BENZOFURAN-4,5-DIONES AS SELECTIVE PEPTIDE DEFORMYLASE INHIBITORS

BACKGROUND OF THE INVENTION

Peptide deformylase (PDF) has been long recognized as important in protein synthesis. Removal of the formyl moiety on the N-terminal methionine of nascent proteins by PDF is a necessary activity for prokaryotic cell viability (Mazel et al., Embo. J. 1994, 13, 914-923). The central role of PDF in bacterial protein synthesis has led to significant efforts to discover antibiotics that selectively target bacterial PDFs (Howard et al., J. Med. Chem. 2004, 47, 6669-6672; Leeds et al., Current Opinion in Pharmacology 2006, 6, 445-452). PDF inhibitors are a promising drug class, as has been demonstrated by the broad spectrum activity in vitro against drug resistant bacterial strains of the clinical drug candidates LBM415 (Watters et al., J. Antimicrob. Chemother. 2006, 57, 914-923) and BB-83698 (Lofland et al., J. Antimicrob. Chemother. 2004, 53, 664-668). The PDF inhibitor BB-83698 has been proposed as a tuberculosis treatment (Teo et al., Antimicrob. Agents Chemother. 2006, 50, 3665-3673).

PDF activity was not believed to be important in eukaryotic cells until recently because nuclear encoded proteins are not N-formylated (Serero et al., J. Biol. Chem. 2003, 278, 52953-52963). However, in eukaryotes, mitochondrial protein synthesis involves the formylation and deformylation of proteins, as evidenced by the presence of the enzymatic machinery to perform these activities in mammals and plants, among other eukaryotes (Giglione et al., Embo. J. 2000, 19, 5916-5929; Takeuchi et al., J. Biol. Chem. 2001, 276, 20064-20068; Takeuchi et al., J. Biol. Chem. 1998, 273, 15085-15090). The human mitochondrial Homo sapiens peptide deformylase (HsPDF) protein, which participates in the N-methionine excision pathway of newly synthesized peptides encoded by the mitochondrial genome, removes the N-terminal formyl group on the initiator methionine, and is important for cancer cell viability (Lee et al., Biochem. Biophys. Res. Commun. 2003, 312, 309-315; Lee et al., J. Clin. Invest. 2004, 114, 1107-1116; Serero et al., 2003 supra). For example, cancer cell lines appear to be more sensitive to HsPDF inhibition than normal non-cancer cell lines (Lee 2003 and Lee 2004 supra). As well, ATP depletion and mitochondrial membrane depolarization result from the inhibition of HsPDF with the PDF inhibitor actinonin. siRNA interference and pharmacologic inhibition both decrease human cell growth. Furthermore, the PDF inhibitor actinonin and its analogs exhibit anti-cancer activity in vitro and in vivo (Xu et al., Clin. Cancer Res. 1998, 4, 171-176).

As of today, most of the research for PDF inhibitors has been focused on the identification of bacterial PDF inhibitors. Nearly all bacterial PDF inhibitors currently in development share a common scaffold based on a peptidomimetic backbone linked to a chelating moiety (Jain et al., Curr. Med. Chem. 2005, 12, 1607-1621). Indeed, many of the reported screens were performed on small “rationally” designed libraries, often focused on chelator-based compounds (Gordon et al., Nature, 1962, 195, 701-702; Jain et al., Curr. Med. Chem. 2005, 12, 1607-1621; Clements et al., Antimicrob. Agents. Chemother. 2001, 45, 563-570). Issues related to the lack of selectivity of such compounds were recently highlighted (Turk et al., Nat. Rev. Drug Discov. 2006, 5, 785-799). Thus, there remains a need to identify PDF inhibitors structurally different from known bacterial PDF inhibitors, such that they might be selective for HsPDF. These observations led to a screen for novel non-peptidomimetic and non-hydroxamic acid based inhibitors of HsPDF as potentially new anti-proliferative agents.

SUMMARY OF THE INVENTION

The present invention pertains to benzofuran-4,5-diones as non-peptidomimetic, non-hydroxamic acid-based inhibitors of peptide deformylase. Preferably, the inhibitors are selective for HsPDF. Also described herein are pharmaceutical compositions comprising benzofuran-4,5-diones and methods of using such compounds and compositions thereof in vitro and in vivo for research purposes and/or for the treatment of diseases such as, for instance, proliferative diseases or infectious diseases.

Certain compounds of the present invention were identified during a high-throughput screening campaign using binding assays adapted specifically to identify compounds active toward HsPDF. Of the primary hits identified, six included a benzofuran-4,5-dione scaffold. These six hits were further characterized to assess their dose response and specificity profiles and were found to demonstrate good selectivity for HsPDF over other metalloproteases. Specifically, the invention discloses the first inhibitors selective for human PDF over E. coli PDF with selectivity of up to greater than 77 fold in a functional assay. Additionally, most of the newly identified HsPDF inhibitors have broad cytotoxicity activity toward cancer cells.

In one aspect, the present invention provides novel benzofuran-4,5-diones and salts thereof. In another aspect, the present invention provides compounds and compositions that may be used to inhibit HsPDF in vivo or in vitro. In yet another aspect, the present invention provides compounds that may be used in the treatment of a disease associated with PDF activity such as, for instance, a proliferative disease or an infectious disease. The invention additionally provides pharmaceutical compositions of the inventive compounds and optionally a pharmaceutically acceptable excipient, and uses thereof.

In certain embodiments, the inventive compounds are of the formula:

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wherein:

R¹is 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 unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR^a; —C(═O)R^a; —CO₂R^a; —CN; —SCN; —SR^a; —SOR^a; —SO₂R^a; —NO₂; —N₃; —N(R^a)₂; —NR^aC(═O)R^a; —NR^aC(═O)N(R^a)₂; —OC(═O)OR^a; —OC(═O)R^a; —OC(═O)N(R^a)₂; —NR^aC(═O)OR^a; or —C(R^a)₃; wherein each occurrence of R^ais independently hydrogen; halogen; a protecting group; an optionally substituted aliphatic or heteroaliphatic moiety; an acyl moiety; or an optionally substituted aryl or heteroaryl moiety;

R²is 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 unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR^b; —C(═O)R^b; —CO₂R^b; —CN; —SCN; —SR^b; —SOR^b; —SO₂R^b; —NO₂; —N₃; —N(R^b)₂; —NR^bC(═O)R^a; —NR^bC(═O)N(R^b)₂; —OC(═O)OR^b; —OC(═O)R^b; —OC(═O)N(R^b)₂; —NR^bC(═O)OR^b; or —C(R^b)₃; wherein each occurrence of R^bis independently hydrogen; halogen; a protecting group; an optionally substituted aliphatic or heteroaliphatic moiety; an acyl moiety; or an optionally substituted aryl or heteroaryl moiety;

wherein R¹and R²when taken together form an optionally substituted, saturated or unsaturated aromatic, heteroaromatic, or nonaromatic 3-8 membered monocyclic or bicyclic ring optionally containing one or more heteroatoms selected from the group consisting of N, O, or S;

R³is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR^c; —C(═O)R^c; —CO₂R^c; —CN; —SCN; —SR^c; —SOR^c; —SO₂R^c; —NO₂; —N₃; —N(R^c)₂; —NR^cC(═O)R^c; —NR^cC(═O)N(R^c)₂; —OC(═O)OR^c; —OC(═O)R^c; —OC(═O)N(R^c)₂; —NR^cC(═O)OR^c; or —C(R^c)₃; wherein each occurrence of R^cis independently hydrogen; halogen; a protecting group; an optionally substituted aliphatic or heteroaliphatic moiety; an acyl moiety; or an optionally substituted aryl or heteroaryl moiety; and

