Macrolide Compounds And Methods Of Making And Using The Same

  • Published: Sep 4, 2008
  • Earliest Priority: Feb 28 2007
  • Family: 9
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MA CROLIDE COMPOUNDS AND METHODS OFMAKINGAND USING THE SAME

RELATED APPLICATIONS

This application incorporates by reference and 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.

FIELD OF THE INVENTION

The present invention relates generally to the field of anti-infective, antiproliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family of triazole 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. Clin. 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 antiproliferative 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 al., Lancet, vol. 358, p. 207 (2001); Gonzales et ah, Lancet, vol 357, p. 1179 (2001); Zurenko et al., Proceedings Of The 39th 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-diarrheal agents, anti-viral agents, and chemotherapeutic agents. The present invention also provides compounds useful as anti- inflammatory 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 compounds having the structure:

or a stereoisomer, pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In the formula, variables G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd and Re are 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 antiproliferative agents and/or anti-infective agents. The compounds can be used without limitation, for example, as anti-cancer, anti-microbial, anti-bacterial, anti-fungal, anti- parasitic 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., =O), 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, or N=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., R2) 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 R2 moieties, then the group can optionally be substituted with one, two, three, four, five, or more R2 moieties, and R2 at each occurrence is selected independently from the definition of R2. 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 where there are nitrogen 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. C1.6 alkyl is intended to include Ci, C2, C3, C4, C5, and Ce alkyl groups. C1-8 alkyl is intended to include C1, C2, C3, C4, C5, Ce, Cη, and Cs 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. C2-6 alkenyl is intended to include C2, C3, C4, C5, and CO alkenyl groups. C2-8 alkenyl is intended to include C2, C3, C4, C5, C6, Cη, and Cs 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. C2-6 alkynyl is intended to include C2, C3, C4, C5, and C6 alkynyl groups. C2-8 alkynyl is intended to include C2, C3, C4, C5, Ce, Cη, and Cg 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 -CH2CH2-, 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, "C 1-6 alkyl- R3" is intended to represent a univalent Ci.6 alkyl group substituted with a R3 group, and "O- C 1-6 alkyl-R3" is intended to represent a bivalent C 1-6 alkyl group, i.e., an "alkylene" group, substituted with an oxygen atom and a R3 group.

As used herein, "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-8 cycloalkyl is intended to include C3, C4, C5, Ce, Cη, 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 -CVFW 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. C1.6 alkoxy, is intended to include Ci, C2, C3, C4, C5, and Cβ alkoxy groups. C1-8 alkoxy, is intended to include C1, C2, C3, C4, C5, Ce, C7, and Cs 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 a sulfur bridge. C 1.6 alkylthio, is intended to include C1, C2, C3, C4, C5, and Ce alkylthio groups. C1-8 alkylthio, is intended to include Ci, C2, C3, C4, C5, Ce, C7, and Cs 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 T). 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, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3Η-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, 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 an existing 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-diarrheal activity, anti-parasitic 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

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 C1-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2-6 alkynyl group, (f) -OH, (g) -OR5, (h) -NR4R4, (i) -C(O)R5, (j) -C(O)OR5, (k) - C(O)-NR4R4, (1) -C(S)R5, (m) -C(S)OR5, (n) -C(O)SR5, (o) -C(S)-NR4R4, (p) -N3, (q) -CN, (r) -CF3, (S) -CF2H, (t) -CFH2, (u) -S(O)PH, (v) -S(O)pR5, (w) -S(O)POH, (x) -S(O)POR5, (y) -S(O)pNR4R4, (z) a C3-12 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;

Ra and Rb independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(=O)R5, (i) - C(=O)OR5, G) -C(=O)-NR4R4, (k) -S(O)pNR4 R4, (1) -C(O)SR5, (m) halogen, (n) -S(O)PH, and (o) - S(O)pR5, wherein (b) -(d) are further optionally substituted with one or more R5 ; alternatively Ra and Rb are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, or (d) -C=NOR5;

