MA CROLIDE COMPOUNDS AND METHODS OF MAKING AND USING THE SAME

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. Patent Application No. 60/904,355, filed February 28, 2007, U.S. Patent Application No. 60/904,396, filed February 28, 2007, U.S. Patent Application No. 60/904,392, filed February 28, 2007, U.S. Patent Application No. 60/904,351, filed February 28, 2007, and U.S. Patent Application No. 60/904,395, filed February 28, 2007, the disclosure of each is incorporated by reference herein.

FIELD OF THE INVENTION The present invention relates generally to the field of anti-infective, anti -proliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family of cycloalkyl containing macrocyclic compounds that are useful as such agents.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the 1940s, many new compounds have been discovered or specifically designed for use as antibiotic agents. It was once believed that infectious diseases could be completely controlled or eradicated with the use of such therapeutic agents. However, such beliefs have been shaken because strains of cells or microorganisms resistant to currently effective therapeutic agents continue to evolve. In fact, virtually every antibiotic agent developed for clinical use has ultimately encountered problems with the emergence of resistant bacteria. For example, resistant strains of Gram-positive bacteria such as methicillin-resistant staphylococci, penicillin-resistant streptococci, and vancomycin-resistant enterococci have developed. These resistant bacteria can cause serious and even fatal results for patients infected with such resistant bacteria. Bacteria that are resistant to macrolide antibiotics have emerged. Also, resistant strains of Gram-negative bacteria such as H. influenzae and M. catarrhalis have been identified. See, e.g., F.D. Lowry, "Antimicrobial Resistance: The Example of Staphylococcus aureus " J. CHn. Invest, vol. 111, no. 9, pp. 1265-1273 (2003); and Gold, H.S. and Moellering, R.C., Jr., "Antimicrobial-Drug Resistance," N. Engl. J. Med., vol. 335, pp. 1445-53 (1996).

The problem of resistance is not limited to the area of anti-infective agents. Resistance has also been encountered with anti-proliferative agents used in cancer

chemotherapy. Therefore, the need exists for new anti-infective and antiproliferative agents that are both effective against resistant bacteria and resistant strains of cancer cells.

Despite the problem of increasing antibiotic resistance, no new major classes of antibiotics have been developed for clinical use since the approval in the United States in 2000 of the oxazolidinone ring-containing antibiotic, linezolid, which is sold under the trade name Zyvox ^® . See, R.C. Moellering, Jr., "Linezolid: The First Oxazolidinone Antimicrobial," Annals of Internal Medicine, vol. 138, no. 2, pp. 135-142 (2003). Linezolid was approved for use as an anti-bacterial agent active against Gram-positive organisms. However, linezolid-resistant strains of organisms are already being reported. See, Tsiodras et ah, Lancet, vol. 358, p. 207 (2001); Gonzales et al., Lancet, vol 357, p. 1179 (2001); Zurenko et al., Proceedings Of The 3& ^h Annual Interscience Conference On Antibacterial Agents And Chemotherapy (ICAAC), San Francisco, CA, USA (September 26-29, 1999).

Another class of antibiotics is the macrolides, so named for their characteristic 14- to 16-membered ring. The macrolides also often have one or more 6-membered sugar-derived rings attached to the main macrolide ring. The first macrolide antibiotic to be developed was erythromycin, which was isolated from a soil sample from the Philippines in 1952. Even though erythromycin has been one of the most widely prescribed antibiotics, its disadvantages are relatively low bioavailability, gastrointestinal side effects, and a limited spectrum of activity. Another macrolide is the compound, azithromycin, which is an azolide derivative of erythromycin incorporating a methyl-substituted nitrogen in the macrolide ring.

Azithromycin is sold under the trade name Zithromax ^® . A more recently introduced macrolide is telithromycin, which is sold under the trade name Ketek ^® . Telithromycin is a semisynthetic macrolide in which a hydroxyl group of the macrolide ring has been oxidized to a ketone group. See Yong-Ji Wu, Highlights of Semi-synthetic Developments from Erythromycin A, Current Pharm. Design, vol. 6, pp. 181-223 (2000); Yong-Ji Wu and Wei- uo Su, Recent Developments on Ketolides and Macrolides, Curr. Med. Chem., vol. 8, no. 14, pp. 1727-1758 (2001); and. Pal, Sarbani, "A Journey Across the Sequential Development of Macrolides and Ketolides Related to Erythromycin, Tetrahedron 62 (2006) 3171-3200.

In the search for new therapeutic agents, researchers have tried combining or linking various portions of antibiotic molecules to create multifunctional or hybrid compounds Other researches have tried making macrolide derivatives by adding further substituents to the large macrolide ring or associated sugar rings. However, this approach for making macrolide derivatives has also met with limited success.

Notwithstanding the foregoing, there is an ongoing need for new anti-infective and antiproliferative agents. Furthermore, because many anti-infective and antiproliferative agents have utility as anti-inflammatory agents and prokinetic agents, there is also an ongoing need for new compounds useful as anti-inflammatory and prokinetic agents. The present invention provides compounds that meet these needs.

SUMMARY OF THE INVENTION

The invention provides compounds useful as anti-infective agents and/or antiproliferative agents, for example, anti-biotic agents, anti-microbial agents, anti-bacterial agents, anti-fungal agents, anti-parasitic agents, anti-viral agents, anti-diarrheal agents, and chemotherapeutic agents. The present invention also provides compounds useful as antiinflammatory agents, and/or prokinetic (gastrointestinal modulatory) agents. The present invention also provides pharmaceutically acceptable salts, esters, N-oxides, or prodrugs of these compounds.

The present invention provides cycloalkyl containing macrolide compounds having the structure:

or a stereoisomer, pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In the formula, variables A, B, C, D, T, R ¹ , R ² , and R ³ can be selected from the respective groups of chemical moieties later defined in the detailed description.

In addition, the invention provides methods of synthesizing the foregoing compounds. Following synthesis, a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a mammal, particularly humans, for use as an anti-cancer, anti-biotic, anti-microbial, anti-bacterial, antifungal, anti-parasitic, anti-diarrheal, or anti-viral agent, or to treat a proliferative disease, an inflammatory disease or a gastrointestinal motility disorder, or to suppress disease states or conditions caused or mediated by nonsense or missense mutations. In certain embodiments,

the compounds of the present invention are useful for treating, preventing, or reducing the risk of microbial infections or for the manufacture of a medicament for treating, preventing, or reducing the risk of microbial infections. Accordingly, the compounds or the formulations can be administered, for example, via oral, parenteral, otic, ophthalmic, nasal, or topical routes, to provide an effective amount of the compound to the mammal.

The foregoing and other aspects and embodiments of the invention can be more fully understood by reference to the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used as anti- proliferative agents and/or anti-infective agents. The compounds can be used without limitation, for example, as anti-cancer, anti-microbial, anti-bacterial, anti-fungal, antiparasitic and/or anti-viral agents. Further, the present invention provides a family of compounds that can be used without limitation as anti-inflammatory agents, for example, for use in treating chronic inflammatory airway diseases, and/or as prokinetic agents, for example, for use in treating gastrointestinal motility disorders such as gastroesophageal reflux disease, gastroparesis (diabetic and post surgical), irritable bowel syndrome, and constipation. Further, the compounds can be used to treat or prevent a disease state in a mammal caused or mediated by a nonsense or missense mutation. Further, the present invention provides a family of compounds that can be used without limitation as anti-diarrheal agents. The compounds described herein can have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described

compounds are also considered to be part of the present invention. Furthermore, the invention also includes metabolites of the compounds described herein.

1. Definitions

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, OrN=N). The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with one or more R ² moieties, then the group can optionally be substituted with one, two, three, four, five, or more R ² moieties, and R ² at each occurrence is selected independently from the definition of R ² . Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

A chemical structure showing a dotted line representation for a chemical bond indicates that the bond is optionally present. For example, a dotted line drawn next to a solid single bond indicates that the bond can be either a single bond or a double bond.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent can be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. In cases wherein there are nitrogens atoms in the compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of the present invention. Thus, shown

and claimed nitrogens are considered to cover both the shown nitrogen and its N-oxide (N-»O) derivative, as appropriate.

As used herein, the term "anomeric carbon" means the acetal carbon of a glycoside. As used herein, the term "glycoside" is a cyclic acetal. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C _1-6 alkyl is intended to include Ci, C ₂ , C3, C4, C5, and C ₆ alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and n-octyl. As used herein, "alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that can occur in any stable point along the chain, such as ethenyl and propenyl. C ₂ - ₆ alkenyl is intended to include C ₂ , C ₃ , C4, C5, and C ₆ alkenyl groups.

As used herein, "alkynyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that can occur in any stable point along the chain, such as ethynyl and propynyl. C _2-6 alkynyl is intended to include C ₂ , C ₃ , C ₄ , C5, and C ₆ alkynyl groups.

Furthermore, "alkyl", "alkenyl", and "alkynyl" are intended to include moieties which are diradicals, i.e., having two points of attachment, an example of which in the present invention is when D is selected from these chemical groups. A nonlimiting example of such an alkyl moiety that is a diradical is -CH ₂ CH ₂ -, i.e., a C2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule.

As used herein, the terms used to describe various carbon-containing moieties, including, for example, "alkyl," "alkenyl," "alkynyl," "phenyl," and any variations thereof, are intended to include univalent, bivalent, or multivalent species. For example, "Ci _-6 alkyl- R ³ " is intended to represent a univalent C _1-6 alkyl group substituted with a R ³ group, and "O- Cj _-6 alkyl-R ³ " is intended to represent a bivalent Cμ ₆ alkyl group, i.e., an "alkylene" group, substituted with an oxygen atom and a R ³ group.

As used herein, "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C ₃ . ₈ cycloalkyl is intended to include C ₃ , C ₄ , Cs, C ₆ , C ₇ , and Cs cycloalkyl groups.

As used herein, "unsaturated" refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds.

As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo substituents.

"Counterion" is used to mean a positively or negatively charged species present in conjunction with an ion of opposite charge. A nonlimiting example of a counterion is an ion or ions present to counterbalance the charge or charges on an organic compound. Nonlimiting examples of counterions include chloride, bromide, hydroxide, acetate, sulfate, and ammonium.

As used herein, "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -C _V F _W where v = 1 to 3 and w = 1 to (2v+l)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

As used herein, "alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C _1-6 alkoxy, is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C5, and C ₆ alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

As used herein, "alkylthio" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an sulfur bridge. Ci _-6 alkylthio, is intended to include Ci, C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkylthio groups.

As used herein, "carbocycle" or "carbocyclic ring" is intended to mean, unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, any of which can be saturated, unsaturated (including partially and fully unsaturated), or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.

Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) and spiro rings are also included. As used herein, the term "heterocycle" means, unless otherwise stated, a stable 3, 4, 5,

6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, which is saturated, unsaturated (including partially and fully unsaturated), or aromatic, and consists of carbon atoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur, and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused or attached to a second ring (e.g., a benzene ring). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N— >O and S(O) _P , where p = 1 or 2). When a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (i.e., a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle can optionally be quaternized. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Spiro and fused rings are also included.

As used herein, the term "aromatic heterocycle" or "heteroaryl" is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring, which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic (e.g., 2,3- dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N-→O and S(O) _P , where p = 1 or 2).

In certain compounds, the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridmyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztiiazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-£]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3η-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, moφholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1 ,2,5-thiadiazinyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1 ,2,3-triazolyl, 1,2,4-triazolyl, 1 ,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

As used herein, the phrase "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, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. 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. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and

organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that 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, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).

Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

As used herein, "treating" or "treatment" includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. "Treating" or "treatment" of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e., arresting its development or its clinical symptoms; and/or (b) relieving the disease-state, i.e., causing regression of the disease state.

As used herein, "preventing" means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.

As used herein, "mammal" refers to human and non-human patients. As used herein, the term "therapeutically effective amount" refers to a compound, or a combination of compounds, of the present invention present in or on a recipient in an amount sufficient to elicit biological activity, for example, anti-microbial activity, anti-fungal activity, anti-viral activity, anti-parasitic activity, anti-diarrheal activity, and/or antiproliferative activity. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiproliferative and/or anti-infective effect, or some other beneficial effect of the combination compared with the individual components.

All percentages and ratios used herein, unless otherwise indicated, are by weight. Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present invention also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

2. Compounds of the Invention

In one aspect, the invention relates to a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein

A and C are independently selected from the group consisting of (a) -Ci_ _δ alkyl-, (b) - C ₂ - ₆ alkenyl-, and (c) -C ₂ -6 alkynyl-, wherein any of the aliphatic carbons atoms in (a), (b) or (c) are optionally replaced with (d) -(C=O)-, (e) -O-, (f) -S-, or (g) -NR ⁴ -, and wherein any of (a), (b), or (c), are optionally further substituted with (h) -OH, (i) -N(R ⁴ ) ₂ , or (j) halogen; B is selected from (a) -cyclopropyl- and (b) -cyclobutyl-; D is selected from (a) G and (b)

G is selected from: (a) -B' and (b) -B'-Z-B", wherein i) each B' is independently selected from (aa) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings and (bb) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 rings and containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (aa) or (bb) optionally contains one or more carbonyl groups, and wherein each (aa) or (bb) optionally is substituted with one or more R ¹¹ or R ^{1 la} ; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc)

-OR ⁹ , (dd) -SH, (ee) -S(O) ₁₅ R ⁹ , (ff) halogen, (gg) -CN, (hh)-N ₃ ,

(ii) -NO ₂ , Oj) -Si(R ¹³ ) ₃ , (kk) -SO ₃ H, (11) -SO ₃ N(R ⁴ ) ₂ , (mm) - SO ₃ R ⁹ , (nn) -NR ⁶ R ⁶ , (oo) -C(O)R ⁹ , (pp) -C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (qq) -OC(0)(CR ⁶ R ⁶ ) _t R ⁹ , (IT) -C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (ss) - NR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (tt) -NR ⁶ C(O)(CR ⁶ R ⁶ )tR ⁹ , (uu) -C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (w) -NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ ,

(ww) -C(=NR ⁶ )(CR ⁶ R ⁶ )tR ⁹ , (xx) -C(=NR ⁶ )NR ⁶ )(CR ⁶ R ⁶ )tR ⁹ , (yy) -NR ⁶ C(=NR ⁶ )NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (zz) -S(CR ⁶ R ⁶ ) _t R ⁹ , (aaa) -S(O) _p (CR ⁶ R ⁶ )tR ⁹ , (bbb) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings, (ccc) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 rings and containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (ddd) -C us alkyl, (eee) -C _2-6 alkenyl, and (fff) a C ₂ -6 alkynyl group; wherein each (bbb) or (ccc) optionally contains one or more carbonyl groups, and wherein each (bbb) or (ccc) optionally is substituted with one or more R ¹ ' or R ^Ua ; wherein each (ddd), (eee), or (fff) is optionally are substituted with one or more R ¹⁴ groups; (iii) Z is selected from (a) a single bond, (b) -Ci- ₆ alkyl-, (c) -C ₂ - ₆ alkenyl-, (d) -C _2-6 alkynyl-, (e) -O-, (f) -NR ⁴ -, (g) -S(O) _P -, (h) -

C(O)-, (0 -C(O)O-, O) -OC(O)-, (k) -OC(O)O-, (i) -

C(O)NR ⁴ -, (m) -NR ⁴ CO-, (n) -NR ⁴ C(O)NR ⁴ -, (o) -C(=NR ⁴ )-, (P) - C(=NR ⁴ )O-, (r) -C(=NR ⁴ )NR ⁴ -, (s) - NR ⁴ C(=NR ⁴ H (t) -C(=S)-, (u) -C(=S)NR ⁴ -, (v) -NR ⁴ C(=SK (w) -C(O)S-, (x) -SC(OK (y) -OC(=S)-, and (z) -C(=S)-O-, wherein any of the aliphatic carbons atoms in (b), (c), or (d) are optionally replaced with -(C=O)-, -0-, -S-, or-NR ⁴ -, and wherein any of (b), (c), or (d), are optionally further substituted with -OH, -NR ⁴ -, or halogen; T is a 14- or 15-membered macrolide connected via a macrocyclic ring carbon atom;

