WO2009006403A2 - Non-peptide macrocyclic histone deacetylase (hdac) inhibitors and methods of making and using thereof - Google Patents

Abstract

Compounds of Formula (I) or (II), and methods of making and using thereof, are described herein. wherein M represents a macrolide subunit, n is a C1-6 group, optionally containing one or more heteroatoms, wherein the carbon atoms and/or heteroatoms are in a linear and/or cyclic arrangement, D is an alkyl or aryl group, A is a linking group connected to D, B is an alkyl, wherein M represents a macrolide subunit, R1, R2 and R4 are independently are selected from hydrogen, a C 1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkanoate group, a C2-6 carbamate group, a C2-6 carbonate group, a C2-6 carbamate group, or a C2-6 thiocarbamate group, R3 is hydrogen or -OR5, R5 is selected from a group consisting of Hydrogen, a C1-6 alkyl hgroup, a C2-6 alkenyl group, a C2-6 alkynyl group, C1-6 alkanoate group, C2-6 carbamate group, C2-6 carbonate group, C2-6 carbamate group, or C2-6 thiocarbamate group.

Description

NON-PEPTIDE MACROCYCLIC HISTONE DEACETYLASE (HDAC) INHIBITORS AND METHODS OF MAKING AND USING

THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of U.S. Provisional Application No.

60/947,036, entitled "Non-Peptide MacrocycHc Histone Deacetylase (HDAC) Inhibitors and Methods of Making and Using Thereof, filed June 29, 2007, by Adegboyega Oyelere.

FIELD OF THE INVENTION The present invention generally relates to non-peptide macrocyclic histone deacetylase (HDAC) inhibitors and methods of making and using thereof.

BACKGROUND OF THE INVENTION HDACs and histone acetyltransferases (HATs) are two functionally opposing enzymes, which tightly regulate the chromatin structure and function via sustenance of equilibrium between the acetylated- and deacetylated-states of nucleosomal histones (Grunstein, M., Nature 389, 349- 352 (1997)). Aberrations in intracellular histone acetylation-deacetylation equilibrium have been linked to the repression of a subset of genes resulting in excessive proliferation and are implicated in a number of malignant diseases (Jenuwein, T.; AlHs, C. D., Science 293, 1074-1080 (2001); Marks, P.; Rifkind, R. A.; Richon, V. M.; Breslow, R.; Miller, T.; KeIIy₅ W. K., Nat. Rev. Cancer, 1, 194-202 (2001)). HDACs function as part of multiprotein complexes that catalyze the removal of acetyl groups from the ε-amino groups of specific lysine residues located near the N-termini of nucleosomal core histones (Rundlett, S. E.; Carmen, A. A.; Kobayashi, R.; Bavykin, S.; Turner, B. M.; Grunstein, M., Proc. Natl. Acad. Sci U.S.A., 93, 14503-14508 (1996); Grozinger, C. M.; Schreiber, S. L., Chem. Biol. 9, 3-16 (2002)). HDAC-catalyzed deacetylation results in positively charged, hypoacetylated histones which bind tightly to the phosphate backbone of DNA, thus inducing gene-specific repression of transcription. Inhibition of HDAC deacetylase function results in the weakening of the bond between histones and DNA, thus increasing DNA accessibility and gene transcription.

Eighteen distinct human HDACs have been identified to date. They are classified into three major HDAC families based on their homology to three Saccharomyces cerevisiae HDACs (RPD3, HDAl, and SIR2). Class I include HDACs 1, 2, 3 and 8. Class II consists of HDACs 4, 5, 6, 7, 9, 10 and 11. The third class of HDACs consists of the sirtuins, which are homologically distinct from all the currently known HDACs. Early observations of HDAC inhibition by small molecules came from Yoshida et al. who reported that the natural product (R)-trichostatin A induced cell differentiation of murine erythroleukemia cells and hyperacetylation of histone proteins at nanomolar concentrations (Yoshida, M.; Kijima, M,; Akita, M.; Beppu, T, J. Biol. Chem. 265, 17174-17179 (1990); Yoshida, M.; Hoshikawa, Y.; Koseki, K.; Mori, K.; Beppu, T., J Antibiot. 43, 1101-1106 (1990)). Subsequently, Breslow and co-workers described suberoylanilide hydroxamic acid (SAHA) as a potent HDAC inhibitor (Richon, V. M,; Webb, Y.; Merger, R.; Sheppard, T.; Jursic, B. et al., Proc. Natl. Acad. Sd. USA. 93, 5705-5708 (1996); Richon, V. M.; Emiliani, S.; Verdin, E.; Webb, Y.; Breslow, R. et al, Proc. Natl Acad. ScL USA. 95, 3003-3007 (1998); Breslow, R.; Belvedere, S.; Gershell, L, HeIv. CMm. Acta 83, 1685-1692 (2000)).

Inhibition of HDACs is an emerging therapeutic strategy in cancer therapy. HDAC inhibitors have demonstrated ability to arrest proliferation of nearly all transformed cell types, including epithelial (melanoma, lung, breast, pancreas, ovary, prostate, colon and bladder) and hematological (lymphoma, leukemia and multiple myeloma) tumors (Kelly, W. K; O'Connor, O. A.; Marks, P. A., Expert. Opin. Investig. Drugs, 11, 1695-1713 (2002)). Additionally, HDAC inhibitors have demonstrated other biological activity including anti-inflammatory, anti-arthritic, anti-infective, anti- malarial, cytoprotective, neuroprotective, chemopreventive and/or cognitive enhancing effects. All HDAC inhibitors so far reported typically fit a three-motif pharmacophoric model namely, a zinc-binding group (ZBG), a hydrophobic linker and a recognition cap-group (Miller, T. A.; Witter, D. J.; Belvedere, S,, J. Med. Chem., 46, 5097-5116 (2003)). Structural modifications of the ZBG yielding hydroxamate isosteres such as benzamide, α-ketoesters, electrophilic ketones, mercaptoamide and phosphonates have been reported. The cap-group may present better opportunities to discover potent and possibly even selective HDAC inhibitors. Toward this end, recent work by Schreiber and co-workers has led to the identification of cap group-modified agents that display differential inhibition against specific HDAC sub-types (Wong, J.; Hong, R.; Schreiber, S., J. Am. Chem. Soc. 125, 5586-5587 (2003); Haggarty, S. J.; Koeller, K. M.; Wong, J. C; Grozinger, C. M.; Schreiber, S. L., Proc. Natl. Acad. Sci. USA, 100, 4389-4394 (2003)).

Cyclic-peptide moieties are the most complex of all HDAC inhibitor cap- groups and present an opportunity for the modulation of the biological activities of HDAC inhibitors. The macrocycle group is made up of hydrophobic amino acids and the prominent difference among the members of this class is in the amino acid side-chain substitution on the ring. Mechanistically, cyclic-peptide HDAC inhibitors could be divided into two classes: (i) reversible HDAC inhibitors and (ii) irreversible HDAC inhibitors, due to the alkylative modification of HDAC enzyme by the epoxy-ketone moiety on their side-chain. HDAC inhibitory activity and selectivity varied significantly by changing the side-chain of each amino acid and the pattern of the combination of amino acid chirality (Komatsu, Y.; Tomizaki, K.; Tsukamoto, M.; Kato, T. et al, Cancer Res. 61 , 4459-4466 (2001);

Furumai, R.; Komatsu, Y.; Nishino, N,; Khochbin, S.; Yoshida, M. et al_> Proc. Natl. Acad. Sci. U.S.A., 98, 87-92 (2001); Nishino, H.; Tomizaki, K.; Kato, T.; Nishino, N,; Yoshida, M.; Komatsu, Y., Peptide ScL- Symp., 189- 192 (1998)). Although cyclic-peptide HDAC inhibitors may possess potent HDAC inhibitory activity (nanomolar range), their broad application in specific therapies, such as cancer therapy, currently remains largely unproven. The absence of clinically effective cyclic-peptide HDAC inhibitors may be in part due to development problems characteristic of large peptides, most especially poor oral bioavailability. In fact, the overall in vivo efficacy of cyclic-peptide HDAC inhibitors is complicated by their membrane penetration ability. HDAC inhibitory potency has been noted to increase with increase in the hydrophobicity of the macrocyclic ring (Meinke, P. T.; Liberator, P., Curr. Med. Chem., 8, 211-235 (2001)). Unfortunately, SAR studies for this class of compounds have been impaired largely because most macrocyclic HDAC inhibitors known to date contain peptide macrocycles. In addition to retaining the pharmacologically disadvantaged peptidyl- backbone, they offer only limited opportunity for side-chain modifications.

To date, several other structurally distinct small molecule HDAC inhibitors have been reported including hydroxamates, benzamides, short- chain fatty acids, electrophilic ketones and cyclic-peptides (Miller, T. A.; Witter, D. J.; Belvedere, S., J. Med. Chem. 46, 5097-5116 (2003); Røsato, R. R.; Grant, S., Expert Opin. Invest. Drugs, 13, 21-38 (2004); Monneret, C, Eur. J. of Med. Chem., 40, 1-13 (2005); Yoo, C. B.; Jones, P. A., Nature Reviews Drug Discovery, 5, 37-50 (2006)). Most of these agents have been shown to non-selectively inhibit the deacetylase activity of class I/II HDAC enzymes. The HDAC inhibitor SAHA has been approved by the FDA for the treatment of cutaneous T cell lymphoma. However, a large number of the identified HDAC inhibitors have elicited only limited in vivo antitumor activities and have not progressed beyond preclinical characterizations. Therefore, there is a need to develop new HDAC inhibitors with improved efficacy, and better pharmacokinetic properties for use as therapeutic agents, such as anti-cancer agents.

It is therefore an object of the invention to provide non-peptide macrocyclic HDAC inhibitors having improved efficacy and methods of making and using thereof. SUMMARY OF THE INVENTION

Compounds of Formula I or II, and methods of making and using thereof, are described herein.

wherein M represents a macrolide subunit, n consists of C_1-6 group, optionally containing one or more heteroatoms, wherein the carbon atoms and/or heteroatoms are in a linear and/or cyclic arrangement,

D is an alkyl or aryl group, A is a linking group connected to D, B is an alkyl, alkylaryl or alkylheteroaryl spacer group,

ZBG is a Zinc Binding Group,

R₁, R₂ and R₄ are independently are selected from the group consisting of hydrogen, a Cl -6 alkyl group, a C_2-6 alkenyl group, a C_2-6 alkynyl group, Cj_-6 alkanoate group, C_2-6 carbamate group, C_2-6 carbonate group, C_2-6 carbamate group, or C_2-6 thiocarbamate group, R₃ is hydrogen or -OR₅,

Rs is selected from a group consisting of Hydrogen, a C_1-6 alkyl group, a C_2-6 alkenyl group, a C_2-6 alkynyl group, C_2-6 alkanoate group, C₂-6 carbamate group, C_2-6 carbonate group, C_2-6 carbamate group, or C_2-6 thiocarbamate group.

The compounds can be administered as the free acid or base, or as a pharmaceutically acceptable salt, prodrug, or solvate. The compounds may be useful as anti-cancer agents, anti-inflammatory agents, anti-infective agents, anti-malarial agents, cytoprotective agents, chemopreventive agents, prokinetic agents, and/or cognitive enhancing agents. The presence of the marolide group allows for the targeted delivery of the HDAC inhibitor in view on the ability of macrolides to accumulate in specific tissues. The compounds described herein can be formulated with a pharmaceutically acceptable earner and, optionally one or more pharmaceutically acceptable excipients, for enteral, parenteral, or topical administration. The compounds can be formulated for immediate release and/or controlled release. Examples of controlled release formulations include sustained release, delayed release, pulsatile release, and combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

"Macrolide", as used herein, includes, but is not limited to, multi- member lactonic ring molecules, wherein "member" refers to the carbon atoms or heteroatoms in the ring, and "multi" is a number greater than about 10, preferably from 10 to about 20, more preferably 12-, 14-, 15-, 16-, 17- or 18-member lactonic rings. Suitable macrolides include, but are not limited to, azithromycin and its derivatives; clarithromycin and its derivatives; erythromycin and its derivatives; bridged bicyclic macrolides, such as EDP- 420 and its derivatives; dirithromycin, 9-dihydro-9-deoxo-9a-aza-9a- homoerythromycin; HMR 3004, HMR 3647; HMR 3787; josamycin; erythromycylamine; ABT 773; TE 802; flurithromycin; tylosin; tilmicosin; oleandomycin; desmycosin; CP- 163505; EDP-420; roxithromycin; miocamycin; rokitamycin and derivatives thereof, such as ketolides (e.g., 3- ketone), lactams (e.g., 8a- or 9a-lactams) and derivatives lacking one or more sugar moieties. "Aryl", as used herein, refers to 5-, 6- and 7-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or bihetereocyclic ring systems, optionally substituted, for example, by halogens, alkyl-, alkenyl-, and alkynyl-groups. Broadly defined, "Ar", as used herein, includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, --CF₃, -CN, or the like. The term "Ar" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles. Examples of heterocyclic ring include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnoϊinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 3,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindoiyl, pyrimidinyϊ, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridmyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl.

"Zinc binding group" or "ZBG", as used herein, refers to a moiety of moieties capable of inhibiting the activity of zinc røetalloenzymes including, but not limited to, HDAC and matrix metalloproteinase (MMP) activity. Suitable examples include, but are not limited to, hydroxamates, N-formyl hydroxylamine (or retro-hydroxamate), carboxylates_f thiols, dithiols, trithiocarbonates, thioesters, benzamide, keto, mercaptoacetamides, 2- ketoamides, epoxides, epoxyketones, trifluoromethyl ketones, hydroxypyridinones, pyrones, hydroxy lpyridinethiones, and thiopyrones.

