyl, C ₁ -C ₃ alkylheteroaryl, heteroaryl-Ci-C3 alkyl, C ₁ -C3 alkylheterocyclyl, heterocyclyl-Ci-C3 alkyl C ₁ -C3 alkylcycloalkyl, cycloalkyl-Ci-C ₃ alkyl, C ₂ -C ₈ alkoxy, C ₂ -C ₈ alkoxy-C ₁ -C ₄ alkyl, Ci-C ₈ alkoxycarbonyl, aryloxycarbonyl, aryl-Ci-C ₃ alkoxycarbonyl, heteroaryloxycarbonyl, heteroaryl-Ci-C ₃ alkoxycarbonyl, Ci-C ₈ acyl, Co-C ₈ alkyl- carbonyl, aryl-Co-C ₈ alkyl-carbonyl, heteroaryl-Co-C ₈ alkyl-carbonyl, cycloalkyl- Co-C ₈ alkyl-carbonyl, Co-C ₈ alkyl-NH-carbonyl, aryl-Co-C ₈ alkyl-NH-carbonyl, heteroaryl-Co-C ₈ alkyl-NH-carbonyl, cycloalkyl-Co-C ₈ alkyl-NH-carbonyl, Co-C ₈ alkyl-0-carbonyl, aryl-Co-C ₈ alkyl-O-carbonyl, heteroaryl-Co-C ₈ alkyl-O- carbonyl, cycloalkyl-Co-C ₈ alkyl-O-carbonyl, Ci-C ₈ alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, Ci-C ₈ alkyl-NH-sulfonyl, arylalkyl-NH-sulfonyl, aryl-NH-sulfonyl, heteroarylalkyl-NH- sulfonyl, heteroaryl-NH-sulfonyl aroyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-Ci-C3 alkyl-, cycloalkyl-Ci-C3 alkyl-, heterocyclyl-Ci-C3 alkyl-, heteroaryl- C ₁ -C ₃ alkyl-, or protecting group, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; or

R ³⁰ and R ³¹ taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents selected from the group consisting of (a) above, a protecting group, and (X ³⁰ -Y ³¹ -), wherein said heterocyclyl may also be bridged (forming a bicyclic moiety with a methylene, ethylene or propylene bridge); wherein

X ³⁰ is selected from the group consisting of Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl-, C ₂ - C ₈ alkynyl-, -C ₀ -C ₃ alkyl -C ₂ -C ₈ alkenyl-C ₀ -C ₃ alkyl, Co-C ₃ alkyl-C ₂ -C ₈ alkynyl-C _o - C ₃ alkyl, Co-C ₃ alkyl-0-Co-C ₃ alkyl-, HO-C ₀ -C ₃ alkyl-, C ₀ -C ₄ alkyl-N(R ³⁰ )-C ₀ - C ₃ alkyl-, N(R ³⁰ )(R ³¹ )-C ₀ -C ₃ alkyl-, N(R ³⁰ )(R ³¹ )-C ₀ -C ₃ alkenyl-, N(R ³⁰ )(R ³¹ )-C ₀ - C ₃ alkynyl-, (N(R ³⁰ )(R ³¹ )) ₂ -C=N-, C ₀ -C3alkyl-S(0)o- ₂ -Co-C ₃ alkyl-, CF ₃ -C ₀ - C ₃ alkyl-, Ci-C ₈ heteroalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-Ci- C ₃ alkyl-, cycloalkyl-Ci-Csalkyl-, heterocyclyl-Ci-Csalkyl-, heteroaryl-Ci- C ₃ alkyl-, N(R ³⁰ )(R ³¹ )-heterocyclyl-Ci-C ₃ alkyl-, wherein the aryl, cycloalkyl, heteroaryl and heterocycyl are optionally substituted with from 1 to 3 substituents from (a); and Y ³¹ is selected from the group consisting of a direct bond, -O- , -N(R ³⁰ )-, -C(O)-, -O-C(O)-, -C(O)-O-, -N(R ³⁰ )-C(O)-, -C(O)-N(R ³⁰ )-, -N(R ³⁰ )-

C(S)-, -C(S)-N(R ³⁰ )-, -N(R ³⁰ )-C(O)-N(R ³¹ )-, -N(R ³⁰ )-C(NR ³⁰ )-N(R ³¹ )-, -N(R ³⁰ )- C(NR ³¹ )-, -C(NR ³¹ )-N(R ³⁰ ), -N(R ³⁰ )-C(S)-N(R ³¹ )-, -N(R ³⁰ )-C(O)-O-, -0-C(O)- N(R ³¹ )-, -N(R ³⁰ )-C(S)-O-, -0-C(S)-N(R ³¹ )-, -S(O) ₀ - ₂ -, -SO ₂ N(R ³¹ )-, -N(R ³¹ )-SO ₂ - and -N(R ³⁰ )-SO ₂ N(R ³¹ )-.

[0060] As a non- limiting example, substituted phenyls include 2-flurophenyl, 3,4- dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within this definition are methylenes (-CH ₂ -) substituted with oxygen to form carbonyl -CO-.

[0061] When there are two optional substituents bonded to adjacent atoms of a ring structure, such as for example phenyl, thiophenyl, or pyridinyl, the substituents, together with the atoms to which they are bonded, optionally form a 5- or 6- membered cycloalkyl or heterocycle having 1, 2, or 3 annular heteroatoms.

[0062] In a preferred embodiment, hydrocarbyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aromatic polycycle, non-aromatic polycycle, polyheteroaryl, non-aromatic polyheterocyclic and mixed aryl and non-aryl polyheterocycle groups are unsubstituted.