X is selected from (a) H, (b) halogen, (c) a Ci_δ alkyl group, (d) a C ₂ -6 alkenyl group, (e) a C _2-6 alkynyl group, (f) -OH, (g) -OR ⁵ , (h) -NR ⁴ R ⁴ , (i) -C(O)R ⁵ , (j) -C(O)OR ⁵ , (k) - C(O)-NR ⁴ R ⁴ , (1) -C(S)R ⁵ , (m) -C(S)OR ⁵ , (n) -C(O)SR ⁵ , (o) -C(S)-NR ⁴ R ⁴ , (p) -N ₃ , (q) -CN,

(r) -CF ₃ , (s) -CF ₂ H, (t) -CFH ₂ , (u) -S(O)pH, (v) -SR ⁵ , (w) -S(O) _P OH, (x) -S(O) _P OR ⁵ , (y) - S(O) _p NR ⁴ R ⁴ , (z) -S(O) _p Ci- ₆ alkyl, (aa) -S(O) _p aτyl, (bb) a C _3-7 saturated, unsaturated, or aromatic carbocycle, and (cc) a 3-7 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur; R ^a and R ^b independently are selected from: (a) -H, (b) -Ci _-6 alkyl, (c) -C _2-6 alkenyl, (d)

-C _2-6 alkynyl, (e) -OH, (f) -OR ⁵ , (g) -NR ⁴ R ⁴ , (h) -C(O)R ⁵ , (i) -C(O)OR ⁵ , (j) -C(O)-NR ⁴ R ⁴ , (k) -C(S)pR ⁵ , (1) -C(S) _P OR ^S , (m) -C(O)SR ⁵ , (n) -C(S) _P -NR ⁴ R ⁴ , (o) halogen, (p) -SH, and (q) - SR ⁵ ; or alternatively R ^a and R ^b are taken together with the carbon to which they are attached to form (a) -C(O)-, (b) -C(=S)-, (c) -C=NR ⁴ -, or (d) -C=NOR ⁵ -, wherein (b) -(d) are further optionally substituted with one or more R ⁵ groups;

R ^c is selected from: (a) H, (b) -Ci _-6 alkyl, (c) -C2-5 alkenyl, (d) -C _2-6 alkynyl, (e) -OR ⁵ , wherein R ⁵ is not H, (f) -NR ⁴ R ⁴ , (g) -C(=O)R ⁵ , (h) -C(=O)OR ⁵ , (i) -C(=O)-NR ⁴ R ⁴ , (j) - S(O) _P NR ⁴ R ⁴ , (k) -C(O)SR ⁵ , (1) -S(O)pH, and (m) - S(O) _P R ⁵ , wherein (b) -<d) are further optionally substituted with one or more R ⁵ groups;

R ^d and R ^e independently are selected from: (a) H, (b) -Ci _-6 alkyl, (c) -C _2-6 alkenyl, (d) -C ₂ -6 alkynyl, (e) -OH, (f) -OR ⁵ , (g) -NR ⁴ R ⁴ , (h) -C(O)R ⁵ , (i) -C(O)OR ⁵ , (j) -C(O)-NR ⁴ R ⁴ , (k) -C(S)R ⁵ , (1) -C(S)OR ⁵ , (m) -C(O)SR ⁵ , (n) -C(S)-NR ⁴ R ⁴ , and (o) halogen, or alternatively, R ^c and R or R ^c and R ^e are taken together to form a carbon-carbon double bond between the carbon atoms to which they are attached; alternatively R ^d and X are taken together to form =CR ⁵ R ⁵ ; or alternatively R ^d and R ^e are taken together with the carbon to which they are attached to form (a) -C(O)-, (b) -C(S)-, (c) -C=NR ⁴ , (d) -C=NOR ⁵ , (e) =CH ₂₎ or (f) 3-12-membered carbocycle or heterocycle optionally substituted with one or more R ⁵ groups; R ¹ and R ³ independently are selected from: (a) -H, (b) -Ci-6 alkyl, (c) -C _2-6 alkenyl, (d)

-C _2-6 alkynyl, (e) -C(O)R ⁵ , (f) -C(O)OR ⁵ , (g) -C(O)-NR ⁴ R ⁴ , (h) -C(S)R ⁵ , (i) -C(S)OR ⁵ , (j) - C(O)SR ⁵ , and (k) -C(S)-NR ⁴ R ⁴ ; alternatively R ¹ and R ³ are taken together with the oxygen to which R ¹ is attached, the nitrogen to which R ³ is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R ⁵ groups; R ² is hydrogen or -OR ¹² ; R ⁴ , at each occurrence, independently is selected from:

(a) H, (b) a Ci _-6 alkyl group, (c) a C _2-6 alkenyl group, (d) a C ₂ ^ alkynyl group,

(e) a C _6- I ₂ saturated, unsaturated, or aromatic carbocycle, (f) a 3-12 membered

saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfiir, (g) -C(O)-Ci _ ₆ alkyl, (h) -C(O)-C _2-6 alkenyl, (i) -C(O)-C _2-6 alkynyl, (j) -C(O)-C _6-12 saturated, unsaturated, or aromatic carbocycle, (k) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-Ci^ alkyl, (m) - C(O)O-C ₂ -*. alkenyl, (n) -C(O)O-C _2- O alkynyl, (o) -C(O)O-C _6- I ₂ saturated, unsaturated, or aromatic carbocycle, (p) -C(O)O-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and (q) -C(O)NR ⁶ R ⁶ , wherein any of (b)-(p) optionally is substituted with one or more R ⁵ groups, alternatively, NR ⁴ R ⁴ forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R ⁴ groups are bonded, wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R ⁴ groups are bonded, with one or more moieties selected from O, S(0) _p , N, and NR ⁸ ; R ⁵ is selected from:

(a) R ⁷ , (b) a Ci-6 alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, (e) a C ₃ - ₁₂ saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, or alternatively two R ⁵ groups, when present on the same carbon atom can be taken together with the carbon atom to which they are attached to form a spiro 3-6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur; wherein any of (b)-(f) immediately above optionally is substituted with one or more R ⁷ groups; R ⁶ , at each occurrence, independently is selected from:

(a) H, (b) -Ci.6 alkyl, (c) -C _2-6 alkenyl, (d) -C _2-6 alkynyl, (e) a C ₃ - _I2 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally is substituted with one or more moieties selected from:

(aa) an acyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br, (fit) I, (gg) CN, (gg) NO ₂ , (ii) -OR ⁸ ,

(hh) -S(O)pR ⁸ , (ii) -C(O)R ⁸ , (jj) -C(O)OR ⁸ , (kk) -OC(O)R ⁸ , (11) -C(O)NR ⁸ R ⁸ , (mm) -OC(O)NR ⁸ R ⁸ , (nn) -C(=NR ⁸ )R ⁸ ,

(oo) -C(R ⁸ )(R ⁸ )OR ⁸ , (PP) -C(R ⁸ ) ₂ OC(O)R ⁸ , (qq) -C(R ⁸ XOR ⁸ XCH ₂ )(NR ⁸ R ⁸ , (rr) -NR ⁸ R ⁸ , (ss) -NR ⁸ OR ⁸ , (tt) -NR ⁸ C(O)R ⁸ , (uu) -NR ⁸ C(O)OR ⁸ , (w) -NR ⁸ C(O)NR ⁸ R ⁸ , (ww) -NR ⁸ S(O) ₁ R ⁸ , (xx) -C(OR ⁸ )(OR ⁸ )R ⁸ ,

(yy) -C(R ⁸ ) ₂ NR ⁸ R ⁸ , (zz) =NR ⁸ ,

(ab) -C(S)NR ⁸ R ⁸ , (ac) -NR ⁸ C(S)R ⁸ , (ad) -OC(S)NR ⁸ R ⁸ , (ae) -NR ⁸ C(S)OR ⁸ , (af) -NR ⁸ C(S)NR ⁸ R ⁸ , (ag) -SC(O)R ⁸ , (ah) a Ci^ alkyl group, (ai) a C ₂ - ₆ alkenyl group, (aj) a

C _2-O alkynyl group, (ak) a C] _-6 alkoxy group, (al) a C ₁ - ₅ alkylthio group, (am) a Ci- ₆ acyl group, (an) -CF ₃ , (ao) -SCF3 , (ap) a C ₃ - ₁₂ saturated, unsaturated, or aromatic carbocycle, and (aq) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR ⁶ R ⁶ forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R groups are attached wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R ⁶ groups are bonded, with one or more moieties selected from O, S(0) _p , N, and NR ⁸ ; alternatively, CR ⁶ R ⁶ forms a carbonyl group; R ⁷ , at each occurrence, is selected from:

(a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g) -CF ₃ , (h) -CN, (i) -N ₃ (j) -NO ₂ , (k) -NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (1) -OR ⁹ , (m) - S(O)pC(R ⁶ R ⁶ )tR ⁹ , (n) -C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (o) -OC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (p) -

SQOXCR^tR ⁹ , (q) -C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (r) -NR ⁶ C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (s) - C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (t) -C(=NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (u) -C(=NNR ⁶ R ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (v) -C(=NNR ⁶ C(O)R ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (w) -C(=NOR ⁹ )(CR ⁶ R ⁶ ) _t R ⁹ , (x) -

NR ⁶ C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (y) -OC(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (z) -

NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (aa) -NR ⁶ S(O)p(CR ⁶ R ⁶ )tR ⁹ , (bb) - S(O) _p NR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (cc) -NR ⁶ S(O)pNR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (dd) -NR ⁶ R ⁶ , (ee) - NR ⁶ (CR ⁶ R ⁶ ), (ff) -OH, (gg) -NR ⁶ R ⁶ , (Wi)-OCH ₃ , (ii) -S(O) _p R ⁶ , (jj) - NC(O)R ⁶ , (kk) -Si(R ^l3 ) ₃ , (11) a C _1-6 alkyl group, (mm) a C _2-6 alkenyl group,

(nn) a C _2-6 alkynyl group, (oo) -C _3- I ₂ saturated, unsaturated, or aromatic carbocycle, and (pp) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (kk)-{oo) optionally is substituted with one or more R ⁹ groups; alternatively, two R ⁷ groups can form -O(CH ₂ ) _U O-; R ⁸ is selected from:

(a) R ⁵ , (b) H, (be) a Ci _-6 alkyl group, (cd) a C ₂ -6 alkenyl group, (de) a C _2-6 alkynyl group, (ef) a C3_i2 saturated, unsaturated, or aromatic carbocycle,

(fg) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (gh) -C(OK _K alkyl, (hi) -C(O)-C _2-6 alkenyl, (ij) -C(O)-C _2-6 alkynyl, (jk) -C(O)-C _3-I2 saturated, unsaturated, or aromatic carbocycle, and (kl) -C(O)-3- 12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (bc)-(k) optionally is substituted with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO ₂ , (hh) OH, (ii) NH ₂ , (jj) NH(Ci _-6 alkyl), (kk) N(C ₁ ^ alkyl) _2>

(11) a Ci _-6 alkoxy group, (mm) an aryl group, (nn) a substituted aryl group, (00) a heteroaryl group, (pp) a substituted heteroaryl group, and (qq) a Ci _-6 alkyl group optionally substituted with one or more moieties selected from an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, F, Cl, Br, I, CN, NO ₂ ,

CF ₃ , SCF ₃ , and OH; R ⁹ , at each occurrence, independently is selected from:

(a) R ¹⁰ , (b) a -C ₁ ^ alkyl, (c) a -C _2-6 alkenyl, (d) -C ₂ ^ alkynyl, (e) a C _3- I ₂ saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally is substituted with one or more R ¹⁰ groups; R ¹⁰ , at each occurrence, independently is selected from:

(a) H, (b) =0, (c) F, (d) Cl, (e) Br, (f) I, (g) -CF ₃ , (h) ^CN, (i) -NO ₂ , (j) - NR ⁶ R ⁶ , (k) -OR ⁶ , (1) -S(O) _p R ⁶ , (m) -C(O)R ⁶ , (n) -C(O)OR ⁶ , (o) -OC(O)R ⁶ , (p) NR ⁶ C(O)R ⁶ , (q) -C(O)NR ⁶ R ⁶ , (r) -C(=NR ⁶ )R ⁶ , (s) -NR ⁶ C(O)NR ⁶ R ⁶ , (t) -

NR ⁶ S(O)pR ⁶ , (u) -S(O)pNR ⁶ R ⁶ , (v) -NR ⁶ S(O)pNR ⁶ R ⁶ , (w) a C _1-6 alkyl group, (x) -C _2-6 alkenyl, (y) -C _2-6 alkynyl, (z) C ₃ . ₁₂ saturated, unsaturated, or aromatic carbocycle, and (aa) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (w)-(aa) optionally is substituted with one or more moieties selected from R ⁶ , F, Cl, Br, I, CN, NO ₂ , -OR ⁶ , -NH ₂ , - NH(Ci_6 alkyl), -N(Ci_6 alkyl) ₂ , a Ci-β alkoxy group, a Q _-6 alkylthio group, and a C^ acyl group; R ¹ ' and R ^{1 la} at each occurrence, independently is selected from:

(a) -0(O)CH ₃ , (b) -C(O)H, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h) NO _2, (i) OR ⁸ , (j) -S(O) _P R ⁸ , (k) -C(O)R ⁸ , (1) -C(O)OR ⁸ , (m) -OC(O)R ⁸ , (n) - C(O)NR ⁸ R ⁸ , (o) -OC(O)NR ⁸ R ⁸ , (p) -C(=NR ⁸ )R ⁸ , (q) -C(R ⁸ )(R ⁸ )OR ⁸ , (r) - C(R ⁸ ) ₂ OC(O)R ⁸ , (s) -C(R ⁸ )(OR ⁸ )(CH ₂ ),NR ⁸ R ⁸ , (t) -NR ⁸ R ⁸ , (u) -NR ⁸ OR ⁸ , (v) -NR ⁸ C(O)R ⁸ , (w) -NR ⁸ C(O)OR ⁸ , (x) -NR ⁸ C(O)NR ⁸ R ⁸ , (y) -NR ⁸ S(O) _p R ⁸ , (z)

-C(OR ⁸ )(OR ⁸ )R ⁸ , (aa) -C(R ⁸ J ₂ NR ⁸ R ⁸ , (bb) =NR ⁸ , (cc) -C(S)NR ⁸ R ⁸ , (dd) - NR ⁸ C(S)R ⁸ , (ee) -OC(S)NR ⁸ R ⁸ , (ff) -NR ⁸ C(S)OR ⁸ , (gg) -NR ⁸ C(S)NR ⁸ R ⁸ , (hh) -SC(O)R ⁸ , (ii) -N ₃ , (jj) -Si(R ¹³ ) ₃ , (kk) NR ⁸ (C=NR ⁸ )R ⁸ , (U) NH(C=NH)NH ₂ , (kkii) a Ci _-6 alkyl group, (lljj) a C _2-6 alkenyl group, (mmkk) a C _2-6 alkynyl group, (nnll) a Ci _-6 alkoxy group, (oomm) a Ci _-6 alkylthio group, (ppnn) a Ci _-6 acyl group, (qqoo) a C ₃ - ₁₂ saturated, unsaturated, or aromatic carbocycle, and (rrpp) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from

nitrogen, oxygen, and sulfur, wherein (kkii)-(mmkk) optionally are substituted with one or more R ⁵ groups; R ¹² is selected from:

(a) H, (b) a C i-6 alkyl group, (c) a C ₂ -6 alkenyl group, (d) a C ₂ -6 alkynyl group, (e) -C(O)R ⁵ , (f) -C(O)OR ⁵ , (g) -C(O)-NR ⁴ R ⁴ , (h) -C(S)R ⁵ , (i) -C(S)OR ⁵ , (j)

-C(O)SR ⁵ , (k) -C(S)-NR ⁴ R ⁴ , (1) a C ₃ -12 saturated, unsaturated, or aromatic carbocycle, (m) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (n) a -(Ci-6 alkyl) -C3-12 saturated, unsaturated, or aromatic carbocycle, and (o) a -(C ₁ - ₅ alkyl)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (a)-(d) and (l)-(o) optionally are substituted with one or more R ⁵ groups; each R ¹³ is independently selected from (a) -Ci^ alkyl and (b) -O-(Ci_ ₆ alkyl):

R ¹⁴ at each occurrence is independently selected from:

(a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO ₂ , (h) OR ⁸ , (i) -S(O) _P R ⁸ , (j) - C(O)R ⁸ , (k) -C(O)OR ⁸ , (1) -OC(O)R ⁸ , (m) -C(O)NR ⁸ R ⁸ , (n) -OC(O)NR ⁸ R ⁸ , (o) -C(=NR ⁸ )R ⁸ , (P) -C(R ⁸ )(R ⁸ )OR ⁸ , (q) -C(R ⁸ ) ₂ OC(O)R ⁸ , (r) -C(R ⁸ )(OR ⁸ )(CH ₂ ),NR ⁸ R ⁸ , (s) -NR ⁸ R ⁸ , (t) -NR ⁸ OR ⁸ ,

(u) -NR ⁸ C(O)R ⁸ , (v) -NR ⁸ C(O)OR ⁸ , (w) -NR ⁸ C(O)NR ⁸ R ⁸ , (x) -NR ⁸ S(O) _p R ⁸ , (y) -C(OR ⁸ )(OR ⁸ )R ⁸ , (z) -C(R ⁸ ) ₂ NR ⁸ R ⁸ , (aa) -C(S)NR ⁸ R ⁸ , (bb) -NR ⁸ C(S)R ⁸ , (cc) -OC(S)NR ⁸ R ⁸ , (dd) -NR ⁸ C(S)OR ⁸ , (ee) -NR ⁸ C(S)NR ⁸ R ⁸ , (ff) -SC(O)R ⁸ , (gg) -N ₃ , (hh) -Si(R ¹³ ) ₃ , (ii) a Q _-6 alkyl group, (jj) a C ₂ ^ alkenyl group, (kk) a C ₂ - ₅ alkynyl group, (11) a C _3-I2 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (ii)-(mm) optionally are substituted with one or more R ⁵ groups; alternatively two R ¹⁴ groups are taken together to form (a) =O, (b) =S, (c)

=NR ⁸ , or (d) =N0R ⁸ ; p at each occurrence is O, 1, or 2; t at each occurrence is O, 1, or 2; and u at each occurrence is 1, 2, 3, or 4.

Wherein the cycloalkyl containing macrolide compound does not include the following compound:

In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or pro-drug thereof, wherein G is selected from G1-G50:

G43 G 44

G47 G 48

G49 GSO

In other embodiments, the present invention relates to a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A, B, C, D, T, R ¹ , R ² , and R ³ are as described herein.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A and C are independently -Ci . ₆ alkyl-, wherein any of the aliphatic carbons atoms is optionally replaced with -(C=O)-, -O-, -S-, or -NR ⁴ -, and wherein the Ci-6 alkyl group is optionally further substituted with -OH, -N(R ⁴ ) ₂ , or halogen.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A is -Ci . ₆ alkyl- and C is selected from (a) -Ci -β alkyl-, wherein any of the aliphatic carbons atoms is optionally replaced with -(C=O)-,-O-,-S-, or-νR ⁴ -, and wherein the Ci-« alkyl group is optionally further substituted with -OH, - ν(R ⁴ ) ₂ , or halogen.

In other embodiments, the present invention relates to a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein A, D, T, R ¹ ,

R ² , and R ³ are as described herein.

In other embodiments, the present invention relates to a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein D, T, R ¹ , R ² , and R ³ are as described herein.

In other embodiments, the present invention relates to a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein D, T, R , R , and R are as described herein.

In other embodiments, the present invention relates to a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R ¹ , R ² , and R ³ are as described herein.

In other embodiments, the present invention relates to a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R ¹ , R ² , R ³ , R\ R ^b , R ^c , R ^d , R ^e , and X are as described herein.

In other embodiments, the present invention relates to a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R ¹ , R ² , R ³ , R ^a , R ^b , R ^c , R ^d , R ^e , and X are as described herein.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester N-oxide, or prodrug thereof, wherein X is selected from the group consisting of (a) H, (b) F, (c) -OH, (d) -O(C i - ₆ alkyl), (e) -S(C _I-6 alkyl), and (f) -SH.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from F, OH, and alkyl).

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is F.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is -0(Ci-^ alkyl).

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is -OCH ₃ . In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^d and R ^e are independently selected from (a) Cl, (b) Br, (c) F, (d) H and (e) Ci-6 alkyl.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^d and R ^e are H. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^c is selected from (a) H, (b) Ci _-6 alkyl, (c) -CF ₃ , (d) -CF ₂ H, and (e) -CFH ₂ .

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^c is H. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^a and R ^b are selected from H, F, OH, and -0(Ci _-6 alkyl).

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^a is H and R ^b is F.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^a is H and R ^b is -OH.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^a is H and R ^b is -0(C ₁ ^ alkyl).

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^a is H and R ^b

Js -OCH ₃ .

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N- •oxide, or prodrug thereof, wherein R ^a is H and R ^b is H.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N- ■oxide, or prodrug thereof, wherein G is B'.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein G is -B'-Z-B".

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, ν- ■oxide, or prodrug thereof, wherein T is:

wherein:

M is selected from:

(a) -C(O)-, (b) -CH(-OR ^U4 )-. Cc) -NR ¹¹⁴ -CH ₂ - (d) -CH ₂ -NR ¹¹⁴ -, (e) - CH(NR ¹¹⁴ R ¹¹ V. (f) -CC=NNR ¹¹⁴ R ¹¹ V Cg) -NR ¹ '"-C(O)-, Ch) -CCO)NR ¹¹⁴ -, (i) -CC=NR ¹¹ V 0) -CR ¹¹⁵ R ¹¹⁵ -, and (k) -C(=NOR ¹² V

R ¹⁰⁰ is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR ¹¹⁴ , and (f) Ci _-6 alkyl, wherein

(f) optionally is substituted with one or more R ¹¹⁵ groups;

R ¹⁰¹ is selected from:

(a) H, (b) Cl, (c) F, (d) Br, (e) I, (f) -NR ¹¹⁴ R ¹¹⁴ , (g) -NR ¹¹⁴ C(O)R ¹¹⁴ , (h) - OR ¹¹⁴ , CO -OC(O)R ¹¹⁴ , O) -OC(O)OR ¹¹⁴ , (k) -OC(O)NR ¹¹⁴ R ¹¹⁴ , (1) -O-C,- C ₆ alkyl, (m) -OC(O)-Ci _-6 alkyl, (n) -OC(O)O-C _1-6 alkyl, (o) -OC(O)NR ¹¹⁴ - C|- ₆ alkyl, (p) C _w alkyl, (q) C ₂ ^ alkenyl, and (r) C _2-6 alkynyl, wherein any of (1) - (r) optionally is substituted with one or more

R ¹¹⁵ groups;

R , 1 ¹ 0 ^U 2 ^Z i ^• s selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR ¹¹⁴ , and (f) Ci _-6 alkyl, wherein (f) optionally is substituted with one or more R ¹¹⁵ groups;

R ¹⁰³ is selected from:

(a) H, (b) -OR ¹¹⁴ , (c) -O-Ci-6 alkyl-R ¹¹⁵ , (d) -OC(O)R ¹¹⁴ ,

(e) -OC(O)-Ci _-6 alkyl-R ¹¹⁵ , (f) -OC(O)OR ¹¹⁴ , (g) -OC(O)O-C ₆ alkyl-R ¹¹⁵ ,

(h) -OC(O)NR ¹¹⁴ R ¹¹⁴ , (i) -OC(O)NR ^{1 !4} -Ci- ₆ alkyl-R ^11S , and

alternatively, R ¹⁰² and R ¹⁰³ taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R ¹¹⁴ groups; alternatively, R ¹⁰¹ and R ¹⁰³ taken together are a single bond between the respective carbons to which these two groups are attached thereby creating a double bond between the carbons to which R ¹⁰⁰ and R ¹⁰² are attached; alternatively, R ¹⁰¹ and R ¹⁰³ taken together with the carbons to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring, wherein said 3-7 membered ring can optionally be substituted with one or more R ¹¹⁴ groups; alternatively, R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ taken together with the carbons to which they are attached form a 5 or 6 membered fused carbocyclic or heterocyclic ring, wherein said fused ring can be optionally substituted with one or more R ¹¹⁴ groups; R ¹⁰⁴ is selected from: (a) H, (b) R ¹¹⁴ , (c) -C(O)R ¹¹⁴ (d) -C(O)OR ¹¹⁴ (e) -C(O)NR ¹¹⁴ R ¹¹⁴ , (f) -Ci _-6 alkyl-K-R ¹¹⁴ , (g) -C _2-6 alkenyl-K-R ^{1 M} , and (h) -C _2-6 alkynyl-K-R ¹¹⁴ ; K is selected from:

(a) -C(O)-, (b) -C(O)O-, (C) -C(O)NR ¹¹⁴ -, (d) -C(^NR ¹¹⁴ )-, (e) - Cf=NR ¹¹⁴ )O-, (f) -C(=NR ^U4 )NR ¹¹⁴ -, (g) -OC(O)-, (h) -OC(O)O-, (i) - OC(O)NR ¹¹⁴ - O) -NR ¹¹⁴ C(O)-, (k) -NR ¹¹⁴ C(O)O-, (1) -NR ¹¹⁴ C(O)NR ¹¹⁴ -,

(m) -NR ¹¹⁴ C(=NR ^I14 )NR' ^l4 -, and (n) -S(O) _p -; alternatively R ¹⁰³ and R ¹⁰⁴ , taken together with the atoms to which they are bonded, form:

wherein R ¹³⁵ and R ¹³⁶ are selected from (a) hydrogen, (b) Ci _-6 alkyl, (c) C _2-6 alkenyl, (d) C2-6 alkynyl, (d) € ₃ . ₁₂ saturated, unsaturated or aromatic carbocycle, (e) 3-12 membered saturated, unsaturated or aromatic heterocycle containing one or more oxygen, nitrogen, or sulfur atoms, (f) F, (g) Br, (h) I, (i) OH, and (j) -N ₃ , wherein (b) through (e) are optionally substituted with one or more R ¹¹⁷ ; or alternatively, R ^13S and R ¹³⁶ are taken together to form =O, =S, =NR ¹¹⁴ , =N0R ¹¹⁴ , =NR ¹¹⁴ , or =N-NR ¹¹⁴ , R ¹¹⁴ , wherein V is selected from (a) -(Ci- ₄ -alkyl)-, (b)-(C ₂ - ₄ -alkenyl)-, (c) O, (d) S, and (e) NR ¹¹⁴ , wherein (a) and (b) are optionally further substituted with one or more R ¹¹⁷ ; R ¹⁰⁵ is selected from:

(a) R ¹¹⁴ , (b) -OR ¹¹⁴ , (c) -NR ¹¹⁴ R ¹¹⁴ , (d) -O-Ci _-6 alkyl-R ¹¹⁵ , (e) -C(O)-R ¹¹⁴ ,

(f) -C(O)-^ _1-6 alkyl-R , 1"15 ³ , (g) -OC(O)-R 1 ¹ 1 ¹ 4 ⁴ , (h) -OC(O)-C _1-6 alkyl-R , 1 15

(i) -OC(O)O-R . 1"14 ⁴ , (j) -OC(O)CM:^ alkyl-R ^us , (k) -OC(O)NR , 1 ¹ 1 ¹ 4 ⁴ rR, 1 14 alkenyl-R ^{1 [} \ and (n) -C(O)-C _2-6 alkynyl-R 115. alternatively, R , 104 a. nd R , 105 , taken together with the atoms to which they are bonded, form

wherein

Q is CH or N, and R R ¹¹²²⁶⁶ iiss - -OORR ¹¹¹¹⁴⁴ ,, --NNlR ¹¹⁴ or R ¹¹⁴ ; alternatively, R ¹⁰⁴ and R ¹⁰⁵ , taken together with the atoms to which they are bonded, form:

wherein i) R , 149 is selected from:

(a) H, (b) Cl, (C) F, (d) Br, (e) I, (f) -NR ¹¹⁴ R ¹¹⁴ , (g) -NR ¹¹⁴ C(O)R ¹¹⁴ , (h) -OR ¹¹⁴ , (i) - OC(O)R ¹¹⁴ , (j) -OC(O)OR ¹¹⁴ , (k) -OC(O)NR ¹¹⁴ R ¹¹⁴ , (1) -0-C ₁ ^ alkyl, (m) -OC(O)-Ci _-6 alkyl, (n) -OC(O)O-Ci _-6 alkyl, (o) -OC(O)NR ¹¹ ^C _1-6 alkyl, (p) C _-6 alkyl, (q) C _2-6 alkenyl, and (r) C _∑ -β alkynyl, wherein any of (1) - (r) optionally is substituted with one or more R ¹¹⁵ groups; ii) R ¹⁵⁰ is H, Ci- ₆ alkyl, or F; ii) alternately, R ¹⁴⁹ and R ¹⁵⁰ can be taken together with the carbon to which they are attached to form a carbonyl group; iii) alternately, R ¹⁴⁹ and R ¹⁵⁰ can be taken together to form the group -O(CR ¹¹⁶ R ¹¹⁶ ) _U O-; alternatively, R ¹⁰⁴ and R ¹⁰⁵ , taken together with the atoms to which they are bonded, form:

wherein in the preceding structure the dotted line indicates an optional double bond i) R ¹³⁰ is -OH, or R ¹¹⁴ ,

R , 1'3 ^J 1 ϋ) ¹ is -OH, or R 114 iii) alternately, R ¹³⁰ and R ¹³¹ together with the carbons to which they are attached form a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R ^{1 M} groups; iv) alternatively, R ¹³⁰ and the carbon to which it is attached or R ¹³¹ and the carbon to which it is attached are each independently -C(=0)-;

alternatively, R ¹⁰⁵ , R ¹³² and M, taken together with the atoms to which they are attached, form:

R ¹⁰⁶ is selected from:

(a) -OR . 1 ¹ 1 "4 ^* , (b) -Ci _-6 alkoxy-R » 1 ¹ 1 °5, (c) -C(O)R . 1' (d) -OC(O)R ¹¹⁴ , (e) - OC(O)OR ¹¹⁴ , (f) -OC(O)NR ¹¹⁴ R ¹¹⁴ , and (g) -NR ¹¹⁴ R ¹¹⁴ , alternatively, R ¹⁰⁵ and R ¹⁰⁶ taken together with the atoms to which they are attached form a 5-membered ring by attachment to each other through a chemical moiety selected from:

(a) -OC(R ¹¹⁵ ) ₂ O-, (b) -OC(O)O-, (c) -OC(O)NR ¹¹⁴ -, (d) -NR ¹¹⁴ C(O)O-,

, 114 , 114

(e) -OC(O)NOR ¹ ' -, (f) -NOR' "-C(O)O-, (g) -OC(O)N[NR ^{1 14} R ^{1 14} ] -, (h) - N[NR ¹¹⁴ R ¹¹⁴ J-C(O)O-, (i) -OC(O)C(R ¹¹⁵ ) ₂ - G) -C(R ^U5 ) ₂ C(O)O-, (k) -