" Alkyl", as used herein, refers to the radical of saturated or unsaturated aliphatic groups, including straight-chain alkyl, alkenyl,, or alkynyl groups, branched-chain alkyl, alkenyl, or alkynyl groups, cycloalkyl, cycloalkenyl, or cycloalkynyl (alicyclic) groups, alkyl substituted cycloalkyl, cycloalkenyl, or cycloalkynyl groups, and cycloalkyl substituted alkyl, alkenyl, or alkynyl groups. Unless otherwise indicated, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Cl- C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.

"Alkoxycarbonyl", as used herein, refers to a substituent having the following chemical formula:

wherein R is a linear, branched, or cyclic alkyl group, wherein j is from about 1 to about 12.

"Alkoxycarbamido", as used herein, refers to a substituent having the following chemical formula:

wherein Rg is alkoxy and R 9 is hydrogen, alkoxy-alkyl, or alkanoyl, and j is from about 1 to about 12.

"Alkylaryl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or hetero aromatic group).

"Heterocycle" or "heterocyclic", as used herein, refers to a cyclic radical attached via a ring carbon or nitrogen of a monocyclic or bicyclic ring containing 3-10 ring atoms, and preferably from 5-6 ring atoms, consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent oτ is H, O, (Ci- 4)alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Examples of heterocyclic ring include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, beπztetrazolyl, benzisoxazolyl, benzisothiazolyl, benαάmidazoUnyl, carbazolyl, 4atf-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl₅ isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1^,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiaanyl, phenoxalhinyl, phenoxazinyl, phthalaanyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H~pyrrolyl, pyrrolyl, quinazoKnyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolmyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5- tbiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl.

"Heteroaryi", as used herein, refers to a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) where Y is absent or is H, O, (Cj-Cg) alkyl, phenyl or benzyl. Non-limiting examples of heteroaryi groups include furyl, imidazolyl, triazolyl, triaziπyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide), quinolyl (or its N-oxϊde) and the like. The term "heteroaryi" can include radicals of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. Examples of heteroaryi can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, xsoxazoyl, thiazolyl, isothiazoyl, pyraxolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl (or its N-oxide), thϊentyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide), quinolyl (or its N-oxide), and the like.

"Halogen", as used herein, refers to fluorine, chlorine, bromine, or iodine.

The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively. For example, the names 1,2- dimethylbenzene and ortho-dimethylbenzene are synonymous. "Pharmaceutically acceptable salt", as used herein, refer to derivatives of the compounds defined by Formula I and II wherein the parent compound is modified by making acid or base salts thereof. Example of pharmaceutically acceptable salts include but are not limited to mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulforac, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic salts.

The pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704; and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," P. Hemrich Stahl and Camille G. Wermuth, Eds., Wiley-VCH, Weinheim, 2002.

As generally used herein "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity,

π irritation^ allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

"Prodrug", as used herein, refers to a pharmacological substance (drug) which is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in the body (in vivo) into the active compound.

"Solvate", as used herein, refers to a compound which is formed by the interaction of molecules of a solute with molecules of a solvent.

"Reverse ester", as used herein, refers to the interchange of the positions of the oxygen and carbon groups in a series of structurally related compounds

"Reverse amide", as used herein, refers to the interchange of the positions of the nitrogen and carbon groups in a series of structurally related compounds. II. Compounds

Compounds of Formula I or II, and methods of making and using thereof, are described herein. R⁴

wherein M represents a macrolide subunit, n is a Ci .₆ group, optionally containing one or more heteroatoms, wherein the carbon atoms and/or heteroatoms are in a linear and/or cyclic arrangement,

D is an alkyl or aryl group, A is a linking group connected to D,

B is an alkyl, alkylaryl or alkylheteroaryl spacer group, ZBG is a Zinc Binding Group,

R₁, R₂ and R₄ are independently are selected from hydrogen, a C_1-6 alkyl group, a C2-₆ alkenyl group, a C_2-6 alkynyl group, a C]_-6 alkanoate group, a C_2-6 carbamate group, a C₂.₆ carbonate group, a C_2-6 carbamate group, or C_2-6 thiocarbamate group,

R3 is hydrogen or -OR₅, wherein

R₅ is selected from hydrogen, a C_1-6 alkyl group, a C₂-<_> alkenyl group, a C₂-₆ alkynyl group, C_1-6 alkanoate group, C_2-6 carbamate group, C_2-6 carbonate group, C_2-6 carbamate group, or C_2-6 thiocarbamate group.

Examples of the linking group A include, but are not limited to, amide, reverse amide, ester, reverse ester, alkoxyl, sulfanyl, sulfinyl, sulfonyl, sulfonamido, ketone, sp³ hybridized carbon, sp² hybridized carbon, sp hybridized carbon, 5 or 6 membered heterocyclic rings including but not limiting to 1,2,3-triazolyl, 1,2,4-triazolyl, 1-tetrazolyl, 1-indolyl, 1- indazolyl, 2-isoindolyl, 7-oxo-2-isoimdolyl,l-pirinyl, 3-isothiazolyl, 4-isothiazolyl and 5- isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazoIinyl or 5-rnethyl-1.3,4- thiadiazol-2-yI, thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4- pyridazinyl, 3-pyrazolyl, 2-<juinolyi. 3-quinolyl, 1-isoqvunolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1 -phthalazinyl, 4-oxo-2-imidazoiyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyI, 4-isoxazolyl, 5-isoxazolyl, 3-ρyrazolyl 4-pyrazolyl, 5-p>τazolyl, 2-oxazolyl, 4-oxazolyl, 4- oxo-2-oxazolyI, 5-oxazolyl, 4,5-dihydrooxazole, 1^,3-oxathiole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, l_>3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole. benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-bopyrrolyl, 4- isopyrrolyl, 5-isopyrrolyl, 1,2,3-oxathiazole-l -oxide, l-2,4-oxadiazol-3-yl, l^,4-oxadiazol-5-yl, 5-oxo-U2,4-oxadiazol-3-yl, l,2,4-thiadiazol-3-yl, 1,2,4- thiadiazol-5-yl, 3-oxo-l,2,4-thiadiazol-5-yl, l,3,4-tbiadiazol-5-yl, 2-oxo- l,3,4-thiadiazol-5-yl, l^,4-triazol-3-yl, l,2,4-triazol-5-yl, 1^2,3,4-tetrazol-5- yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl. Each of these moieties may be substituted as appropriate. B is an alkyl, alkyJaryϊ or alkylheteroaryl spacer group. Suitable alkyl spacer group chain length ranges from about C₄ to about Cj₂, optionally substituted by one or more double and/or triple bonds. The total number of atoms in the alkylaryl and alkylheteroaryl groups is from about 6 to about 50. M is a macroBde subunit. Suitable macrolide subunits include, but are not limited to, multi-member lactonic ring molecules, wherein "member" refers to the carbon atoms or heteroatoms In the ring, and "multi" is a number greater than about 10, preferably from 10 to about 20, more preferably 12-, 14-, 15-, 16-, 17- or 18-tnember lactonic rings. Exemplary macroiides include, but are not limited to, azithromycin and its derivatives; clarithromycin and its derivatives; erythromycin and its derivatives; bridged bicyclic macrolide, such as EDP -420 and its derivatives; dirithromycm, 9- dihydro-9-deoxo-9a-aza-9a-homoerythromycin; HMR 3004, HMR 3647; HMR 3787; josamycin; erythromycylamine; ABT 773; flurithrorøycin; tylosin; tilmicosin; oleandomycin; desmycosin; CP- 163505; EDP-420; roxithromycin; miocamycin; rokitamycin and derivatives thereof, such as ketolides (e.g., 3-ketone), lactams (e.g., 8a- or 9a-lactams) and derivatives lacking one or more sugar moieties. Other suitable macroiides are shown in Table 1:

Table 1. Macrolide Subunits

In another embodiment, the points of attachment of the ZBG are 06 and 09 in the 14-membered macrolides shown in Table 2: Table 2. 14-Membered Macrolides

In M25 and M26, the bond between the starred carbon and the nitrogen can be a single bond or a double bond. This is represented by a dashed line in the structures of M25 and M26.

Macrolide antibiotics have been in use for over 50 years for the treatment of respiratory tract infections. Over the past 20 years, macrolides have also been shown to have other non-antibiotic properties. For example, they have demonstrated anti-inflammatory and immunomodulatory effects making them potential candidates for the management of diseases of chronic airway inflammation. Fourteen-membered and fifteen-membered macrolides, such as erythromycin, clarithromycin, and azithromycin, the structures of which are shown below, have shown improved pulmonary function, and decrease morbidity and mortality in. patients with diffuse panbroncMolitis (DPB).

= H)

= WIe) Azithromycin Tetithromyciπ (Ketek)

Spiramycin

Cethromycϊn (ABT-773) Additionally, clarithromycin and azithromycin a positive immunomodulatory effects in patients with non-small-cell cancer. However, a direct role of macrolides in cancer therapy is still being investigated. Earlier observations by Parajuli et al. showed that clarithromycin alone did not have a therapeutic effect on the growth and organ metastasis of human non-small cell lung cancer cells in severe combined immunodeficient (SCID) mouse models (see also Sassa, K.; Mizushima, Y.; Fujishita, T.; Oosaki, R.; Kobayashi, M._} Antimicrob. Agents Chemother., 43, 67-72 (1999)). Yatsunami et al. investigated the effects of macrolide antibiotics on tumor angiogenesis and found that two 14-membered ring macrolide antibiotics, roxithromycin and clarithromycin, significantly reduced the dense capillary network area in a mouse dorsal air sac angiogenesis model (Yatsunami, J.; Fukuno, Y.; Nagata, M.; Tominaga, M.; Aoki, S.; Tsuruta, N. et al., Clin. Exp. Metastasis, 17, 361-367 (1999)). Also, evidence has begun to emerge on the beneficial effect of azithromycin in cystic fibrosis (CF) management. The compounds described herein may have one or more chiral centers and thus exist as one or more stereoisomers. Such stereoisomers can exist as a single enantiomer, a mixture of diastereomers or a racemic mixture.

As used herein, the term "stereoisomers" refers to compounds made up of the same atoms having the same bond order but having different three- dimensional arrangements of atoms which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomers" refers to two stereoisomers which are non- superimposable mirror images of one another. As used herein, the term "optical isomer" is equivalent to the term "enantiomer". As used herein the term "diastereomer" refers to two stereoisomers which are not mirror images but also not superimposable. The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. Choice of the appropriate chiral column, eluent, and conditions necessary to effect separation of the pair of enantiomers is well known to one of ordinary skill in the art using standard techniques (see e.g. Jacques, J. et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc. 1981).

Non-limiting examples of HDAC inhibitors of Formula I and II are shown in Table 3.

Table 3. Additional HDAC Inhibitors

It is believed that substitution of the cyclic peptide moiety of a prototypical cyclic-peptide HDAC inhibitor with macrolide skeletons will generate a new class of potent HDAC inhibitors. Furthermore, this class of HDAC inhibitors may possess targeted activity, such as targeted anti-cancer activity due to selective tissue distribution conferred by the macrolide moiety. The biological effects of macrolides are aided by their high distribution into target tissues. Macrolides accumulate in higher concentration within leukocytes as compared to levels found in serum (Labro, M. T. Effects of macrolides on leukocytes and inflammation. In

Expanding Indications of the New Macrolides, Azalides and Streptogramins (Zinner, S., Young, S. & Acar, J., Eds), Marcel Dekker, Inc., New York_> NY, USA. pp. 101-116 (1997)). III. Formulations Formulations containing one or more of the compounds described herein may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. As generally used herein "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, pH modifying agents, preservatives, antioxidants, solubility enhancers, and coating compositions. Carrier also includes all components of coating compositions which may include plasticizers, pigments, colorants, stabilizing agents, and glidants. Delayed release, extended release, and/or pulsatile release dosage formulations may be prepared as described in standard references such as "Pharmaceutical dosage form tablets", eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), "Remington ~ The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6^tn Edition, Ansel et al., (Media, PA: Williams and Wilkins, 1995). These references provide information on carriers, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.

Examples of suitable coating materials include, but are not limited lo, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcelMose phthalate and hydroxypropyl methylceUulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGΪT® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.

Optional pharmaceutically acceptable excipients present in the drug- containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacryϊic acid/polymethacrylic acid and polyvinylpyrrolidone.

Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcelMose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp).

Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2- ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-.beta. -alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoarnphoacetate, lauryl betaine and lauryl sulfobetaine. If desired, the tablets, beads, granules, or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives. A. Other Active Agents The HDAC inhibitors described herein can. be administered adjunctively with other active compounds. These compounds include but are not limited to analgesics, anti-inflammatory drags, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltylcs, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics, "Adjunctive administration", as used herein, means the HDAC inhibitors can be administered in the same dosage form or in separate dosage forms with one or more other active agents. Specific examples of compounds that can be adjunctively administered with the GDAC inhibitors include, but are not limited to, aceclofenac, acetaminophen, adomexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetroπ, azatadine, beclomethasone, beriactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butήptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazme, choline salicylate, citalopram, clomipramine, clonazepam, clonidme, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptiline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproxex, dizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamates, fenoprofen, fentanyl, fiudiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, ginko bilboa, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketaserin, ketoprofen, ketorolac, lesopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotilme, mazindol, mefenaniic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone_? methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methylsalicylate, methysergid(e), metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (an anti- narcoleptic), molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxafiozane, oxaprazin, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetϊn, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirlindole, piroxicam, pizotϊfen_f pizotyline, pramipexole, prednisolone, prednisone, pregabalin, propanolol, propizepine, propoxyphene, prot^ήptyline, quazepam, quinupramine, reboxitine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenozine, thiazides, thioridazine, thiothixene, tiapride, tiasipirone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E₅ zimeldine, ziprasidone, zolmitriptan, Zolpidem, zopiclone and isomers, salts, and combinations thereof.