[0063] In other preferred embodiments, hydrocarbyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aromatic polycycle, non-aromatic polycycle, polyheteroaryl, non-aromatic polyheterocyclic and mixed aryl and non-aryl polyheterocycle groups are substituted with from 1 to 3 independently selected substituents. [0064] Preferred substituents on alkyl groups include, but are not limited to, hydroxyl, halogen (e.g., a single halogen substituent or multiple halo substituents; in the latter case, groups such as CF ₃ or an alkyl group bearing more than one Cl), cyano, nitro, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, -OR ^U , -SR ^U , -S(=O)R ^y , -S(=O) ₂ R ^y , -P(=O) ₂ R ^y , -S(=O) ₂ OR ^y , -P(=O) ₂ OR ^y , -NR ^V R ^W , -NR ^v S(=O) ₂ R ^y , -NR ^v P(=O) ₂ R ^y , -S(=O) ₂ NR ^V R ^W , -P(=O) ₂ NR ^V R ^W , -C(=O)OR ^y , -C(=O)R ^U , -C(=O)NR ^V R ^W , -OC(=O)R ^U , -0C(=0)NR ^v R ^w , -NR ^v C(=0)0R ^y , -NR ^X C(=O)NR ^V R ^W , -NR ^X S(=O) ₂ NR ^V R ^W , -NR ^X P(=O) ₂ NR ^V R ^W , -NR ^V C(=O)R ^U or -NR ^v P(=O) ₂ R ^y , wherein R ^u is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; R ^v , R ^w and R ^x are independently hydrogen, alkyl, cycloalkyl, heterocycle or aryl, or said R ^v and R ^w together with the N to which they are bonded optionally form a heterocycle; and R ^y is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl. In the aforementioned

exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.

[0065] Preferred substituents on alkenyl and alkynyl groups include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited as preferred alkyl substituents. [0066] Preferred substituents on cycloalkyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited about as preferred alkyl substituents. Other preferred substituents include, but are not limited to, spiro-attached or fused cyclic substituents, preferably spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0067] Preferred substituents on cycloalkenyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited as preferred alkyl substituents. Other preferred substituents include, but are not limited to, spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. [0068] Preferred substituents on aryl groups include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groups recited above as preferred alkyl substituents. Other preferred substituents include, but are not limited to, fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalky, cylcoalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. Still other preferred substituents on aryl groups (phenyl, as a non-limiting example) include, but are not limited to, haloalkyl and those groups recited as preferred alkyl substituents.

[0069] Preferred substituents on heterocylic groups include, but are not limited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, nitro, oxo (i.e., =0), cyano, alkyl, substituted alkyl, as well as those groups recited as preferred alkyl substituents. Other preferred substituents on heterocyclic groups include, but are not limited to, spiro-attached or fused cylic substituents at any available point or points of attachement, more preferably spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloakenyl, fused heterocycle

and fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0070] In a preferred embodiment, a heterocyclic group is substituted on carbon, nitrogen and/or sulfur at one or more positions. Preferred substituents on nitrogen include, but are not limited to N-oxide, alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Preferred substituents on sulfur include, but are not limited to, oxo and Ci_ ₆ alkyl. In certain preferred embodiments, nitrogen and sulfur heteroatoms may independently be optionally oxidized and nitrogen heteroatoms may independently be optionally quaternized.

[0071] Especially preferred substituents on alkyl groups include halogen and hydroxy. [0072] Especially preferred substituents on ring groups, such as aryl, heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy and alkyl.

[0073] Preferred substituents on aromatic polycycles include, but are not limited to, oxo, Q-Qalkyl, cycloalkylalkyl (e.g. cyclopropylmethyl), oxyalkyl, halo, nitro, amino, alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl and OR ^aa , such as alkoxy, wherein R ^aa is selected from the group consisting of H, Ci-Cβalkyl, C ₄ -Cς)Cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ )o- _ό Z ^a R , wherein Z ^a is selected from the group consisting of O, NR ^CC , S and S(O), and R ^bb is selected from the group consisting of H, Ci-C ₆ alkyl, C ₄ - C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkylalkyl, aryl, mixed aryl and non- aryl polycycle, heteroaryl, arylalkyl, (e.g. benzyl), and heteroarylalkyl (e.g. pyridylmethyl); and R ^cc is selected from the group consisting of H, C ₁ -C ₆ -UlCyI, C ₄ -C ₉ cycloalkyl, C ₄ - Cgheterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl) and amino acyl.

[0074] Preferred substituents on non-aromatic polycycles include, but are not limited to, oxo, C ₃ -C ₉ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Unless otherwise noted, non-aromatic polycycle substituents include both unsubstituted cycloalkyl groups and cycloalkyl groups that are substituted by one or more suitable substituents, including but not limited to, C ₁ -C ₆ EiIlCyI, oxo, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR ^aa , such as alkoxy. Preferred substituents for such cycloalkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl. [0075] Preferred substituents on carbon atoms of polyheteroaryl groups include but are not limited to, straight and branched optionally substituted C ₁ -C ₆ EUlCyI, unsaturation (i.e., there are one or more double or triple C-C bonds), acyl, oxo, cycloalky, halo, oxyalkyl,

alkylamino, aminoalkyl, acylamino, OR ^aa (for example alkoxy), and a substituent of the formula -0-(CH ₂ CH=CH(CH ₃ )(CH ₂ )) ₁ -3H. Examples of suitable straight and branched C ₁ - Cβalkyl substituents include but are not limited to methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec -butyl, t-butyl and the like. Preferred substituents include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl. Preferably substitutions on nitrogen atoms include, for example by N-oxide or R ^cc . Preferred substituents on nitrogen atoms include H, Ci-C ₄ alkyl, acyl, aminoacyl and sulfonyl. Preferably sulfur atoms are unsubstituted. Preferred substituents on sulfur atoms include but are not limited to oxo and lower alkyl.

[0076] Preferred substituents on carbon atoms of non-aromatic polyheterocyclic groups include but are not limited to straight and branched optionally substituted Ci-Cβalkyl, unsaturation (i.e., there are one or more double or triple C-C bonds), acyl, oxo, cycloalky, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and OR ^aa , for example alkoxy. Examples of suitable straight and branched Ci-Cβalkyl substituents include but are not limited to methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl and the like. Preferred substituents include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl. Preferably substitutions on nitrogen atoms include, for example, N-oxide or R ^cc . Preferred N substituents include H, C ₁ -C ₄ alkyl, acyl, aminoacyl and sulfonyl. Preferably, sulfur atoms are unsubstituted. Preferred S substituents include oxo and lower alkyl.