OC(S)O-, (1) -OC(S)NR , 1 ¹ 1 ¹ 4 ⁴ -, (m) -NR 1 ¹ 1 ¹ 4X, (S)O-, (n) -OC(S)NOR ¹¹⁴ -, (o) -

, 114 , 114, ₅ 114

NOR" ⁴ -C(S)O-, (p) -OC(S)N[NR ^{1 14} R ^{1 14} ]- (q) -N[NR ¹¹⁴ R ^{1 14} J-C(S)O-, (r) -

OC(S)C(R ^{1 1} V. (s) -C(R ¹¹ O ₂ C(S)O-, (t) -OC(O)CR ¹¹⁵ [S(O)pR ¹¹⁴ ] - (u) - 1 H _n I M

OC(O)CR , 1 ¹ 1^5r , [NR ¹¹⁴ R ^{1 14} ] - (v) -CR 1 ¹ 1 ¹ 5 ³ [rNR ¹¹⁴ R ¹¹⁴ ]C(O)O-, and (w) - CR ^{1 15} IS(O) _P R ^{1 14} ]C(0)0-;

alternatively, R , 1OS , r R> 106 , and R .133 . taken together with the atoms to which they are attached form:

alternatively, M, R ¹⁰⁵ , and R ¹⁰⁵ taken together with the atoms to which they are attached form:

wherein J ¹ and J ² are selected from hydrogen, Cl, F, Br, I, OH, -Ci _-6 alkyl, and -0(Ci- ₆ alkyl) or are taken together to form =O, =S, =NR 1'14 , =N0R v 1' 14 , =NR , 1'1 ¹ 4 ⁴ , or =N-NR' ¹⁴ R' alternatively, M and R , 104 taken together with the atoms to which they are attached form:

wherein U is selected from (a) -(Ci- ₄ -alkyl)- and (b)-(C ₂ - ₄ -alkenyl)-, wherein (a) and (b) are optionally further substituted with one or more R ¹¹⁷ ;

. 105 alternatively, M and R are taken together with the atoms to which they are attached to form:

R ¹⁰⁷ is selected from

(a) H, (b) -C 1.6 alkyl, (c) -C2-6 alkenyl, which can be further substituted with Ci-6 alkyl or one or more halogens, (d) -C2-6 alkynyl, which can be further substituted with Ci-^ alkyl or one or more halogens, (e) aryl or heteroaryl, which can be further substituted with C _\ ^ alkyl or one or more halogens, (f) — C(O)H, (g) -COOH, (h) -CN, (i) -COOR ¹¹⁴ , 0) -C(O)NR ¹¹⁴ R ¹¹⁴ , (k) - C(O)R ¹¹⁴ , and (1) -C(O)SR ¹¹⁴ , wherein (b) is further substituted with one or more substituents selected from (aa) -OR ¹¹⁴ , (bb) halogen, (cc) -SR ¹¹⁴ , (dd) Ci- ₆ alkyl, which can be further substituted with halogen, hydroxyl, Ci-ealkoxy, or amino, (ee) -OR ¹¹⁴ , (ff) -SR ¹¹⁴ , (gg) -NR ¹¹⁴ R ¹¹⁴ , (hh) -CN,

, 114

(ii) -NO ₂ , (ij) -NC(O)R ¹¹⁴ , (kk) -COOR" ⁴ , (11) -N ₃ , (mm) =N-O-R ^{1 14} , (nn)

=NR , 1' (00) =N-NR ^{( 14} R ¹¹⁴ , (pp) =N-NH-C(O)R' ¹⁴ , and (qq) =N-NH-

C(O)NR ¹¹⁴ R ^{1 14} ; alternatively R ¹ and R ¹⁰⁷ are taken together with the atom to which they are attached to form an epoxide, a carbonyl, an exocyclic olefin, or a substituted exocyclic olefin, or a C ₃ - C ₇ carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a Ci- ₆ alkyl;

R ¹⁰⁸ is selected from:

(a) Ci-6 alkyl, (b) C2-6 alkenyl, and (c) C ₂ - ₅ alkynyl, wherein any of (a)-(c) optionally is substituted with one or more R ¹¹⁴ groups;

R ¹⁰⁹ is H, C _w alkyl, or F; R ¹¹⁴ , at each occurrence, independently is selected from:

(a) H, (b) Ci _-6 alkyl, (c) C _2-6 alkenyl, (d) C2-6 alkynyl, (e) C3.12 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-C _1-6 alkyl, (h) -C(O)-C ₂ -O alkenyl, (i) -C(O)-C2-5 alkynyl, (j) -C(O)-Cs-I ₂ saturated, unsaturated, or aromatic carbocycle, (k) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-Ci _-6 alkyl, (m) -C(O)O-C _2-6 alkenyl, (n) - C(O)O-C2-6 alkynyl, (o) -C(O)O-C3_i2 saturated, unsaturated, or aromatic carbocycle, (p) -C(O)O-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (q) -C(O)NR ¹¹⁶ R ¹¹⁶ , (r) -NR ¹¹⁶ CO-Ci _-6 alkyl, (s) - NR ¹¹⁶ CO-C _3- I ₂ saturated, unsaturated, or aromatic carbocycle, (t) -NR ¹¹⁶ C(O)- 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (u) -(Cj _-6 alkyl)-O-(C _1-6 alkyl), (v) -(C _1-6 alkyl)-O-(C _1-6 alkyl)-O-(Ci- ₆ alkyl), (w) -OH, (x) -OR ¹¹⁵ , (y) -NH(C _1-6 alkyl), (z) -N(C ₆ alkyl) ₂ , (aa) -(C _1-6 alkyl)-S(O) _p - (C _1-6 alkyl), (bb) -(C _-6 alkyl)- S(O) _P -(C^ alkyl)-S(O) _p -(C _1-6 alkyl), (cc) -(C _N ; alkyl)-O-(C _1-6 311CyI)-S(O) _P -(C ₁ * alkyl), (dd) -(C _1-6 alkyl)- S(O) _p -(C _1-6 alkyl)-O-(C 1 * alkyl), and (ee) -NH ₂ ; wherein the terminal alkyl group in any of (u)-(v) or (aa)-(dd) includes cycloalkyl, wherein any of (b)-(v) or (aa)-(dd) optionally is substituted with one or more R ¹¹⁵ groups, wherein one or more non-terminal carbon moieties of any of (b)-(d) optionally is replaced with oxygen, S(0) _p , or -NR ¹¹⁶ alternatively, NR ¹¹⁴ R ¹¹⁴ forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R ¹¹⁴ groups are bonded and optionally one or more moieties selected from O, S(O) _P , N, and NR ¹¹⁸ ;

R ¹¹⁵ is selected from: (a) R ¹¹⁷ , Qa) Cι-6 alkyl, (c) C _2-6 alkenyl, (d) C ₂ * alkynyl, (e) C _3-12 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -OCi _-6 alkyl, (h) -OC _2-6 alkenyl, and (i) -

OC _2-6 alkynyl,

wherein any of (b)-(f) optionally is substituted with one or more R ¹¹⁷ groups; R ¹¹⁶ , at each occurrence, independently is selected from:

(a) H, (b) Ci _-6 alkyl, (c) C _2-6 alkenyl, (d) C _2-6 alkynyl, (e) C ₃ -I ₂ saturated, unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein one or more non-terminal carbon moieties of any of (b)-(d) optionally is replaced with oxygen, S(O) _P , or -NR ¹¹⁸ , wherein any of (b)- (f) optionally is substituted with one or more moieties selected from:

(aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) N ₃ , (ii) NO ₂ , Gj) OR ¹¹⁸ , (kk) -S(O) _P R ¹¹⁸ , (11) - C(O)R ¹¹⁸ , (mm) -C(O)OR ¹¹⁸ , (nn) -OC(O)R ¹¹⁸ , (oo) - C(O)NR ¹¹⁸ R ¹¹⁸ , (pp) -OC(O)NR ¹¹⁸ R ¹¹⁸ , (qq) -C(=NR ¹¹⁸ )R ¹¹⁸ ,

(rr) -C(R ^I18 )(R ^ll8 )OR ¹¹⁸ , (SS) -C(R ¹¹⁸ ) ₂ OC(O)R ¹¹⁸ , (tt) - C(R ¹¹⁸ XOR ¹¹⁸ XCH ₂ XNR ¹¹⁸ R ¹¹⁸ , (uu) -NR ¹¹⁸ R ¹¹⁸ ; (w) - NR ¹¹⁸ OR ¹¹⁸ , (ww) -NR ¹¹⁸ C(O)R ¹¹⁸ , (xx) -NR ¹¹⁸ C(O)OR ¹¹⁸ , (yy) -NR ¹¹⁸ C(O)NR ¹¹⁸ R ¹¹⁸ , (zz) -NR ¹¹⁸ S(O) ₁ R ¹¹⁸ , (ab) - C(OR ¹¹⁸ XOR ¹¹⁸ )R ¹¹⁸ , (ac) -C(R ¹¹⁸ ) ₂ NR ¹¹⁸ R ¹¹⁸ , (ad) =NR ¹¹⁸ ,

(ae) -C(S)NR ¹¹⁸ R ¹¹⁸ , (af) -NR ¹¹⁸ C(S)R ¹¹⁸ , (ag) - OC(S)NR ¹¹⁸ R ¹¹⁸ , (ah) -NR ¹¹⁸ C(S)OR ¹¹⁸ , (ai) - NR ¹¹⁸ C(S)NR ¹¹⁸ R ¹¹⁸ , (aj) -SC(O)R ¹¹⁸ , (ak) C _1-6 alkyl, (al) C _2-6 alkenyl, (am) C _2-6 alkynyl, (an) Ci _-6 alkoxy, (ao) Ci^ alkylthio, (ap) Ci _-6 acyl, (aq) saturated, unsaturated, or aromatic

C _3-12 carbocycle, and (ar) saturated, unsaturated, or aromatic 3-12 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR ¹¹⁶ R ¹ ' forms a 3- 12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R ¹¹⁶ groups are attached and optionally one or more moieties selected from O, S(0) _p , N, and NR ¹¹⁸ ; alternatively, CR ¹¹⁶ R ¹¹⁶ forms a carbonyl group; R ¹¹⁷ , at each occurrence, is selected from:

(a) H, (b) =0, (c) F, (d) Cl, (e) Br, (f) I, (g) (CR ¹¹⁶ R ^{1 16} ) _r CF ₃ , (h)

(CR ¹¹⁶ R ¹¹⁶ ) _r CN, (i) (CR ¹¹⁶ R ^{1 16} XNO ₂ , (j) (CR ^{1 16} R ^{1 16} )rNR ^{1 16} (CR ¹¹⁶ R ¹¹⁶ ),R ⁿ⁹ ,

(k) (CR ^{1 16} R ^{1 16} XOR ¹¹⁹ , (1) (CR ¹¹⁶ R ¹¹⁶ ) _r S(O) _p (CR' ¹⁶ R ¹¹⁶ ),R ¹¹⁹ ,

(m) (CR ^{I 16} R ^{1 16} ) _r C(O)(CR ¹¹⁶ R ¹¹⁶ ),R ^{1 19} , (n) (CR ¹¹⁶ R ¹¹⁶ XOC(O)(CR ¹¹⁶ R ¹¹⁶ ^R ¹¹⁹ , (o) (CR ¹¹⁶ R ^{1 16} ) _r SC(O)(CR ^{1 16} R ^{1 16} ),R ¹¹⁹ ,

(p) (CR ¹¹⁶ R ^{1 16} ) AO)O(CR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ ,

(q) (CR ¹¹⁶ R ^{1 16} XNR ^{1 16} C(O)(CR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ ,

(γ) (CR ¹¹⁶ R ¹¹⁶ XC(O)NR ^{1 16} (CR' ¹⁶ R ^{1 16} XR ¹¹⁹ , (S)

(CR ¹¹⁶ R ¹¹⁶ XQ=NR ¹¹⁶ XCR ¹¹⁶ R ¹¹⁶ ),R' ¹⁹ , (t) (CR ¹¹⁶ R ¹¹⁶ XC(=NNR ^{I 16} R ¹¹⁶ XCR ¹¹⁶ R ¹¹⁶ ),R ¹¹⁹ ,

(u) (CR ^{1 16} R ^{1 16} XC(=NNR' ¹⁶ C(O)R ¹¹⁶ XCR ¹¹⁶ R ^{1 16} XR ^{1 19} ,

(v) (CR ^{1 16} R ^{1 16} ) _r C(=NOR ¹¹⁹ )(CR' ¹⁶ R ¹¹⁶ ) _t R ^{] 19} ,

(w) (CR ¹¹⁶ R ¹¹⁶ XNR ¹¹⁶ C(O)O(CR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ ,

(x) (CR ¹¹⁶ R ¹¹⁶ XOC(O)NR ¹¹⁶ (CR ^{] 16} R ¹¹⁶ XR ¹¹⁹ , (y) (CR ¹¹⁶ R ^{1 16} XNR ¹¹⁶ C(O)NR ^{1 1} ^CR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ ,

(z) (CR ^{1 16} R ^{1 16} XNR ^{1 16} S(O)p(CR' ¹⁶ R ¹¹⁶ ),R ¹¹⁹ ,

(aa) (CR ¹¹⁶ R ^{1 16} XS(O) _P NR ¹¹⁶ (CR' ¹⁶ R ¹¹⁶ XR ¹¹⁹ ,

(bb) (CR ¹¹⁶ R ¹¹⁶ XNR ¹¹⁶ S(O) _P NR' ¹⁶ (CR' ¹⁶ R ¹¹⁶ XR ¹¹⁹ ,

(cc) (CR ^{1 16} R ¹¹⁶ XNR ¹¹⁶ R ¹¹⁶ , (dd) C _1-6 alkyl, (ee) C _2-6 alkenyl, (ff) C _2-6 alkynyl, (gg) (CR ¹¹⁶ R ¹¹⁶ ) _r -C3-i2 saturated, unsaturated, or aromatic carbocycle, (hh)

(CR ¹¹⁶ R ¹¹⁶ ) _r -3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and (ii) -P(O)(O(C _1-6 alkyl)) ₂ , wherein any of (dd)-(hh) optionally is substituted with one or more R ¹¹⁹ groups; alternatively, two R ¹¹⁷ groups can form -0(CH ₂ ) _u 0-;

11 Jt

R is selected from:

(a) H, (b) Ci _-6 alkyl, (c) C _2-6 alkenyl, (d) C _2-6 alkynyl, (e) C ₃ - ₁₂ saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-Ci-O alkyl, (h) -C(O)-C _2-6 alkenyl, (i) -C(O)-C _2-6 alkynyl, (j) -C(O)-Ca-U saturated, unsaturated, or aromatic carbocycle, and (k) -C(O)-3-12 membered saturated, unsaturated, or aromatic

heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(k) optionally is substituted with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO ₂ , (hh) OH, (ii) NH ₂ , (jj) NH(C _1-6 alkyl), (kk) N(C ₁ * alkyl) ₂ ,

(U) Ci* alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C ₁ * alkyl, optionally substituted with one or more moieties selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO ₂ , and OH; R ¹¹⁹ , at each occurrence, independently is selected from:

(a) R ¹²⁰ , (b) C _1-6 alkyl, (c) C ₂ ^ alkenyl, (d) C _2-5 alkynyl, (e) C _3-I2 saturated, unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally is substituted with one or more R ¹¹⁴ groups; R ¹²⁰ , at each occurrence, independently is selected from:

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR ¹¹⁶ R ¹¹⁶ ) _r CF ₃ , (h) (CR ¹¹⁶ R ¹¹⁶ XCN, (i) (CR ¹¹⁶ R ¹¹⁶ XNO ₂ , (j) (CR ¹¹⁶ R ¹¹⁶ XNR ¹¹⁶ R ¹¹⁶ , (k) (CR ¹¹⁶ R ¹¹⁶ ) _r OR ¹¹⁴ , (1) (CR ¹¹⁶ R ¹¹⁶ ) _r S(O) _p R ¹¹⁶ , (m) (CR ¹¹⁶ R ¹¹⁶ XC(O)R ¹¹⁶ ,

(n) (CR ¹¹⁶ R ¹¹⁶ XC(O)OR ¹¹⁶ , (o) (CR ¹¹⁶ R ^U6 ) _r OC(O)R ¹¹⁶ , (p) (CR ¹¹⁶ R ¹¹⁶ XNR ¹¹⁶ C(O)R ¹¹⁶ , (q) (CR ¹¹⁶ R ¹¹⁶ XC(O)NR ¹¹⁶ R ¹¹⁶ , (r) (CR ¹¹⁶ R ¹¹⁶ XC(=NR ¹¹⁶ )R ¹¹⁶ , (s) (CR ¹¹⁶ R ¹ ^) ₁ NR ^{1 16} C(O)NR ¹¹⁶ R ¹¹⁶ , (t) (CR ¹¹⁶ R ¹¹⁶ XNR ¹¹⁶ S(O) _n R ¹¹⁶ , (u) (CR ¹¹⁶ R ¹¹⁶ ) _r S(O) _p NR ^{I 16} R ¹¹⁶ , (v) (CR ¹¹⁶ R ¹¹⁶ XNR ¹¹⁶ S(O) _p NR ¹¹⁶ R ¹¹⁶ , (w) C _1-6 alkyl, (x) C _2-6 alkenyl, (y)

C _2-6 alkynyl, (z) (CR ¹¹⁶ R ¹¹⁶ ) _r -C3-i ₂ saturated, unsaturated, or aromatic carbocycle, and (aa) (CR ¹¹⁶ R ¹¹⁶ ) _r -3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (w)-(aa) optionally is substituted with one or more moieties selected from R ¹¹⁶ , F, Cl, Br, I, CN, NO ₂ , -OR ¹¹⁶ , -NH ₂ , - NH(Ci* alkyl), -N(Ci* alkyl) ₂ , Ci* alkoxy, Ci* alkylthio, and

Ci* acyl;

R ¹²¹ , at each occurrence, independently is selected from:

(a) H, (b) -OR ¹¹⁸ , (c) -O-Ci^ alkyl-OC(O)R ¹¹⁸ , (d) -O-d-e alkyl- OC(O)OR ¹¹⁸ , (e) -O-Ci^ alkyl-OC(O)NR ¹¹⁸ R ¹¹⁸ , (f) -Ch-C ₁ * alkyl- C(O)NR ¹¹⁸ R ¹¹⁸ , (g) -0-C _1-6 alkyl-NR ¹¹⁸ C(O)R ¹¹⁸ , (h) -O-Ci^ alkyl- NR ¹¹⁸ C(O)OR ¹¹⁸ , (i) -O-C,^ alkyl-NR ¹¹⁸ C(O)NR ¹¹⁸ R ¹¹⁸ , (j) -OCi _-6 alkyl-

NR ¹¹⁸ C(=N(H)NR' ¹⁸ R ¹¹⁸ ), (IC) -O-C,^ alkyl-S(O) _p R ¹¹⁸ , (1) -C-C ₂ * alkenyl- OC(O)R ¹¹⁸ , (m) -O-Cz- ₆ alkenyl-OC(0)0R ¹¹⁸ , (n) -0-C ₂ ^ alkenyl- OC(O)NR ¹¹⁸ R ¹¹⁸ , (o) -0-C _2-6 alkenyl-C(O)NR ¹¹⁸ R ¹¹⁸ , (p) -0-C _2-6 alkenyl- NR ¹¹⁸ C(O)R ¹¹⁸ , (q) -0-C ₂ ^ alkenyl-NR ¹¹⁸ C(O)OR ¹¹⁸ , (r) -0-C ₂ ^ alkenyl- NR ¹¹⁸ C(O)NR ¹¹⁸ R ¹¹⁸ , (s) -0-C _2-6 alkenyl-NR ^U8 C(=N(H)NR ¹¹⁸ R ¹¹⁸ ), (t) -O-

C ₂ ^ alkenyl-S(O)pR ¹¹⁸ , (u) -0-C ₂ ^ alkynyl-OC^R ¹¹⁸ , (v) -0-C ₂ ^ alkynyl- OC(O)OR ¹¹⁸ , (w) -0-C ₂ ^ alkynyl-OC(O)NR ¹¹⁸ R ¹¹⁸ , (x) -0-C ₂ ^ alkynyl- C(O)NR ¹¹⁸ R ¹¹⁸ , (Y) -O-C ₂ ^, alkynyl-NR ¹¹⁸ C(O)R ¹¹⁸ , (z) -O-C _2-6 alkynyl- NR ¹¹⁸ C(O)OR ¹¹⁸ , (aa) -O-C ₂ ^ alkynyl-NR ¹¹⁸ C(O)NR ¹¹⁸ R ¹¹⁸ , (bb) -O-C2-6 alkynyl-NR ¹¹⁸ C(=N(H)NR ¹¹⁸ R ¹¹⁸ ), (cc) -Ch-C ₂ * alkynyl-

S(O)pR ¹¹⁸ , (dd) -NR ¹¹⁸ R ¹¹⁸ , (ee) -C^ alkyl-O-C^ alkyl, (ff) -C _1-6 alkyl- NR ¹ ^-C _1-6 alkyl, (gg) -C ₁ ^ alkyl-S(O) _p -C,^ alkyl, (hh) -OC(O)NR ¹¹⁴ (C^ alkyl)-NR ¹¹⁴ -(Ci^ alkyl) -R ¹¹⁴ , (ii) -OH, (Jj) -Ci _-6 alkyl, (kk) C _2-6 alkenyl, (11) C _2-6 alkynyl, (mm) -CN, (nn) -CH ₂ S(O) _p R ¹³⁷ , (00) -CH ₂ OR ¹³⁷ , (pp) - CH ₂ N(OR ¹³⁸ )R ¹³⁷ , (qq) -CH ₂ NR ¹³⁷ R ¹³⁹ , (rr) -(CH ₂ ) _v (C ₆ -io aiyl), and (ss)-

(CH ₂ ) _v (5-10 membered heteroaryl), wherein (jj)-(ss) are optionally substituted by 1, 2, or 3 R ¹⁴⁰ groups _; alternatively, two R ¹²¹ groups taken together form =O, =NOR ¹¹⁸ , or =NNR ¹¹⁸ R ¹¹⁸ ;

R ¹²⁷ is R ¹¹⁴ , a monosaccharide or a disaccharide (including amino sugars and halogenated sugar(s)), -S(O) _P R ¹⁴⁸ ,

-(CH ₂ ) _n -(O-CH ₂ CH ₂ -) _m -O(CH ₂ ) _n CH ₃ ,

-(CH ₂ ) _n -[S(O) _p -CH ₂ CH ₂ -] _m -S(O) _p (CH ₂ ) _n CH ₃ ,

-<CH ₂ ) _n -[S(O)p-CH ₂ CH ₂ -] _m -OR ¹⁴⁸ , -OCH ₂ -O-(CH ₂ ) _n -[S(O)p-CH ₂ CH ₂ -] _m -S(O)p(CH ₂ ) _n CH _3,

-OCH ₂ -O-(CH ₂ ) _n -[S(O) _p -CH ₂ CH ₂ -] _m -OR ^M8 ,

-0-[C ₃ - _I2 sanirated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R ¹¹⁴ ,

-O-[3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur], wherein said heterocycle is further optionally substituted with one or more R ¹¹⁴ , -S(O) _p -[C ₃ -i ₂ saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R ¹¹⁴ , or -S(O) _p -[3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur], wherein said heterocycle is further optionally substituted with one or more R ¹¹⁴ ; R ¹²⁸ is R ¹¹⁴ ; R ¹²⁹ is R ¹¹⁴ ; alternatively both R ¹²⁸ substituents can be taken together with the carbons to which they are attached to form carbonyl or =NR ¹¹⁴ , or a saturated or unsaturated C ₃ - ₆ spiro ring or a 3-6 membered saturated or unsaturated heterospiro ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R ¹¹⁷ groups, alternatively both R ¹²⁹ substituents can be taken together with the carbons to which they are attached to form carbonyl or =NR ¹¹⁴ , or a saturated or unsaturated C ₃₄ spiro ring or a 3-6 membered saturated or unsaturated heterospiro ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R ¹¹⁷ groups, alternatively an R ¹²⁸ and an R ¹²⁹ substituent can be taken together with the carbons to which they are attached to form a C ₃ _i ₂ saturated or unsaturated ring or saturated or unsaturated bicyclic ring, or a 3-12 membered saturated or unsaturated heterocyclic ring or saturated or unsaturated heterobicyclic ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R ¹⁷⁴ groups, alternatively both R ¹²⁸ groups and both R ¹²⁹ groups can be taken together with the carbons to which they are attached to form an unsaturated bond between the carbon atoms to which R ¹ and R are attached and a C3-1 ₂ unsaturated or aromatic ring or unsaturated or aromatic bicyclic ring, or a 3-12 membered unsaturated or aromatic heterocyclic ring or unsaturated or aromatic heterobicyclic ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R ¹¹⁷ groups,

R ¹¹⁰ is R" ⁴ ;

alternatively, R ¹⁰⁹ and R ¹¹⁰ taken together with the carbons to which they are attached form:

R ¹³² , R ¹³³ , and R ¹³⁴ are each independently selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -OR ¹¹⁴ , (f) -SR ¹¹⁴ , (g) -NR ¹¹⁴ R ¹¹⁴ , and (h) C _w alkyl, wherein (h) optionally is substituted with one or more R ¹¹⁵ groups; alternatively, R ¹³² and R ¹³³ are taken together to form a carbon-carbon double bond; alternatively, R ¹³³ and R ¹³⁴ are taken together to form =O, =S, =N0R ¹¹⁴ , =NR ¹¹⁴ , or =N-NR ¹¹⁴ R ¹¹⁴ ; alternatively, R ¹⁰⁵ and R ¹³⁴ are taken together with the carbons to which they are attached to form a 3-membered ring, said ring optionally containing an oxygen or nitrogen atom, and said ring being optionally substituted with one or more R ¹¹⁴ groups; alternatively when M is a carbon moiety, R ¹³⁴ and M are taken together to form a carbon-carbon double bond;

R ¹³⁷ is independently (a) H, (b) Ci _-6 alkyl, (c) C _2-6 alkenyl, (d) C _2-6 alkynyl, (e) - (CH ₂ ) _q CR ¹⁴¹ R ¹⁴² (CH ₂ ) _n NR ¹⁴³ R ¹⁴⁴ , -CCH ₂ ) _V (C ₆ -Cio aryl), or -(CH ₂ )v(5-10 membered heteroaryl); or where R ¹³⁷ Js-CH ₂ NR ¹³⁷ R ¹³⁹ , R ¹³⁹ and R ¹³⁷ may be taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S, and -N(R ¹³⁷ )-, in addition to the nitrogen to which R ¹³⁹ and R ¹³⁷ are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 , 2, or 3 R ¹⁴⁰ groups; each R ¹³⁸ is independently H or Ci - ₆ alkyl; each R ¹⁴¹ , R ¹⁴² , R ¹⁴³ , and R ¹⁴⁴ is independently selected from H, Cr ₆ alkyl, - (CH2) _m (C ₆ -Cio aryl), and -(CH ₂ ) _m (5-10 membered heteroaryl), wherein the foregoing R ¹⁴¹ , R ¹⁴² , R ¹⁴³ , and R ¹⁴⁴ groups, except H, are optionally substituted by 1 , 2, or 3 R ¹⁴⁰ groups;

or R ¹⁴¹ and R ¹⁴³ are taken together to form -(CHi) ₀ - wherein o, at each occurrence is 0, 1, 2, or 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds; or R ¹⁴³ and R ¹⁴⁴ are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and - N(R ¹³⁷ )-, in addition to the nitrogen to which R ¹⁴³ and R ¹⁴⁴ are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1, 2, or 3 R ¹⁴⁰ groups; R ¹³⁹ is H, C i-6 alkyl, C ₂ -C _O alkenyl, or C ₂ -Ce alkynyl, wherein the foregoing

R ¹³⁹ groups, except H, are optionally substituted by 1 , 2, or 3 substituents independently selected from halo and -OR ¹³⁸ ; each R ¹⁴⁰ is independently selected from halo, cyano, nitro, trifluoromethyl, azido, -C(O)R ¹⁴⁵ , -C(O)OR ¹⁴⁵ , -OC(O)OR ¹⁴⁵ , -NR ¹⁴⁶ C(O)R ¹⁴⁷ , -NR ¹⁴⁶ R ¹⁴⁷ , OH, C,- ₆ alkyl, Cr ₆ alkoxy, -(CH ₂ ) _v (C6-Ci ₀ aryl), and -(CH ₂ ) _v (5-10 membered heteroaryl), wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, - C(O)R ¹⁴⁵ ,-C(O)OR ¹⁴⁵ , -OC(O)OR ¹⁴⁵ , -NR ¹⁴⁶ C(O)R ¹⁴⁷ , -C(O)NR ¹⁴⁶ R ¹⁴⁷ , -NR ¹⁴⁶ R ¹⁴⁷ , OH, C i- ₆ alkyl, and Ci -6 alkoxy; each R ¹⁴⁵ is independently selected from H, Ci- ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -Ce alkynyl, -(CH ₂ )v(C ₆ -Cio aryl), and -(CH ₂ )v(5-10 membered heteroaryl); each R ¹⁴⁶ and R ¹⁴⁷ is independently H, hydroxyl, d-β alkoxy, Ci- ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ -6 alkynyl, -(CH ₂ ) _v (C6-io aryl), or -(CH ₂ ) _V (5- 10 membered heteroaryl); R ¹⁴⁸ is Ci-6 alkyl, C3- ₁ 2 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further optionally substituted with one or more R ¹¹⁴ , or 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said heterocycle is further optionally substituted with one or more R ¹¹⁴ ; p, at each occurrence is O, 1 , or 2; k, at each occurrence is 0, 1 , or 2; m, at each occurrence is 0, 1, 2, 3, 4, or 5; n, at each occurrence is 1, 2, or 3; r, at each occurrence is 0, 1 , or 2; t, at each occurrence is 0, 1 , or 2;

v, at each occurrence is 0, 1, 2, 3, or 4; q, at each occurrence is 0, 1, 2, or 3; and u at each occurrence is 1, 2, 3, or 4.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, Q, R ¹⁰⁴ , R ¹¹⁴ , R ¹²⁶ , R ¹²⁷ , R ¹²⁸ , R ¹²⁹ , R ¹⁴⁹ , and R ¹⁵⁰ are as described herein. In other embodiments, the present invention relates to a compound having the structure, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from Tl through T93:

T16 T17 T18

T21 T22

T29

T30

T57

T58

T59

T60

T61

T62

T63

T64

T65

T66

T67

T68

T69

T70

T71

T72

T73

T74

T83 T84

T92 and T93

In other embodiments, the present invention relates to a compound having the structure corresponding to any one of the structures listed in Table 1, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

In other embodiments, the present invention relates to an intermediate used in the preparation of the compounds of the present invention.

In other embodiments, the present invention relates to a composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, and a pharmaceutically acceptable carrier.

In other embodiments, the present invention relates to a method for treating or preventing a disease state in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of the invention.

In other embodiments, the present invention relates to a method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention. In other embodiments, the present invention relates to a compound of the invention in the manufacture of a medicament for treating a microbial infection in a mammal.