IV. Methods of Preparation Compound numberings, e.g., 1, 2, 3, etc. as used below are for reference within this section only are not to be confused with any similar numberings in the synthetic schemes described below or in the examples.

The schemes below describe exemplary chemistries that can be used to synthesize the compounds described herein. It is to be appreciated the compounds described herein may be synthesized by other methods known in the art.

General Synthetic Schemes

Scheme la-c illustrates representative general syntheses of compounds of types 5 and 6, 9 and 10, and 12 and 13, The starting des-N- methyl macrolide 1 could be sourced from a variety of N-demethylation reactions of the tertiary amines of basic sugars on macrolides known in the art (see Fϊynn et al. (1954) J. Am. Chem. Soc, 76: 3121; U.S. Patent No. 3,725,385; Ku et al. (1997) Bioorg. Med Chem. Lett., 7: 1203; Stenmark et al. (2000) J Org. Chem., 65: 3875; Randolph et al. (2004) J Med. Chem., 47, 1085; and U.S. Patent No. 7,335,753).

Reaction of 1 with electrophiles 2 and 7 yields alkynes and nitriles 3 and 8 respectively. Reactions of azide 4 and nitrile oxide 11 with alkynes 3 generate two regioisomeric triazole and isoxazole products 5 and 6 and 12 and 13 respectively. The triazole products' regioisomeric ratios and reaction rates could be altered by heating the reaction and/or by the use of catalysts (such as, but not limited to, copper (ϊ) and Ru (H) salts and complexes: see Rostovtsev et al. (2002) Angew. Chem. Int. Ed, 41: 2596; Tornoe et al. (2002) J Org. Chem., 67: 3057; Zhang et al. (2005) J Am. Chem. Soc, 127: 15998). Similarly, reaction of nitrile 8 and azide 4 generates two regioisomeric tetrazole products, 9 and 10. The ZBG in azide 4 can be protected if necessary. Suitable ZBG protecting groups include are described herein. Scheme 2 illustrates representative general syntheses of compounds with amide as the linker-cap group connection moiety and benzamide compounds of types 17 and 19 and 21 and 23 respectively. Reaction of 1 with electrophile 14 yields ester 15. Compound 15 can be directly reacted with ZBG amine 18 to yield compound 19. Alternatively, 19 can be obtained from acid 16 and ZBG amine 18 through carbodiimide coupling. Additionally, hydroxamate 17, containing an appropriate aromatic moiety and appropriate alkyl chain length can be obtained from the reaction of hydroxylamine with ester 15. Similarly, benzamide compounds 21 and 23 can be prepared from the reaction of ester 15 or acid 16 with anilines 20 and 22. In the case of the para-substituted benzamide 23, the intermediate nitro anilide must be reduced to obtain the desired benzamide 23. The synthesis of para-substituted nitro aniline 22 is known in the art (for example, see Moradei et al. (2007) J Med. Chem., 45, 5543).

Scheme 2

-15: R = OMe

LtOH j 19 -16: R = OH NH₂OH —17: R = NHOH

Scheme 3 illustrates representative general syntheses of ketolide and bridged-ketolide based triazole derivatives. Clarithromycin 24 can be N- demethylated to give des-N-methyl clarithromycin 25. Reaction of 25 with electrophile 2 yields alkyne 26. Alternatively, alkyne 26 can be obtained by reductive animation of appropriate aldehydes and ketones. Descladinose 27 can be prepared from the treatment of alkyne 26 with dilute mineral acid, such as HCl. Compound 27, whereR^ is CH_3J can be similarly obtained from reaction of 24 with dilute mineral acid. Selective acyϊation of the hydroxyl group of the amine sugar can be achieved by treatment of compound 27 with acetic anhydride in appropriate non-protic solvents such as, but not limited to, acetone, in the absence of base to yield compound 28. Oxidation of 28 under Corey-Kim or similar conditions (see Corey & Kim (1972) J. Am. Chem. Soc, 94: 7586; Pfitzner & Moffatt (1965) J. Am. Chem. Soc, 87: 5661 ; Ley et al. (1994) Synthesis, 639) leads to ketolide 29. Treatment of 29 with carbonyldiimidazole and NaHMDS will give carbamate 30. Reaction of 30 with amines 31, 32 and ethane- 1,2-diamine will afford intermediate 33, 34, and 35, respectively (see U.S. Patent No. 5,631 ,355; Kashimura et al (2003), J AntibioL, 56: 1062; Randolph et al (2004) J. Med Chem., 47, 1085; Plata et al. (2004) Tetr., 60: 10171). Subsequent reactions of intermediates 33, 34, and 35 with azide 4 will lead to bridged-ketolides 36 and 37, 38 and 39, and 40 and 41, respectively. When R₁₃ contains an appropriate aromatic moiety and alkyl chain length, ketolide 29 can be modified to form compound 30 by methanolysis at elevated temperatures. Subsequent reaction of 30 with azide 4 will furnish ketolide 43. Again, it should be appreciated that the ZBG in azides of type 4 can be appropriately protected. Moreover, similar chemistries can be applied for the synthesis of the tetrazoles and oxazoles analogs of the ketolide and bridged-ketolide exemplified in scheme 3. Scheme 3

37 (1 ,5-ιsomer) 39 {1 ,5-isoiτiΘr) 41 (1 ,5-ιsomer)

Scheme 4 illustrates representative general synthesis of triazole compounds with HDAC recognition cap-group connected to the macrocyclic ring at 06 position of 14-membered macrolide such as, but not limiting to, erythromycin. Adapting known protocols (see, Plata et al. (2004) Tetra., 60: 10171), the aryl alkyne 47 can be obtained from readily available erythromycin A-9-oxime (see, Morimoto et al (1990) J Antibiot, 43:286) through the intermediacy of 45. Sequential base treatment with aqueous alkali and potassium carbonate in methanol will lead to alkyne 48 which can be reacted with azide 4 to give triazole 49. Methanolysis of 49 will afford triazole 50. Triazole 50 can be modified to form compound 51 by treatment with dilute mineral acid. Alternatively, methanolysis of alkyne 48 yields alkyne 51. Reaction of 51 with azide 4 will yield triazole 50. Scheme 4

Scheme 5 illustrates representative general syntheses of triazole compounds with HDAC recognition cap-groups connected to the macrocyclic ring at the 06 position of 14-membered ketolides and carbamate modified macrolides. Selective benzoyl deprotection and silyl group removal will afford aryl alkyne 53, The oxime group in 53 can be removed by heating 53 in a THF/H₂O containing NaHSCh and L-tartaric acid to afford aryl alkyne 54 (adapting protocols described by Plata et al. (2004) Tetra, 60: 10171). Reaction of 54 with azide 4 followed by debenzoylation by sequential treatment with potassium carbonate in methanol and methanolysis at elevated temperatures will yield triazole 55. Triazole 55 can be modified to form compound 56 by treatment with dilute mineral acid. Aryl alkyne 54 can be modified to form aryl alkyne 57 by adapting procedures exemplified for similar transformations in scheme 3 or alternative protocols described in the art (see U.S. Patent No. 5,631,355; Kashimura et al. (2003), J Antibiot, 56: 1062; Randolph et al (2004) J. Med. Chem., 47, 1085; Plata et al. (2004) Tetra., 60: 10171). Reaction of 57 with azide 4 followed by debenzoylation by sequential treatment with potassium carbonate in methanol and methanolysis at elevated temperatures will yield triazole 58. Triazole 58 can be converted to compound 59 by treatment with dilute mineral acid. A direct treatment of 57 with dilute mineral acid will afford alcohol 60. Oxidation of 60 under Corey-Kim or similar conditions followed by methanolysis at elevated temperatures will yield alkyne ketolide 61. Reaction of 61 with azide 4 will yield triazole 62. Scheme 5

Intermediates such as electrophiles 2, 7 and 14, azide 4, nJtrile oxide 11, amine 30 and carbonate alkyne 46 are all easily accessible by synthetic protocols known in the art. Exemplary examples for the synthesis of compounds whose general structures fit the forgoing are illustrated in schemes 6, 7, 8, and 9. Halogenated aryl alkyne 63 can undergo Heck coupling with ethyl acrylate to furnish α,β-unsaturated ester 64. Reduction of 64 with DΪBAL should generate alkenol 65, which can be transformed to carbonate 66 using methods known in the art (see US Patent No. 6,579,986; Plata et al. (2004), Tetra, 60: 10171). Alternatively, alkenol 65 can be prepared from alkenol 67 through Hagihara-Sonogashira coupling (Belema et at. Tet, Lett., (2004), 45: 1693). Reactions of carboxylic acid 68 with thionyl chloride in methanol follow by treatment with sodium azide should furnish azido methyl ester 69. Treatment of 69 with hydroxylamine should provide azido hydroxamate 70 (Ho et al., (2005), J Org, Chem., 70, 4873). The hydroxamate group of 70 can be appropriately protected with a silyl group to provide silyl azide 71 (Muri et al Org. Lett, (2000) 2: 539). Hagihara-Sonogashira coupling between alcohol 72 and TMS-acetylene should yield alkyne 73. TMS deprotection should furnish alkyne 74, which can be reacted with MsCl to provide mesylate 75. Reaction of phthalimide salt with 75 should provide phthalimide 76, which can be converted to amine 77 by hydrazinolysis or other suitable protocol known in the art. Treatment of alcohol 78, incorporating ZBG (appropriately protected when necessary), with oxidants such as PDC, should provide aldehyde 79. Reaction of 79 with hydroxylamine should furnish oxime 80, which can be converted to nitrile oxide 81 by treatment with NBS or other reagents such NCS₅ chloramine T, etc. Because of the likely instability of nitrile oxides, the generation of nitrile oxide can be performed in the presence of the appropriate alkyne 3 (scheme 1) to furnish the regioisomeric mixture of the isoxazoles.

Schemes 10 and 11 illustrate the synthesis of compounds 7-14 and 23-30 in Table 3.

Scheme 11: Synthesis of compounds 23-30

Scheme 12 illustrates the synthesis of compounds 36 and 38 in Table

3.

Scheme 12: Synthesis of compounds 36 and 38

Schemes 13, 14 and 15 below illustrate the synthesis of compounds

40, 44 and 47 in Table 3. Scheme 13: Synthesis of compound 40

THF, Argon,

Scheme 14: Synthesis of compound 44

Scheme 15: Synthesis of compound 47

V. Methods of Use and Administration

The compounds described herein may be used as anti-cancer agents, anti-inflammatory agents, anti-infective agents, anti-malarial agents, cytoprotective agents, neuroprotective agents, chemopreventive agents, prokinetic agents, and/or cognitive enhancing agents. Examples of cancer which may be treated include, but are not limited to, lung cancer, myeloma, leukemia, lymphoma, breast cancer, prostate cancer, pancreatic cancer, cervical cancer, ovarian cancer, and liver cancer. The compounds can be formulated for enteral, parenteral, and/or topical (e.g., transdermal, mucosal, etc.) administration. The compounds of general formula I and II and their pharmaceutically-acceptable addition salts, prodrugs, and/or solvates can also be used in the form of pharmaceutical preparations which facilitate bioavailability. One or more compounds of Formula I and II may be administered in a single dosage form or in multiple dosage forms Enteral Formulations

Pharmaceutical compositions for oral administration can be liquid or solid. Liquid dosage forms suitable for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to an encapsulated or unencapsulated HDAC inhibitor, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants, wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. As used herein, the term "adjuvant" refers to any compound which is a nonspecific modulator of the immune response. In certain preferred embodiments, the adjuvant stimulates the immune response. Any adjuvant may be used in accordance with the present invention. A large number of adjuvant compounds are known in the art (Allison, Dev, Biol. Stand, 92:3, 1998; Unkeless et al., Λnnu. Rev. Immunol. 6:251, 1998; and Phillips et al., Vaccine 10: 151, 1992). Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, caplets, dragees, powders and granules. In such solid dosage forms, the encapsulated or unencapsulated compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dϊcalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid compositions of a similar type may also be employed as fill materials in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Parenteral Formulations Pharmaceutical preparations in the form suitable for injection are subjected to conventional pharmaceutical operations such as sterilization and/or may contain adjuvants including, but not limited to, preservatives, stabilizers, wetting or emulsifying agents, and buffers.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated as known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils can be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectable formulations. In a particularly preferred embodiment, the compound is suspended in a carrier fluid containing 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v) TWEEN^M 80. The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Topical Formulations. The compounds described here can also be formulated for topical, transdermal, or mucosal delivery. Dosage forms for topical or transdermal administration include, but are not limited to, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The compounds are typically admixed under sterile conditions with a pharmaceutically acceptable carrier and any excipients (e.g., preservatives, buffers, etc.) that may be required. Ophthalmic formulations, ear drops and eye drops can also be prepared. The ointments, pastes, creams and gels may contain, in addition to the active agent, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compounds described herein in a proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the comρound(s) in a polymer matrix or gel.

Powders and sprays can contain, in addition to the active agent, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these drugs. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound(s).

The formulations contain an effective amount of one or more HDAC inhibitors. The doses in which the HDAC inhibitors and their salts, prodrugs, or solvates can be administered may vary widely depending on the condition of the patient and the symptoms to be treated. One of ordinary skill in the art can readily determine the necessary dosage based on the condition of the patient and the disease to be treated. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Examples Materials

"Preparative TLC" or "prep TLC" refers to preparative thin layer chromatography and was performed on Analtech preparative TLC plates (UV 254, 2000 μm), unless otherwise stated. "Column chromatography" or "flash column chromatography" was performed with 200-400 Mesh silica gel, unless otherwise noted.