[0077] Preferred substituents on mixed aryl and non-aryl polyheterocycle groups include, but are not limited to, nitro or as described above for non-aromatic polycycle groups. Preferred subsituents on carbon atoms include, but are not limited to, -N-OH, =N-0H, optionally substituted alkyl, unsaturation (i.e., there are one or more double or triple C-C bonds), oxo, acyl, cycloalky, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and OR ^aa , for example alkoxy. Preferably substitutions on nitrogen atoms include, for example, N-oxide or R ^cc . Preferred N substituents include H, Ci- ₄ alkyl, acyl aminoacyl and sulfonyl. Preferably sulfur atoms are unsubstituted. Preferred S substituents include oxo and lower alkyl. [0078] A "halohydrocarbyl" is a hydrocarbyl moiety in which from one to all hydrogens have been replaced with one or more halo.

[0079] The term "halogen" or "halo" is intended to mean chlorine, bromine, fluorine, or iodine. As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acylamino" refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group attached at the carbonyl carbon atom (i.e., NH ₂ -CO-). The nitrogen atom of an acylamino or carbamoyl substituent is additionally optionally substituted. The term "sulfonamide" refers to a sulfonamide

substituent attached by either the sulfur or the nitrogen atom. The term "amino" is meant to include NH ₂ , alkylamino, arylamino, and cyclic amino groups. The term "ureido" as employed herein refers to a substituted or unsubstituted urea moiety.

[0080] The term "radical" is intended to mean a chemical moiety comprising one or more unpaired electrons.

[0081] Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. [0082] In addition, substituents on cyclic moieties (i.e., cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 9-14 membered bi-cyclic moieties fused to the parent cyclic moiety to form a bi- or tri-cyclic fused ring system. Substituents on cyclic moieties also include 5-6 membered mono- and 9-14 membered bi-cyclic moieties attached to the parent cyclic moiety by a covalent bond to form a bi- or tri-cyclic bi-ring system. For example, an optionally substituted phenyl includes, but is not limited to, the following:

[0083] An "unsubstituted" moiety (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as defined above that does not have an optional substituent. Thus, for example, "unsubstituted aryl" does not include phenyl substituted with a halo.

[0084] The term "protecting group" is intended to mean a group used in synthesis to temporarily mask the characteristic chemistry of a functional group because it interferes with another reaction. A good protecting group should be easy to put on, easy to remove and in high yielding reactions, and inert to the conditions of the reaction required. A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. One skilled in the art will recognize that during any of the processes for preparation of the compounds in the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as but not limited to Bn- (or -CH ₂ Ph), -CHPh ₂ , alloc (or CH ₂ =CH-CH ₂ -O-C(O)-), BOC-, -Cbz (or Z-), -Fmoc, -C(O)-CF ₃ , N-Phthalimide,l-Adoc-, TBDMS-, TBDPS-, TMS-, TIPS-, IPDMS-, -SiR ₃ , SEM-, t-Bu-, Tr-, THP- and AlIyI-. These protecting groups may be removed at a convenient stage using methods known from the art.

[0085] The term "therapeutically effective amount" as that term is used herein refers to an amount which elicits the desired therapeutic effect. The therapeutic effect is dependent upon the disease being treated and the results desired. As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disease and/or inhibition (partial or complete) of progression of the disease. Further, the therapeutic effect can be inhibition of HDAC in the brain. The amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the patient. Optimal amounts can also be determined based on monitoring of the patient's response to treatment. Administration may be by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain particularly preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route. [0086] Some compounds of the invention may have one or more chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers. The invention also comprises all tautomeric forms of the compounds disclosed herein.

[0087] The present invention also includes prodrugs of compounds of the invention. The term "prodrug" is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo. Prodrugs of compounds of the invention include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I)), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.

[0088] The compounds of the invention may be administered as is or as a prodrug, for example in the form of an in vivo hydrolyzable ester or in vivo hydrolyzable amide. An in vivo hydrolyzable ester of a compound of the invention containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Ci_ ₆ -alkoxymethyl esters {e.g., methoxymethyl), Ci_ ₆ -

alkanoyloxymethyl esters (e.g., for example pivaloyloxymethyl), phthalidyl esters, C _3-8 - cycloalkoxycarbonyloxyCi_ ₆ -alkyl esters (e.g., 1-cyclohexylcarbonyloxy ethyl); 1,3-dioxolen- 2-onylmethyl esters (e.g., 5-methyl-l,3-dioxolen-2-onylmethyl; and C _1-6 - alkoxycarbonyloxyethyl esters (e.g., 1-methoxycarbonyloxy ethyl) and may be formed at any appropriate carboxy group in the compounds of this invention. [0089] An in vivo hydrolyzable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(NN- dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), NN-dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring. A suitable value for an in vivo hydrolyzable amide of a compound of the invention containing a carboxy group is, for example, a N-Ci_ ₆ -alkyl or ν,ν-di-Ci_ ₆ -alkyl amide such as N-methyl, N-ethyl, N-propyl, NN-dimethyl, N-ethyl-N-methyl or NN-diethyl amide. [0090] For simplicity, and unless stated otherwise, a moiety is written in the direction corresponding to the order given in Formula (I). For example, if moiety J is -Co- ₆ alkyl-aryl- C ₂ - ₆ heteroalkyl-, it is meant that the -Co- ₆ alkyl- portion is attached to Q and the -C _2-6 heteroalkyl- portion is attached to L.

[0091] The foregoing merely summarizes some aspects and preferred embodiments thereof and is not intended to be limiting in nature. These aspects and preferred embodiments thereof are described more fully below.