In other embodiments, the present invention relates to a method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound of the present invention, wherein the microbial infection is selected from the group consisting of: a skin infection, nosocomial pneumonia, community acquired pneumonia, post- viral pneumonia, a respiratory tract infection such as CRTI, a skin and soft tissue infection (SSTI) including uncomplicated skin and soft tissue infections (uSSTIs) and complicated skin and soft tissue infections, as an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, surgical prophylaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus infection, a vancomycin-resistant Enterococci infection, a linezolid-resistant organism infection, and tuberculosis.

In other embodiments, the present invention relates to a method of treating a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention.

In other embodiments, the present invention relates to a method of treating a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention.

In other embodiments, the present invention relates to a method of treating a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention.

In other embodiments, the present invention relates to a method of treating a viral infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention.

In other embodiments, the present invention relates to a method of treating an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention. In other embodiments, the present invention relates to a method of treating a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound of the invention.

In other embodiments, the present invention relates to a method of treating diarrhea in a mammal comprising administering to the mammal an effective amount of the compound of the invention.

In other embodiments, the present invention relates to a method of treating or preventing a disease state in a mammal caused or mediated by a nonsense or missense mutation comprising administering to a mammal in need thereof an effective amount of a compound of the invention to suppress expression of the nonsense or missense mutation. In other embodiments, the present invention relates to a method or use wherein the compound of the invention is administered otically, opthalmically, nasally, orally, parentally, or topically.

In other embodiments, the present invention relates to a method of synthesizing a compound of the invention. In other embodiments, the present invention relates to a medical device containing a compound of the invention.

In other embodiments, the present invention relates to a medical device containing a compound of the invention, wherein the device is a stent.

As is seen from the foregoing, the compounds of the present invention can include a wide range of structures. Examples of such macrolide components and their syntheses are provided in the following documents, all of which are incorporated by reference in their entirety: PCT Application No. WO 2007/025284, published March 1, 2007, to Rib-X Pharmaceuticals, Inc.; PCT Application No. WO 2007/025098, published March 1, 2007, to

Rib-X Pharmaceuticals, Inc.; PCT Application No. WO 2007/ 025089, published March 1, 2007, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/118610, published December 15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/085266, published September 15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/049632, published June 2, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/042554, published May 12, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2004/078770, published September 16, 2004, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2004/029066, published April 8, 2004, to Rib-X Pharmaceuticals, Inc.; U.S. Patent No.; U.S. Patent No. 6,992,069, to Gu et al., issued January 31 , 2006; U.S. Patent No. 6,953,782, to Phan et al., issued October 11, 2005; U.S. Patent No. 6,939,861, to Ashley et al., issued September 6, 2005; U.S. Patent No., 6,927,057, to Khosla et al., issued August 9, 2005; U.S. Patent No. 6,794,366, to Chu et al., issued September 21, 2004; U.S. Patent No. 6,762,168, to Chu, issued July 13, 2004; U.S. Patent No. 6,756,359, to Chu et al, issued June 29, 2994; U.S. Patent No. 6,750,205, to Ashley et al, issued June 15, 2004; U.S. Patent No. 6,740,642, to Angehrn et al., issued May 25, 2004; U.S. Patent No. 6,727,352, to Cheng et al., issued April 27, 2004; U.S. Patent Application Publication No. US 2006/0154881, to Or et al., published July 13, 2006; U.S. Patent Application Publication No. US 2006/0142215, to Tang et al., published June 29, 2006; U.S. Patent Application Publication No. US 2006/0142214, to Or et al, published June 29, 2006; U.S. Patent Application Publication No. US 2006/0122128, to Or et al., published June 8, 2006; U.S. Patent Application Publication No. US 2006/0069048, to Or et al. published March 30, 2006; U.S. Patent Application Publication No. US 2005/0272672, to Li et al., published December 8, 2005; U.S. Patent Application Publication No US 2005/0009764, to Burger et al, published January 13, 2005; PCT application No. WO 2006/067589, to Pfizer Products Inc., published June 29, 2006; PCT application No. WO 2004/096823, to Chiron Corporation, published November 11 , 2004; PCT application No. WO 2004/096822, to Chiron Corporation, published November 11, 2004; PCT application No. WO 2004/080391, to Optimer Pharmaceuticals, Inc., published September 23, 2004; PCT application No. WO 2004/078771, to Taisho Pharmaceutical Co., Ltd., published September 16, 2004; PCT application no. WO 03/061671, to Kosan Biosciences, Inc. published July 31, 2003; European Patent Document EP 1 256 587 Bl, to the Kitasato Institute, granted March 29, 2006; WO 98/54197, published December 3, 1998, to Abbott Laboratories; and WO 97/17356, published May 15, 1997, to Abbott Laboratories.

3. Synthesis of the Compounds of the Invention

The invention provides methods for making the compounds of the invention. The following schemes depict exemplary chemistries available for synthesizing the compounds of the invention. Scheme 1 illustrates the typical general synthesis of the macrolide compounds of the present invention.

The synthesis starts with a known macrolide core component such as, for example, erythromycin, azithromycin, clarithromycin, roxithromycin, telithromycin, etc. The macrolide core component is then converted to the 3'-N-desmethyl macrolide compound. For example, erythromycin can be converted to the 3'-N-desmethyl compound as described in the scientific and patent literature. See U.S. Patent No. 3,725,385; Flynn et al. (1954) J. Am. Chem. Soc. 76: 3121; Ku et al. (1997) Bioorg. Med. Chem. Lett. 7: 1203; Stenmark et al. (2000) J. Org. Chem. 65: 3875). Analogous chemical procedures can be used to convert azithromycin, clarithromycin, roxithromycin, telithromycin, and other macrolide core components to their corresponding 3'-N-desmethyl forms. The 3'-N-desmethyl compounds can be further modified to provide yet further 3'-N-desmethyl compounds for use herein.

In one embodiment, the 3'-N-desmethyl macrolide compound is N-alkylated with an ester such as a terminally substituted ester having a suitable leaving group (e.g. halogen, tosylate, mesylate, bromide, etc.) to yield a 3'-N-alkyl ester compound. For example, terminal halogenated esters such as terminal bromo esters can be used. One example according to the present invention includes esters of acids comprising a cyclopropane or a cyclobutane ring, and possessing terminal sulfonate group, terminal iodide, terminal bromide or another terminal leaving group. The 3'-N-alkyl ester compounds are then converted to acids, which are reacted with the desired amine to yield the final desired macrolide compound.

Alternatively, the desired macrolide compound can be obtained directly from the 3'- N-desmethyl macrolide compound, which can be N-alkylated with an amide containing a cyclopropane ring, such as a terminally substituted amide having a suitable leaving group (e.g. halogen, tosylate, mesylate, bromide, etc.) to yield a 3'-N-alkyl amide compound. In another embodiment, the 3'-N-desmethyl macrolide compound is N-alkylated with an aldehyde ester, using one of the reductive amination protocols known in the art. For example, an ester aldehyde is condensed with secondary amine group of the 3'-N-desmethyl macrolide compound, and the intermediate thus formed is reduced to the alkylamino ester.

This ester compound is then converted to the desired macrolide compound. Alternatively, the desired macrolide compound can be obtained directly from the 3'-N-desmethyl macrolide compound, which can be N-alkylated with an amide containing a cyclopropane ring, such as a terminally substituted amide possessing an aldehyde group. Typically, the 3'-N-alkyl ester compound is converted to a 3'-N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the desired amino compound to couple the two components via an amide linkage.

Scheme 1 The general reaction steps of scheme 1 can be described as follows:

Macrolide Core Compound → Desmethyl Macrolide

Desmethyl Macrolide + Terminally Substituted Ester -» N-Alkyl Ester Compound

Desmethyl Macrolide + Aldehyde Ester — > N-Alkyl Ester Compound

N-Alkyl Ester Compound -» N-Alkyl Carboxylic Acid N-Alkyl Carboxylic Acid + Amino Compound — > Final Macrolide Compound

Desmethyl Macrolide + Terminally Substituted Amide — > Final Macrolide Compound

Desmethyl Macrolide + Aldehyde Amide → Final Macrolide Compound

The following is an illustration of Scheme 1 using erythromycin as a starting material

(analogous reactions can be run starting with other macrolide compounds such as azithromycin, clarithromycin, roxithromycin, etc.). The variables G, X, R ^a , R ^b , R ^c , R ^d , and R ^e are as defined above.

Erythromycin N-Desmethyl erythromycin

Ester hydrolysis

Amine Compound

N-Alkyl Carboxyhc Acid Macrolide Compound

N-Desmethyl erythromycin

substituted amide

4. Characterization of Compounds of the Invention

Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, for example, as anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also, it can be possible to assay how the compounds interact with a ribosome or ribosomal subunit and/or are effective as modulators (for example, inhibitors) of protein synthesis using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening. Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. (1) Surface Binding Studies. A variety of binding assays can be useful in screening new molecules for their binding activity. One approach includes surface plasmon resonance (SPR) that can be used to evaluate the binding properties of molecules of interest with respect to a ribosome, ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or more macromolecules in real-time through the generation of a quantum-mechanical surface plasmon. One device, (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, NJ.) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor "chip") and a buffer compartment that can be regulated by the user. A 100 nm thick "hydrogel" composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film. When the focused light interacts with the free electron cloud of the gold film, plasmon resonance is enhanced. The resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance. By separating the reflected polychromatic light into its component wavelengths (by means of a prism), and determining the frequencies that are depleted, the BIAcore establishes an optical interface which accurately reports the behavior of the generated surface plasmon resonance. When designed as above, the plasmon resonance (and thus the depletion spectrum) is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel). If one component of an interacting pair is immobilized to the hydrogel, and the interacting partner is provided through the buffer compartment, the interaction between the two components can be measured in real time based on the accumulation of mass in the evanescent field and its corresponding effects of the plasmon resonance as measured by the depletion spectrum. This system permits rapid and sensitive

real-time measurement of the molecular interactions without the need to label either component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is a measurement technique that can readily be applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to derive IC50S and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore. This is generally the smaller molecule in the system (in this case, the compound of interest). The sample mixture, containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured. Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-tum depends on whether the probe-ligand conjugate is free in solution, or is bound to a receptor. Binding assays based on FP have a number of important advantages, including the measurement of IC ₅₀ S and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions. (3) Protein Synthesis. It is contemplated that, in addition to characterization by the foregoing biochemical assays, the compound of interest can also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays can be performed by administering the compound to a whole organism, tissue, organ, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC ₅₀ ) for inhibiting protein synthesis. Incorporation of ³ H leucine or ³⁵ S methionine, or similar experiments can be performed to investigate protein synthesis activity. A change in the amount or the rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis. A decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.

(4) Antimicrobial assays and other evaluations Furthermore, the compounds can be assayed for anti-proliferative or anti-infective properties on a cellular level. For example, where the target organism is a microorganism, the activity of compounds of interest can be assayed by growing the microorganisms of interest in media either containing or lacking the compound. Growth inhibition can be indicative that the molecule can be acting as a protein synthesis inhibitor. More specifically, the activity of the compounds of interest against bacterial pathogens can be demonstrated by the ability of the compound to inhibit growth of defined strains of human pathogens. For this purpose, a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized. Use of such a panel of organisms permits the determination of structure-activity relationships not only in regards to potency and spectrum, but also with a view to obviating resistance mechanisms.

Minimum inhibitory concentrations (MICs) are determined by the microdilution method, typically in a final volume of 100 microliters, according to protocols outlined by The Clinical and Laboratory Standards Institute [CLSI; formerly the National Committee for Clinical Laboratory Standards (NCCLS)]. See CLSI: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. Wayne, PA: NCCLS; 2000. The assays can be also be performed in microtiter trays according to conventional methodologies as published by the CLSI. See CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition. CLSI Document M7-A7 [ISBN 1-56238-587-9] CLSI, 940 West Valley Road, Suite 1400, Wayne Pennsylvania 19087-1898 USA, 2006.).

The antimicrobial and other drug properties of the compounds can further be evaluated in various in vivo mammalian assays, such as a mouse or rat peritonitis infectious models, skin and soft tissue models (often referred to as the thigh model), or a mouse pneumonia model. There are septicemia or organ infection models known to those skilled in the art. These efficacy models can be used as part of the evaluation process and can be used as a guide of potential efficacy in humans. Endpoints can vary from reduction in bacterial burden to lethality. For the latter endpoint, results are often expressed as a PD ₅₀ value, or the dose of drug that protects 50% of the animals from mortality.

To further assess a compound's drug-like properties, measurements of inhibition of cytochrome P450 enzymes and phase π metabolizing enzyme activity can also be measured

either using recombinant human enzyme systems or more complex systems like human liver microsomes. Further, compounds can be assessed as substrates of these metabolic enzyme activities as well. These activities are useful in determining the potential of a compound to cause drug-drug interactions or generate metabolites that retain or have no useful antimicrobial activity.

To get an estimate of the potential of the compound to be orally bioavailable, one can also perform solubility and Caco-2 assays. The latter is a cell line from human epithelium that allows measurement of drug uptake and passage through a Caco-2 cell monolayer often growing within wells of a 24-well microtiter plate equipped with a 1 micron membrane. Free drug concentrations can be measured on the basolateral side of the monolayer, assessing the amount of drug that can pass through the intestinal monolayer. Appropriate controls to ensure monolayer integrity and tightness of gap junctions are needed. Using this same system one can get an estimate of P-glycoprotein mediated efflux. P-glycoprotein is a pump that localizes to the apical membrane of cells, forming polarized monolayers. This pump can abrogate the active or passive uptake across the Caco-2 cell membrane, resulting in less drug passing through the intestinal epithelial layer. These results are often done in conjunction with solubility measurements and both of these factors are known to contribute to oral bioavailability in mammals. Measurements of oral bioavailability in animals and ultimately in man using traditional pharmacokinetic experiments will determine the absolute oral bioavailability.

Experimental results can also be used to build models that help predict physical- chemical parameters that contribute to drug-like properties. When such a model is verified, experimental methodology can be reduced, with increased reliance on the model predictability. 5. Formulation and Administration

The compounds of the invention can be useful in the prevention or treatment of a variety of human or other animal, including mammalian and non mammalian, disorders, including for example, bacterial infection, fungal infections, viral infections, parasitic diseases, diarrhea, and cancer. It is contemplated that, once identified, the active molecules of the invention can be incorporated into any suitable carrier prior to use. The dose of active molecule, mode of administration and use of suitable carrier will depend upon the intended recipient and target organism. The formulations, both for veterinary and for human medical

use, of compounds according to the present invention typically include such compounds in association with a pharmaceutically acceptable carrier.

The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient. Pharmaceutically acceptable carriers, in this regard, are intended to include any and all solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds (identified or designed according to the invention and/or known in the art) also can be incorporated into the compositions. The formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/microbiology. In general, some formulations are prepared by bringing the compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention should be formulated to be compatible with its intended route of administration. Examples of routes of administration include oral or parenteral, for example, otic, ophthalmic, intravenous, intradermal, inhalation/nasal, transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington's

Pharmaceutical Sciences. (Gennaro, A., ed.), Mack Pub., (1990). Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. The parenteral preparation can

be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration also can be prepared by mixing the drug with a non- irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body temperatures. Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalenes. Formulations for direct administration can include glycerol and other compositions of high viscosity. Other potentially useful parenteral carriers for these drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administration can be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil- in-water emulsion or a water-in-oil emulsion. The drug can also be administered in the form of a bolus, electuary or paste. A tablet can be made by compressing or moulding the drug optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets can be made by moulding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent. Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients. Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound in the fluid carrier and are applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as

magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Particularly useful are carriers capable of forming a film or layer over the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage. Alternatively, tissue-coating solutions, such as pectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used. Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations. In the case of self-propelling solution and spray formulations, the effect can be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size. For administration by inhalation, the compounds also can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts.

Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be

apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Furthermore, administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag). Where adhesion to a tissue surface is desired the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound then can be painted, sprayed or otherwise applied to the desired tissue surface. Alternatively, the drugs can be formulated for parenteral or oral administration to humans or other mammals, for example, in therapeutically effective amounts, e.g., amounts that provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect. Where the active compound is to be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of tissue or organ from the donor. The compound can be provided to the donor host. Alternatively or, in addition, once removed from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue, as by injection to the tissue, or it can be provided systemically, e.g., by oral, otic, ophthalmic, topic, or nasal or parenteral administration, using any of the methods and formulations described herein and/or known in the art. Where the drug comprises part of a tissue or organ preservation solution, any commercially available preservation solution can be used to advantage. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and lactated Ringer's solution.

The compounds of the present invention can be administered directly to a tissue locus by applying the compound to a medical device that is placed in contact with the tissue. An example of a medical device is a stent, which contains or is coated with one or more of the compounds of the present invention. For example, an active compound can be applied to a stent at the site of vascular injury. Stents can be prepared by any of the methods well known in the pharmaceutical art. See, e.g., Fattori, R. and Piva, T., "Drug Eluting Stents in Vascular Intervention," Lancet, 2003, 361, 247-249; Morice, M. C, "A New Era in the Treatment of Coronary Disease?" European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al., "Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings," Z. Kardiol., 2002, 91 (3), 49-57. The stent can be fabricated from stainless steel or another bio-compatible metal, or it can be made of a bio-compatible polymer. The active compound can be linked to the stent surface, embedded and released from polymer materials coated on the stent, or surrounded by and released through a carrier which coats or spans the stent. The stent can be used to administer single or multiple active compounds to tissues adjacent to the stent.

Active compound as identified or designed by the methods described herein can be administered to individuals to treat disorders (prophylactically or therapeutically). In conjunction with such treatment, pharmacogenomics {i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.

In therapeutic use for treating, or combating, bacterial infections in mammals, the compounds or pharmaceutical compositions thereof will be administered orally, otically, opthalmically, nasally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective. Generally, an effective amount of dosage of active component will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg of body weight/day. The amount administered will also likely depend on such variables as the type and extent of disease or

indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage can be smaller than the optimum and the daily dosage can be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times per day.

Various disease states or conditions in humans and other mammals are found to be caused by or mediated by nonsense or missense mutations. These mutations cause or mediate the disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking and/or function. Examples of disease states or conditions in which an appreciable percentage of the disease or condition is believed to result from nonsense or missense mutations include hemophilia (factor VTII gene), neurofibromatosis (NFl and NF2 genes), retinitis pigmentosa (human USH2A gene), bullous skin diseases like Epidermolysis bullosa pruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosis transmembrane regulator gene), breast and ovarian cancer (BRCAl and BRC A2 genes), Duchenne muscular dystrophy (dystrophin gene), colon cancer (mismatch repair genes, predominantly in MLHl and MSH2), and lysosomal storage disorders such as Neimann-Pick disease (acid sphingomyelinase gene). See Sanders CR, Myers JK. Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004;33:25-51; National Center for Biotechnology Information (U.S.) Genes and disease Bethesda, MD : NCBI, NLM ID: 101138560; and Raskό, Istvan; Downes, C S Genes in medicine : molecular biology and human genetic disorders 1st ed. London ; New York : Chapman & Hall, 1995. NLM ID: 9502404. The compounds of the present invention can be used to treat or prevent a disease state in a mammal caused or mediated by such nonsense or missense mutations by administering to a mammal in need thereof an effective amount of the present invention to suppress the nonsense or missense mutation involved in the disease state.

6. Examples Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance 300 or

Avance 500 spectrometer, or in some cases a GE-Nicolet 300 spectrometer. Common reaction solvents were either high performance liquid chromatography (HPLC) grade or

American Chemical Society (ACS) grade, and anhydrous as obtained from the manufacturer unless otherwise noted. "Chromatography" or "purified by silica gel chromatography" refers to flash column chromatography using silica gel (EM Merck, Silica Gel 60, 230-400 mesh) unless otherwise noted. The compounds of the present invention can be prepared using known chemical transformations adapted to the particular situation at hand. Examples of chemical transformations useful in the present invention can be found in: U.S. Patent No. 7,091,196 B2, to Wang et al., issued August 15, 2006; PCT application No. WO 2005/085266 A2, to Rib-X Pharmaceuticals, Inc., published September 15, 2005; PCT application No. PCT/US2006/33645, to Rib-X Pharmaceuticals, Inc., filed August 24, 2006; PCT application No. PCT/US2006/33170, to Rib-X Pharmaceuticals, Inc., filed August 24, 2006; and PCT application No. PCT/US2006/33157, to Rib-X Pharmaceuticals, Inc. filed August 24, 2006, which are incorporated by reference herein in their entirety.

Some of the abbreviations used in the following experimental details of the synthesis of the examples are defined below: h or hr = hour(s); min = minute(s); mol = mole(s); mmol = millimole(s); M = molar; μM = micromolar; g = gram(s); μg = microgram(s); rt = room temperature; L = liters); mL = milliliter(s); Et ₂ O = diethyl ether; THF = tetrahydrofuran; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; EtjN = triethylamine; /-Pr ₂ NEt or DIPEA = diisopropylethylamine; CH ₂ CI2 = methylene chloride; CHCI ₃ = chloroform; CDCI ₃ = deuterated chloroform; CCl ₄ deuterated methanol; EtOH = ethanol; DMF = dimethylformamide; BOC = t- butoxycarbonyl; CBZ = benzyloxycarbonyl; TBS = f-butyldimethylsilyl; TBSCl = t- butyldimethylsilyl chloride; TFA = trifluoroacetic acid; DBU = diazabicycloundecene; TBDPSCl = f-butyldiphenylchlorosilane; Hunig's Base= N,N-diisopropylethylamine;

DMAP = 4-dimethylaminopyridine; CuI = copper (I) iodide; MsCl = methanesulfonyl chloride; νaν3 = sodium azide; Na ₂ SO ₄ = sodium sulfate; NaHCθ ₃ = sodium bicarbonate; NaOH = sodium hydroxide; MgSO ₄ = magnesium sulfate; K ₂ CO ₃ = potassium carbonate; KOH = potassium hydroxide; NH ₄ OH = ammonium hydroxide; NH ₄ Cl = ammonium chloride; SiO ₂ = silica; Pd-C = palladium on carbon; Pd(dppf)Cl ₂ = dichloro[l,l '- bis(diphenylphosphino)ferrocene] palladium (H).

Exemplary compounds synthesized in accordance with the invention are listed in Table 1. A bolded or dashed bond is shown to indicate a particular stereochemistry at a chiral

center, whereas a wavy bond indicates that the substituent can be in either orientation or that the compound is a mixture thereof. It should also be known that in the interest of space, the chemical structures have been condensed, for example the methyl and ethyl group substituents are designated with just a carbon backbone representation, and the unsaturated bonds in the triazole rings might not always be visible.

The compounds of the present invention can be prepared, formulated, and delivered as salts, esters, and prodrugs. For convenience, the compounds are generally shown without indicating a particular salt, ester, or prodrug form.

Compounds of the present invention are shown in Table 1. LCMS (liquid chromatography mass spectral) data are provided, where available. The LCMS data is provided using the convention for m/z in the format, [M + H] ⁺ , except for these with an asterisk * where the format is [(M + 2H)/2] ⁺ .

Table 1

Compound No. Structure LCMS

100

982.3

104

105

506*

106

524*

107

53V

112

531*

113

534*

114

534*

115

1002.9

116

1002.9

117

536*

118

536"

124

559*

125

574*

126

574*

127

In the present invention, the variable G is further selected from -B' or -B'-Z-B". Tables 1 A-II provide examples of chemical moieties or fragments for -Z-B" when G is selected from -B'-Z-B". Note that in Tables 1 A-II, the chemical moieties or fragments for "- Z-B" are drawn such that the chemical moiety or fragment is bonded to -B from the left of the chemical moiety or fragment as drawn. For example, using the first chemical moiety or fragment from Table IA as an example, it can alternatively be drawn as shown immediately below.

This fragment would then be attached to B', as shown immediately below.

As a further nonlimiting example, in the macrolide structure shown below, variable G, could be selected from -B '-Z-B". If, for example, B' is then selected from phenyl, then -Z- B" could be further selected from the first chemical moiety or fragment of Table IA to give the indicated compound.

Exemplary macrolide compound of the present invention showing variable G.

Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B".

Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B", wherein B' is phenyl.

Exemplary macrolide compound of the present invention showing variable G selected form -B '-Z-B" wherein B' is phenyl and -Z-B" is selected from the first chemical moiety or fragment of Table IA.

Examples 1 - 6: Synthesis of 3'-N-desmethyl macrolide intermediate compounds Examples 1-6 describe the synthesis of various 3'-N-desmethyl macrolide compounds which are useful intermediates for making the compounds of the present invention.

Example 1: Synthesis of 3'-N-desmethyl erythromycin from erythromycin

3'-N-desmethyl erythromycin is synthesized from erythromycin according to the procedure described in U.S. Patent No. 3,725,385; Flynn et al. (1954) J. Am. Chem. Soc. 76: 3121; Ku et al. (1997) Bioorg. Med. Chem. Lett. 7: 1203; and Stenmark et al. (2000) J. Org. Chem. 65: 3875).

Example 2: Synthesis of 3'-7Y-desmethyl azithromycin from azithromycin Azithromycin (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50 ⁰ C followed by addition of iodine (I ₂ ) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes, however, stirring was continued for 2 hours. TLC (CH ₂ Cl ₂ ZMeOHZNH ₄ OH 10:1 :0.05) after 2 hours showed a single major product (Rf= 0.66). The reaction was cooled to room temperature, poured into H ₂ O (75 mL) containing NH ₄ OH (1.5 mL) and extracted with CHCI3 (3 x 30 mL). The combined organic layers were washed with H ₂ O (30 mL) containing NH ₄ OH (1.5 mL), dried over Na ₂ SO ₄ and the solvent evaporated to give a white

residue. The crude was purified on a silica gel column eluting with CH ₂ Cl ₂ ZMeOHZNH ₄ OH 18:1:0.05 to 10:1 :0.05 to provide the 3'-N-desmethyl azithromycin (0.41 g, 55%).

Example 3: Synthesis of 3'-7V-desmethyl clarithromycin from clarithromycin To a mixture of clarithromycin (1.00 g, 1.3 mmol) and νaOAcβH ₂ 0 (0.885 g, 6.5 mmol) was added MeOH-H ₂ O (20 mL, 4:1), and the mixture heated to 55-60 ⁰ C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and the reaction stirred at 55-60 ⁰ C for 3 h. The reaction mixture was poured into 50 mL CHCI3 containing 1 mL ammonium hydroxide. It was extracted with CHCI3 (4 x 50 mL), washed with water (70 mL) containing 5 mL ammonium hydroxide, dried (anhydrous Na2SO4), concentrated, and purified by flash chromatography (silica gel, CHCl ₃ MeOHiNH ₄ OH 100:10:0.1) to afford 3'-N-desmethyl clarithromycin. Yield: 0.9g (92%).

Example 4: Synthesis of 3'-/V-desmethyl roxithromycin from roxithromycin

To a mixture of roxithromycin (850 mg, 0.914 mmol, 90%) and NaOAc (828 mg, 10.000 mmol) in a mixture of MeOH (6.0 mL) and water (1.5 mL) at 48°C was added I ₂ in four portions (each portion: 63.5 mg) over 30 min, after each portion I ₂ , followed by IN NaOH (400μL). The reaction was continued for 30 min. The solvent was removed and EtOAc (100 mL) was added, followed by water (20 mL). The organic phase was washed with brine (40 mLX2), dried with Na2SO4. The residue was separated by FC (6/94/0.2 MeOHZCH ₂ Cl ₂ ZNH ₄ OH), gave 600 mg of the 3'-N-desmethyl roxithromycin in 80% yield. LCMS (ESE) m/e 824 (MGH) ⁺ .

Example 5: Synthesis of 3'-JV-Desmethyl telithromycin from telithromycin

To a solution of telithromycin (3.0 g, 3.60 mmol) in anhydrous acetonitrile (70 mL) was added N-iodosuccinimide (NIS) (0.98 g, 4.32 mmol) in two portions within 30 min at 0 ⁰ C under argon atmosphere. The mixture was allowed to warm to rt and stirred overnight. CH ₂ Cl ₂ (250 mL) and 5 % Na ₂ S ₂ O ₃ (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na ₂ S ₂ O ₃ (1 X 80 mL), dilute NH ₄ Cl (1 X 80 mL) and dried over Na ₂ SO ₄ . Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 8 % methanolic ammonia (2N NH ₃ ) in CH ₂ Cl ₂ to give 3'-N-desmethyl telithromycin as white solid (1.95 g, 68 %). MS (ESI) M/E; M+H ⁺ 798.6.

Example 6: Synthesis of 3'-N-Desmethyl ketolide type macrolides

Most of the 3'-N-desmethyl ketolide intermediates are not made directly. Instead, the ketolide function, i.e. the 1,3-diketone, is introduced after the 3'-N-desmethyl functionality has been further transformed to an N-alkynyl intermediate. In an exemplary process, clarithromycin is converted to 3'-N-desmethyl clarithromycin. This compound is then alkylated to form an alkynyl intermediate. The cladinose sugar is then cleaved from this intermediate and the resulting free hydroxyl group is oxidized to the ketone.

Example 7 Synthesis of Compounds Compounds 119, 120, 121, and 122, and Intermediates A, and B are generally ca. 1 :1 mixtures of the (R, R)- and (S, S)-diastereomers on the cyclopropyl linker. These compounds were synthesized from racemic 2-formylcyclopropanecarboxylate via a reductive amination protocol. The following Scheme illustrates the synthesis of compound 119.

N-desmethylclarithromycin

1) LiOH

2) H ₃ O ⁺

Intermediate B

Synthesis of Intermediate A:

N-Desmethylclarithromycin (20.0 g, 27.25 mmol), THF (75 mL) and isopropanol (100 mL) were stirred at room temperature. Trimethyl orthoformate (11.57 g, 11.94 mL, 109 mmol) was added, followed by ethyl 2-formylcyclopropanecarboxylate (15.49 g, 109 mmol) and sodium cyanoborohydride NaBH ₃ CN (7.71 g, 122.6 mmol). After 40 min, MgCl ₂ (13.0 g, 136.2 mmol) was introduced and stirring was continued at room temperature. After 2 h, the reaction mixture was partitioned between EtOAc (300 mL) and saturated NH ₄ C1/2O% NH ₄ OH/H ₂ O solution (200 mL). The organic phase was washed with saturated NH ₄ C1/2O% NH ₄ OH/H ₂ O solution (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography [Si-gel 230-400 mesh, 3% v/v 2M

NH ₃ ZMeOH in CH ₂ Ch] affording the product as a white solid, which crystallized overnight (EtOAc, 40 mL). This gave intermediate A (14.98 g, 64%) as colorless needles; LCMS (CI) m/z 860 (M+H) ⁺ .

Synthesis of Intermediate B:

Intermediate A (5.4 g, 6.28 mmol) was dissolved in THF (25 mL). The mixture was stirred at room temperature, under argon. Methanol (110 mL) was added, followed by 5% L1OH/H ₂ O solution (25 mL). After stirring for 4 h, the mixture was concentrated in vacuo to 50 mL and then partitioned between CH ₂ Cl ₂ (200 mL) and saturated KH ₂ POVH ₂ O (300 mL). The aqueous phase was extracted with EtOAc (2x150 mL). The organic phases were combined, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by flash chromatography [Si-gel 230-400 mesh, 2% Et ₃ N - 5% MeOH - 93% CH ₂ Cl ₂ ], affording intermediate B as a white solid (3.80 g, 73%); LCMS (CI) m/z 832 (M+H) ⁺ .