Nuclear magnetic resonance (NMR) spectra were recorded on a Varian-Gemini 400 magnetic resonance spectrometer. ¹H NMR spectra were recorded in parts per million (ppm) relative to the peak OfCDCl₃, (7.24 ppm), CD₃OD (3.31 ppm), or DMSO-d₆ (2.49 ppm). ¹³C spectra were recorded relative to the central peak of the CDCI₃ triplet (77.0 ppm), CD₃OD (49.0 ppm), or the DMSO-d$ septet (39.7 ppm), and were recorded with complete hetero-decoupling.

Common reaction solvents were either high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade, and used without further purification. Anhydrous solvents and other reagents were purchased and used without further purification. Fluor de Lys^τu is a fluorescence based HDAC activity assay comprising a combination of fluorogenic Histone deAcetylase Lysyl substrate and a developer. The kit is a highly sensitive and convenient alternative to radiolabeled, acetylated histones or peptide/HPLC methods for the assay of histone deacetylases. This assay is based on the ability of HeLa nuclear extract, which is enriched in HDAC activity, to mediate the deacetylation of the acetylated lysine side chain of the Fluor de Lys substrate. The assay procedure requires two steps. First, incubation of the HeLa nuclear extract with the Fluor de Lys substrate results in substrate deacetylation and thus sensitizes it to the second step. In the second step, treatment of the deacetylated substrate with the Fluor de Lys developer produces a fhiorophore. The substrate-developer reaction, under normal circumstances goes to completion in less than 1 min at 25°C. The kit used was the Fluorimetric Assay/Drug Discovery Kit - AK-500 Manual Fluorescent Assay System available from BIOMOL® International, Plymouth Meeting, PA. The numbers used to identify the compounds described in the examples correspond to the references numbers in Table 4 and/or reaction schemes 10-15. Example 1. Synthesis of Compounds 7-14 and 23-30 in Table 3 Synthesis of AzithromycJn-N-phenylacetylene (3)

To a solution of JV-demethylated azithromycin 1 (2.0 g, 2.56 mraol) in anhydrous DMSO (30 ml) was added Hunig's base (4 ml) and 4- ethynylbenzyl methanesulfonate 2 (0.760 g, 3.60 mmol). The reaction mixture was heated with stirring under argon at 85°C for 2.5 h. The reaction was cooled and diluted with ethyl acetate (EtOAc, 100 mL) and washed with saturated NaHCO₃ (3 x 60 mL) and saturated brine (60 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by flash chromatography (silica, 12: 1 :0.05 CEbC^/MeOH/conc. NH₄OH) to give 1.2 g (52%) of 3 as a brownish white solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.84 (m), 0.97 (d, J= 7.6 Hz), 1.04 (m), 1.12-1.32 (m), 1.36-1.53 (m), 1.66-1.75 (m), 1.81-2.07 (m), 2.19 (s), 2.25-2.29 (m), 2.48 (m), 2.63-2.73 (m), 2.89 (bs), 2.96 (t, J= 9.8 Hz), 3.02 (s), 3.08 (s), 3.27- 3.32 (m), 3.38-3.45 (m), 3.56 (d, J= 6.8 Hz), 3.63 (s), 3.72 (d, J= 13.2 Hz), 3.97 (m), 4.19 (m), 4.36 (d, J= 7.2Hz), 4.63 (d, J= 10 Hz), 5.04 (d, J= 4.4 Hz)₅ 7.21 (d, J= 8 Hz)₅ 7.39 (d, J= 8 Hz) ; ¹³C-NMR (CDCl₃, 100MHz) δ 7.5, 9.2, 11.3, 14.9, 16.3, 18.3, 21.3,. 21.4, 21.6, 22.0, 26.8, 27.6, 29.6, 34.7, 36.3, 36.9, 42.0, 42.3, 45.2, 49.2, 57.7, 62.3, 63.7, 65.4, 68.5, 70.0, 70.6, 72.7, 73.5, 73.8, 74.2, 77.1, 77.9, 78.0, 83.4, 83.7, 94.5, 102.6, 120.8, 128.5, 132.0, 139.6, 178.3; HRMS (FAB, mnba) calc for [C₄₆H₇₆N₂Oi₂ + H]⁺ 849.5476, found 849.5411.

Synthesis of Azithromycin-arylalkyltriazolyl methyl ester (17) Azithromycin-N-phenylacetylene 3 (0.045 g, 0.053 mmol) and azido- ester 16 (0.014 g, 0.080 mmol) were dissolved in anhydrous THF (5 mL) and stirred under argon at room temperature. Copper (I) iodide (0.010 g, 0.053 mmol), and Hunig's base (0.05 mL) were then added to the reaction mixture, and stirring continued for 12 h. The reaction mixture was diluted with CH₂Cl₂ (30 mL) and washed with 1 :4 NH₄OH/saturated NH₄Cl (3 x 25 mL) and again with saturated NH₄CI (25 niL). The organic layer was dried over Na₂SC₄ and concentrated under vacuum. The crude product was purified by preparative TLC, eluting with Hexane/EtOAc/Et₃N 3:2:0.1 to give 50 mg (92%) of 17 as a white-brown solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.82- 0.90 (m), 0.98 (d, J= 7.6 Hz), 1.05-1.13 (m), 1.19-1.23 (m), 1.25-1.30 (m), 1.40-1.52 (m), 1.60-1.74 (m), 1.80-1.96 (m), 2.00-2.06 (m), 2.22-2.37 (m), 2.56 (m), 2.67 (m), 2.95 (t, J= 9.8 Hz), 3.07 (s), 3.29-3.34 (m), 3.46 (bs), 3.54 (<LJ= 6.8 Hz), 3.61 (5), 3.68 (bs), 3.77 (m), 3.97 (m), 4.18 (m), 4.34- 4.38 (m), 4.69 (m), 5.06 (d, J- 4 Hz), 7.32 (d, J= 6.4 Hz), 7.73-7.75 (m); ¹³C-NMR (CDCl₃, 100MHz) δ 8.7, 9.2, 11.3, 14.2, 14.7, 16.5, 18.2, 21.4, 21.5, 22.2, 24.2, 25.9, 26.6, 27.3, 29.7, 30.0, 33.6, 34.6, 36.4, 36.9, 42.4, 45.3, 45.8, 49.3, 50.0, 51.5, 57.7, 63.9, 65.5, 68.6, 69.4, 70.5, 72.7, 73.8, 74.2, 77.2, 77.6, 78.0, 83.4, 94.4, 102,7, 119.3, 125.5, 129.1, 129.4, 147.2, 173.4, 178.1. MS (FAB, mnba) 1020.3 (M+H)⁺.

Synthesis of Descladmoseazithromvcia-Tarylalkvltriazolyl methyl ester (18)

A mixture of compound 3 (0.12 g, 0.14 mmol) in 0.25 N HQ (15 mL) was stirred at room temperature for 20 h and poured into EtOAc (20 mL). The two layers were separated and the aqueous layer was washed with EtOAc (2 x 20 mL), basified with concentrated NH₄OH and then extracted with 5 % MeOH in CH₂Cb (2 x 30 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over Na₂SO₄. Solvent was evaporated off to give 89 mg (91 %) of descladinose compound 4 as a white solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.81-0.87 (m), 0.90-1.07 (m), 1.17-1.27 (m), 1.31-1.59 (m), 1.68-1.71 (m), 1.80-1.87 (m), 1.99-2.03 (m), 2.08 (s), 2.23-2.27 (m), 2,31 (s), 2.44-2.48 (m), 2.59-2.73 (m), 3.32-3.39 (m), 3.48- 3.53 (m), 3.60-3.65 (m), 3.73 (d,J= 9.6 Hz), 3.84-3.91 (m), 4.43 (d, J= 7.2 Hz), 4.69-4.72 (m), 7.16 (d, J= 8.0 Hz), 7.39 (d, J= 8.4 Hz); ¹³C NMR (CDCl₃, 100MHz) δ 7.7, 7.9, 10.9, 14.2, 16.], 20.9, 21.1, 21.2, 25.9, 26.6, 29.3, 36.0, 36.4, 37.1, 42.1, 44.5, 57.6, 60.3, 62.5, 65.3, 69.9, 70.5, 70.9, 73.0, 74.1, 75.4, 77.2, 79.5, 83.3, 94.9, 106.5, 120.8, 128.3, 132.0, 139.3, 177.2. MS (FAB, mnba) 691.2 (M+H)⁺. The descladinose compound 4 (0.080 g, 0.Ϊ 15 mmol) and azido-ester 16 (0.030 g, 0.173 mmol) were dissolved in anhydrous THF (5 mL) and stirred under argon at room temperature. Copper (I) iodide (0.010 g, 0.053 mmol), and Hunig's base (0.05 mL) were then added to the reaction mixture, and stirring continued for 12 h. The reaction mixture was diluted with

CH₂Cl₂ (30 mL) and washed with 1 :4 NH₄OH/saturated NH₄Cl (3 x 25 mL) and again with saturated NH₄Cl (25 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by preparative TLC₅ eluting with Hexane/EtOAc/Et₃N 3:2:0.1 to give 65 mg (65%) of 18 as a white-brown solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.79- 0.86 (m), 1.00-1.07 (m), 1.17-L35 (m), 1.42-1.51 (m), 1.55-1.72 (m), 1.80- 1.94 (m), 2.00-2.05 (m), 2.1 (s), 2.23-2.27 (m), 2.33 (s), 2.47 (d, J- 10.4 Hz), 2.58-2.72 (m), 3.32-3.41 (m), 3.52-3.73 (m), 3.92-4.00 (m), 4.34 (t, J = 7.0 Hz), 4.41 (d, J= 7.6 Hz), 4.69 (d, J= 10.8 Hz), 7.24 (d, J= 8.4 Hz)₅ 7.71 (d, J= 8 Hz), 7.73 (s); ¹³C NMR (CDCl₃, 100MHz) δ 7.7, 7.9, 8.7, 10.9, 16.1, 16.1, 20.9, 21.2, 24.2, 25.8, 25.9, 26.6, 29.2, 29.6, 30.0, 33.6, 36.0, 36.3, 37.1, 42.0, 44.5, 45.8, 50.0, 51.5, 57.7, 62.6, 65.I₇ 69.9, 70.4, 73.1, 74.1, 75.3, 79.4, 94.8, 106.4, 119.3, 125.5, 128.9, 129.6, 138.2, 147.1, 173.4, 177.2. MS (FAB, mnba) 862.2 (M+H)⁺. Synthesis of Azithromycin-iV-phenyltriazolyihexahydroxamic acid (T)

Method A

To a solution of compound 17 (0.04 g, 0.04 mmol) in 1 :1 THF/MeOH (3 mL) was added hydroxylamine (50 % in H₂O) (0.03 mL, 0.54 mmol) and a catalytic amount of KCN. The mixture was stirred at room temperature for 24 h. The reaction was partitioned between 5 % MeOH in CH₂Cl₂ (30 mL) and saturated sodium bicarbonate (25 mL), the two layers were separated and the aqueous layer was extracted with 5 % MeOH in CH₂CI₂ (2 x 20 mL). The combined organic layer was washed with saturated brine (40 mL) and dried over Na₂SO₄. Solvent was evaporated off and the crude was purified by preparative TLC, eluting with CH₂Cl₂/ MeOH/NH4OH 10:1:0.1 to give compound 7 (6.5 mg, 16 %) as brown-white solid. Method B

Azithromycin-iV-phenylacetylene 3 (0.100 g, 0.109 mmol) and 6- azidohexahydroxamic acid 15a (0.081 g, 0.117 mmol) were dissolved in anhydrous THF (5 mL) and stirred under argon at room temperature. Copper (I) iodide (0.011 g, 0.07 mmol) and Hunig's base (0.5 mL) were then added to the reaction mixture, and stirring continued for 4 h. The reaction mixture was diluted with CH₂Cl₂ (40 mL) and washed with 1 :4 NH₄OH/saturated NH₄Cl (3 x 30 mL) and saturated NH₄Cl (30 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by prep TLC (silica, 12:1:0.1 CH₂Cl₂/MeOH/conc. NH₄OH) to give 71 mg (59%) of 7 as a brownish white solid.

Method C

Azithromycin-N-phenylacetylene 3 (0.045 g, 0.050 mmol) and 6- azido-O-silyl hexahydroxamate 6 (0.060 g, 0.146 mmol) were dissolved in anhydrous THF (5 mL) and stirred under argon at room temperature (Note: compound 6 was prepared from the corresponding azido carboxylic acid, t- BuPh₂SiCl and NaH, according to the procedure described by Muri et ah ORG. LETT (2000) 2: 539). Copper (I) iodide (0.010 g, 0.05 mmol), Hunig's base (0.5 mL) and tris[(l-benzyl-1H-1,2,3-triazol-4- yl)methyl]amine, (TBTA) (0.016 g, 0.030 mmol) were then added to the reaction mixture, and stirring continued for 2 h (Note: TBTA was synthesized according to Chen et al Org. Lett., (2004) 6: 2853). The reaction mixture was diluted with CH₂Cl₂ (40 mL) and washed with 1 :4 MLjOH/saturated NH₄Cl (2 x 30 mL) and saturated NH₄Cl (30 mL). The organic layer was dried over Na_ZSO₄ and concentrated in vacuo. The crude product was purified by prep TLC (silica, 12:1:0.1 CH₂Cl₂/MeOH/conc. NH₄OH) to give 38 mg (60%) of silyl protected compound 6 as a brownish white solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.82-0.92 (m), 1.00-1.14 (m), 1.17-1.27 (m), 1.30-1.32 (m), 1.35-1.59 (m), 1.73-1.92 (m), 2.01-2.15 (m), 2.24-2.32 (m), 2.36 (br s), 2.56 (d, J= 10.4 Hz), 2.69 (m), 2.98 (d, J= 10 Hz), 3.07-3.09 (m), 3.32-3.36 (m), 3.42-3.46 (m), 3.55-3.63 (m), 3.66 (s)_> 3.78 (d, J= 13.2 Hz), 4.01 (m), 4.15-4.25 (m), 4.40 (d, J- 6.8 Hz)₅ 4.63 (d, J = 7.2 Hz)₅ 4.69 (s), 5.10 (d, J= 4.4 Hz)₅ 7.31-7.43 (m), 7.65-7.75 (m).