Compounds

[0092] In a first aspect, the invention provides novel inhibitors of histone deacetylase. In a first embodiment, the novel inhibitors of histone deacetylase are represented by Formula (I):

[0093] and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein

[0094] 4-7 member heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, or cycloalkyl, wherein each cycloalkyl and heterocyclyl moiety is optionally substituted; [0095] Y is selected from the group consisting of H, -Co-C ₄ alkyl-aryl, -Co-C ₄ alkyl- heteroaryl, -C ₀ -C ₄ alkyl-cycloalkyl, -C ₀ -C ₄ alkyl-heterocyclyl, -C ₀ -C ₄ alkyl-C(O)O-Ci- C ₆ alkyl, -Co-C ₄ alkyl-C(0)-Ci-C ₆ alkyl, -Co-C ₄ alkyl-C(0)-Ci-C ₆ alkyl-aryl, -C _o -C ₄ alkyl- C(O)-Ci-C ₆ alkyl-heteroaryl, -Co-C4alkyl-S(0)2-Co-C ₆ alkyl-aryl, -Co-C ₄ alkyl-S(0) ₂ -Co- Cealkyl-heteroaryl, -Zi-Z-Z ₂ -D or -Co-Csalkyl-Z-Zs-Z-D, wherein each alkyl, aryl, cycloalkyl or heterocyclyl moiety is optionally substituted; wherein [0096] Zi is selected from the group consisting of chemical bond, alkylene, arylene, heterocyclylene, cycloalkylene, heteroarylene, -C(aryl)(Ri)-, -C(heteroaryl)(Ri)-, -C(heterocyclyl)(Ri)-, -C(cycloalkyl)(Ri)-, -C(alkyl)(Ri)-, -C(alkenyl)(Ri)-, -C(alkynyl)(Ri)-, wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl moiety is optionally substituted and each of which is optionally fused to one or more aryl or heteroaryl rings, or one or more saturated or partially unsaturated cycloalkyl or heterocyclyl rings, each of each ring is optionally substituted;

[0097] Z is selected from the group consisting of chemical bond, -O-, -NRi-, -NR ^a R -, -NR ^C -, -N(C ₂ -C ₄ alkyl-ORi)-, -C(O)-, -C(NORi)-, -CHF-, -CH(CONRiR ₂ )-CONRiR ₂ -, -CH(NRiR ₂ )-CONRiR ₂ -, -CH(CONReR _f )-CONRiR ₂ -, -CH(NReR _f )-CONRiR ₂ -, -CH(heteroaryl) -CONRiR ₂ -, -CH(heteroaryl-aryl) -CONRiR ₂ -, -CH(heteroaryl-heteroaryl) -CONRiR ₂ -, -C(O)-C(O)NRi-, -S(O) ₀ - ₂ -, -NRiS(O) ₂ -, -S(O) ₂ NRi-, -NRiS(O) ₂ NR ₂ -, -NRiC(O)-, -C(O)NRi-, -OC(O)-, -C(O)O-, -NRiC(NR ₂ )-, -C(NR ₂ )NRi-, -NRiC(O)NR ₂ -, -NRiC(O)O-, -OC(O)NRi-, -NRiC(S)-, -C(S)NRi-, -NRiC(S)NR ₂ -, -NRiC(S)O-, -OC(S)NRi-, -O-C ₂ -C ₄ alkyl-NRi-, -NRi-C ₂ -C ₄ alkyl-O-, -O-C ₂ -C ₄ alkyl-NR ^C -, -NR ^C - C ₂ -C ₄ alkyl-O-, -O-Ci-C ₄ alkyl-S(O) ₂ NRi-, -S(O) ₂ NRi-C ₂ -C ₄ alkyl-O-, -O-C ₂ -C ₄ alkyl -NRiS(O) ₂ -, -NRiS(O) ₂ -Ci-C ₄ alkyl-O-, -C(O)-Ci-C ₄ alkyl-NRi-, -NRi-Ci-C ₄ alkyl-C(O)-, -O- Ci-C ₄ alkyl-C(O)NRi-, -C(O)NRi-C ₂ -C ₄ alkyl-O-, -O-C ₂ -C ₄ alkyl-NRiC(O)-, -NRiC(O)- Ci-C ₄ alkyl-O-, -O-Ci-C ₄ alkyl-C(O)-, -C(O)-Ci-C ₄ alkyl-O-, -NRi-Ci-C ₄ alkyl-C(O), -C(O)- Ci-C ₄ alkyl-NRi-,-O-Ci-C ₄ alkyl-C(S)-, -C(S)-Ci-C ₄ alkyl-O-, -NRi-Ci-C ₄ alkyl-C(S), -C(S)- Ci-C ₄ alkyl-NRi-, -NRi-Ci-C ₄ alkyl-C(S)-, -O-Ci-C ₄ alkyl-C(S)NRi-, -C(S)NRi-C ₂ -C ₄ alkyl-

O-, -O-C ₂ -C ₄ alkyl-NRiC(S)-, -NRiC(S)-Ci-C ₄ alkyl-O-, -NRi-Ci-C ₄ alkyl-S(O) ₂ -, -O- Ci-C ₄ alkyl-S(O) ₂ NRi-, -S(O) ₂ NRi-C ₂ -C ₄ alkyl-O-, -O-C ₂ -C ₄ alkyl-NRiS(O) ₂ -, -NRiS(O) ₂ - Ci-C ₄ alkyl-O-, -O-C ₂ -C ₄ alkyl-OC(O)NRi-, -O-C ₂ -C ₄ alkyl-OC(S)NRi-; [099] Z ₂ is selected from the group consisting of chemical bond, alkyl, alkenyl, -C(F)(R ₁ )-, -C(OR ₂ )(Ri)-, -C(aryl)(Ri)-, -C(heteroaryl)(Ri)-, -C(heterocyclyl)(Ri)-, -C(cycloalkyl)(Ri)-, -C(alkyl)(Ri)-, -C(alkenyl)(Ri)-, -C(alkynyl)(Ri)-, wherein each alkyl, aryl, alkenyl or alkynyl moiety is optionally substituted;