R⁴is 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 unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR^d; —C(═O)R^d; —CO₂R^d; —CN; —SCN; —SR^d; —SOR^d; —SO₂R^d; —NO₂; —N₃; —N(R^d)₂; —NR^dC(═O)R^d; —NR^dC(═O)N(R^d)₂; —OC(═O)OR^d; —OC(═O)R^d; —OC(═O)N(R^d)₂; —NR^dC(═O)OR^d; or —C(R^d)₃; wherein each occurrence of R^dis independently hydrogen; halogen; a protecting group; an optionally substituted aliphatic or heteroaliphatic moiety; an acyl moiety; or an optionally substituted aryl or heteroaryl moiety, or a pharmaceutically acceptable salt thereof; and

wherein the compound is not of one of the formulae:

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In some embodiments, the present invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a compound of the formula:

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wherein:

In another aspect, the invention provides methods of inhibiting PDF or uses of the inventive compounds for inhibiting PDF. PDF may be inhibited in vivo or in vitro. Methods of inhibiting PDF in vivo may comprise administering to a subject in need thereof a benzofuran-4,5-dione in an amount effective to inhibit PDF. Methods of inhibiting PDF in vitro may comprise contacting a cell or biological sample with a benzofuran-4,5-dione in an amount effective to inhibit PDF. In certain embodiments, the inhibited PDF is a eukaryotic PDF. In certain embodiments, the eukaryotic PDF is human PDF (HsPDF). In certain embodiments, the inhibited PDF is a prokaryotic PDF. In certain embodiments, the inhibited PDF is a bacterial PDF.

Conditions and/or diseases that may be treated using the inventive compounds, compositions, or methods include, by way of nonlimiting example, conditions, and/or diseases wherein the inhibition of PDF is desirable (e.g., a proliferative, infectious, or inflammatory disease). In certain embodiments, the inhibition of a eukaryotic PDF is desirable (e.g., in the treatment of a proliferative disease). In certain embodiments, the inhibition of human PDF is desirable. In certain embodiments, the inhibition of a prokaryotic PDF is desirable (e.g., in the treatment of an infectious disease). In some embodiments, the invention provides methods of inducing apoptosis in a cell in vivo or in vitro using an inventive benzofuran-4,5-dione. In some embodiments, the invention provides methods of inhibiting the proliferation of cancer cells in vivo or in vitro using an inventive benzofuran-4,5-dione. In some embodiments, the invention provides methods of inhibiting growth of a microorganism in vivo or in vitro using a benzofuran-4,5-dione. In certain embodiments, the microorganism is bacterial. In certain embodiments, the microorganism is fungal. All methods of use and/or treatment described herein may comprise the use of a benzofuran-4,5-dione of the present invention or a composition containing a benzofuran-4,5-dione of the present invention, and/or salts thereof.

In some embodiments, the invention provides methods for preparing benzofuran-4,5-diones.

All publications and patent documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if the contents of each individual publication or patent document were included herein.

DEFINITIONS

Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^thEd., 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; Smith and March, March's Advanced Organic Chemistry, 5^thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

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 is 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, aliphatic and heteroaliphatic, carbon and heteroatom substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have 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 diseases, including, but not limited to cancer. The term “stable”, as used herein, typically 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.

Certain compounds of the present invention can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, 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 are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.

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, the invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds.

Where a particular enantiomer is desired, it may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.” “Optically enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a particular enantiomer. In other embodiments the compound is made up of at least about 95%, 96%, 97%, 98%, or 99% by weight of a desired enantiomer. A desired enantiomer may be isolated from a racemic mixture by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) or the formation and crystallization of chiral salts, or the enantiomer may be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

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).

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, and 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 unsubstituted groups. In certain embodiments, as used herein, “lower alkyl” is used to indicate those alkyl groups (substituted or unsubstituted, branched or unbranched) having 1-6 carbon atoms.

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-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

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, —CH₂-cyclobutyl, cyclopentyl, —CH₂-cyclopentyl, cyclohexyl, —CH₂-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.

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.

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.

Some examples of substituents of the above-described aliphatic (and other) moieties 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; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_x; —CO₂(R_x); —CON(R_x)₂; —OC(O)R_x; —OCO₂R_x; —OCON(R_x)₂; —N(R_x)₂; —S(O)₂R_x; —NR_x(CO)R_x; wherein each occurrence of R_xindependently 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.

In general, the term “aryl”, 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 “aryl” refers to a planar ring 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. 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”.

In general, the term “heteroaryl”, 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 “heteroaryl” refers to a planar ring comprising at least one 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.

It will also be appreciated that aryl and heteroaryl moieties, as defined herein may be attached via an alkyl or heteroalkyl moiety and thus also include -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl, and -(heteroalkyl)heteroaryl moieties. Thus, as used herein, the phrases “aryl or heteroaryl moieties” and “aryl, heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl, and -(heteroalkyl)heteroaryl” are interchangeable. Substituents 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.

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.

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, O, 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.

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; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_x; —CO₂(R_x); —CON(R_x)₂; —OC(O)R_x; —OCO₂R_x; —OCON(R_x)₂; —N(R_x)₂; —S(O)R_x; —S(O)₂R_x; —NR_x(CO)R_xwherein each occurrence of R_xindependently 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 described herein.

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; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_x; —CO₂(R_x); —CON(R_x)₂; —OC(O)R_x; —OCO₂R_x; —OCON(R_x)₂; —N(R_x)₂; —S(O)₂R_x; —NR_x(CO)R_x; wherein each occurrence of R_xindependently 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.

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 or unsaturated. 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; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_x; —CO₂(R_x); —CON(R_x)₂; —OC(O)R_x; —OCO₂R_x; —OCON(R_x)₂; —N(R_x)₂; —S(O)₂R_x; —NR_x(CO)R_x, wherein each occurrence of R_xindependently 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 described herein.

The term “heterocycloalkyl,” “heterocycle,” 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 a heteroatom selected from O, S, and N (wherein the nitrogen or sulfur heteroatom may 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, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl, thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, dithiazolyl, dithiazolidinyl, tetrahydrofuryl, and benzofused derivatives thereof. 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; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_x; —CO₂(R_x); —CON(R_x)₂; —OC(O)R_x; —OCO₂R_x; —OCON(R_x)₂; —N(R_x)₂; —S(O)₂R_x; —NR_x(CO)R_xwherein each occurrence of R_xindependently 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 described herein.

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 described herein. The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine.

The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine.

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.

The term “amino”, as used herein, refers to a primary (—NH₂), secondary (—NHR_x), tertiary (—NR_xR_y), or quaternary (—N⁺R_xR_yR_z) amine, where R_x, R_yand R_zare independently an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, or heteroaryl 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.

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. In certain embodiments, the alkylidene moiety has 1 to 6 carbon atoms.

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. In certain embodiments, the alkenylidene moiety has 2 to 6 carbon atoms.

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 or double bonds and wherein a triple or double bond can exist between the first carbon of the chain and the rest of the molecule. In certain embodiments, the alkynylidene moiety has 2 to 6 carbon atoms.