To a solution of silyl protected compound 6 (0.025 g, 0.02 mmol) in THF (1 mL) was added 1 M TBAF in THF (0.030 mL, 0.030 mmol) and the mixture was stirred at room temperature for 2 h during which TLC revealed a near quantitative conversion to a lower Rf product. The reaction was partitioned between CH₂Cl₂ (30 mL) and saturated NH₄Cl (25 mL), the two layers were separated and the organic layer dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by prep TLC (silica_> 12:1:0.1 CH₂CyMeOHZEt₃N) to give 15 mg (73%) of 7 as a brownish white solid.

¹H-NMR (Acetone-d6, 400MHz) δ 0.83-0.92 (m), 1.02 (d, J= 7.6 Hz), 1.08-1.11 (m), 1.14 (d, J= 7.6 Hz)₅ 1.18 (d₅ J= 6 Hz)₅ 1.24-1.29 (m), 1.33-1.47 (m), 1.54 (dd, J = 4.8 Hz₅ 15.2 Hz), 1.66 (m), 1.80-2.01 (m), 2.06- 2.12 (m), 2.18-2.24 (m), 2.26 (s), 2.28-2.31 (m), 2.35-2.41 (m), 2.51 (d, J = 10 Hz), 2.65-2.96 (m), 3.12 (s), 3.22-3.29 (m), 3.41-3.47 (m), 3.54-3.69 (m), 3.81 (d,J= 13.2 Hz), 4.11 (m), 4,24 (m), 4.45 (t,J= 7.0 Hz)₅4.50 (d, J= 6.8 Hz)₅ 4.75 (d, J= 7.2 Hz), 4.97 (d, J= 5.2 Hz), 7.42 (d, J= 8.0 Hz), 7.84 (d, J = 8.0 Hz), 8.35 (s). MS (FAB₅ mnba) 1021.2 (M+H)⁺. Synthesis of Descladinose-Azithromycin-iV-phenvltriazolylhexa- hydroxamlc acid (8)

Method A

To a solution of compound 18 (0.04 g, 0.05 mmol) in 1:1 THF/MeOH (3 mL) was added hydroxylamine (50 % in H₂O) (0.04 mL, 0.54 mmol) and a catalytic amount of KCN. The mixture was stirred at room temperature for 24 h. The reaction was partitioned between 5 % MeOH in CH₂Cl₂ (30 mL) and saturated sodium bicarbonate (25 mL), the two layers were separated and the aqueous layer was extracted with 5 % MeOH in CH₂Cl₂ (2 x 20 mL). The combined organic layer was washed with saturated brine (40 mL) and dried over Na₂SO₄. Solvent was evaporated off and the crude was purified by preparative TLC₅ eluting with CH₂Cl₂/MeOH/NH4OH 10:1:0.1 to give compound 8 (9.0 rag, 23 %) as brown-white solid. Method B

Reaction of descladinose-azithromycin-iV-phenylacetylene 4 (0.134 g, 0.188 mmol) and 6-azidohexahydroxamic acid 15a (0.130 g_} 0.755 mmol) within 8 h (according to the protocols of Method B described for the synthesis of compound 7 above), followed by prep TLC (silica, 10:1:0.1 CH₂Cl₂/MeOH/conc. NH₄OH) gave 73 mg (43%) of 8 as a brownish white solid.

³H-NMR (Acetone-dό_? 400MHz) δ 0.82-0.90 (m), 1.02 (d, J- 7.2 Hz), 1.07 (s), 1.09 (d, J= 6.8 Hz), 1.18-1.23 (m), 1.28 (bs), 1.31-1.39 (m), 1.46-1.56 (m), 1.65 (m), 1.81-1.83 (m), 1.87-1.99 (m), 2.05-2.11 (m), 2.18- 2.21 (m), 2.18-2.21 (m), 2.24 (s), 2.25-2.29 (m), 2.35 (s), 4.47 (d, J= 9.2 Hz), 2.61-2.67 (m), 2.70-2.77 (m), 3.30-3.34 (m), 3.41 (m), 3.52-3.65 (m), 2.81 (d, J- 13.2 Hz)₅ 4.44 (t, J= 7.0 Hz), 4.59 (d, J= 7.6 Hz), 4.87 (dd, J- 1.8 Hz, 11.0 Hz), 7.43 (d, J= 8.4 Hz), 7.83 (d, J= 8.4 Hz), 8.34 (m); HMRS (ESI) calcd for [C₄₄H₇₄N₆O₁, + H]⁺ 863.5488, found 863.5528.

Accordingly, compounds 9-14 and 23-30 (in this section) were synthesized according to the protocols of Method B described for the synthesis of compound 7 above.

Synthesis of Azithromycin-N-phenyltriazolylheptahydroxamic acid (9)

Reaction of azithromycin-iV-phenylacetylene 3 (0.134 g, 0.158 mmol) and 7~azϊdoheptahydroxamic acid 15b (0.125 g, 0.672 mmol) within 4 h, followed by prep TLC (silica, 12:1 :0.1 CH₂Cl₂/MeOH/conc. NH₄OH) gave 93 mg (56%) of 9 as a brownish white solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.81-1.51 (m), 1.54-1.65 (m), 1.70-2.14 (m), 2.20-2.38 (m), 2.46-2.56 (m), 2.60-2.70 (m), 3.00 (s), 3.31 (t, J= 8.8 Hz), 3.38-3.54 (m), 3.60 (s), 3.78 (d, J= 12.8 Hz)₅ 3.98-4.20 (m), 4.36 (d,J- 7.2 Hz), 4.49 (d,J= 7.2 Hz)₅ 5.11 (d, J= 4.0 Hz), 7.32 (d, J= 7.6 Hz), 7.73 (s), 7.75 (d, J= 7.6 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 6.6, 8.8, 11.5, 14.4, 16.6, 17.7, 21.3, 21.6, 21.8, 25.1, 26.0, 26.7, 27.1, 28.2, 29.2, 29.6, 30.0, 33.1, 34.5, 35.7, 36.7, 41.8, 42.7, 45.3, 49.3, 50.3, 50.7, 57.9, 62.7, 63.0, 65.8, 68.6, 69.4, 70.4, 72.6, 73.2, 73.8, 77.8, 78.1, 78.2, 83.5, 94.4, 102.8, 119.3, 125.7, 129.4, 129.7, 138.4, 147.4, 171.3, 178.4; HMRS (ESI) caJcd for [Cs₃H₉₀N₆O₁₄ + H]⁺ 1035.6587, found 1035.6628.

Synthesis of Pescladinojse- Azitbromvcin-iV-phcnvltriazolvlhepta" hydroxamie acid (10)

Reaction of descladinose-azithromycin-iV-phenylacetylene 4 (0.130 g, 0.188 mmol) and 7-azidoheptahydroxamic acid 15b (0.130 g, 0.755 mmol) within 8 h, followed by prep TLC (silica, 10:1:0.1 CH₂Cl₂/MeOH/conc. NH₄OH) gave 78 mg (47%) of 10 as a brownish white solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.66-2.32 (m), 2.47 (d,J= 10.8 Hz), 2.63-2.70 (m), 3.34-3.51 (m), 3.62-3.69 (m), 4.20-4.40 (m), 4.74 (br s), 7.26 (br s), 7.73 (br s); ¹³C NMR (CDCl₃, 100 MHz) δ 7.4, 7.9, 10.7, 16.0, 16.1, 20.9, 21.1, 25.0, 25.7, 26.5, 28.0, 28.9, 29.8, 35.8, 36.3, 36.9, 42.0, 44.4, 50.1, 57.9, 62.7, 63.9, 69.9, 70.4, 70.8, 73.3, 74.1, 75.2, 79.5, 94.9, 106.6, 119.7, 125.7, 129.2, 129.6, 138.4, 147.3, 177.5; HMRS (ESI) calcd for [C₄₅H₇₆N₆O₁, + H]⁺ 877.5645, found 877.5665.

Synthesis of Azithromvcin--V-pheαvltriazolvloctahydro^amic acid

(11)

Reaction of aathromycin-Λf-phenylacetylene 3 (0.10 g, 0.120 mmol) and 8-azidooctahydroxamic acid 15c (0.047 g, 0.24 mmol) within 2.5 h, followed by prep TLC (silica, 12:1:0.1 CføCh/MeOH/conc. NH₄OH) gave 72 mg (58 %) of 11 as a brownish white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.85 (t, J= 4.0 Hz), 0.87-1.22 (m), 1.29 (s), 1.30-2.28 (m), 2.29 (s), 2.30- 3.00 (m), 3.10 (s), 3.20-3.79 (m), 3.99-4.03 (m), 4.35-4.40 (m)_> 4.65 (d, J= 8.0 Hz), 5.11 (d, J = 4.8 Hz)₅ 7.34 (d, J= 8.0 Hz), 7.72 (s), 7.77 (d, J= 8.0 Hz); ¹³C NMR (DMSO-d₆, 400MHz) δ 7.5, 9.8, 11.6, 15.4, 18.2, 19.1, 21.5, 22.1, 22.7, 25.6, 26.3, 26.6, 28.7, 29.0, 29.6, 30.2, 32.0, 32.8, 35.2, 36.4, 37.2, 42.2, 45.3, 49.2, 50.1, 58.3, 63.2, 65.4, 67.7, 70.8, 73.3, 74.2, 77.0, 78.4, 83.4, 102.8, 121.6, 125.6, 129.7, 130.0, 135.0, 147.0, 177.8; HRMS (FAB, thioglycerol) calc for [C₅₄H_9ZN₆O₁₄ + H]⁺ 1049.6749, found 1049.6648. Synthesis of Descladinose-Azjtfaromycip-N-phepyltriazolvlocta- hydioxamic acid (\ 2)

Reaction of azithromycin-iV-phenylacetylene 4 (0.10 g, 0.144 mmol) and 8-azidooctahydroxamic acid 15c (0.049 g, 0.246 mmol) within 2.5 h, followed by prep TLC (silica, 10:1 :0.1 CH₂Cl2/MeOH/conc. NH₄OH) gave 94 mg (73 %) of 12 as a brownish white solid. HRMS (FAB, thioglycerol) calc for [C₄₆H₇₉N₆On + H]⁺ 891 ,5806, found 891.5910.

Synthesis of Azithromycin-N-phenyltria2Plylnonahydroxaniic acid

(13)

Reaction of azfthromycin-N-phenylacetylene 3 (0.10 g, 0.120 mmol) and 9-azidononahydroxamic acid 15d (0.043 g, 020 mmol) within 2.5 h, followed by prep TLC (silica, 12:1 :0.1 CH₂Cl2/MeOH/conc. NH₄OH) gave 64 mg (51 %) of 13 as a brownish white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.84- 1.30 (m), 1.33-2.26 (m), 2.30 (s), 2.38-2.68 (m), 2.99 (s), 3.32-3.84 (m), 4.03-4.08 (m), 4.35-4.41 (m), 4.53 (d, J= 8.0 Hz), 5.13 (d, J= 4.0 Hz), 7.35 (d, J= 8.0 Hz), 7.75 (s), 7.78 (d, J= 8.0 Hz); ¹³C NMR (DMSO-dβ, 400MHz) δ 6.9, 9.0, 11.6, 14.7, 16.9, 18.0, 21.6, 21.8, 22.1, 25.6, 26.4, 26.9, 27.3, 28.8, 29.0, 29.1, 29.5, 29.9, 30.4, 34.8, 36.0, 37.0, 42.1, 43.0, 45.6, 49.5, 50.5, 58.1, 63.5, 66Λ, 68.8, 70.7, 72.9, 74.1, 78.1, 78.3, 78.5, 83.7, 94.4, 94.7, 103.1, 119.6, 126.0, 129.7, 130.0, 147.6, 178.7; LRMS (MALDI) calc for [C₅₅H₉₄N₆Oi₄ + H]⁺ 1063.6, found 1063.7.