[0098] Z ₃ is selected from the group consisting of C ₂ -Csalkyl, aryl, heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, cycloalkyl or heteroaryl, wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl moiety is optionally substituted and each of which is optionally fused to one or more aryl or heteroaryl rings, or one or more saturated or partially unsaturated cycloalkyl or heterocyclyl rings, each of each ring is optionally substituted; [0099] D is selected from the group consisting of H, aryl, heteroaryl, alkyl, cycloalyl and heterocyclyl, aryl-heterocyclyl, -aryl-Co-C ₃ alkyl-0-Co-C ₃ alkyl-aryl, -aryl-Co-C ₃ alkyl-0- Co-C ₃ alkyl-heteroaryl, -heteroaryl-Co-C ₃ alkyl-0-Co-C ₃ alkyl-aryl, -heteroaryl-Co-Csalkyl-O- Co-C ₃ alkyl-heteroaryl, -aryl-Co-Csalkyl-NRi-Co-Csalkyl-aryl, -aryl-C ₀ -C ₃ alkyl-NRi- Co-C ₃ alkyl-heteroaryl, -heteroaryl-Co-Qalkyl-NRi-Co-Qalkyl-aryl, -heteroaryl-Co-C ₃ alkyl-NRi-Co-C ₃ alkyl-heteroaryl, aromatic polycycles, non-aromatic polycycles, polyheteroaryl groups, non-aromatic polyheterocyclic, mixed aryl and non-aryl polyheterocycle, each of which is optionally substituted and each of which is optionally fused to one or more aryl or heteroaryl rings, or one or more saturated or partially unsaturated cycloalkyl or heterocyclyl rings, each of each ring is optionally substituted; [0100] Ri and R ₂ are independently selected from the group consisting of -H, -alkyl, -aryl, -aryl-aryl, -hetetoaryl, heteroaryl-aryl, heteroaryl-heteroaryl, alkyl-heteroaryl and -alkyl-aryl, wherein each aryl and heteroaryl moiety is optionally substituted; [0101] each R ^a and R ^b together with the nitrogen to which they are bound form a 4 to 7 membered heterocyclyl having 1 or 2 annular heteroatoms, or a 5 to 8 membered bridged heterocyclyl having 1 or 2 annular heteroatoms, the heterocyclyl being optionally substituted with 1-3 substituents independently selected from the group consisiting of H, OH, oxo (i.e., =0), -N(R ^c )(R ^d ), Ci-C ₆ alkyl, aryl, heteroaryl, -Ci-C ₆ alkyl-aryl, -Ci-C ₆ alkyl-heteroaryl, -Ci-C ₃ alkoxy-Ci-C ₃ alkyl, -C ₂ -C ₃ alkyl-OH, -C ₂ -C ₃ alkyl-O-Ci-C ₄ alkyl, -C ₅ -C ₆ cycloalkyl, -Co-C ₃ alkyl-N(H)-C(0)-Ci-C ₃ alkyl, -Co- ₃ alkyl-N(H)-C(0)-haloalkyl, -C ₀ -C ₃ alkyl-NHC(O)O-Ci-C ₃ alkyl-aryl, -C ₀ -C ₃ alkyl-CF ₃ , -C ₀ -C ₃ alkyl-NHC(O)O-Ci-C ₃ alkyl-heteroaryl and -C ₀ -C ₃ alkyl-NH ₂ , wherein said

heterocyclyl is optionally fused to an aryl or heteroaryl, wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl moiety is optionally substituted,

[0102] each R ^c and R ^d is independently selected from the group consisting of H, -Ci-C ₆ alkyl, -C ₂ -C ₃ alkyl-OR ^e , -C(O)ORi, -C(O)NRiR ₂ , -C(S)ORi, -C(S)NRiR ₂ , -C(O)Ri, -C(S)Ri, -S(O) ₂ Ri, -S(O) ₂ NRiR ₂ , aryl, heteroaryl, -heteroaryl-heteroaryl, -heteroaryl-aryl, -aryl-heteroaryl, -C(O)-aryl, -Ci-C ₃ -alkoxy-Ci-C ₃ -alkyl, -C ₂ -C ₃ alkyl-OR ₂ , -C ₂ -C ₃ alkyl-NR ^a R ^b , -C ₂ -C ₃ alkyl-NR ^e R ^f , -CH ₂ -C(CH ₃ ) ₂ -NR ^a R ^b , -CH ₂ -C(CH ₃ ) ₂ -NR ^e R ^f , in which each aryl and heteroaryl is optionally substituted with one, two or three substituents independently selected from amino, OCH ₃ and OH; and

[0103] each R ^e and R ^f is independently selected from the group consisting of -H, -alkyl, -aryl, -aryl-aryl, -hetetoaryl, heterocyclyl, heteroaryl-aryl, heteroaryl-heteroaryl, -Ci-C ₆ alkyl- C(O)NRiR ₂ , -C(O)-alkyl, -C(O)heteroaryl, -C(O)cycloalkyl, -C(O)aryl, -C(O)O-alkyl, -C(O)Oheteroaryl, -C(O)Ocycloalkyl, -C(O)Oaryl, -C(O)NRi-alkyl, -C(O)NRiheteroaryl, -C(O)NRicycloalkyl, -C(O)NRiaryl and -C(O)CF ₃ .

[0104] In one embodiment of the first aspect, the invention provides the compounds of formula (I), according to formula (Ia),

I(a)

[0105] wherein Y is defined as for formula (I).

[0106] In another embodiment, the invention provides the compounds of formula (I), according to formula (Ib),

I(b)

[0107] wherein p is 0, 1, 2, 3 or 4; and D is as defined for formula (I). [0108] In another aspect, the invention comprises compounds according to the previous embodiments in which D of formula I(b) is an aromatic polycyclyl, non-aromatic polycyclyl, polyheteroaryl, non-aromatic polyheterocyclyl, mixed aryl and non-aryl polyheterocyclyl, each of which is optionally substituted and each of which is optionally fused to one or more aryl or heteroaryl rings or one or more saturated or partially unsaturated cycloalkyl or heterocyclyl rings, and each such fused ring is optionally substituted;

[0109] In another aspect, the invention comprises compounds according to the previous embodiments in which D of formula I(b) is

each of each ring is optionally substituted and R ^e is defined in formula I;

[0110] In another embodiment, the invention provides the compounds offormula (I), according to formula (Ic),

I(c)

[0111] wherein p is 0, 1, 2, 3 or 4; and D is as defined for formula (I). [0112] In another embodiment, the invention provides the compounds according to formula (I), (Ia), (Ib), and (Ic), wherein wherein D is phenyl, naphtyl or indolyl. [0113] In another embodiment, the invention provides the compounds according to formula (I) selected from the group consisting of