Unless otherwise indicated, as used herein, the terms “alkyl”, “alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, “alkylidene”, alkenylidene”, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)heteroaryl, 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 “cycloalkenyl”, “cycloalkynyl”, “heterocycloalkenyl”, “heterocycloalkynyl”, “aromatic”, “heteroaromatic, “aryl”, “heteroaryl” and the like encompass both substituted and unsubstituted groups.

The phrase, “pharmaceutically 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. The biological activity of 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 enzyme-catalyzed oxidation and reduction reactions. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.

By the term “protecting group”, as used herein, it is meant that a particular functional moiety, e.g., 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 certain 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. For example, in certain embodiments, as detailed herein, certain exemplary oxygen protecting groups are utilized. These oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM or MPM (p-methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and ketals. In certain other exemplary embodiments, nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N-Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain other 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 present invention. Additionally, a variety of protecting groups are 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.

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 are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. 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, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C_1-4alkyl)₄salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.

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.

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.

As used herein, the term “tautomer” includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.

As used herein, the term “isomers” includes any and all geometric isomers and stereoisomers. For example, “isomers” include cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. For instance, an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.” “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound of the present invention is made up of at least about 90% by weight of a particular enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a particular enantiomer. A desired enantiomer may be isolated from a racemic mixture by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) or the formation and crystallization of chiral salts, or the enantiomer may be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

“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” that 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 embodiments, natural-product-like small molecules are utilized.

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 multicellular 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 subject 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, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, 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. If desired, the biological sample may be subjected to preliminary processing, including preliminary separation techniques.

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. In certain 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.

As used herein, the term “test subject” or “subject” refers to any organism to which a composition of this invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.). In some embodiments, a subject may be infected with, suffering from, and/or susceptible to a disease, disorder, and/or condition.

The term HsPDF as used herein refers to not only to native HsPDF (SEQ ID NO.:1), but also includes any structural modifications thereof. Structural modifications include any additions, deletions, and/or substitutions to the native HsPDF amino acid sequence, of bound metal(s), and/or of coordinating solvates, hydrates, or non-covalently bound ligands.

The term PDF as used herein refers to both bacterial and eukaryotic peptide deformylase proteins. Exemplary bacterial PDF include, but are not limited to, Escherichia coli PDF; Streptococcus pneumoniae PDF; Haemophilus influenzae PDF; Sthaphylococcus aureus PDF; Arabidopsis thaliana PDF; Pseudomonas aeruginosa PDF; Leptospira interrogans PDF; Thermotoga maritima PDF; Bacillus stearothermophilus PDF; B. subtilis PDF; P. aeruginosa PDF; Malaria parasite (Plasmodium falciparum PDF); Thermus thermophilus PDF; T. maritima PDF; Chlamydia trachomatis PDF; C. pneumoniae PDF; C. psittaci PDF; and C. pecorum PDF.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Structures of the six primary hits from high-throughput screening with the benzofuran-4,5-dione scaffold.

FIG. 2. Cytotoxicity profile of the six primary hits from high-throughput screening with a benzofuran-4,5-dione scaffold.

FIG. 3. Design of benzofuran-4,5-dione derivatives. A. Halogen substitutions at α- and β-positions on the 4,5-orthodione moiety. B. Effect of methoxy substituents at −2, −3 and −4 positions on the benzoyl moiety. C. Replacement of the benzofurandione moiety by a naphtofurandione moiety.

FIG. 4. The IC₅₀in μM for HsPDF for each of the six primary hits and the cytotoxicity profile in seven different cell lines.

FIG. 5. Specificity profiling of the derivatives of benzofuran-4,5-diones.

FIG. 6. Compared potency for fourteen newly synthesized derivatives of benzofuran-4,5-diones toward HsPDF and EcPDF. The IC₅₀in μM for each compound for both enzymes as assessed using the FP assay is summarized in the table.

FIG. 7. Cytotoxicity profiling for the thirty-three (33) derivatives of benzofuran-4,5-diones toward HsPDF and EcPDF. The IC₅₀in μM for each compound toward each cell line is summarized as a heat map.

FIG. 8. Structures of the first generation benzofuran-4,5-dione derivatives evaluated in vivo.

FIG. 9. In vivo efficacy assessment of the first generation benzo-4,5-diones SKI 396848 and SKI 3968489. A. In vivo assessment of SKI 396848 in a mouse xenogrant model using ALL-3 cells isolated from a patient with acute lymphoblastic leukemia refractory to imatinib. B. In vivo efficacy assessment of SKI 396849 in a mouse xenogrant model using acute T-cell leukemia Jurkat cells.

FIG. 10. Design of benzofuran-4,5-dione derivatives. A. Exploration of various substituents at the meta and para positions of the phenyl ring B. Replacement of the phenyl ring with a bicyclic heterocycle. C. Replacement of the phenyl ring with a heterocycle.

FIG. 11. Structures of 26 benzofuran-4,5-dione derivatives with A, B, and C modifications as described in FIG. 10.

FIG. 12. Exemplary scheme for synthesizing benzofuran-4,5-dione derivatives.

FIG. 13. Exemplary scheme for synthesizing acid derivatives of benzofuran-4,5-diones.

FIG. 14. Cytotoxicity profiling of 26 benzofuran-4,5-diones using a panel of eight cancer cell lines. R₁, R₂, and R₃are based on the chemical structures in FIG. 10.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS of the Invention

In prokaryotes and a small subset of eukaryotes, protein synthesis is initiated with an N-formylated methionine. In bacteria, the N-formyl group is subsequently removed from most proteins by peptide deformylase (PDF). The resulting free amine moiety then undergoes further processing by methionine aminopeptidase and other enzymes to yield mature proteins. HsPDF (human mitochondrial peptide deformylase) is a specific type of peptide deformylase recently discovered to exhibit selective anti-proliferative properties in cancer cells. Thus, HsPDF provides an exciting new target for broadly acting anti-proliferative agents.

The majority of research on PDF inhibitors has focused on bacterial PDF inhibitors, most of which currently in development have a peptidomimetic backbone linked to a chelating moiety. However, these chelator-based compounds often lack selectivity. Thus, there remains a need to identify novel non-peptidomimetic and non-hydroxamic acid-based inhibitors with improved selectivity toward human PDF.

Compounds of the present invention were originally identified during a high-throughput screening campaign. This campaign used binding assays specifically adapted to identify compounds active toward human PDF. Six of the primary hits obtained have a benzofuran-4,5-dione scaffold. These six compounds were subsequently characterized to assess their dose response and specificity profiles by using fluorescence polarization profiling methods and fluorescamine-based functional assays adapted specifically for human PDF (Antczak et al., J. Biomol. Screen 2007, 12:5, 21-35; Antczak et al., J. Biomol. Screen 2008, 13, 285-294). Indeed, the six lead compounds were found to demonstrate good selectivity for human PDF over certain other metalloproteases (e.g., E. coli PDF). In addition to their enhanced selectivity, most of the newly identified human PDF inhibitors also have broad cytotoxicity activity toward cancer cells. Data obtained from the above-mentioned study led to the design, synthesis, and analysis of a series of benzofuran-4,5-dione derivatives.

Exemplary cancer cell lines screened herein include HL-60 (human acute promyelocytic leukemia), Jurkat (human acute T cell leukemia), Molt3 (acute lymphoblastic leukemia), CWR22 (prostate carcinoma), HEK293 (human embryonic kidney), K562 (human chronic myeloid leukemia lymphoblasts), Y79 (human retinoblastoma), NCEB-1 (human non-hodgkin lymphoma), HL-60/RV+ (a P-glycoprotein-overexpressing multi-drug resistant HL-60 variant selected by continuous exposure to vincristine), and ALL-3 (acute lymphoblastic leukemia). Cancer cells may also be derived from a tumor.