Synthesis of AzJthromycin--V-phenyhria2olyIdecahvdroxamic aci<|

(14)

Reaction of azithromycin-JV-phenylacetvlene 3 (0.10 g, 0.120 mmol) and 10-azido-decahydroxamic acid 15e (0.045 g, 0.20 mmol) within 4.5 h, followed by prep TLC (silica, 12:1:0.1 CH₂Cl₂ZMeOHZcOnC NH₄OH) gave 70 mg (56 %) of 14 as a brownish white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.85-1.36 (m), 1.41-2.24 (m), 2.28, 2.36 (s), 2.33-3.10 (m), 3.05 (s), 3.23- 3.82 (m), 4.06-4.10 (m), 4.36-4.41 (m), 4.49 (d, J= 8.0 Hz), 5.15 (d, J= 4.0 Hz), 7.34 (d, J= 8 Hz), 7.75 (s), 7.78 (d, J= 8.0 Hz); ¹³C NMR (DMSO-O₅, 400MHz) 66.7, 9.0, 11.7, 14.6, 16.9, 17.9, 21.6, 21.9, 22.0, 25.6, 26.4, 26.8, 27.0, 27.3, 28.8, 29.0, 21.9, 29.3, 29.5, 29.9, 30.3, 33.6, 34.9, 35.8, 37.0, 42.1, 43.0, 45.6, 49.6, 50.6, 51.6, 58.0, 62.8, 63.9, 66.2, 68.9, 69.6, 70.7, 72.9, 73.5, 74.O₁ 74.1, 78.2, 78.6, 83.6, 94.6, 103.0, 119.6, 126.0, 129.6, 129.9, 138.9, 147.6, 178.6; HRMS (MALDI) calc for [C₅₆H₉₆N₆O₁₄ + H]⁺ 1077.7057, found 1077.6971. Synthesis of Clarithromycin-JV-phenylacetylene (20)

To a solution of iV-demethylated clarithromycin 19 (2.40 g, 3.34 mmol) in anhydrous DMSO (30 ml) was added Hunig's base (3 ml) and 4- ethynylbenzyl methanesulfonate 2 (0.920 g, 4.34 mmol). The reaction mixture was then heated with stirring under argon at 85°C for 2.5 h. The reaction was cooled and diluted with EtOAc (100 niL) and washed with saturated NaHCO₃ (3 x 60 mL) and saturated brine (60 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by flash chromatography (silica, gradient 12:1; 10:1; 8: 1 ; CH₂Cl₂/acetone) to give 1.8 g (63%) of 20 as a brownish white solid. ¹H- NMR (CDCl₃, 400MHz) δ 0.82 (t, J= 7.2 Hz), 1.03-1.28 (m), 1.37 (s), 1.40- 1.55 (m), 1.65-1.90 (m), 2.03 (d, J= 10.0 Hz), 2.22 (s), 2.30 (d, J= 15.2 Hz), 2.40-2,60 (m), 2.80-2.90 (m), 2.94-3.00 (m), 3.04 (s), 3.09 (s), 3.16 (s), 3.24-3.29 (m), 3.38-3.46 (m), 3.59 (d, J= 6.8 Hz), 3.70-3.75 (m), 3.88-3.95 (m), 4.37 (d, J= 7.2 Hz), 4.88 (d, J= 4.4 Hz), 5.02 (dd, J= 11.6, 2.4 Hz), 7.23 (d, J= 12.0 Hz), 7.42 (d, J- 8.0 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 9.2_S 10.7, 12.4, 16.1, 18.1, 18.7, 19.9, 21.1, 21.5, 29.3, 32.4, 34.8, 36.9, 37.2, 39.2, 45.0, 45.2, 49,3, 50.6, 53.4, 57.6, 63.3, 65.6, 68.5, 69.0, 70.6, 72.5, 74.2,76.5, 77,8, 78.1, 78.2, 80.8, 95.8, 102.5, 120.9, 128.6, 132.0, 133.5, 139.4, 175.4; HRMS (ESI) calc for [C₄₆H₇₃NOi₃ + H]⁺ 848,5155, found 848. 5181.

Synthesis of Descladinose-Clarithromycin-TV-phenylacetylene (21) To a solution of clarithromycin-iV-phenylacetylene 20 (0.500 g, mmol) in ethanol (20 mL) was added IN HCl (20 mL), and stirring continued for 22 h at room temperature. The reaction mixture was basified with concentrated NH₄OH to about pH = 9. The reaction mixture was diluted with distilled water (40 mL) and extracted with EtOAc (3 x 60 mL), The combined organic layers were washed with saturated brine (40 mL), dried over Na₂SO₄, and concentrated in vauo. The crude product was purifed by flash chromatography (silica, 8:1 CH₂Cl₂/acetone) to give 320 mg (79%) of 21 as a brownish white solid. ¹H-NMR (CDCI₃, 400MHz) δ 0.82 (t, J = 7.6 Hz), 1.09-1.28 (m), 1.34 (s), 1.40-1.55 (m), 1.70-1.74 (m), 1.87-1.94 (in), 2.08-2.15 (m), 2.54-2.66 (m), 2.94-2.98 (m), 3.05 (s), 3.25 (s), 3.31-3.42 (m), 3.48-3.56 (m), 3.66 (d, J= 10.0 Hz), 3.82 (s), 3.90 (s), 4.35 (d,J= 7.6 Hz), 5.14 (dd,J= 10.8, 2.0 Hz), 7.18 (d,J= 8.0 Hz), 7.42 (d,J= 8.4 Hz); ¹³C NMR (CDCl₃, 100 MHz) 5 8.4, 10.5, 12.7, 15.3, 16.3, 17.8, 18.8, 21.4, 29.2, 35.9, 36.6, 37.5, 38.7, 44.5, 45.5, 49.6, 57.8, 65.0, 69.7, 70.1, 70.6, 74.1, 77.9, 78.9, 83.3, 88.5, 106.5, 121.0, 128.4, 132.1, 139.1, 174.7; HRMS (ESI) calc for [C₃₈H₅₉NOi₀+ H]⁺ 690.4212, found 690.4259.

Synthesis of Clarithromvcin- N-phenvltriazolvlhexahvdroxamic add (23)

Reaction of clarithromycin-N-phenylacetylene 20 (0.100 g, 0.120 mmol) and 6-azidohexahydroxainic acid 15a (0.080 g, 0.470 mmol) within 2.5 h, followed by prep TLC (silica, 12:1:0.1 CH^VMeOH/conc. NH₄OH) gave 70 mg (58%) of 23 as a brownish white solid. ¹H-NMR (CDCU, 400MHz) δ 0.81 (t, J^» 7.6 Hz), 1.03-1.52 (m), 1.62-1.92 (m) 2.04-2.29 (m), 2.48-2.60 (m), 2.82-2.90 (m), 2.93-2.99 (m), 3.09 (s), 3.19 (s), 3.28-3.33 (m), 3.42-3.46 (in), 3.60 (d, J= 7.6 Hz), 3.70-3.80 (m), 3.90-3.98 (m), 4.37-4.40 (m), 4.87 (d, J= 4.8 Hz), 5.03 (dd, J= 11.6, 2.4 Hz), 7.34 (d, J= 7.6 Hz), 7.77 (d, J= 7.6 Hz), 7.82 (s); ¹³C NMR (CDCl₃, 100 MHz) δ 9.1, 10.5, 12.2, 15.9, 17.9, 18.5, 19.7, 20.9, 21.2, 21.4, 24.3, 25.5, 29.4, 29.6, 34.7, 36.8, 37.1, 39.0, 39.1, 45.0, 45.1, 49.3, 49.9, 50.5, 53.3, 57.5, 63.6, 65.5, 68.5, 69.0, 70.7, 72.4, 74.2, 77.8, 78.2, 80.9, 95.9, 102.6, 119.8, 125.6, 129.4, 147.4, 175.8; HMRS (ESI) calcd for [C₅₂H₈₅N₅O₁₅ + H]⁺ 1020.6114, found 1020.6121.

Synthesis of Descladinose-Clarithromvcin-vV-phenyltriazolvlhexa- hvdrpxamic acid (24)

Reaction of descladinose-clarithromycin- N-phenyJacetylene 21 (0.075 g, 0.109 mmol) and 6-azidohexahydroxamic acid 15a (0.040 g, 0.233 mmol) within 4 h, followed by prep TLC (silica, 10 : 1 :0.1 CH₂Cl₂/MeOH/conc. NH₄OH) gave 47 mg (51%) of 24 as a brownish white solid, ¹H-NMR (CDCl₃, 400MHz) δ 0.79 (t, J= 7.2 Hz)₉ 1.08- 1.32 (m), 1.39-1.64 (m), 1.71-1.81 (m), 1.82-1.96 (m), 2.04-2.18 (m), 2.51-2,70 (m), 2.92-2.98 (m), 3.18-3.38 (m), 3.45-3.55 (m), 3,60-3.74 (m), 3.81 (s), 3.90 (s), 4.33 (br s), 5.13 (d, J = 10.4 Hz), 7.29 (br s), 7.74 (br s); ¹³C NMR (CDCl₃, 100 MHz) δ 8.6, 10.7, 12.9, 15.5, 16.4, 18.O₅ 19.0, 21.5, 21.6, 29.5, 29.9, 36.1, 36.7, 37.7, 39.0, 44.7, 45.7, 49.8, 50.3. 58.2, 64.6, 70.0, 70.3, 70.9, 74.4, 78.3, 79.1, 88.5, 106.7, 120.3, 126.1, 129.6, 129.9, 147.7, 175.4; HMRS (ESI) calcd for [C₄₄H₇₁NsO₁₂ + H]⁺ 862.5172, found 862.5155. Synthesis of Claritnromycin'N-phenyitriazolylheptahvdroxamic acid

05)

Reaction of clarithromycin-iV-phenylacetylene 20 (0.130 g, 0.153 mmol) and 7-azidoheptahydroxamic acid 15b (0.105 g, 0.565 mmol) within 2.5 h, followed by prep TLC (silica, 12:1:0.1 CH₂Cl₂/MeOH/conc. NH₄OH) gave 105 mg (67%) of 25 as yellowish solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.82 (t, J= 8.0 Hz), 1.04-1.52 (m), 1.67-1.92 (m), 2.14-2.29 (m), 2.52-2.60 (m), 2.82-2.90 (m), 2.95-3.00 (m), 3.10 (s), 3.16 (s), 3.27-3.32 (m), 3.41-3.46 (m), 3.59 (d, J- 6.8 Hz), 3.69-3.79 (m), 3.90-3.95 (m), 4.34-4.39 (m), 4.87 (d, J= 4.4 Hz), 5.02 (d, J= 9.2 Hz), 7.33 (d, J= 6.4 Hz), 7.77 (d, J= 8.4 Hz); ¹³C NMR (CDCl₃, 100 MHz) S 9.1, 10.5, 12.2, 15.9, 17.9, 18.5, 19.8, 20.9, 21.2 , 21.4, 24,7, 25.5, 27.7, 29.8, 34.7, 36.8, 37.1, 39.1, 45,0, 45.2, 49.3, 50.0, 50.5, 57.6, 63.6, 65.6, 68.6, 69.0, 70.7, 72.4, 74.2, 77.8, 78.3, 80.9, 95.9, 102.7, 119.5, 125.7, 129.4, 147.5, 175.8; HMRS (ESI) calcd for [C₅₃Hs₇N₅Oi₅ +^■ H]⁺ 1034.6271, found 1034.6246. Synthesis of Descladinose-Clarithromycin-JV-phenyltriazpl yl- herjtahydroxamic acid (26)

Reaction of descladinose-c!aritnromycin~.V~phetιylacetylene 21 (0.075 g, 0.109 mmol) and 7-azidoheptahydroxamic acid 15b (0.040 g, 0.233 mmol) within 4 h, followed by prep TLC (silica, 10: 1 :0.1 CH₂CI₂/MeOH/conc. NH₄OH) gave 80 mg (84%) of 26 as a brownish white solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.78 (t, J= 7.2 Hz), 1.06-1.31 (m), 1.40-1.53 (m), 1.71 (d, J= 11.6 Hz), 1.80-1.91 (m), 2.01-2.20 (m), 2.50-2.65 (m), 2.91-2.97 (m), 3.16 (t, J= 6.4 Hz), 3.26-3.35 (m), 3.42-3.54 (m), 3.64- 3.71 (m), 3.80 (br s), 3.90 (br s), 4.30-4.34 (m), 5.12 (dd, J=* 11.6, 2.4 Hz), 7.27 (d, J- 8.0 Hz), 7.72 (d, J= 7.2 Hz), 7.80 (s); ¹³C NMR (CDCl₃, 100 MHz) δ 8.3, 10.3, 12.5, 15.2, 16.1, 17.6, 18.6, 21.1, 21.3, 24.8, 25.1, 25.5, 26.2, 27.8, 28.5, 29.1, 29.6, 29.7, 32.3, 35.8, 36.3, 37.4, 38.6, 44.3, 45.4, 49.5, 50.0, 51.2, 57.8, 64.2, 69.7, 69.9, 70.6, 74.1, 77.9, 78.7, 88.0, 106.3, 119.9, 125.7, 129.3, 129.5, 138.3, 147.3, 175.1; HMRS (ESI) calcd for [C₄₅H₇₃N₅O₁₂ + H]⁺ 876.5329, found 876.5301.

Synthesis of Clarithromycin- iV-Phenyltriazolyioctahvdroxamic acid (27)

Reaction of clarithromycin- N-phenylacetylene 20 (0.101 g, 0.120 mmoi) and 8-azidooctahydroxamic acid 15c (0.047 g, 0.24 mmol) within 2.5 h, followed by prep TLC (silica, 12:1:0.1 OfeClj/MeOH/conc. NH₄OH) gave 92 mg (74%) of 27 as a brownish white solid. ¹H NMR (CDCl₃, 400 MHz) 80.81 (t,J= 7.2 Hz), 1.04-2.05 (m), 2.22 (s), 2.19-2.82 (m), 3.00 (s), 3.08 (s), 2.91-3.80 (m), 3.95 (m), 4.38 (m), 4.88 (d, J= 4.4 Hz), 5.04 (dd, J= 10.8, 2.0 Hz), 7.33 (d, J= 7.6 Hz), 7.71 (s), 7.77 (d, J= 8.0 Hz); ¹³C NMR (CDCl₃, 400MHz) δ 8.8, 9.4, 10.8, 12.5, 16.2, 18.2, 18.8, 20.0, 21.2, 21.5, 21.6, 25.1, 26.0, 26.7, 28.2, 28.6, 28.9, 29-9, 30.1, 35.0, 36.9, 37.4, 39.2, 39.4, 45.2, 45.4, 46.1, 49.6, 50.4, 50.8, 51.6, 58.1, 63.6, 65.9, 68.4, 69.3, 70.9, 72.8, 74.4, 78.0, 78.5, 81.2, 96.1, 120.1, 102.6, 126.1, 130.2, 147.4, 176.0 ; HRMS (ESI) calc for [C₅₄Hi)_ON₅O₁₅H-Hl⁺ 1048.6427, found 1048.6486.