2-(8-benzyl-8-azabicyclo[3.2.1]octan-3-ylidene)-N-hydroxy acetamide;

2-(l-benzylpiperidin-4-ylidene)-N-hydroxyacetamide;

N-hydroxy-2-(l-(naphthalen-2-ylmethyl)piperidin-4-ylidene )acetamide;

N-hydroxy-2-(l-(3-phenylpropyl)piperidin-4-ylidene)acetam ide; tert-butyl 4-(2-(hydroxyamino)-2-oxoethylidene)piperidine- 1 -carboxylate;

N-hydroxy-2-(l-phenethylpiperidin-4-ylidene)acetamide;

N-hydroxy-2-(l-(naphthalen-2-ylsulfonyl)piperidin-4-ylide ne)acetamide;

2-(l-(cyclohexylmethyl)piperidin-4-ylidene)-N-hydroxyacet amide;

N-hydroxy-2-(l-((l-methyl-lH-indol-3-yl)methyl)piperidin- 4-ylidene)acetamide;

2-(l-benzoylpiperidin-4-ylidene)-N-hydroxyacetamide; and and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and

enantiomers thereof.

[0114] In a second aspect, the invention provides a composition comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound according to any embodiment of the first aspect of the invention.

[0115] In a third aspect, the invention provides a method of inhibiting a histone deacetylase, preferably HDAC-8, the method comprising contacting the histone deacetylase or a cell containing the histone deacetylase, with a histone deacetylase inhibiting amount of a compound a compound according to any embodiment of the first aspect of the invention. [0116] Some examples of the compounds according to the first aspect of the invention are given below. These examples merely serve to exemplify some of the compounds of the first aspect of the invention and do not limit the scope of the invention.

Synthetic Schemes and Experimental Procedures

[0117] The compounds of the invention can be prepared according to the reaction schemes for the examples illustrated below utilizing methods known to one of ordinary skill in the art. These schemes serve to exemplify some procedures that can be used to make the compounds of the invention. One skilled in the art will recognize that other general synthetic procedures may be used. The compounds of the invention can be prepared from starting components that are commercially available. Any kind of substitutions can be made to the starting components to obtain the compounds of the invention according to procedures that are well known to those skilled in the art. Scheme 1

Example Ia

2-(8-benzyl-8-azabicyclo[3.2.1]octan-3-ylidene)-N-hydroxy acetamide 7 [0118] Step 1: tert-butyl 3-(2-ethoxy-2-oxoethylidene)-8-azabicyclo[3.2.1]octane-8- carboxylate 3

[0119] To a stirring solution of sodium hydride (0.614g, 15.34 mmol) in THF (60 niL) was added a solution of triethyl phosphonoacetate 2 (3.44g, 15.34 mmol) in THF (12 mL) drop wise over 40 minutes at room temperature. A solution of tert -butyl 3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate 1 (2.88g, 12.78 mmol) in THF (15 mL) was then added drop wise to the reaction mixture and further stirred 1 h then diluted with brine and extracted with EtOAc. The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to provide crude 3 (3.67g, 97% yield) as a viscous yellow oil which was used in the next step without further purification. [0120] LRMS (ESI): 295.37 (calc) 296.2 (MH)+ [0121] Step 2: ethyl 2-(8-azabicyclo[3.2.1]octan-3-ylidene)acetate 4 [0122] To a stirring solution of 3 (3.67g, 12.42 mmol) in DCM (5.71 mL) was added TFA (1.0 mL) at room temperature. The reaction mixture was allowed to stir for 1 h then all solvents were removed under reduced pressure and the residue was diluted with brine. Addition of aq. NaOH was continued until pH=13, followed by extraction with EtOAc. The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to provide ethyl 2-(8-azabicyclo[3.2.1]octan-3-ylidene)acetate 4 (2.13g, 88% yield) as a viscous yellow oil which was used without further purification. [0123] LRMS(ESI): 195.26 (calc) 196.2 (MH)+

[0124] Step 3: ethyl 2-(8-benzyl-8-azabicyclo[3.2.1]octan-3-ylidene)acetate 6 [0125] A solution of ethyl 2-(8-azabicyclo[3.2.1]octan-3-ylidene)acetate 4 (2.13g, 10.91 mmol), benzyl bromide 5 (2.239g, 13.09 mmol) and triethylamine (4.42g, 43.6 mmol) in THF (20 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with brine, basified to pH=12 with aq. NaOH, and extracted with EtOAc. The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to provide ethyl 2-(8-benzyl-8- azabicyclo[3.2.1]octan-3-ylidene)acetate 6 (1.16g, 37% yield) as a colorless oil after purification by flash chromatography (0 to 75% EtOAc in Hexanes). [0126] LRMS (ESI): 285.38 (calc) 286.2 (MH)+

[0127] Step 4: 2-(8-benzyl-8-azabicyclo[3.2.1]octan-3-ylidene)-N-hydroxyace tamide 7 To a stirring solution of ethyl 2-(8-benzyl-8-azabicyclo[3.2.1]octan-3-ylidene)acetate 6

[0128] (1.16g, 4.06 mmol) in 1: 1 THF: MeOH (24 niL) was added 50% aqueous hydroxylamine (4.08 niL, 61.8 mmol) followed by the addition of 4M KOH (6.1 niL). The resulting solution was stirred for 1 h at room temperature then diluted with brine, acidified to pH=8 using aq. HCl, and extracted with EtOAc. The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to provide title compound 7 (0.009g, 0.8% yield) as a pale yellow oil after purification by flash chromatography (0 to 20% MeOH in EtOAc with NH40H).

[0129] IH NMR: (MeOD-d4) 7.53-7.45 (m,2H), 7.44-7.32 (m,3H), 5.70 (s,lH), 3.90- 3.81 (m,2H), 3.61-3.50 (m,3H), 2.82-2.73 (m,lH), 2.54-2.45 (m,lH), 2.20-2.10 (m,3H), 1.75- 1.63 (m,2H). LRMS (ESI): (calc.) 272.3 (found) 273.2 (MH)+ Table 2: Title compounds according to Scheme 1.