Exemplary cancers that may be treated using an inventive benzofuran-4,5-dione, or composition thereof, include bone cancer, brain cancer, blood cancer, breast cancer, pancreatic cancer, lung cancer, kidney cancer, stomach cancer, ovarian cancer, prostate cancer, colorectal cancer, endometrial cancer, bladder cancer, non-Hodgkin lymphoma, leukemia, neuroblastoma, lymphomas, rhabdomyosacroma, Wilms' tumor, osteosarcoma and Ewing's sarcoma. In certain embodiments, the cancer is leukemia.

The subject with one of the above-mentioned cancers can be a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, or baboon. In some embodiments, the subject is a bird, reptile, amphibian, fish, and/or worm. In some embodiments, an animal may be an experimental animal, a transgenic animal, genetically-engineered animal, and/or a clone.

Compounds of the Invention

In part, the present invention encompasses the recognition that there remains a need to identify structurally diverse PDF inhibitors that are structurally different from known bacterial PDF inhibitors and are potentially selective for human, bacterial, or prokaryotic PDF. In one aspect, the present invention provides novel compounds that may be used in the treatment of an infectious and/or proliferative disease. In certain embodiments, inventive compounds described herein are of the formula:

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wherein:

In certain embodiments, the inventive compound is not of the following formulae:

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In some embodiments, R¹is hydrogen. In some embodiments, R¹is halogen. In certain embodiments, R¹is fluorine. In certain embodiments, R¹is chlorine. In certain embodiments, R¹is bromine. In certain embodiments, R¹is iodine. In some embodiments, R¹is cyclic aliphatic. In some embodiments, R¹is acyclic aliphatic. In some embodiments, R¹is substituted aliphatic. In some embodiments, R¹is unsubstituted aliphatic. In some embodiments, R¹is branched aliphatic. In some embodiments, R¹is unbranched aliphatic. In some embodiments, R¹is C_1-6alkyl. In some embodiments, R¹is methyl. In some embodiments, R¹is ethyl. In some embodiments, R¹is propyl. In some embodiments, R¹is butyl. In some embodiments, R¹is pentyl. In some embodiments, R¹is hexyl. In some embodiments, R¹is cyclic heteroaliphatic. In some embodiments, R¹is acyclic heteroaliphatic. In some embodiments, R¹is substituted heteroaliphatic. In some embodiments, R¹is unsubstituted heteroaliphatic. In some embodiments, R¹is branched heteroaliphatic. In some embodiments, R¹is unbranched heteroaliphatic. In some embodiments, R¹is substituted acyl. In some embodiments, R¹is unsubstituted acyl. In some embodiments, R¹is branched acyl. In some embodiments, R¹is unbranched acyl. In some embodiments, R¹is substituted aryl. In some embodiments, R¹is unsubstituted aryl. In some embodiments, R¹is substituted hetereoaryl. In some embodiments, R¹is unsubstituted heteroaryl. In some embodiments, R¹is —OR^a. In some embodiments, R¹is —C(═O)R^a. In some embodiments, R¹is —CO₂R^a. In some embodiments, R¹is —CN. In some embodiments, R¹is —SCN. In some embodiments, R¹is —SR^a. In some embodiments, R¹is —SOR^a. In some embodiments, R¹is —SO₂R^a. In some embodiments, R¹is —NO₂. In some embodiments, R¹is —N₃. In some embodiments, R¹is —N(R^a)₂. In some embodiments, R¹is —NR^aC(═O)R^a. In some embodiments, R¹is —NR^aC(═O)N(R^a)₂. In some embodiments, R¹is —OC(═O)OR^a. In some embodiments, R¹is —OC(═O)R^a. In some embodiments, R¹is —OC(═O)N(R^a)₂. In some embodiments, R¹is —NR^aC(═O)OR^a. In some embodiments, R¹is —C(R^a)₃. In some embodiments, each occurrence of R^ais independently hydrogen. In some embodiments, each occurrence of R^ais independently halogen. In some embodiments, each occurrence of R^ais independently a protecting group. In some embodiments, each occurrence of R^ais independently an optionally substituted aliphatic. In some embodiments, each occurrence of R^ais independently a heteroaliphatic moiety. In some embodiments, each occurrence of R^ais independently an acyl moiety. In some embodiments, each occurrence of R^ais independently an optionally substituted aryl moiety. In some embodiments, each occurrence of R^ais independently a heteroaryl moiety.

In some embodiments, R²is hydrogen. In some embodiments, R²is halogen. In certain embodiments, R²is fluorine. In certain embodiments, R²is chlorine. In certain embodiments, R²is bromine. In certain embodiments, R²is iodine. In some embodiments, R²is cyclic aliphatic. In some embodiments, R²is acyclic aliphatic. In some embodiments, R²is substituted aliphatic. In some embodiments, R²is unsubstituted aliphatic. In some embodiments, R²is branched aliphatic. In some embodiments, R²is unbranched aliphatic. In some embodiments, R²is C_1-6alkyl. In some embodiments, R²is methyl. In some embodiments, R²is ethyl. In some embodiments, R²is propyl. In some embodiments, R²is butyl. In some embodiments, R²is pentyl. In some embodiments, R²is hexyl. In some embodiments, R²is cyclic heteroaliphatic. In some embodiments, R²is acyclic heteroaliphatic. In some embodiments, R²is substituted heteroaliphatic. In some embodiments, R²is unsubstituted heteroaliphatic. In some embodiments, R²is branched heteroaliphatic. In some embodiments, R²is unbranched heteroaliphatic. In some embodiments, R²is substituted acyl. In some embodiments, R²is unsubstituted acyl. In some embodiments, R²is branched acyl. In some embodiments, R²is unbranched acyl. In some embodiments, R²is substituted aryl. In some embodiments, R²is unsubstituted aryl. In some embodiments, R²is substituted hetereoaryl. In some embodiments, R²is unsubstituted heteroaryl. In some embodiments, R²is —OR^b. In some embodiments, R²is —C(═O)R^b. In some embodiments, R²is —CO₂R^b. In some embodiments, R²is —CN. In some embodiments, R²is —SCN. In some embodiments, R²is —SR^b. In some embodiments, R²is —SOR^b. In some embodiments, R²is —SO₂R^b. In some embodiments, R²is —NO₂. In some embodiments, R²is —N₃. In some embodiments, R₂is —N(R^b)₂. In some embodiments, R²is —NR^bC(═O)R^b. In some embodiments, R²is —NR^bC(═O)N(R^b)₂. In some embodiments, R²is —OC(═O)OR^b. In some embodiments, R²is —OC(═O)R^b. In some embodiments, R²is —OC(═O)N(R^b)₂. In some embodiments, R²is —NR^bC(═O)OR^b. In some embodiments, R²is —C(R^b)₃. In some embodiments, each occurrence of R^bis independently hydrogen. In some embodiments, each occurrence of R^bis independently halogen. In some embodiments, each occurrence of R^bis independently a protecting group. In some embodiments, each occurrence of R^bis independently an optionally substituted aliphatic. In some embodiments, each occurrence of R^bis independently a heteroaliphatic moiety. In some embodiments, each occurrence of R^bis independently an acyl moiety. In some embodiments, each occurrence of R^bis independently an optionally substituted aryl moiety. In some embodiments, each occurrence of R^bis independently an optionally substituted heteroaryl moiety.