Rc is selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OR5, wherein R5 is not H, (f) -NR4R4, (g) -C(=O)R5, (h) -C(=O)OR5, (i) -C(=O)-NR4R4, O) -S(O)PNR4 R4, (k) -C(O)SR5, (1) -S(O)13H, and (m) - S(O)PR5, wherein (b) -(d) are further optionally substituted with one or more R5; Rd and Re independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(=O)R5, (i) - C(=O)OR5, 0) -C(=O)-NR4R4, (k) -S(O)PNR4 R4, (1) -C(O)SR5, (m) halogen, (n) -S(O)PH, and (o) - S(O)pR5, wherein (b) -(d) are further optionally substituted with one or more R5, or alternatively Rd and Re are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, or (d) -C=NOR5; alternatively, Rc and Rd or Rc and Re are taken together to form a carbon-carbon double bond between the carbon atoms to which they are attached; alternatively Rd and X are taken together to form =CR5R5; or alternatively Rd and Re are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, (d) -C=NOR5, (e) =CH2, or (f) 3-12- membered carbocycle or heterocycle optionally substituted with one or more R5;

R1 and R3 independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -C(O)R5, (f) -C(O)OR5, (g) -C(O)-NR4R4, (h) - C(S)R5, (i) -C(S)OR5, G) -C(O)SR5, and (k) -C(S)-NR4R4; alternatively R1 and R3 are taken together with the oxygen to which R1 is attached, the nitrogen to which R3 is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R5 groups; R2 is hydrogen or -OR12; 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 R11 or RUa; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) - OR9, (dd) -SH, (ee) -S(O)PR9, (ff) halogen, (gg) -CN, (hh)-N3, (ii) -NO2, Oj) -Si(R13K (kk) -SO3H, (11) -SO3N(R4)2, (mm) - SO3R9, (nn) -NR6R6, (oo) -C(O)R9, (pp) -C(O)(CR6R6)tR9, (qq) -OC(O)(CR6R6)tR9, (rr) -C(O)O(CR6R6)tR9, (ss) NR6(CR6R6)tR9, (tt) -NR6C(O)(CR6R6)tR9, (uu) - C(O)NR6(CR6R6)tR9, (w) -NR6C(O)NR6(CR6R6)tR9, (ww) - C(=NR6)(CR6R6)tR9, (xx) -C(=NR6)NR6)(CR6R6)tR9, (yy) - NR6C(=NR6)NR6)(CR6R6)tR9, (zz) -S(CR^tR9, (aaa) - S(O)p(CR6R6)tR9, (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) -C1-6 alkyl, (eee) -C2-6 alkenyl, and (fff) a C2-6 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 R11 or Rl la; wherein each (ddd), (eee), or (fff) is optionally are substituted with one or more R14 groups; (iii) Z is selected from (a) a single bond, (b) -C1-6 alkyl-, (c) -C2-^ alkenyl-, (d) -C2-6 alkynyl-, (e) -O-, (f) -NR4-, (g) -S(O)P-, (h) - C(O)-, (i) -C(O)O-, (j) -OC(O)- (k) -OC(O)O-, (1) -C(O)NR4- , (m) -NR4CO-, (n) -NR4C(O)NR4- (o) -C(=NR4)-, (p) - C(=NR4)O-, (q) -OC(=NR4)-, (r) -C(=NR4)NR4-, (s) - NR4C(=NR4)-, (t) -C(=S)-, (u) -C(=S)NR4-, (v) -NR4C(=S)-, (w) -C(O)S-, (x) -SC(O)-, (y) -OC(=S)-, and (z) -C(=S)-O-, wherein any of the aliphatic carbons atoms in (b), (c), or (d) is optionally replaced with -(C=O)-, -O-, -S-, or -NR4-, and wherein any of (b), (c), or (d), are optionally further substituted with -OH, -NR4-, or halogen; R4, at each occurrence, independently is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-12 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 sulfur, (g) -C(O)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-12 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-C1-6 alkyl, (m) - C(O)O-C2-6 alkenyl, (n) -C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 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)NR6R6, wherein any of (b)-(p) optionally is substituted with one or more R5 groups, alternatively, NR4R4 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R4 groups are bonded, wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R4 groups are bonded, with one or more moieties selected from O, S(O)P, N, and NR8; R5 is selected from:

(a) R7, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-12 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, wherein any of (b)-(f) immediately above optionally is substituted with one or more R7 groups; alternatively two R5 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 3-12 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of these ring systems formed from two R5 groups optionally is substituted with one or more R7 groups; R6, at each occurrence, independently is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-12 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, wherein any of (b)-(f) optionally is substituted with one or more moieties selected from: (aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) NO2, (ii) -OR8, (jj) -S(O)pR8, (kk) - C(O)R8, (11) -C(O)OR8, (mm) -OC(O)R8, (nn) -C(O)NR8R8, (oo) -OC(O)NR8R8, (pp) -C(=NR8)R8, (qq) -C(R8)(R8)OR8, (rr) - C(R8)2OC(O)R8, (ss) -C(R8)(OR8)(CH2)rNR8R8, (tt) -NR8R8, (uu) -NR8OR8, (w) -NR8C(O)R8, (ww) -NR8C(O)OR8, (xx) - NR8C(O)NR8R8, (yy) -NR8S(O)rR8, (zz) -C(OR8)(OR8)R8, (ab) - C(R8)2NR8R8, (ac) =NR8, (ad) -C(S)NR8R8, (ae) -NR8C(S)R8, (af) -OC(S)NR8R8, (ag) -NR8C(S)OR8, (ah) -NR8C(S)NR8R8, (ai) -SC(O)R8, (aj) a Cj-6alkyl group, (ak) a C2-6 alkenyl group, (al) a C2-O alkynyl group, (am) a C1-6 alkoxy group, (an) a C1-6 alkylthio group, (ao) a C1-6 acyl group, (ap) -CF3, (aq) -SCF3, (ar) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (as) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR6R6 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R6 groups are attached wherein said ring is optionally replaced at a position other than the nitrogen atom to which the R6 groups are bonded, with one or more moieties selected from -O-, -S(O)p-, -N=, and -NR8-; alternatively, CR6R6 forms a carbonyl group; R7, at each occurrence, is selected from:

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -N3 (j) -NO2, (k) - NR6(CR6R6)tR9, (1) -OR9, (m) -S(O)pC(R6R6)tR9, (n) -C(O)(CR6R6)tR9, (o) - OC(O)(CR6R6)tR9, (p) -SC(O)(CR6R6)tR9, (q) -C(O)O(CR6R6)tR9, (r) - NR6C(O)(CR6R6)tR9, (s) -C(O)NR6(CR6R6)tR9, (t) -C(=NR6)(CR6R6)tR9, (u) - C(=NNR6R6)(CR6R6)tR9, (v) -C(=NNR6C(O)R6)(CR6R6)tR9, (w) - C(=NOR9)(CR6R6)tR9, (x) -NR6C(O)O(CR6R6)tR9, (y) -OC(O)NR6(CR6R6)tR9, (z) -NR6C(O)NR6(CR6R6)tR9, (aa) -NR6S(O)p(CR6R6)tR9, (bb) - S(O)pNR6(CR6R6)tR9, (cc) -NR6S(O)pNR6(CR6R6)tR9, (dd) -NR6R6, (ee) - NR6(CR6R6), (fϊ) -OH, (gg) -NR6R6, (hh) -OCH3, (ii) -S(O)pR6, Oj) -NC(O)R6, (kk) -Si(R13)3, (11) a C1_6 alkyl group, (mm) a C2.6 alkenyl group, (nn) a C2.6 alkynyl group, (oo) -C3-12 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 (ll)-(pp) optionally is substituted with one or more R9 groups; alternatively, two R7 groups can form -O(CH2)UO-, =O, or =S; R8 is selected from:

(a) R5, (b) H, (c) a C1-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2.6 alkynyl group, (f) a C3-12 saturated, unsaturated, or aromatic carbocycle, (g) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (h) -C(O)-C1-6 alkyl, (i) - C(O)-C2-6 alkenyl, 0') -C(O)-C2-6 alkynyl, (k) -C(O)-C3-12 saturated, unsaturated, or aromatic carbocycle, and (1) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (c)-(l) optionally is substituted with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, (jj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2, (11) a C1-6 alkoxy group, (mm) an aryl group, (nn) a substituted aryl group, (oo) a heteroaryl group, (pp) a substituted heteroaryl group, and (qq) a C1-6 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, NO2, CF3, SCF3, and OH; R9, at each occurrence, independently is selected from:

(a) R10, (b) a C1-6 alkyl group, (c) a C2.6 alkenyl group, (d) a C2.6 alkynyl group, (e) a C3-12 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, wherein any of (b)-(f) optionally is substituted with one or more R10 groups; R10, at each occurrence, independently is selected from: (a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -NO2, G) -NR6R6, (k) -OR6, (1) -S(O)pR6, (m) -C(O)R6, (n) -C(O)OR6, (o) -OC(O)R6, (p) NR6C(O)R6, (q) -C(O)NR6R6, (r) -C(=NR6)R6, (s) -NR6C(O)NR6R6, (t) - NR6S(O)pR6, (u) -S(O)pNR6R6, (v) -NR6S(O)pNR6R6, (w) a C1-6 alkyl group, (x) a C2.6 alkenyl group, (y) a C2.6 alkynyl group, (z) a C3-I2 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 R6, F, Cl, Br, I, CN, NO2, -OR6, -NH2, -NH(C1-6 alkyl), - N(C1-6 alkyl)2, a C1-6 alkoxy group, a C1-6 alkylthio group, and a C1-6 acyl group; Rn and Rl la at each occurrence, independently is selected from:

(a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h) NO2, (i) OR8, (j) -S(O)pR8, (k) -C(O)R8, (1) -C(O)OR8, (m) -OC(O)R8, (n) - C(O)NR8R8, (o) -OC(O)NR8R8, (p) -C(=NR8)R8, (q) -C(R8)(R8)OR8, (r) - C(R8)2OC(O)R8, (s) -C(R8)(OR8)(CH2)rNR8R8, (t) -NR8R8, (u) -NR8OR8, (v) -NR8C(O)R8, (w) -NR8C(O)OR8, (x) -NR8C(O)NR8R8, (y) -NR8S(O)PR8, (z) -C(OR8)(OR8)R8, (aa) -C(R8)2NR8R8, (bb) =NR8, (cc) -C(S)NR8R8, (dd) - NR8C(S)R8, (ee) -OC(S)NR8R8, (ff) -NR8C(S)OR8, (gg) -NR8C(S)NR8R8, (hh) -SC(O)R8, (ii) -N3, (jj) -Si(R13)3, (kk) a C1-6 alkyl group, (11) a C2-6 alkenyl group, (mm) a C2-6 alkynyl group, (nn) a C1-6 alkoxy group, (oo) a C1-6 alkylthio group, (pp) a C1-6 acyl group, (qq) a C3-12 saturated, unsaturated, or aromatic carbocycle, (rr) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (ss) -B(OH)2, (tt) -B(OC1-6 alkyl)2, (uu) - B(OH)(OC1-6 alkyl), (w) -B[-OC(CH3)2(CH3)2CO-], (ww) -P(OH)2, (xx) - P(OC1-6 alkyl)2, (yy) -P(OH)(OC1-6 alkyl), and (zz) -NR8(C=NR8)R8 wherein (kk)-(mm) optionally are substituted with one or more R5 groups; R12 is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -C(O)R5, (f) -C(O)OR5, (g) -C(O)-NR4R4, (h) -C(S)R5, (i) -C(S)OR5, (j) -C(O)SR5, (k) -C(S)-NR4R4, (1) a C3-12 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 -(C1-6 alkyl) -C3-12 saturated, unsaturated, or aromatic carbocycle, and (o) a -(C1-6 alkyl)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (b)-(d) and (l)-(0) optionally are substituted with one or more R5 groups; each R13 is independently selected from (a) -C1-6 alkyl and (b) -O-(C1-6 alkyl): wherein R14 at each occurrence is independently selected from:

(a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)PR8, Q) - C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8, (o) -C(=NR8)R8, (P) ^C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) - C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) - NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)pR8, (y) -C(OR8)(OR8)R8, (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -OC(S)NR8R8, (dd) -NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) -N3, (hh) - Si(R13)3, (ϋ) a C1-6 alkyl group, (jj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl group, (11) a C3-12 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 R5 groups; p at each occurrence is 0, 1, or 2; r at each occurrence is 0, 1, or 2; t at each occurrence is 0, 1 , or 2; and u at each occurrence is 1, 2, 3, or 4.

In the present invention, the macrolide, "T" is defined to include various 14- and 15- membered ring systems, which can contain one or more heteroatoms. Also, as defined herein, the macrolide, "T" is connected via a macrocyclic ring carbon atom, which means that the connection or bond is made to a carbon atom on the 14- or 15-membered ring of the macrolide moiety. The macrolide can include further substituents, including ring substituents. For example, the substituent designated as R103 can in certain embodiments be a sugar moiety, e.g. a cladinose sugar, or the substituents such as R104 and R105 are taken together in certain embodiments to form a bridged bicyclic ring system with the macrolide ring, or the substituents R105 and R106 , are taken together in certain embodiments to form a fused bicyclic ring system with the macro lide ring, or the substituents or components M, R105, and R are taken together to form a fused tricyclic ring system with the macrolide ring, etc. It is also recognized in the present invention that "T" is depicted as being connected to a 6- membered ring, for example in certain embodiments a desosamine sugar ring.