Compositions

[0130] In a second aspect, the invention provides compositions comprising an inhibitor of histone deacetylase according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method known in the art and may be prepared for administration by any route, including, without limitation,

parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route. The compositions may be in any form, including but not limited to, liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops or aerosols. The compositions of the invention may be administered systemically or locally. [0131] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, or other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990.

[0132] As used herein, the term "pharmaceutically acceptable salts" is intended to mean salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR + Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). As used herein, the term "salt" is also meant to encompass complexes, such as with an alkaline metal or an alkaline earth metal.

[0133] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver an inhibition effective amount without causing

serious toxic effects. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art. [0134] In certain preferred embodiments of the second aspect of the invention, the composition further comprises an antisense oligonucleotide that inhibits the expression of a histone deacetylase gene. The combined use of a nucleic acid level inhibitor (e.g., antisense oligonucleotide) and a protein level inhibitor (i.e., inhibitor of histone deacetylase enzyme activity) results in an improved inhibitory effect, thereby reducing the amounts of the inhibitors required to obtain a given inhibitory effect as compared to the amounts necessary when either is used individually. The antisense oligonucleotide according to this aspect of the invention is complementary to regions of RNA or double- stranded DNA that encode one or more of, for example, HDAC-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC- 7, HDAC-8, HDAC-9, HDAC-10 and HDAC-I l (see e.g., GenBank Accession Number U50079 for HDAC-I, GenBank Accession Number U31814 for HDAC-2, and GenBank Accession Number U75697 for HDAC-3).

Inhibition of Histone Deacetylase

[0135] In a third aspect, the present invention provides a method of inhibiting histone deacetylase, comprising contacting the histone deacetylase with an inhibition effective amount of an inhibitor of histone deacetylase of the present invention. [0136] In one embodiment, the histone deacetylase is HDAC-8. [0137] In another embodiment of the third aspect, the invention provides a method of inhibiting histone deacetylase in a cell, comprising contacting the cell in which inhibition of histone deacetylase is desired with an inhibition effective amount of an inhibitor of histone deacetylase, or composition thereof, according to the present invention. [0138] Because compounds of the invention inhibit histone deacetylase, they are useful research tools for in vitro study histone deacetylases and their role in biological processes. [0139] Measurement of the enzymatic activity of a histone deacetylase can be achieved using known methodologies. For Example, Yoshida et al., J. Biol. Chem., 265: 17174-17179 (1990), describes the assessment of histone deacetylase enzymatic activity by the detection of acetylated histones in trichostatin A treated cells. Taunton et al, Science, 111: 408-411 (1996), similarly describes methods to measure histone deacetylase enzymatic activity using endogenous and recombinant HDAC-I.

[0140] In some preferred embodiments, the histone deacetylase inhibitor interacts with and reduces the activity of all histone deacetylases in a cell. In some other preferred embodiments according to this aspect of the invention, the histone deacetylase inhibitor interacts with and reduces the activity of fewer than all histone deacetylases in the cell. In certain preferred embodiments, the inhibitor interacts with and reduces the activity of one histone deacetylase (e.g., HDAC-8), but does not interact with or reduce the activities of other histone deacetylases (e.g., HDAC-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC- 6, HDAC-7, HDAC-9, HDAC-10 and HDAC-I l).

[0141] The term "inhibition effective amount" is meant to denote a dosage sufficient to cause inhibition of histone deacetylase activity in a cell, which cell can be in a multicellular organism. The multicellular organism can be a plant or an animal, preferably a mammal, more preferably a human. If in a multicellular organism, the method according to this aspect of the invention comprises administering to the organism a compound or composition according to the present invention. Administration may be by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain particularly preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route.

[0142] In certain preferred embodiments of the third aspect of the invention, the method further comprises contacting a histone deacetylase enzyme or a cell expressing histone deacetylase activity with an antisense oligonucleotide that inhibits the expression of a histone deacetylase gene. The combined use of a nucleic acid level inhibitor (e.g., antisense oligonucleotide) and a protein level inhibitor (i.e., inhibitor of histone deacetylase enzyme activity) results in an improved inhibitory effect, thereby reducing the amounts of the inhibitors required to obtain a given inhibitory effect as compared to the amounts necessary when either is used individually. The antisense oligonucleotides according to this aspect of the invention are complementary to regions of RNA or double-stranded DNA that encode, for example, HDAC-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10 and HDAC-Il (see e.g., GenBank Accession Number U50079 for HDAC-I, GenBank Accession Number U31814 for HDAC-2, and GenBank Accession Number U75697 for HDAC-3).

[0143] For purposes of the invention, the term "oligonucleotide" includes polymers of two or more deoxyribonucleosides, ribonucleosides, or 2'-substituted ribonucleoside residues, or any combination thereof. Preferably, such oligonucleotides have from about 6 to

about 100 nucleoside residues, more preferably from about 8 to about 50 nucleoside residues, and most preferably from about 12 to about 30 nucleoside residues. The nucleoside residues may be coupled to each other by any of the numerous known internucleoside linkages. Such internucleoside linkages include without limitation phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate and sulfone internucleoside linkages. In certain preferred embodiments, these internucleoside linkages may be phosphodiester, phosphotriester, phosphorothioate, or phosphoramidate linkages, or combinations thereof. The term oligonucleotide also encompasses such polymers having chemically modified bases or sugars and/or having additional substituents, including without limitation lipophilic groups, intercalating agents, diamines and adamantane. [0144] For purposes of the invention the term "2' -substituted ribonucleoside" includes ribonucleosides in which the hydroxyl group at the 2' position of the pentose moiety is substituted to produce a 2'-O-substituted ribonucleoside. Preferably, such substitution is with a lower alkyl group containing _1-6 saturated or unsaturated carbon atoms, or with an aryl or allyl group having 2-6 carbon atoms, wherein such alkyl, aryl or allyl group may be unsubstituted or may be substituted, e.g., with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl, carbalkoxyl, or amino groups. The term "2' -substituted ribonucleoside" also includes ribonucleosides in which the 2 '-hydroxyl group is replaced with an amino group or with a halo group, preferably fluoro.