In certain embodiments, at least one occurrence of R¹and R²is hydrogen. In certain embodiments, both R¹and R²are hydrogen. In some embodiments, at least one occurrence of R¹or R²is a halogen. In some embodiments, at least one occurrence of R¹or R²is a halogen, and the other is hydrogen. In some embodiments, at least one occurrence of R¹or R²is fluorine. In some embodiments, at least one occurrence of R¹or R²is bromine. In some embodiments, at least one occurrence of R¹or R²is chlorine. In some embodiments, each occurrence of R¹and R²is independently a halogen. In some embodiments, both R¹and R²are fluorine. In some embodiments, both R¹and R²are bromine. In some embodiments, both R¹and R²are chlorine. In some embodiments, at least one occurrence of R¹or R²is an isotopic label. By way of nonlimiting example, isotopic labels include ¹⁸F, ¹²³I, ¹²⁵I, ¹³¹I, ¹¹C, ¹³N, and/or ¹⁵O.

In certain embodiments, R¹and R²taken together form a fused aryl or heteroaryl. In certain embodiments, R¹and R²taken together form a fused aryl. In certain embodiments, R¹and R²taken together form a fused phenyl. In certain embodiments, R¹and R²taken together form a fused unsubstituted phenyl.

In some embodiments, R³is hydrogen. In some embodiments, R³is halogen. In certain embodiments, R³is fluorine. In certain embodiments, R³is chlorine. In certain embodiments, R³is bromine. In certain embodiments, R³is iodine. In some embodiments, R³is cyclic aliphatic. In some embodiments, R³is acyclic aliphatic. In some embodiments, R³is substituted aliphatic. In some embodiments, R³is unsubstituted aliphatic. In some embodiments, R³is branched aliphatic. In some embodiments, R³is unbranched aliphatic. In some embodiments, R³is C_1-6alkyl. In some embodiments, R³is methyl. In some embodiments, R³is ethyl. In some embodiments, R³is propyl. In some embodiments, R³is butyl. In some embodiments, R³is pentyl. In some embodiments, R³is hexyl. In some embodiments, R³is cyclic heteroaliphatic. In some embodiments, R³is acyclic heteroaliphatic. In some embodiments, R³is substituted heteroaliphatic. In some embodiments, R³is unsubstituted heteroaliphatic. In some embodiments, R³is branched heteroaliphatic. In some embodiments, R³is unbranched heteroaliphatic. In some embodiments, R³is substituted acyl. In some embodiments, R³is unsubstituted acyl. In some embodiments, R³is branched acyl. In some embodiments, R³is unbranched acyl. In some embodiments, R³is substituted aryl. In some embodiments, R³is unsubstituted aryl. In some embodiments, R³is substituted hetereoaryl. In some embodiments, R³is unsubstituted heteroaryl. In some embodiments, R³is —OR^c. In some embodiments, R³is —C(═O)R^c. In some embodiments, R³is —CO₂R^c. In some embodiments, R³is —CN. In some embodiments, R³is —SCN. In some embodiments, R³is —SR^c. In some embodiments, R³is —SOR^c. In some embodiments, R³is —SO₂R^c. In some embodiments, R³is —NO₂. In some embodiments, R³is —N₃. In some embodiments, R³is —N(R^c)₂. In some embodiments, R³is —NR^cC(═O)R^c. In some embodiments, R³is —NR^cC(═O)N(R^c)₂. In some embodiments, R³is —OC(═O)OR^c. In some embodiments, R³is —OC(═O)R^c. In some embodiments, R³is —OC(═O)N(R^c)₂. In some embodiments, R³is —NR³C(═O)OR^c. In some embodiments, R³is —C(R^c)₃. In some embodiments, at least one occurrence of R^cis independently hydrogen. In some embodiments, at least one occurrence of R^cis independently halogen. In some embodiments, at least one occurrence of R^cis independently a protecting group. In some embodiments, at least one occurrence of R^cis independently an optionally substituted aliphatic. In some embodiments, at least one occurrence of R^cis independently a heteroaliphatic moiety. In some embodiments, at least one occurrence of R^cis independently an acyl moiety. In some embodiments, at least one occurrence of R^cis independently an optionally substituted aryl moiety. In some embodiments, at least one occurrence of R^cis independently a heteroaryl moiety.

In some embodiments, R⁴is hydrogen. In some embodiments, R⁴is halogen. In certain embodiments, R⁴is fluorine. In certain embodiments, R⁴is chlorine. In certain embodiments, R⁴is bromine. In certain embodiments, R⁴is iodine. In some embodiments, R⁴is cyclic aliphatic. In some embodiments, R⁴is acyclic aliphatic. In some embodiments, R⁴is substituted aliphatic. In some embodiments, R⁴is unsubstituted aliphatic. In some embodiments, R⁴is branched aliphatic. In some embodiments, R⁴is unbranched aliphatic. In some embodiments, R⁴is C_1-6alkyl. In some embodiments, R⁴is methyl. In some embodiments, R⁴is ethyl. In some embodiments, R⁴is propyl. In some embodiments, R⁴is butyl. In some embodiments, R⁴is pentyl. In some embodiments, R⁴is hexyl. In some embodiments, R⁴is cyclic heteroaliphatic. In some embodiments, R⁴is acyclic heteroaliphatic. In some embodiments, R⁴is substituted heteroaliphatic. In some embodiments, R⁴is unsubstituted heteroaliphatic. In some embodiments, R⁴is branched heteroaliphatic. In some embodiments, R⁴is unbranched heteroaliphatic. In some embodiments, R⁴is substituted acyl. In some embodiments, R⁴is unsubstituted acyl. In some embodiments, R⁴is branched acyl. In some embodiments, R⁴is unbranched acyl. In some embodiments, R⁴is optionally substituted benzoyl. In some embodiments, R⁴is substituted aryl. In some embodiments, R⁴is unsubstituted aryl. In some embodiments, R⁴is substituted hetereoaryl. In some embodiments, R⁴is unsubstituted heteroaryl. In some embodiments, R⁴is —OR^d. In some embodiments, R⁴is —C(═O)R^d. In some embodiments, R⁴is —CO₂R^d. In some embodiments, R⁴is —CN. In some embodiments, R⁴is —SCN. In some embodiments, R⁴is —SR^d. In some embodiments, R⁴is —SOR^d. In some embodiments, R⁴is —SO₂R^d. In some embodiments, R⁴is —NO₂. In some embodiments, R⁴is —N₃. In some embodiments, R⁴is —N(R^d)₂. In some embodiments, R⁴is —NR^dC(═O)R^d. In some embodiments, R⁴is —NR^dC(═O)N(R^d)₂. In some embodiments, R⁴is —OC(═O)OR^d. In some embodiments, R⁴is —OC(═O)R^d. In some embodiments, R⁴is —OC(═O)N(R^d)₂. In some embodiments, R⁴is —NR³C(═O)OR^d. In some embodiments, R⁴is —C(R^d)₃. In some embodiments, at least one occurrence of R^dis independently hydrogen. In some embodiments, at least one occurrence of R^dis independently halogen. In some embodiments, at least one occurrence of R^dis independently a protecting group. In some embodiments, at least one occurrence of R^dis independently an optionally substituted aliphatic. In some embodiments, at least one occurrence of R^dis independently a heteroaliphatic moiety. In some embodiments, at least one occurrence of R^dis independently an acyl moiety. In some embodiments, at least one occurrence of R^dis independently an optionally substituted aryl moiety. In some embodiments, at least one occurrence of R^dis independently a heteroaryl moiety.