Synthesis of DescIadinose«Clarithromvcui- JV-Phenyltriazolvl- octahvdroxamic acid (28^

Reaction of clarithromycin- iV-phenylacetylene 21 (0.10 g, 0.144 mmol) and 8-azidooctahydroxamic acid ISc (0.049 g, 0.246 mmol) within 2.5 h, followed by prep TLC (silica, 10:1:0.1 CHiCVMeOH/conc. NH₄OH) gave 117 mg (90 %) of 28 as a brownish white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.81 (t, J= 7.2 Hz), 1.10-2.09 (m), 2.18 (s), 2.19-2.68 (m), 2.98-3.73 (m), 3.83 (s), 3.93 (m), 4.36 (m), 5.16 (d, J= 8.0 Hz), 7.31 (d, J= 8.0 Hz), 7.77 (2H, d, J= 8.0 Hz), 7.79 (IH, s); '³C NMR (CDCl₃, 400MHz) δ 8.5, 10.6, 12.8, 15.4, 16.4, 17.9, 18.9, 21.4, 21.6, 29.4, 36.1, 36.7, 37.7, 38.9, 44.7, 45.7, 49.8, 58.0, 65.2, 70.0, 70.4, 70.8, 74.4, 76.8, 78.2, 79.2, 83.6, 88.8, 106.9, 121.3, 128.7, 132.5, 139.6, 175.2 ; HRMS (FAB, thioglycerol) calc for [C₄₆H₇₆N₅O₁₂ + H]⁺ 890.5490, found 890.5562.

Synthesis of Clarithromycin- N-Phenyltriazolylnpnahvdroxamic acid (29)

Reaction of clarithromycin- N-phenylacetylene 20 (0.100 g, 0.120 mmol) and 9-azidononahydroxamic acid 15d (0.043 g, 0.20 mmol) within 2.5 h, followed by prep TLC (silica, 12:1:0.1 CH₂Cl₂/MeOH/conc. NH₄OH) gave 54 mg (42%) of 29 as a brownish white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.81 (t, J= 7.2 Hz), 1.04-2.02 (m), 2.24 (s), 2.10-2.97 (m), 3.00 (s), 3.09 (s), 3.20-3.82 (m), 3.88 (m), 4.39 (m), 4.88 (d, J= 4.0 Hz), 5.05 (d, J= 10.0 Hz), 7.35 (d, J= 8.0 Hz), 7.77 (d, J= 4.0 Hz); ¹³C NMR (CDCl₃, 400MHz) δ 9.0, 9.3, 10.8, 12.5, 16.1, 18.2, 18.8, 21.2, 21.5, 21.6, 21.7, 21.8, 26.3, 26.8, 28.7, 28.9, 29.1, 29.9, 30.3, 35.0, 37.0, 37.4, 39.3, 39.4, 45.2, 45.4, 49.6, 50.5, 50,8, 51.6, 57.8, 63.8, 65.8, 68.8, 69.2, 70.9, 72.7, 74.5, 76.8, 78.1, 78.4, 78.5, 81.1, 96.1, 102.9, 119.7, 125.9, 129.6, 129.9, 138.7, 147.6, 176.1; HRMS (ESI) calc for [C₅₅H_9IN₅O₁₅ + H]⁺ 1062.6584, found 1062.6586.

Synthesis of Clarithromycin- N-Phenyltriazolvldecahydrosamic acid (30)

Reaction of clarithromycin- iV-phenylacetylene 20 (0.10 g, 0.120 mmol) and 10-azidodecahydroxamic acid 15e (0.045 g, 0.197 mmol) within 2.5 h, followed by prep TLC (silica, 12:1 :0.1 CH₂Cl₂/MeOH/conc. NH₄OH) gave 68 mg (53 %) of 30 as a brownish white solid. ¹H NMR (CDCl₃, 400 MHz) 0.82 (t, J^» 7.2 Hz), 1.05-2.12 (m), 2.24 (s), 2.26-2.97 (m), 3.01, 3.10 (s), 3.19-3.80 (m), 3.95 (m), 4.39 (m), 4.89 (d, J= 4.0 Hz), 5.04 (d, J= 8.0 Hz), 7.35 (d, J^ 8.0 Hz), 7.76 (s), 7.79 (d, J= 8.0 Hz); ¹³C NMR (CDCl₃, 400MHz) 89.3, 10.8, 12.5, 16.1, 18.2, 18.8, 20.0, 21.2, 21.5, 21.7, 25.4, 26.2, 28.9, 29.0, 29,3, 29.6, 29.9, 30.2, 35.0, 37.0, 37.4, 39.3, 39.4, 45.2, 45.4, 49.6, 50.5, 50.8, 51.6, 57.8, 63.8, 65.8, 68.8, 69.2, 70.9, 72.7, 74.5, 76.8, 78.1, 78.5, 81.1, 96.1, 102.9, 119.7, 125.9, 129.6, 129.8, 138.9, 147.6, 176.1 ; HRMS (ESI) cak for [C₅₆Hp₃N₅Oi_S + H]⁺ 1076.6740, found 1076.

6667.

Example 2. Synthesis of Compounds 36 and 38 in Table 3

Synthesis of Methyl 8-(4-(hydroxymethyl)phenylamino)-8- oxooctanoate (33):

To a mixture of 8-methoxy-8-oxooctanoic acid (0.40 g, 2.10 mmol), benzotriazole (0.28 g, 2.23 mmol) in anhydrous CH2CI₂ (15 mL) was added SOCl₂ (0.17 mL, 2.23 mmol) at O°C, the mixture was kept stirring at O°C for 2.5 h and then filtered. The solvent was evaporated off to give crude acid chloride 31 which was used without further purification.

To a solution of (4-aminophenyl)methanol 32 (0.31 g, 2.50 mmol) in anhydrous pyridine (8 mL) was added chlorotriniethylsilane (0.32 mL, 2.50 mmol) at room temperature and stirring continued for 2 h. The mixture, together with a catalytic amount of DMAP, was added to a mixture of crude chloride 31 (obtained as described above) in pyridine at 0°C. The reaction was allowed to warm to room temperature and stirring continued overnight. Water (5 mL) and 1 M TBAF in tetrahydrofuran (THF) (0.25 mL, 0.25 mmol) were added and stirring continued for additional 30 min. EtOAc (50 mL) and IN HCl (30 mL) were added, the two layers were separated, the organic layer was washed with IN HCl (30 mL) and saturated brine (30 mL) and dried over Na₂SO₄. Solvent was evaporated off and the crude was purified by preparative TLC, eluting with acetone/hexanes 1:1 to give compound 33 (195 mg, 30 %) as yellow-white solid. ¹H-NMR (CDCI₃, 400MHz) δ 1. 24 (4H, m), 1.49-1.59 (4H, m), 2,17-2.25 (4H, m), 3.58 (3H, s), 4.50 (2H, s), 7.13 (2H, d, J = 8.4 Hz), 7.37 (2H, d, J = 8.4 Hz). Synthesis of Azithromvcin-arylalkyl methyl ester (35) To a solution of crude preparation of compound 33 (0,64 g, 2,20 mmol) in CH₂Cl₂ (15 mL) and triethylamine (Et₃N) (0.90 mL, 6.60 mmol) was added mesyl chloride (0.70 mL, 8.85 mmol) at O°C and the reaction was allowed to warm to room temperature. Stirring continued for 2h, CH₂CI₂ (40 mL) and saturated sodium bicarbonate (30 mL) were added. The two layers were separated; the organic layer was washed with sodium bicarbonate (1 x 30 mL)_? saturated brine (30 mL) and dried over Na₂S O₄. Solvent was evaporated off and the crude was purified by flash chromatography (silica gel, eluting with Hexane/EtOAc, gradient 3:1, 2: 1_? 1:1) to give compound 34 (320 mg, 40 %) as white solid. A mixture of 4'-Desmethylazithromycin 1 (0.45 g, 0.62 mmol), compound 34 (0.32 g, 0.86 mmol), catalytic amount of potassium iodide in THF (15 mL) and Hunig's base (3 mL) was heated under refiuxing condition for 48 h. CH₂CI₂ (80 mL) and saturated sodium bicarbonate (40 mL) were added and the two layers were separated. The organic layer was washed with sodium bicarbonate (40 mL), saturated brine (40 mL) and dried over Na₂SO₄. Solvent was evaporated off and the crude was purified by preparative TLC, eluting with EtOAc/hexanes/ Et₃N 3:2:0.1 to give compound 35 (176 mg, 28 %) as brown-white solid. ¹H-NMR (CDCl₃, 400MHz) δ 0.79-0.83 (m), 0.94- 1.01 (m), 1.09-1.20 (m), 1.22-1.32 (m), 1.37-1.59 (m), 1.62- 1.73 (m), 1.77- 2.01 (m), 2.08-2.28 (m), 2.38-2.52 (m), 2.61-2.71 (m), 2.91-3.01 (m), 3.11 (s), 3.25-3.33 (m), 3.42 (m), 3.54-3.65 (m), 3.97 (m), 4.18 (m), 4.36 (d, J= 6.8 Hz), 4.61 (m), 5.03 (d, J= 4.4 Hz)₅ 7.14 (d, J= 8.4 Hz), 7.42 (d, J= 8.4 Hz), 7.73 (s), 8.97 (bs) ; ¹³C-NMR (CDC13, 100MHz) δ 7.5, 9.1, 1 L3, 14.8, 16.2, 16.9, 18.2, 20.5, 23.2, 21.4, 21.5, 21.9, 24.6, 25.3, 26.7, 27.5, 28.7, 29.6, 33.9, 34.7, 36.2, 36.7, 37.3, 39.1, 41.9, 42.2, 45.1, 48.5, 49.3, 51.4, 57.3, 62.2, 64.3, 65.4, 68.5, 69.9, 70.5, 72.7, 73.5, 73.8, 74.1, 77.7, 77.9, 83.4, 94.4, 102.6, 119.5, 129.0, 134.2, 137.0, 171.0, 173.8, 178.4. MS (FAB, mnba) 1010.3 (M+H)⁺.

Synthesis of Azithromycin-arylalkyl hydroxamic acid (36) To a solution of compound 35 (0.09 g, 0.09 mmol) in 1 : 1 THF/MeOH

(3 mL) was added hydroxyϊamine (50 % in H₂O) (0.03 mL, 0.54 mmol) and a catalytic amount of KCN. The mixture was stirred at room temperature for 24 h. The reaction was partitioned between 5 % MeOH in CH₂Cl₂ (30 mL) and saturated sodium bicarbonate (25 mL), the two layers were separated and the aqueous layer was extracted with 5 % MeOH in CH₂Cl₂ (2 x 20 mL). The combined organic layer was washed with saturated brine (40 mL) and dried over Na₂SO₄. Solvent was evaporated off and the crude was purified by preparative TLC, eluting with CH₂Cl₂/MeOH/NH₄OH 10:1:0.1 to give compound 36 (22 mg_» 25 %) as brown-white solid. ¹H-NMR (CD₃OD, 400MHz) δ 0.87-0.92 (m), 1.02-1.12 (m), 1.17-1.37 (m), 1.43-1.69 (m), 1.75-1.88 (m), 1.99 (m). 2.08 (m), 2.13-2.19 (m), 2.24 (s), 2.30 (s), 2.33-2.41 (m), 2.54 (d, J= 11.2 Hz), 2.75-2.80 (m) , 3.00 (d, J= 9.6 Hz), 3.19 (bs), 3.47-3.51 (m), 3.60 (bs), 3.63-3.78 (m), 4.14-4.22 (m), 4.50 (d, J= 7.2 Hz), 5.02 (d, J- 4.8 Hz), 7.29 (d, J= 8.0 Hz), 7.49 (d, J= 8.4 Hz). MS (FAB, mnba) lO11.3 (M+H)⁺.

Synthesis of Desclasmose-azithromycin-arylalkyl hvdroxamic acid £38)

A mixture of compound 35 (0.05 g, 0.05 mmol) in 0.25 N HCl (15 mL) was stirred at room temperature for 20 h and poured into EtOAc (20 niL). The two layers were separated and the aqueous layer was washed with EtOAc (2 x 20 mL), basified with concentrated NH4OH and then extracted with 5 % MeOH in CH₂Cl₂ (2 x 30 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over Na₂SO₄. Solvent was evaporated off to give compound 37 which was used for the next reaction without further purification.