Synthesis of compounds 119, 120, 121, and 122:

The synthesis of oxazolidinone amines used for the amide formation reactions was accomplished using previously described approaches (Morpholino- Mohan, Rao Dodda; Krishna, Reddy Pingili. (Symed Labs Limited, India; Mohan Rao, Dodda; Krishna Reddy, Pingili). PCT Int. Appl. (2005), 22 pp. WO 2005099353; Fluorophenyl- Lee, Jae-gul; Leem, Won-bin; Cho, Jong-hwan; Choi, Sung-hak; Lee, Jong-jin; Park, Sang-kuk; Lee, Tae-

hoo; Kim, Dong-goo; Sung, Hyun-jung. (Dong A Pharm. Co., Ltd., S. Korea). PCT Int. Appl. (2001), 199 pp. WO 2001094342 ).

Intermediate B

Intermediate B

Intermediate B

Intermediate B

General procedure for coupling of intermediate B with amines

The respective amine (0.25 mmol), acid intermediate B (ca. 0.4 mmol, 1.50 equiv), HBTU (1.66 equiv), DIPEA (2.8 equiv) and anhydrous DMF (4.0 mL) were stirred under argon, at room temperature. After 2 h, the reaction mixture was partitioned between EtOAc (70 mL) and saturated KH ₂ PO ₄ /H ₂ O (70 mL). The organic phase was washed with saturated KH ₂ PO ₄ /H ₂ O (50 mL), dried over Na ₂ SQ*, filtered, and concentrated in vacuo. The product was purified by flash chromatography [Si-gel 230-400 mesh, 3-6% v/v 2M NH ₃ /MeOH in CH ₂ Cl ₂ ], followed by preparative HPLC (60μ, C- 18, 41.4 mm Dynamax column + guard; 65%-100% MeOH+0.1% NH ₄ OH). The following products were obtained (yields: 24-65%)

Compounds 123, 124, 125, and 126 were prepared as single isomers. Compound 123 was prepared following the methodology depicted in the Scheme below:

Synthesis of compound 123:

(R, λ)-2-(Toluene-4-sulfonyloxymethyl)cyclopropanecarboxylic acid ethyl ester (0.61 g, 2.04 mmol), N-desmethylclarithromycin (1.54 g, 2.1 mmol), diisopropylethylamine (10 mL), and toluene (8 mL) were placed in a 35 mL Schlenk vessel. The vessel was purged with argon and sealed. The mixture was heated at 105 ⁰ C, with stirring. After 18 h, the reaction mixture was concentrated in vacuo to dryness and purified by flash column chromatography [Si-gel 230-400 mesh, 2% v/v 2M NH ₃ /Me0H in CH ₂ Cl ₂ ]. The solid thus obtained was crystallized (EtOH, 15 mL), affording the (R, .^-cyclopropane-linked ester as a white powder (1.37 g; 78%); LCMS (CI) m/z 860 (M+H) ⁺ .

A portion of this sample (1.12 g, 1.30 mmol) was dissolved in THF (10 mL), MeOH (8 mL) was added, followed by 5% LiOH/H ₂ O (3 0 mL, 6 2 mmol) The mixture was stirred at room temperature overnight, and then concentrated to 5 mL and partitioned between saturated KH ₂ PO ₄ ZH ₂ O (100 mL) and CH ₂ Cl ₂ (100 mL). The aqueous phase was washed with EtOAc (2x50 mL). The organic phases were combined, dried over Na ₂ SO ₄ , filtered, and

concentrated in vacuo to dryness. The crude product was purified by flash column chromatography [Si-gel 230-400 mesh, 2% Et ₃ N - 5% MeOH - 93% CH ₂ Cl ₂ ], affording the (R, λ)-cyclopropane-linked acid as a colorless, glassy solid (0.663 g, 61%); LCMS (CI) m/z 832 (M+H) ⁺ . (5)-5-Aminomethyl-3-[4-(2-aminopyrimidin-5-yl)-3-fluoropheny l]-oxazolidin-2-one (75 mg, 0.247 mmol), the (R, λ)-cyclopropane-linked acid (282 mg, 0.339 mmol), HBTU (140 mg, 0.37 mmol), diisopropylethylamine (121 μL, 89.4 mg, 0.692 mmol), and anhydrous DMF (3.0 mL) were placed in a 15 mL Schlenk tube. The vessel was purged with argon and sealed. The mixture was stirred at room temperature for 2h, and then it was partitioned between EtOAc (50 mL) and saturated KH ₂ PO ₄ ZH ₂ O (70 mL). The organic phase was washed with saturated KH ₂ PO ₄ ZH ₂ O (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. This afforded a glassy solid, which was purified by flash chromatography [Si-gel 230-400 mesh, 5% vZv 2M NH ₃ ZMeOH in CH ₂ Cl ₂ ]. The product was further purified by preparative HPLC (60μ, C-18, 41.4 mm Dynamax column + guard; 70%-100% MeOH+0.1% NH ₄ OH), affording compound 123 as a crystalline white solid (53.2 mg, 19%); LCMS (CI) m/z 559 (M+2H) ²⁺ /2.

-I l l-

Compound 124 was prepared following the Scheme below:

N-desmethylclaπthromyαn

Synthesis of compound 124'

Compound 124 was synthesized from (5, 5)-2-(toluene-4- sulfonyloxymethyl)cyclopropanecarboxylic acid ethyl ester and N-desmethylclarithromycin according to the three-step experimental protocol described above for the synthesis of the isomeric compound 123. The last step of the synthetic sequence followed by HPLC purification afforded compound 124 (102.9 mg, 36%) as a white solid; LCMS (CI) m/z 559 (M+2H) ²⁺ /2.

Synthesis of (R, R)- 2-(toluene-4-sulfonyloxymethyl)-cycIopropanecarboxylic acid ethyl ester and (S, S)- 2-(toluene-4-sulfonyloxymethyl)-cyclopropanecarboxylic acid ethyl ester

The precursors, diastereomerically and enantiomerically pure 2- benzyloxycyclopropanecarboxylic acid ethyl esters shown below

EtOOC

COOEt -

were synthesized from commercially available enantiomerically pure benzylglycidyl ethers following the method disclosed by Armstrong (Armstrong, A.; Scutt, J. N. Organic Letters 2003, 5, 2331-2334). Each of the two benzyl ethers thus obtained was subsequently converted to the corresponding 2-(toluene-4-sulfonyloxymethyl)-cyclopropanecarboxylic acid ethyl ester following the transformations shown on the Scheme below for the (R, /?)-isomer,

1) H ₂ , Pd/C 1 2) TsCl, pyridine, DIPEA

(JMO 188-295, JMO 188-296) according to the synthetic pathway described in: Armstrong, A.; Scutt, J. N. Chemical Communications 2004, 510-511.

Compounds 125 and 126 were prepared according to the Scheme below:

Synthesis of compounds 125 and 126: The acid [the above described (S, 5)-linked acid precursor to compound 124] (0.54 g,

0.65 mmol), methanol (10 mL), aniline (0.89 mL, 0.909 g, 9.76 mmol), and methoxylamine hydrochloride (0.652g, 7.8 mmol) were heated at 65 ⁰ C, for 3 h. The mixture was cooled and partitioned between EtOAc (70 mL) and 0.05N HC1/H ₂ O (100 mL). The phases were separated, the aqueous layer was washed with EtOAc (30 mL), and the organic phases were combined, dried over Na _ϊ SO- _t , filtered and concentrated to dryness. This sample was purified

by flash column chromatography [Si-gel 230-400 mesh, 4% Et ₃ N - 15% MeOH - 81% CH ₂ Cl ₂ ], affording a ca. 1:1 EIZ mixture of 9-N-methoxyimine derivatives of (S ₅ S)- cyclopropane-linked acid as a white solid (0.53 g, 95%); LCMS (CI) m/z 861 (M+H) ⁺ .

This acid (0.53 g, 0.615 mmol), (5)-5-aminomethyl-3-[4-(2-aminopyrimidin-5-yl)-3- fluorophenyl]-oxazolidin-2-one (130 mg, 0.247 mmol), HBTU (260 mg, 0.685 mmol), diisopropylethylamine (225 μL, 167 mg, 1.29 mmol), and anhydrous DMF (5.0 mL) were placed in a 15 mL Schlenk tube. The vessel was purged with argon and sealed. The mixture was stirred at room temperature for Ih, and then it was partitioned between EtOAc (70 mL) and saturated KH ₂ PO ₄ /H ₂ O (70 mL). The organic phase was washed with saturated KH ₂ PO ₄ /H ₂ O (30 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. This afforded a solid (0.68 g), which was purified by flash chromatography [Si-gel 230-400 mesh, 5% v/v 2M NH ₃ /MeOH in CH ₂ Cl ₂ ]. The product was further purified by preparative HPLC (60μ, C- 18, 41.4 mm Dynamax column + guard; 65%- 100% MeOH+0.1% NH ₄ OH) affording, in order of elution: (a) compound 125 as a white solid (154.5 mg, 22 %); R,= 28 min.; LCMS (CI) m/z 574 (M+2H) ²⁺ /2, and (b) compound 126 as a white solid (52 mg, 7.4 %); R _t = 31 min.; LCMS (CI) m/z 574 (M+2H) ²⁺ /2.

Compound 113 was prepared as single isomer, starting from N-desmethylazithromycin, according to the Scheme below

N-desmethylazιthromyαn

Synthesis of compound 113

(5yS)-2-(Toluene-4-sulfonyloxymethyl)cyclopropanecarboxylic acid ethyl ester (1.0 g, 3.43 mmol), N-desmethylazithromycin (1.80 g, 2.45 mmol), diisopropylethylamine (20 mL), and toluene (8 mL) were placed in a 100 mL flask, purged with argon, and then heated at 115 ⁰ C, with stirring. After 14 h, the reaction mixture was cooled to room temperature, concentrated in vacuo to dryness and purified by flash column chromatography [Si-gel 230- 400 mesh, 10% v/v 0.4M NH ₃ MeOH in CH ₂ Cl ₂ ] affording the (S, 5)-cyclopropane-linked ester as a white powder (2.05 g; 97%); LCMS (CI) m/z 431 (M+2H) ²⁺ /2.

(S, .^-cyclopropane-linked ester (2.50 g, 2.90 mmol) was dissolved in MeOH (10 mL), IN NaOH/H ₂ O (26.0 mL, 26 mmol) was added, the mixture was stirred at 55°C for 2 h

and cooled to room temperature. Water (12 mL) and IN HCI/H ₂ O (6 mL) were added, the mixture was extracted with CH ₂ CI ₂ (4 x 25 mL). The organic phases were combined, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to dryness, affording the (S, S)- cyclopropane-linked acid as a colorless, glassy solid (1.0 g, 41%); LCMS (CI) m/z 417 (M+2H) ²⁺ /2.

The (S, 5)-cyclopropane-linked acid (103 mg, 0.124 mmol), (S)- 2-amino-3-(2-fluoro- 4-thiazol-5-yl-phenyl)-propan-l-ol (29 mg, 0.115 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 29 mg, 0.151 mmol), HOBt (17 mg, 0.125 mmol) and CH ₂ Cl ₂ (5 mL) were stirred under argon, at room temperature. N,N-Diisopropylethyl- amine (44μL, 0.250 mmol) was added and stirring was continued for 24 h.

The reaction mixture was partitioned between CH ₂ CU (20 mL) and H ₂ O (50 mL). The organic phase was washed with saturated NaCl/H ₂ θ (20 mL), dried over MgSO ₄ , filtered, and concentrated in vacuo. The thus obtained glassy solid was purified by flash chromatography [Si-gel 230-400 mesh, 10% v/v 2M NH ₃ /MeOH in CH ₂ Cl ₂ ] affording compound 113, a white solid (36.6 mg, 30%); LCMS (CI) m/z 534 (M+2H) ²⁺ /2.

Compound 114 was prepared as single isomer, starting from N-desmethylazithromycin, according to the Scheme below

Synthesis of compound 114

The synthesis of compound 114, starting from azithromycin and (λ^?)-2-(toluene-4- sulfonyloxymethyl)cyclopropanecarboxylic acid ethyl ester, followed the procedures described above for the synthesis of compound 113. In the last step of the synthetic route as depicted in the Scheme above, EDCI-mediated coupling of (λ _f λ)-cyclopropane-linked acid and (S)- 2-amino-3-(2-fluoro-4-thiazol-5-yl-phenyl)-propan-l-ol afforded compound 114 as a white solid (52 5 mg, 40 5%), LCMS (CI) m/z 534 (M+2H) ²⁺ /2

General procedure for the synthesis of the amines useful in the synthesis of the compounds of the present invention. (2-Amino-3-fluoro-l-[4-(6-methyl-pyridin-3-yl)- phenyl]-propan-l-ol and 2-Amino-3-fluoro-l-(4-pyridin-3-yl-phenyl)-propan-l-ol TFA salt)

B(OH) ₂

3-Pyridine-boronic acid (0.25 g, 2 mmol, 1 eq.), 0.8 g of [l-fluoromethyl-2-hydroxy- 2-(4-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (iodo-intermediate, 2.02 mmol, 1 eq.), 0.07 g of tetrakis(triphenylphosphine)palladium(0) (0.061 mmol, 0.03 eq.) and 0.84 g of K2CO3 (6.06 mmol, 3 eq.) were suspended in toluene/ethanol/ϊhO (v/v/v = 3:1 :1, total volume about 5 ml). The resulting reaction mixture was degassed and heated to 90 -100 ⁰ C for 4-5 hrs. When TLC and LCMS showed no starting material, the reaction mixture was cooled to RT and extracted with ethyl acetate. The organic layer was concentrated and applied directly onto preparative TLC, affording 0.664 g of the Boc-protected amine, which was reacted with TFA in CH ₂ CI ₂ to afford the free amine. Analogous transformations can be carried out with other macrolide cores to prepare compounds of the present invention.

Amine compounds useful in the synthesis of the compounds of the present invention are readily made using generally known chemistries. Exemplary amino compounds are shown below in Table 2.

Antimicrobial activity

The compounds of the present invention were tested for antimicrobial activity. These data are presented in Table 3. The compounds were run against Streptococcus pneumoniae (wild type strain 02J1016) and Streptococcus pyogenes (wild type strain SS1542) using a standard microdilution assay to determine minimum inhibitory concentrations (MICs). The data is presented whereby a "+" indicates that the compound has an MIC value of 16 micrograms/ml or less and a "-" indicates that the compound has an MIC value greater than 16 micrograms/ml. A "N/A" means that data is unavailable. It will be recognized by one skilled in the art that the compounds can be assessed against other bacterial organisms and that the presentation of data for activity against Streptococcus pneumoniae and Streptococcus pyogenes is for illustrative purposes and in no way is intended to limit the scope of the present invention. The compounds of the present invention can be assayed against a range of other microorganisms depending upon the performance activity desired to be gathered. Furthermore, the "+", "-", and "N/A" representation and the selection of a cutoff value of 16 micrograms/ml is also illustrative and in no way is intended to limit the scope of the present invention. For example, a "-" is not meant to indicate that the compound necessarily lacks activity or utility, but rather that its MIC value against the indicated microorganism is greater than 16 micrograms/ml.

Streptococcus Streptococcus

TABLE 3 pneumoniae pyogenes

Compound

107 + N/A

108 + N/A

109 + N/A

110 + +

111 + +

112 + +

113 + +

114 + +

115 + +

116 + +

117 + +

118 + +

119 + +

120 + +

121 + +

122 + N/A

123 + N/A

124 + +

125 + +

126 + +

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.