In certain embodiments, the compound is of the formula:

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wherein

R¹, R², and R³are as described above; and

R⁵is 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 aryl; substituted or unsubstituted heteroaryl; —OR^e; —SR^e; —N(R^e)₂; —NR^eC(═O)R^e; —NR^eC(═O)N(R^e)₂; —OC(═O)OR^e; —OC(═O)R^e; —OC(═O)N(R^e)₂; —NR^eC(═O)OR^e; or —C(R^e)₃; wherein at least one occurrence of R^eis independently hydrogen; halogen; a protecting group; an optionally substituted aliphatic or heteroaliphatic moiety; an acyl moiety; or an optionally substituted aryl or heteroaryl moiety, or a pharmaceutically acceptable salt thereof.

In certain embodiments, R⁵is hydrogen. In certain embodiments, R⁵is cyclic aliphatic. In certain embodiments, R⁵is acyclic aliphatic. In certain embodiments, R⁵is substituted aliphatic. In certain embodiments, R⁵is unsubstituted aliphatic. In certain embodiments, R⁵is branched aliphatic. In certain embodiments, R⁵is unbranched aliphatic. In some embodiments, R⁵is unbranched aliphatic. In some embodiments, R⁵is C_1-6alkyl. In some embodiments, R⁵is methyl. In some embodiments, R⁵is ethyl. In some embodiments, R⁵is propyl. In some embodiments, R⁵is butyl. In some embodiments, R⁵is pentyl. In some embodiments, R⁵is hexyl. In certain embodiments, R⁵is cyclic heteroaliphatic. In certain embodiments, R⁵is acyclic heteroaliphatic. In certain embodiments, R⁵is substituted heteroaliphatic. In certain embodiments, R⁵is unsubstituted heteroaliphatic. In certain embodiments, R⁵is branched heteroaliphatic. In certain embodiments, R⁵is unbranched heteroaliphatic. In certain embodiments, R⁵is substituted aryl. In certain embodiments, R⁵is unsubstituted aryl. In some embodiments, R⁵optionally substituted phenyl. In certain embodiments, R⁵is substituted heteroaryl. In certain embodiments, R⁵is unsubstituted heteroaryl. In certain embodiments, R⁵is substituted heteroaryl. In certain embodiments, R⁵is substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, R⁵is a substituted or unsubstituted heteroaryl moiety selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrazinyl, piperazinyl, triazinyl, trithianyl, indolizinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, quinuclidinyl, carbazolyl, acridinyl, phenazinyl, phenothialinyl, phenoxazinyl, indenyl, naphthalenyl, azulenyl, fluorenyl, anthracenyl, norbornanyl, and adamatanyl. In certain embodiments, R⁵is substituted or unsubstituted 6-membered heteroaryl. In certain embodiments, R⁵is thiophenyl. In certain embodiments, R⁵is 2-thiophenyl. In certain embodiments, R⁵is 3-thiophenyl. In certain embodiments, R⁵is a substituted or unsubstituted, bicyclic heterocyclic moiety. In certain embodiments, R⁵is an unsubstituted heterocyclic bicycle. In certain embodiments, R⁵is a substituted or unsubstituted, bicyclic heteroaryl moiety. In certain embodiments, R⁵is —OR^e. In certain embodiments, R⁵is —OH. In certain embodiments, R⁵is —SR^e. In certain embodiments, R⁵is —N(R^e)₂. In certain embodiments, R⁵is —NR^eC(═O)R^e. In certain embodiments, R⁵is —NR^eC(═O)N(R^e)₂. In certain embodiments, R⁵is —OC(═O)OR^e. In certain embodiments, R⁵is —OC(═O)R^e. In certain embodiments, R⁵is —OC(═O)N(R^e)₂. In certain embodiments, R⁵is —NR^eC(═O)OR^e. In certain embodiments, R⁵is or —C(R^e)₃. In certain embodiments, at least one occurrence of R^eis independently hydrogen. In certain embodiments, at least one occurrence of R^eis independently halogen. In certain embodiments, at least one occurrence of R^eis independently a protecting group. In certain embodiments, at least one occurrence of R^eis independently optionally substituted aliphatic. In some embodiments, R^eis C_1-6alkyl. In some embodiments, R^eis methyl. In some embodiments, R^eis ethyl. In some embodiments, R^eis propyl. In some embodiments, R^eis butyl. In some embodiments, R^eis pentyl. In some embodiments, R^eis hexyl. In certain embodiments, at least one occurrence of R^eis independently optionally substituted heteroaliphatic. In certain embodiments, at least one occurrence of R^eis independently an acyl moiety. In certain embodiments, at least one occurrence of R^eis independently an optionally substituted aryl. In certain embodiments, at least one occurrence of R^eis independently an optionally substituted heteroaryl moiety.

In certain embodiments, R⁵is —OR^e, wherein R^eis C_1-6alkyl. In certain embodiments, R⁵is —OR^e, wherein R^eis methyl. In certain embodiments, R⁵is —OR^e, wherein R^eis ethyl. In certain embodiments, R⁵is —OR^e, wherein R^eis propyl. In certain embodiments, R⁵is —OR^e, wherein R^eis butyl. In certain embodiments, R⁵is —OR^e, wherein R^eis phenyl.

In certain embodiments, R⁵is —SR^e, wherein R^eis C_1-6alkyl. In certain embodiments, R⁵is —SR^e, wherein R^eis methyl. In certain embodiments, R⁵is —SR^e, wherein R^eis ethyl. In certain embodiments, R⁵is —SR^e, wherein R^eis propyl. In certain embodiments, R⁵is —SR^e, wherein R^eis butyl. In certain embodiments, R⁵is —SR^e, wherein R^eis phenyl.

In certain embodiments, R⁵is —N(R^e)₂, wherein at least one occurrence of R^eis independently C_1-6alkyl. In certain embodiments, R⁵is —N(R^e)₂, wherein at least one occurrence of R^eis independently methyl. In certain embodiments, R⁵is —N(R^e)₂, wherein at least one occurrence of R^eis independently ethyl. In certain embodiments, R⁵is —N(R^e)₂, wherein at least one occurrence of R^eis independently propyl. In certain embodiments, R⁵is —N(R^e)₂, wherein at least one occurrence of R^eis independently butyl. In certain embodiments, R⁵is —N(R^e)₂, wherein at least one occurrence of R^eis independently phenyl.

In certain embodiments, the compound is of the formula:

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wherein:

R¹, R², and R³are as described herein;

m is an integer between 0-5, inclusive; and

at least one occurrence of R^fis independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR^g; —C(═O)R^g; —CO₂R^g; —CN; —SCN; —SR^g; —SOR^g; —SO₂R^g; —NO₂; —N₃; —N(R^g)₂; —NR^gC(═O)R^g; —NR^gC(═O)N(R^g)₂; —OC(═O)OR^g; —OC(═O)R^g; —OC(═O)N(R^g)₂; —NR^gC(═O)OR^g; or —C(R^g)₃; wherein at least one occurrence of R^gis independently hydrogen; halogen; a protecting group; an optionally substituted aliphatic or heteroaliphatic moiety; an acyl moiety; or an optionally substituted aryl or heteroaryl moiety, or a pharmaceutically acceptable salt or derivative thereof.