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 G48

G49 GS0

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, X, R , R2, R3, R\ Rb, Rc, Rd, and Re are as described above.

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, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described above.

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, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described above.

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 (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -CN, (g) -CF3, (h) -CF2H, (i) -CFH2, Q) -O(C1-6 alkyl), (k) -N3, (1) -COOH, (m) -COO(C1-6 alkyl), (n) -NH2, (o) -NH(C1-6 alkyl), (p) -N(C1-6 alkyl)2, (q) -C(O)NH2, (r) -C(O)NH(C1-6 alkyl), (s) -C(O)N(C1-6 alkyl)2, (t) -NHC(O)H, (u) - NHC(O)(C1-6 alkyl), (v) -N(C1-6 alkyl)C(O)H, and (w) -N(C1-6 alkyl)C(O)N(C1-6 alkyl)2.

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 and 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 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 R and Re are selected from (a) Cl, (b) Br, (c) F, (d) H and (e) C1-6 alkyl.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are H.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rc is selected from (a) H, (b) C1-6 alkyl, (c) -CF3, (d) -CF2H, and (e) -CFH2.

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

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra and Rb are independently selected from (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -O(Cj-6 alkyl), (g) -N3, (h) -COOH, (i) -COO(C1-6 alkyl), (j) -CN, (k) -NH2, (1) -NH(C1-6 alkyl), (m) -N(C1-6 alkyl)2, (n)-C(O)NH2, (o) -C(O)NH(C1-6 alkyl), (p) -C(O)N(C1-6 alkyl)2, (q) -NHC(O)H, (r) - NHC(O)(C-6 alkyl), (s) -N(C1-6 alkyl)C(O)H, (t) -N(C1-6 alkyl)C(O)N(C1-6 alkyl)2, (u) -SH, and (v) -S(C1-6 alkyl), or alternatively Ra and Rb are taken together with the carbon to which they are attached to form (aa) -C(O)- or (bb) -C(=S)-.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein Ra and Rb are independently selected from -H, -F, -OH, -OCH3, -SH, and -SCH3.

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

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -OCH3.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -SH.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -SCH3.

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

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 is H.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R2 is H.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is C1-6 alkyl.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is methyl.

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 B' is selected from: (a) an aryl group, (b) a heteroaryl group, (c) a biaryl group, and (d) a fused bicyclic or tricyclic unsaturated or aromatic ring system optionally containing one or more carbonyl groups and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (a)-(d) optionally is substituted with one or more R1 ' groups. 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, N-oxide, or prodrug thereof, wherein B' and B" are independently selected from: (a) saturated or unsaturated heterocycle, (b) an aryl group, (c) a heteroaryl group, (d) a biaryl group, and (e) a fused bicyclic or tricyclic unsaturated or aromatic ring system optionally containing one or more carbonyl groups and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (a)-(e) optionally is substituted with one or more R11 groups, and Z is selected from (aa) a single bond, (bb) -O-, (cc) -NR4-, (dd) -C(O)-, (ee) -C(S)-, (ff) -S(O)P-, (gg) -S(O)p(CI-6 alkyl)-and (hh) a C1-6 alkyl.

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, X, R1, R2, and R3 are as described above.

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, R1, R2, and R3 are as described above.

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, X, R1, R2, and R3 are as described above.

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, R1, R2, and R3 are as described above.

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, X, R1, R2, and R3 are as above. 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, R1, R2, and R3 are as described above.

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, X, R1, R2, and R3 are as described above.

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, R1, R2, and R3 are as described above.

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, X, R1, R2, and R3 are as described above.

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, R1, R2, and R3 are as described above.

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

where B", Z, and R1 ' are as described above.

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

where B", Z, and R1 ' are as described above. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:

where B", Z, and R are as described above.