To a solution of compound 37 (obtained as described above) in 1:1 THF/MeOH (2 mL) was added hydroxylamine (50 % in H₂O) (0.05 mL_}

0.79 mmol) and a catalytic amount of KCN. The mixture was stirred at room temperature for 24 h. The reaction was partitioned between 5 % MeOH in CH₂CI₂ (30 mL) and saturated brine (20 mL), the two layers were separated and the organic layer was dried over Na₂SO₄. Solvent was evaporated off and the crude was purified by preparative TLC, eluting with CH₂Cl₂/

MeOH/NH₄OH 9:1:0.1 to give compound 38 (7 mg, 16 %) as brown-white solid. ¹H-NMR (CD₃OD, 400MHz) δ 0.78 (m), 0.85 (d, J= 7.2 Hz), 0.91 (d, J= 8.0 Hz), 0.99 (S), 1.11 (m), 1,26-1.76 (m), 1.98 (t, J= 7.4 Hz), 2.08 (m), 2.17 (s), 2.25 (t, J= 7.4 Hz)₅ 2.40 (bs), 2.58 (m), 2.95 (bs), 3.24 (m), 3.37- 3.56 (m), 3.67 (d, J= 13.2 Hz), 4.53 (d, J= 7.6 Hz)_> 7.19 (d, J= 8.4 Hz), 7.39 (d, J= 8.4 Hz). MS (FAB, mnba) 853.3 (M+H)⁺. Example 3. Synthesis of Compounds 40, 44 and 47 in Table 3

Synthesis of Azithromycin-iV-pheiiyltria2:olyϊhepta-2-methyl ketone (40)

Compound 3 (0.040 g, 0.047 mmol) and azido-2-methyl ketone 39 (O.Ollg, 0.071 mmol) were dissolved in anhydrous THF (7 mL) and stirred under argon at room temperature. Copper (I) iodide (0.010 g, 0.053 mmol) and Hunigs' base (0.1 mL) were then added to reaction mixture and stirring continued for 2 h. The reaction mixture was diluted with CHaCl₂ (40 mL) and washed with 1 :4 NH₄OH/saturated NH₄Cl (3 x 30 mL) and saturated NH₄Cl (30 mL). The organic layer was dried over Na₂SC^ and concentrated in vacuo. The crude product was purified by preparative TLC (12:1 CH₂Cl₂: MeOH) to give 38 mg (81%) of 40 as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.86-0.89 (t, J- 7.2 Hz), 0.92-0.98 (m), LOl -1.02 (d, J- 7,2 Hz)₅ 1.086 (s), 1.12-1.24 (m), 1.29-1.34 (m), 1.42-1.66 (m), 1.74-1.78 (d, J = 16 Hz), 1.84-2.08 (m), 2.11 (s), 2.15 (m), 2.26-2.48 (m), 2.56-2.74 (m), 2.84 (s), 2.74-3.08 (m), 3.11 (s), 3.32-3.40 (m), 3.46-3.84 (m), 3.98-4.46 (m), 4.23 (broad singlet), 4.38-4.51 (m), 4.72 (broad singlet), 5.06-5.12 (m), 7.31-7.38 (m), 7.75 (s), 7.77-7.79 (d, J= 8 Hz); HRMS (ESI) calc for [C₅₃H₈₉N₅O₁₃ + H]⁺ 1004.6529, found 1004.6482. Synthesis of Azidobenzamide (43)

A solution of azido acid 41 (0.150 g_} 0.877 mmol) in dry THF (10 mL) was treated with 1 ,2-diaminobenzene 42 (0.568 g, 5.26 mmol) and EDC (0.219 g, 1.14 mmol) . The resulting mixture was stirred at room temperature for about 24 h and then concentrated in vacuo. The crude was diluted with EtOAc (40 mL), washed in succession with water (30 mL) and brine (30 mL) and the organic layer was dried over Na₂SO₄. Solvent was evaporated off and the crude was purified by flash chromatography (silica, Hexanes/ EtOAc 1 :2) to give 79 mg (35%) of 43 as a yellow solid, ¹H NMR (CDCl₃, 400 MHz) δ 1.34-1.68 (m), 2.27-2.31 (m), 3.84 (s), 6.72-6.75 (m), 7.00-7.05 (m), 7.09- 7.11 (d, J = 8 Hz); HRMS (ESI) calcd for [C₁₃H₁₉N₅O + H]⁺ 262.1662, found 262.1635. Synthesis of Azitϊiromycin-N-phenyltriazolylheptabenzamide (44) Compound 3 (0.050 g, 0.059 mmol) and azido benzamide 43 (0.023 g, 0.088 mmol) were dissolved in anhydrous THF (10 niL) and stirred under argon at room temperature. Copper (I) iodide (0.010 g, 0.0526 mmol) and Hunigs' base (0.1 mL) were then added to reaction mixture and stirring continued for 2 h. The reaction mixture was diluted with CH₂CI₂ (40 mL), washed with 1:4 NH₄OH/saturated NH₄Cl (3 x 30 mL) and saturated NH₄Cl (30 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude product is purified by prep TLC (12:1 CH₂Cl₂ZMeOH) to give 38 mg (59%) of 44 as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.80-1.57 (m), 1.70-1.75 (m), 1.85-1.91 (m), 2.01-2.07 (m), 2.13 (s), 2.22* 2.26(m), 2.36-2.41 (m), 2.58 (br s), 2.68 (br s), 2.75-3.07 (m), 3.25-3.62 (m), 3.69 (s), 3.81 (br s), 3.98 (br s), 4.17 (s), 4.32-4.48 (m), 4.72 (br s) 5.05 (s), 6.70-6.76 (m), 6.92-7.02 (m), 7-18-7.21 (d, J= 12 Hz), 7.32 (br s), 7.71-7.73 (d, J = 8 Hz), 7.78 (s). 7.87 (br s); HRMS (ESI) calcd for [C₅₉H₉₅N₇Oi₃ + H]⁺ 1110.7060, found 1110.7012.

Synthesis of Descladinose-clarithromvcin- iV-phenvlacetylens-O- Acetate (45)

Descladinose-clarithromycin- JV-phenylacetylene 21 (3.80 g, 5.5 mmol) was dissolved in acetone (20 ml) followed by addition of acetic anhydride (0.62 g, 6.0 mmol) and stirred at 4O°C for 36 h. The reaction mixture was diluted with EtOAc (100 mL), washed with aqueous NaHCO₃ and brine, and then purified on silica column eluting with 6: 1 CH₂Cl₂/ Acetone to obtain 2.8g (70%) of 45 as a brownish white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.80 (t, J= 7.2 Hz)₉ 0.90 (d, J= 7.2 Hz), 1.08- 1.47 (m), 1.58 (s), 1.63-2.05 (m), 2.08 (s), 2.16 (s), 2.42-2.80 (m), 2.92 (s), 2.94-3.00 (m), 3.03-3.68 (m), 3.79 (s), 3.94 (s), 4.08 (m), 4.54 (d, J= 8.0 Hz), 4.80 (m), 5.15 (dd, J= 11.6, 2.4 Hz), 7.17 (d, J= 8.4 Hz), 7.38 (d, J= 8.0 Hz). Synthesis of clarithromycin- iV-phenylacetylene ketolide (46)

Methyl sulfide (0.35 g, 5.7 mmol), was added to a mixture of JV- chlorosuccinimide (0.65 g, 4.8 mmol) and CH₂Cl₂ (3 mL) while maintaining the temperature at -15°C. Compound 45 (2.5 g₅ 3.4 mmol) dissolved in CH₂Cl₂ (20 mL) was added to the reaction mixture, followed by triethylamine (0.39 g, 3.8 mmol). The mixture was stirred at -15°C for 3.5 h and partitioned between EtOAc (100 mL) and 0.5 N aqueous NaOH (150 mL). The organic layer was separated, washed with brine (70 niL), and dried over Na₂SO₄. Solvent was evaporated off and the crude was purified on silica column eluting with 1:4:0.1 EtOAc/Hexane/EtsN, increasing solvent polarity to 2:3:0.1, to afford 2.0 g (80%) of 46 as off-white solid. ¹H NMR (CDCl₃, 400 MHz) δ 0.80-0.86 (m), 1.09-1.57 (m)₅ 1.58 (s), 1.62-2,02 (m), 2.05 (s), 2.15 (s), 2.44-2.80 (m), 2.92 (s), 2.95-3.00 (pa), 3.05-3.82 (m), 4.Ϊ2 (m), 4.38 (d, J= 8.0 Hz), 4.79-4.83 (m), 5.14 (dd, J= 11.2, 2.0 Hz), 7.16 (d, J= 7.6 Hz)₉ 7.38 (d, J= 7.6 Hz).

Synthesis of Ketolide-N-phenyltriazolylheptabenzamide (47) Ketolide 46 (0.050 g, 0.069 mmol) and azido benzamide 43 (0.027 g, 0.103 mmol) were dissolved in anhydrous THF ( 10 mL) and stirred under argon at room temperature. Copper (I) iodide (0.010 g, 0.0526 mmol) and Hunigs' base (0.1 mL) were then added to reaction mixture and stirring continued for 2 h. The reaction mixture was diluted with CH₂Cl₂ (40 mL) and washed with 1 :4 NH4θH/saturated NH₄Cl (3 x 30 mL) and saturated NH₄Cl (30 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude was purified by prep TLC (3:2 CH₂Cl₂/ Acetone) to give 51 mg (75%) of 47 as a white solid. ¹H NMR (CDCl₃, 400 MHz) θ 0.78-0.88 (m), 1.18-1.25 (m), 1.31-1.70 (m), 1.87-2.00 (m), 2.14 (s), 2.28-2.35 (m), 2.42-2.51(m), 2.62-2.75 (m), 3.12 (s), 3.31-3.35 (t, J= 8 Hz)₁ 3.42 (s), 3,47 (br s), 3.62-3.82 (m), 4.32-4.40 (m), 5.05-5.09 (d, J= 16 Hz), 5.44 (s), 5.77 (s), 6.64-6.74 (m), 6.95-7.00 (m), 7.10-7.15 (m), 7.18-7.21 (m), 7.27-7.31 (m), 7.60 (s) 7.72-7.74 (d, J= 8 Hz), 7.77 (s).

Example 4. Anii-HDAC activity of nonpeptide πaacrocycHc HDAC inhibitors Inhibition of HeLa nuclear extract HDAC 1 /2 and HDAC8 by compounds 7-14, 23-30, 36, and 38 was evaluated in a Fluor de Lys assay according to the manufacture's protocol. Each ΪC₅₀ value was obtained by averaging three independent experiments. This data is shown in Table 4. The compounds displayed both linker-length and macrolϊde-type dependent HDAC inhibition activities with IC₅₀ in low nanomolar range. Table 4. Inhibitory activity of HDAC inhibitors

Example 4. Evaluating in vitro anti-cancer activity of HDAC inhibitors

The potency of compounds in Table 5 were investigated by determining the drug concentrations necessary for 50 % inhibition of cell viability (IC₅₀) in SKMES 1 , NCI-H69, DU 145 cells, lung fibroblasts, and HMEC. Drug concentrations necessary for 50 % inhibition of cell viability (ECso) were quantitatively measured using trypan blue exclusion according to literature protocol (Mosmann, T. (1983) J. Immunol Methods 65: 55; Chen et al (2008) Bioorg. Med. Chem, 16: 4839). Table 5 shows the EC≤₀ values for each compound. All compounds inhibit the proliferation of the transformed cells studied with EC₅₀ in low micromolar range. Most importantly, these compounds are less toxic to untransformed cell-lines (lung fibroblast and HMEC) that we have studied to date. Table 5. Cell growth inhibitory data

Claims

I claim:

1. A compound of Formula I or II :

wherein M represents a macrolide subunit, n is a C i-₆ group, optionally containing one or more heteroatoms, wherein the carbon atoms and/or heteroatoms are in a linear and/or cyclic arrangement,

D is an alkyl or aryl group,

A is a linking group connected to D,

B is an alkyl, alkylaryl or alkylheteroaryl spacer group,

ZBG is a Zinc Binding Group,

R], Kz and R₄ are independently selected from the group consisting of hydrogen, a Cl -6 alkyl group, a C_2-6 alkenyl group, a Oι-_d alkynyi group, a C 1-₆ alkanoate group, a C_2-6 carbamate group, a C₂^ carbonate group, a C_2-6 carbamate group, or a C₂.₆ thiocarbamate group,

R₃ is hydrogen or -ORs,

Rs is selected from the group consisting of hydrogen, a C_\.(, alkyl hgroup, a C_2-6 alkenyl group, a C_2-6 alkynyi group, a C_1-e alkanoate group, a C_2-6 carbamate group, a C_2-6 carbonate group, a C_2-6 carbamate group, or a C_2-6 thiocarbamate group.

2. The compound of claim 1 , wherein the macrolide subunit is a multi- member lactonic ring structure.

3. The compound of claim 2, wherein the multi-member lactonic ring structure is selected from the group consisting of the compounds in Table 1.

4. The compound of claim 2, wherein the multi-member lactonic ring structure is selected from the group consisting of the compounds in Table 2.

5. The compound of any one of claims 1 to 4, wherein Rj-R-3 is hydrogen.

6. The compound of any one of claims 1-5, wherein n is 1, 2, or 3.

7. The compound of any one of claims 1-6, wherein D is a phenyl, biphenyl, or naphthyl group.

8. The compound of any one of claims 1 -7, wherein A is an amide or 1,2,3-triazolyl group.

9. The compound of any one of claims 1 -8, wherein B is an alkyl group having from 4-6 carbon atoms.

10. The compound of any one of claims 1 -9, wherein the zinc binding group is selected from the group consisting of hydroxamate and N-formyl hydroxylamine.

11. The compound of any one of claims 1-10 selected from the group consisting of the compounds in Table 3.

12. The compound of claim 11 , wherein the compound is azithromycin- arylalkyltriazolyl hydroxamate or clarithromycin-arylalkyltriazolyl hydroxamate.

13. The compound of claim 11 , wherein the compound is desclasmoseazithromycin-arylalkyltriazolyl hydroxamate or desclasinoseclarithromycin-ary lalkyltriazolyl hydroxamate .

14. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1-13 in combination with a pharmaceutically acceptable diluent, excipient, or carrier.

15. The composition of claim 14, wherein the composition is administered enterally,

16. The composition of claim 14, wherein the composition is administered parenterally.

17. The composition of claim 14 , wherein the composition is formulated for immediate release, modified release, and combinations thereof.

18. The composition of claim 17, wherein the formulation is selected from the group consisting of delayed release, extended release, pulsatile release, and combinations thereof.

19. A method of treating a disease or disorder in a human or animal comprising administering an effective amount of a compound of any one of claims 1-13.

20. The method of claim 19 wherein the disease or disorder to be treated is selected from the group consisting of cancer, inflammation, infections, and cognitive disorders.

21. The method of claim 20, wherein the disease or disorder to be treated is cancer,

22. The method of claim 21 , wherein the cancer is selected from the group consisting of lung cancer, myeloma, leukemia, lymphoma, breast cancer, prostate cancer, pancreatic cancer, cervical cancer, ovarian cancer, and liver cancer.

23. The method of claim 19 wherein the compound is administered enterally.

24. The method of claim 23, wherein the compound is formulated in a solid oral dosage form selected from the group consisting of tablets, capsules, dragees, and caplets.

25. The method of claim 23, wherein the compound is formulated in a liquid oral dosage form selected from the group consisting of solutions, suspensions, and syrups.

26. The method of claim 19, wherein the compound is administered parenterally.