In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.

In certain embodiments, at least one occurrence of R^fis independently hydrogen. In certain embodiments, at least one occurrence of R^fis independently halogen. In certain embodiments, at least one occurrence of R^fis independently fluorine. In certain embodiments, at least one occurrence of R^fis independently chlorine. In certain embodiments, at least one occurrence of R^fis independently bromine. In certain embodiments, at least one occurrence of R^fis independently iodine. In certain embodiments, at least one occurrence of R^fis independently cyclic aliphatic. In certain embodiments, at least one occurrence of R^fis independently acyclic aliphatic. In certain embodiments, at least one occurrence of R^fis independently substituted aliphatic. In certain embodiments, at least one occurrence of R^fis independently unsubstituted aliphatic. In certain embodiments, at least one occurrence of R^fis independently branched aliphatic. In certain embodiments, at least one occurrence of R^fis independently unbranched aliphatic. In certain embodiments, at least one occurrence of R^fis independently C_1-6alkyl. In certain embodiments, at least one occurrence of R^fis independently methyl. In certain embodiments, at least one occurrence of R^fis independently ethyl. In certain embodiments, at least one occurrence of R^fis independently propyl. In certain embodiments, at least one occurrence of R^fis independently butyl. In certain embodiments, at least one occurrence of R^fis independently pentyl. In certain embodiments, at least one occurrence of R^fis independently hexyl. In certain embodiments, at least one occurrence of R^fis independently cyclic heteroaliphatic. In certain embodiments, at least one occurrence of R^fis independently acyclic heteroaliphatic. In certain embodiments, at least one occurrence of R^fis independently substituted heteroaliphatic. In certain embodiments, at least one occurrence of R^fis independently unsubstituted heteroaliphatic. In certain embodiments, at least one occurrence of R^fis independently substituted acyl. In certain embodiments, at least one occurrence of R^fis independently unsubstituted acyl. In certain embodiments, at least one occurrence of R^fis independently branched acyl. In certain embodiments, at least one occurrence of R^fis independently unbranched aryl. In certain embodiments, at least one occurrence of R^fis independently substituted aryl. In certain embodiments, at least one occurrence of R^fis independently unsubstituted aryl. In certain embodiments, at least one occurrence of R^fis independently substituted phenyl. In certain embodiments, at least one occurrence of R^fis independently unsubstituted phenyl. In certain embodiments, at least one occurrence of R^fis independently substituted heteroaryl. In certain embodiments, at least one occurrence of R^fis independently unsubstituted heteroaryl. In certain embodiments, at least one occurrence of R^fis —OR^g. In certain embodiments, at least one occurrence of R^fis —C(═O)R^g. In certain embodiments, at least one occurrence of R^fis —CO₂R^g. In certain embodiments, at least one occurrence of R^fis —CO₂H. In certain embodiments, at least one occurrence of R^fis —CN. In certain embodiments, at least one occurrence of R^fis —SCN. In certain embodiments, at least one occurrence of R^fis —SR^g. In certain embodiments, at least one occurrence of R^fis —SOR^g. In certain embodiments, at least one occurrence of R^fis —SO₂R^g. In certain embodiments, at least one occurrence of R^fis —NO₂. In certain embodiments, at least one occurrence of R^fis —N₃. In certain embodiments, at least one occurrence of R^fis —N(R^g)₂. In certain embodiments, at least one occurrence of R^fis —NR^gC(═O)R^g. In certain embodiments, at least one occurrence of R^fis —NR^gC(═O)N(R^g)₂. In certain embodiments, at least one occurrence of R^fis —OC(═O)OR^g. In certain embodiments, at least one occurrence of R^fis —OC(═O)R^g. In certain embodiments, at least one occurrence of R^fis —OC(═O)N(R^g)₂. In certain embodiments, at least one occurrence of R^fis —NR^gC(═O)OR^g. In certain embodiments, at least one occurrence of R^fis —C(R^g)₃. In certain embodiments, at least one occurrence of R^gis independently hydrogen. In certain embodiments, at least one occurrence of R^gis independently halogen. In certain embodiments, at least one occurrence of R^gis independently a protecting group. In certain embodiments, at least one occurrence of R^gis independently optionally substituted aliphatic. In certain embodiments, at least one occurrence of R^gis independently C_1-6alkyl. In certain embodiments, at least one occurrence of R^gis independently methyl. In certain embodiments, at least one occurrence of R^gis independently ethyl. In certain embodiments, at least one occurrence of R^gis independently propyl. In certain embodiments, at least one occurrence of R^gis independently butyl. In certain embodiments, at least one occurrence of R^gis independently pentyl. In certain embodiments, at least one occurrence of R^gis independently hexyl. In certain embodiments, at least one occurrence of R^gis independently optionally substituted heteroaliphatic. In certain embodiments, at least one occurrence of R^gis independently an acyl moiety. In certain embodiments, at least one occurrence of R^gis independently optionally substituted aryl. In certain embodiments, at least one occurrence of R^gis independently optionally substituted heteroaryl.

In certain embodiments, R⁵is of the formula:

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In certain embodiments, R⁵is of one of the formulae:

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In certain embodiments, R⁵is of the formula:

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In certain embodiments, R⁵is of one of the formulae:

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In certain embodiments, the two R^fform a cyclic structure with the intervening carbon atoms. In certain embodiments, the cyclic structure is five-membered or six-membered. In certain embodiments, the two R^fform a carbocyclic structure with the intervening carbon atoms. In certain embodiments, the two R^fform a heterocyclic structure with the intervening carbon atoms. In certain embodiments, R⁵is of the formula:

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In certain embodiments, R⁵is of one of the formulae:

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In certain embodiments, R⁵is of the formula:

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In certain embodiments, R⁵is of one of the formulae:

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In certain embodiments, R⁵is of the formula:

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In some embodiments, at least one occurrence of R^fis —OR^g. In some embodiments, at least one occurrence of R^fis —OH. In some embodiments, at least one occurrence of R^fis —OR^g, wherein R^gis a protecting group. In some embodiments, at least one occurrence of R^fis —OR^g, wherein R^gis C_1-6alkyl. In some embodiments, at least one occurrence of R^fis —OR^g, wherein R^gis methyl, ethyl, propyl, or butyl. In some embodiments, at least one occurrence of R^fis —OMe. In some embodiments, at least two occurrences of R^fare —OMe. In some embodiments, at least three occurrences of R^fare —OMe. In some embodiments, at least four occurrences of R^fare —OMe. In some embodiments, at least five occurrences of R^fare —OMe. In some embodiments, all occurrences of R^fare —OMe. In some embodiments, at least one occurrence of R^fis —OEt. In some embodiments, at least two occurrences of R^fare —OEt. In some embodiments, at least three occurrences of R^fare —OEt. In some embodiments, at least four occurrences of R^fare —OEt. In some embodiments, all five occurrences of R^fare —OEt. In some embodiments, all occurrences of R^fare —OEt.