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

where B", Z, and R are as described above.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is selected from H and F.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is H.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is F.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1_6 alkyl group, (b) a C2_6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) H, (g) -OH (h) -SH, (i) F, (j) Cl, (k) Br, (1) I, (m) -CF3, (n) -CN, (o) -N3 (p) -NO2, (q) -NR6(CR6R6)tR9, (r) -OR9, (s) -S(CR6R6)tR9, (t) -S(O)(CR6R6)tR9, (u) -S(O)2(CR6R6)tR9 (v) - C(O)(CR6R6)tR9, (w) -OC(O)(CR6R6)tR9, (x) -OC(O)O(CR6R6)tR9, (y) -SC(O)(CR6R6)tR9, (z) -C(O)O(CR6R6)tR9, (aa) -NR6C(O)(CR6R6)tR9, (bb) -C(O)NR6(CR6R6)tR9, (cc) - C(=NR6)(CR6R6)tR9, (dd) -C(=NNR6R6)(CR6R6)tR9, (ee) -C [-NNR6C(O)R6] (CR6R6)tR9, (ff) -NR6C(O)O(CR6R6)tR9, (gg) -OC(O)NR6(CR6R6)tR9, (hh) -NR6C(O)NR6(CR6R6)tR9, (ii) -NR6S(O)p(CR6R6)tR9, (jj) -S(O)pNR6(CR6R6)tR9, (kk) -NR6R6, (11) -NR6(CR6R6)tR9, (mm) -SR6, (nn) -S(O)R6, (oo) -S(O)2R6, (pp) -NR6C(O)R6, (qq) -Si(R13)3, and (rr) -

C(=O)H; wherein t at each occurrence is 0, 1, or 2, further wherein (a)-(e) optionally are substituted with one or more R14 groups;

R14 at each occurrence is independently selected from:

(a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)PR8, (j) - C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8, (o) - C(=NR8)R8, (p) -C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) - C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) - NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)pR8, (y) -C(OR8)(OR8)R8, (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -OC(S)NR8R8, (dd) - NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) -N3, (hh) -Si(R13)3, (ii) a C1-6 alkyl group, (jj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl group, (11) a C3-12 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 R5 groups; alternatively two R14 groups are taken together to form =O, =S, =NR8, or =NOR8. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1_6 alkyl group, (b) a C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) -CF3, (g) -

NR6(CR6R6)tR9, (h) -OR9, (i) -S<CR6R6)tR9, (j) -S(O)(CR6R6)tR9, (k) -S(O)2 (CR6R6)tR9 (1) - C(O)(CR6R6)tR9, (m) -OC(O)(CR6R6)tR9, (n) -OC(O)O(CR6R6)tR9, (o) -SC(O)(CR6R6)tR9, (p) -C(O)O(CR6R6)tR9, (q) -NR6C(O)(CR6R6)tR9, (r) -C(O)NR6(CR6R6)tR9, (s) - C(=NR6)(CR6R6)tR9, (t) -C(=NNR6R6)(CR6R6)tR9, (u) -C[=NNR6C(O)R6](CR6R6)tR9, (v) - NR6C(O)O(CR6R6)tR9, (w) -OC(O)NR6(CR6R6)tR9, (x) -NR6C(O)NR6(CR6R6)tR9, (y) -

NR6S(O)p(CR6R6)tR9, (z) -S(O)pNR6(CR6R6)tR9, (aa) -NR6R6, (bb) -NR6(CR6R6)tR9, (cc) - SR6, (dd) -S(O)R6, (ee) -S(O)2R6, and (ff) -NR6C(O)R6, wherein (a)-(e) optionally are substituted with one or more R14 groups. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1_6 alkyl group, (b) a C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, wherein (a)-(e) optionally are substituted with one or more R14 groups.

In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) -NR6(CR^tR9, (b) -OR9, (c) -S(CR6R6)tR9, (d) -S(O)(CR6R6)tR9, (e) - S(O)2(CR6R6)tR9, (f) -C(O)(CR6R6)tR9, (g) -OC(O)(CR6R6)tR9, (h) -OC(O)O(CR6R6)tR9, (i) -SC(O)(CR6R6)tR9, G) -C(O)O(CR6R6)tR9, (k) -NR6C(O)(CR6R6)tR9, (1) - C(O)NR6(CR6R6)tR9, (m) -C(=NR6)(CR6R6)tR9, (n) -C(=NNR6R6)(CR6R6)tR9, (o) - C[=NNR6C(O)R6](CR6R6)tR9, (p) -NR6C(O)O(CR6R6)tR9, (q) -OC(O)NR6(CR6R6)tR9, (r) - NR6C(O)NR6(CR6R6)tR9, (s) -NR6S(O)P(CR6RO)1R9, (t) -S(O)pNR6(CR6R6)tR9, (u) - NR6R6, (v) -NR6(CR6R6)tR9, (w) -SR6, (x) -S(O)R6, (y) -S(O)2R6, and (z) -NR6C(O)R6.