[0145] Particularly preferred antisense oligonucleotides utilized in this aspect of the invention include chimeric oligonucleotides and hybrid oligonucleotides. [0146] For purposes of the invention, a "chimeric oligonucleotide" refers to an oligonucleotide having more than one type of internucleoside linkage. One preferred example of such a chimeric oligonucleotide is a chimeric oligonucleotide comprising a phosphorothioate, phosphodiester or phosphorodithioate region, preferably comprising from about 2 to about 12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region (see e.g., Pederson et al. U.S. Patent Nos. 5,635,377 and 5,366,878). Preferably, such chimeric oligonucleotides contain at least three consecutive internucleoside linkages selected from phosphodiester and phosphorothioate linkages, or combinations thereof. [0147] For purposes of the invention, a "hybrid oligonucleotide" refers to an oligonucleotide having more than one type of nucleoside. One preferred example of such a hybrid oligonucleotide comprises a ribonucleotide or 2 '-substituted ribonucleotide region,

preferably comprising from about 2 to about 12 2'-substituted nucleotides, and a deoxyribonucleotide region. Preferably, such a hybrid oligonucleotide contains at least three consecutive deoxyribonucleosides and also contains ribonucleosides, 2' -substituted ribonucleosides, preferably 2'-0-substituted ribonucleosides, or combinations thereof (see e.g., Metelev and Agrawal, U.S. Patent No. 5,652,355).

[0148] The exact nucleotide sequence and chemical structure of an antisense oligonucleotide utilized in the invention can be varied, so long as the oligonucleotide retains its ability to inhibit expression of the gene of interest. This is readily determined by testing whether the particular antisense oligonucleotide is active. Useful assays for this purpose include quantitating the mRNA encoding a product of the gene, a Western blotting analysis assay for the product of the gene, an activity assay for an enzymatically active gene product, or a soft agar growth assay, or a reporter gene construct assay, or an in vivo tumor growth assay, all of which are known in the art, or are as described in detail in this specification or in, for example, Ramchandani et al. (1997) Proc. Natl. Acad. Sci. USA 94: 684-689. [0149] Antisense oligonucleotides utilized in the invention may conveniently be synthesized on a suitable solid support using well known chemical approaches, including H- phosphonate chemistry, phosphoramidite chemistry, or a combination of H-phosphonate chemistry and phosphoramidite chemistry (i.e., H-phosphonate chemistry for some cycles and phosphoramidite chemistry for other cycles). Suitable solid supports include any of the standard solid supports used for solid phase oligonucleotide synthesis, such as controlled- pore glass (CPG) (see, e.g., Pon, R.T. (1993) Methods in Molec. Biol. 20: 465-496). [0150] Particularly preferred oligonucleotides have nucleotide sequences of from about 13 to about 35 nucleotides which include the nucleotide sequences shown in Table 44. Yet additional particularly preferred oligonucleotides have nucleotide sequences of from about 15 to about 26 nucleotides which include the nucleotide sequences shown in Table 7.

Table 7

Lu

[0151] In certain preferred embodiments of the invention, the antisense oligonucleotide and the HDAC inhbitor of the present invention are administered separately to a mammal, preferably a human. For example, the antisense oligonucleotide may be administered to the mammal prior to administration to the mammal of the HDAC inhibitor of the present invention. The mammal may receive one or more dosages of antisense oligonucleotide prior to receiving one or more dosages of the HDAC inhibitor of the present invention. [0152] In another embodiment, the HDAC inhibitor of the present invention may be administered to the mammal prior to administration of the antisense oligonucleotide. The mammal may receive one or more dosages of the HDAC inhibitor of the present invention prior to receiving one or more dosages of antisense oligonucleotide. [0153] In certain other preferred embodiments of the present invention, the HDAC inhibitor of the present invention may be administered together with another HDAC inhibitor known in the art or which will be discovered. Administration of such HDAC inhibitor(s) may be done sequentially or concurrently. In certain preferred embodiments of the present invention the composition comprises an HDAC inhibitor of the present invention and/or an antisense oligonucleotide and/or another HDAC inhibitor known in the art or which will be discovered. The active ingredients of such compositions preferably act synergistically to produce a therapeutic effect.

[0154] In certain embodiments, the known HDAC inhibitor is selected from the group consisting of, but not limited to, trichostatin A, depudecin, trapoxin, HC-toxin, suberoylanilide hydroxamic acid, FR901228, MS-27-275, CI-994, sodim butyrate, MGCD0103, PXDlOl, FK228, LBH-589, LAQ-824, CRA-024781, valproic acid, ITF-2357, SB-939, JNJ-16241199, and those compounds found in WO 2003/024448, WO 2004/069823, WO 2001/038322, US 6,541,661, WO 01/70675, WO 2004/035525 and WO 2005/030705.

[0155] The following examples are intended to further illustrate certain preferred embodiments of the invention, and are not intended to limit the scope of the invention.

ASSAY EXAMPLES

Assay Example 1 Inhibition of Histone Deacetylase Enzymatic Activity

[0156] The following protocol is used to assay the compounds of the invention. In the assay, the buffer used is 25 mM HEPES, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl ₂

and the subtrate is Boc-Lys(Ac)-AMC in a 50 mM stock solution in DMSO. The enzyme stock solution is 4.08 μg/mL in buffer.

[0157] The compounds are pre-incubated (2 μL in DMSO diluted to 13 μL in buffer for transfer to assay plate) with enzyme (20 μL of 4.08 μg/mL) for 10 minutes at room temperature (35 μL pre-incubation volume). The mixture is pre-incubated for 5 minutes at room temperature. The reaction is started by bringing the temperature to 37 ⁰ C and adding 15 μL substrate. Total reaction volume is 50 μL. The reaction is stopped after 20 minutes by addition of 50 μL developer, prepared as directed by Biomol (FLUOR DE LYS™ developer, Cat. # KI- 105). A plate is incubated in the dark for 10 minutes at room temperature before reading (λ _EX =360nm, λ _Em =470nm, Cutoff filter at 435nm).

[0158] All compounds exemplified have an IC ₅₀ value less than or equal to 10 μM against HDAC-8 .

[0159] Table 1 shows selected examples. In Table 1, A < lμM; 0., 1< B < 5 μM;

Table 1

[0160] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.