In some embodiments, at least one occurrence of R^fis —SR^g. In some embodiments, at least one occurrence of R^fis —SH. In some embodiments, at least one occurrence of R^fis —SR^g, wherein R^gis a protecting group. In some embodiments, at least one occurrence of R^fis —SR^g, wherein R^gis C_1-6alkyl. In some embodiments, at least one occurrence of R^fis —SR^g, wherein R^gis methyl, ethyl, propyl, or butyl. In some embodiments, at least one occurrence of R^fis —SMe. In some embodiments, at least two occurrences of R^fare —SMe. In some embodiments, at least three occurrences of R^fare —SMe. In some embodiments, at least four occurrences of R^fare —SMe. In some embodiments, at least five occurrences of R^fare —SMe. In some embodiments, all occurrences of R^fare —SMe. In some embodiments, at least one occurrence of R^fis —SEt. In some embodiments, at least two occurrences of R^fare —SEt. In some embodiments, at least three occurrences of R^fare —SEt. In some embodiments, at least four occurrences of R^fare —SEt. In some embodiments, all five occurrences of R^fare —SEt. In some embodiments, all occurrences of R^fare —SEt.

In some embodiments, at least one occurrence of R^fis —N(R^g)₂. In some embodiments, at least one occurrence of R^fis —NH(R^g). In some embodiments, at least one occurrence of R^fis —NH₂. In some embodiments, at least one occurrence of R^fis —N(R^g)₂, wherein at least once occurrence of R^gis a protecting group. In some embodiments, at least one occurrence of R^fis —NH(R^g), wherein R^gis a protecting group. In some embodiments, at least one occurrence of R^fis —N(R^g)₂, wherein at least one occurrence of R^gis a C_1-6alkyl.

In some embodiments, at least one occurrence of R^fis a halogen. In some embodiments, at least one occurrence of R^fis fluorine. In some embodiments, at least one occurrence of R^fis chlorine. In some embodiments, at least one occurrence of R^fis bromine. In some embodiments, at least one occurrence of R^fis iodine.

In some embodiments, at least one occurrence of R^fcomprises an isotopic label. Exemplary isotopic labels include ²H, ³H, ¹⁸F, ¹²³I, ¹²⁵I, ¹³¹I, ¹¹C, ¹⁴C, ¹³N, and/or ¹⁵O. In certain embodiments, at least one occurrence of R^fis ¹⁸F. In certain embodiments, at least one occurrence of R^fis ¹²³I. In some embodiments, at least one occurrence of R^fis ¹²⁵I. In some embodiments, at least one occurrence of R^fis ¹³¹I.

In certain embodiments, at least one occurrence of R^fis C_1-6alkyl. In certain embodiments, at least two occurrences of R^fare C_1-6alkyl. In certain embodiments, at least three occurrences of R^fare C_1-6alkyl. In certain embodiments, at least four occurrences of R^fare C_1-6alkyl. In certain embodiments, all five occurrences of R^fare C_1-6alkyl. In certain embodiments, at least one occurrence of R^fis methyl. In certain embodiments, at least two occurrences of R^fare methyl. In certain embodiments, at least three occurrences of R^fare methyl. In certain embodiments, at least four occurrences of R^fare methyl. In certain embodiments, all five occurrences of R^fare methyl. In certain embodiments, at least one occurrence of R^fis ethyl. In certain embodiments, at least two occurrences of R^fare ethyl. In certain embodiments, at least three occurrences of R^fare ethyl. In certain embodiments, at least four occurrences of R^fare ethyl. In certain embodiments, all five occurrences of R^fare ethyl. In certain embodiments, at least one occurrence of R^fis propyl. In certain embodiments, at least two occurrences of R^fare propyl. In certain embodiments, at least three occurrences of R^fare propyl. In certain embodiments, at least four occurrences of R^fare propyl. In certain embodiments, all five occurrences of R^fare propyl. In certain embodiments, at least one occurrence of R^fis butyl. In certain embodiments, at least two occurrences of R^fare butyl. In certain embodiments, at least three occurrences of R^fare butyl. In certain embodiments, at least four occurrences of R^fare butyl. In certain embodiments, all five occurrences of R^fare butyl. In certain embodiments, at least one occurrence of R^fis pentyl. In certain embodiments, at least one occurrence of R^fis hexyl. In some embodiments, at least one occurrence of R^fis an aliphatic moiety optionally substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine, or iodine. Exemplary moities include, but are not limited to, —CF₃, —CF₂H, —CFH₂, and —CF₂CF₃.

In some embodiments, m is 1, and R^fis —OR^g.

In some embodiments, m is 2 and at least one occurrence of R^fis —OR^g.

In some embodiments, m is 3 and at least one occurrence of R^fis —OR^g.

In some embodiments, m is 4 and at least one occurrence of R^fis —OR^g.

In some embodiments, m is 5 and at least one occurrence of R^fis —OR^g.

In certain embodiments, at least one occurrence of R^gis hydrogen. In certain embodiments, at least two occurrences of R^gare hydrogen. In certain embodiments, at least three occurrences of R^gare hydrogen. In certain embodiments, at least four occurrences of R^gare hydrogen. In certain embodiments, all five occurrences of R^gare hydrogen.

In certain embodiments, at least one occurrence of R^gis C_1-6alkyl. In certain embodiments, at least two occurrences of R^gare C_1-6alkyl. In certain embodiments, at least three occurrences of R^gare C_1-6alkyl. In certain embodiments, at least four occurrences of R^gare C_1-6alkyl. In certain embodiments, all five occurrences of R^gare C_1-6alkyl. In certain embodiments, at least one occurrence of R^gis methyl. In certain embodiments, at least two occurrences of R^gare methyl. In certain embodiments, at least three occurrences of R^gare methyl. In certain embodiments, at least four occurrences of R^gare methyl. In certain embodiments, all five occurrences of R^gare methyl. In certain embodiments, at least one occurrence of R^gis ethyl. In certain embodiments, at least two occurrences of R^gare ethyl. In certain embodiments, at least three occurrences of R^gare ethyl. In certain embodiments, at least four occurrences of R^gare ethyl. In certain embodiments, all five occurrences of R^gare ethyl. In certain embodiments, at least one occurrence of R^gis propyl. In certain embodiments, at least two occurrences of R^gare propyl. In certain embodiments, at least three occurrences of R^gare propyl. In certain embodiments, at least four occurrences of R^gare propyl. In certain embodiments, all five occurrences of R^gare propyl. In certain embodiments, at least one occurrence of R^gis butyl. In certain embodiments, at least two occurrences of R^gare butyl. In certain embodiments, at least three occurrences of R^gare butyl. In certain embodiments, at least four occurrences of R^gare butyl. In certain embodiments, all five occurrences of R^gare butyl. In certain embodiments, at least one occurrence of R^gis pentyl. In certain embodiments, at least one occurrence of R^gis hexyl.

In certain embodiments, at least one occurrence of R^gis a protecting group. Exemplary protecting groups include silyl protecting groups, acyl groups, benzyl groups, benzoyl groups, and sulfonates.

In some embodiments, at least one occurrence of R^gis an aliphatic moiety optionally substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine, or iodine. Exemplary moities include, but are not limited to, —CF₃, —CF₂H, —CFH₂, and —CF₂CF₃.

In certain embodiments, R⁵is of the formula:

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In certain embodiments, R⁵is of the formula:

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In certain embodiments, R⁵is of the formula:

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In certain embodiments, R⁵is of the formula:

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In certain embodiments, R⁵is one of the formulae:

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In certain embodiments, R⁵is one of the formulae:

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In certain embodiments, R⁵is one of the formulae:

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In certain embodiments, R⁵is of the formula:

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In certain embodiments, the compound is of the formula:

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In certain embodiments, the compound is of the formula:

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In other embodiments, the compound of the invention is of any one of the formulae:

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