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

wherein:

M is selected from:

» 114x

(a) -C(O)-, (b) -CH(-OR11V, (c) -NR114-CH2- (d) -CH2-NR114-, (e) - CH(NR114R11V, (f) -C(=NNR114R11V, (g) -NR114-C(O)-, (h) -C(O)NR114-, (i) - 0') -CR115R115- and (k) -C(=NOR127)-;

R100 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR114, and (f) C1-6 alkyl, wherein (f) optionally is substituted with one or more R115 groups; R101 is selected from:

(a) H, (b) Cl, (c) F, (d) Br, (e) I, (f) -NR114R114, (g) -NR114C(O)R114, (h) -OR114, (i) -OC(O)R114, (j) -OC(O)OR114, (k) -OC(O)NR114R114, (1) -O-C1-C6 alkyl, (m) -OC(O)-C1-6 alkyl, (n) -OC(O)O-C1-6 alkyl, (o) -OC(O)NR114-C1-6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2-6 alkynyl, wherein any of (1) - (r) optionally is substituted with one or more

R115 groups;

R102 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR114, and (f) Cj-6 alkyl, wherein (f) ooptionally is substituted with one or more R115 groups; R103 is selected from:

(a) H, (b) -OR114, (c) -O-C1-6 alkyl-R115, (d) -OC(O)R114, (e) -OC(O)-C1- 6 alkyl-R115, (f) -OC(O)OR114, (g) -OC(O)O-C1-6 alkyl-R115, (h) - OC(O)NR114R114, (i) -OC(O)NR114-C1-6 alkyl-R115, and

alternatively, R102 and R103 taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-12 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups; alternatively, R101 and R103 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 R100 and R102 are attached; alternatively, R101 and R103 taken together with the carbons to which they are attached form a 3-12 membered carbocyclic or heterocyclic ring, wherein said 3-12 membered ring can optionally be substituted with one or more R114 groups; alternatively, R100, R101, R102, and R103 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 R114 groups; R104 is selected from:

(a) H, (b) R114, (c) -C(O)R114 (d) -C(O)OR114 (e) -C(O)NR114R114, (f) -C1-6 alkyl-K-R114, (g) -C2-6 alkenyl-K-R114, and (h) -C2-6 alkynyl-K-R114; K is selected from:

(a) -C(O)-, (b) -C(O)O-, (C) -C(O)NR114-, (d) -C(=NR114)-, (e) -C(^NR114)O-, (f) -C(=NR114)NR114-, (g) -OC(O)-, (h) -OC(O)O-, (i) -OC(O)NR114- G) - NR114C(O)-, (k) -NR114C(O)O-, (1) -NR114C(O)NR114- (m) - NR114C(=NR114)NR114-, and (n) -S(O)P-; alternatively R103 and R104, taken together with the atoms to which they are bonded, form:

wherein R135 and R136 are selected from (a) hydrogen, (b) C1-O alkyl, (c) C2-6 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 oxygen, nitrogen, or sulfur atoms, (g) F, (h) Br, (i) I, (j) OH, and (k) -N3, wherein (b) through (f) are optionally substituted with one or more R117; or alternatively, R135 and R136 are taken together to form =O, =S, =NR114, ^=NOR114, =NR114, or =N-NR114R114, wherein V is selected from (a) -(C^-alkyl)-, (b)-(C2-4-alkenyl)-, (c) O, (d) S, and (e) NR114, wherein (a) and (b) are optionally further substituted with one or more R117;

R 105 is selected from:

(a) (d) -O-C1-6 alkyl-R115, (e) -C(O)-R114, (f) - C(O)-C1-6 alkyl-R115, (g) -OC(O)-R114, (h) -OC(O)-C1-6 alkyl-R115, (i) -OC(O)O- R114, O) -OC(O)O-C1-6 alkyl-R115, (k) -OC(O)NR114R114, (1) -OC(O)NR114-C( * alkyl-R » 111 °5, (m) -C(O)-C2-6 alkenyl-R 1115 , and (n) -C(O)-C2-6 alkynyl-R , 115. alternatively, R , 104 and R , 105 , taken together with the atoms to which they are bonded, form

wherein Q is CH or N, and R 112/6o is -OR1 , -NR114 or R , 114. alternatively, R104 and R105, taken together with the atoms to which they are bonded, form:

, wherein i) R149 is selected from:

(a) H, (b) Cl, (C) F, (d) Br, (e) I, (f) -NR114R114, (g) -NR114C(O)R114, (h) -OR114, (i) - OC(O)R114, (j) -OC(O)OR114, (k) -OC(O)NR114R114, (1) -O-C1-6 alkyl, (m) -OC(O)-C1-6 alkyl, (n) -OC(O)O-C1-6 alkyl, (o) -OC(O)NR114-C1-6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2-6 alkynyl, wherein any of (1) - (r) optionally is substituted with one or more R115 groups; ii) R150 is H, C1-6 alkyl, or F; ii) alternately, R149 and R150 can be taken together with the carbon to which they are attached to form a carbonyl group; iii) alternately, R149 and R150 can be taken together to form the group -O(CR116R116)UO-; iv) alternatively, R104 and R105, 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) R130 is -OH, or R114, ii) R131 is -OH, or R114, iii) alternately, R130 and R131 together with the carbons to which they are attached form a 3-12 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups; iv) alternatively, R130 and the carbon to which it is attached or R131 and the carbon to which it is attached are each independently -C(=O)-; v) alternatively, R105, R132 and M, taken together with the atoms to which they are attached, form:

R106 is selected from:

(a) -OR114, (b) -C1-6 alkoxy-R115, (c) -C(O)R114, (d) -OC(O)R114, (e) - OC(O)OR114, (f) -OC(O)NR114R114, and (g) -NR114R114, alternatively, R105 and R106 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(R115)2O-, (b) -OC(O)O-, (c) -OC(O)NR114-, (d) -NR114C(O)O-, (e) - OC(O)NOR114-, (f) -NOR114-C(O)O-, (g) -OC(O)N[NR114R114] - (h) - N[NR114R114]-C(O)O-, (i) -OC(O)C(R115)2- (j) -C(R115)2C(O)O-, (k) -OC(S)O-, (1) -OC(S)NR114-, (m) -NR114C(S)O-, (n) -OC(S)NOR114-, (o) -NOR114-C(S)O-, (p) -OC(S)N[NR114R114]-, (q) -N[NR114R114J-C(S)O-, (r) -OC(S)C(R115)2- (s) - C(R115)2C(S)O-, (t) -OC(O)CR115[S(O)pR114] - (u) -OC(O)CR11^NR114R114] -, (v) -CR115[NR114R114]C(O)O-, and (w) -CR11^S(O)PR114]C(O)O-; alternatively, R105, R106, and R133 taken together with the atoms to which they are attached form:

alternatively, M, R105, and R , 1i0υ6t) . taken together with the atoms to which they are attached form:

wherein J1 and J2 are selected from hydrogen, Cl, F, Br, I, OH, -C1-6 alkyl, and -O(C1-6 alkyl) or are taken together to form =O, =S, =NR114, =NOR114, =NR114, or =N-NR114R114, alternatively, M and R104 taken together with the atoms to which they are attached form:

wherein U is selected from (a) -(Q-4-alkyl)- and (b)-(C2-4-alkenyl)-, wherein (a) and (b) are optionally further substituted with one or more R117; alternatively, M and R105 are taken together with the atoms to which they are attached to form:

R107 is selected from

(a) H, (b) -C1-6 alkyl, (c) -C2-6 alkenyl, which can be further substituted with C1-6 alkyl or one or more halogens, (d) -C2-6 alkynyl, which can be further substituted with C1-6 alkyl or one or more halogens, (e) aryl which can be further substituted with C1-6 alkyl or one or more halogens, (f) heteroaryl, which can be further substituted with C1-6 alkyl or one or more halogens, (g) - C(O)H, (h) -COOH, (i) -CN, O) -COOR114, (k) -C(O)NR114R114, (1) - C(O)R114, and (m) -C(O)SR114, wherein (b) is further substituted with one or more substituents selected from (aa) -OR114, (bb) halogen, (cc) -SR114, (dd) C1-6 alkyl, which can be further substituted with halogen, hydroxyl, C1-6alkoxy, or amino, (ee) -OR114, (ff) -SR114, (gg) -NR114R114, (hh) -CN, (ii) -NO2, (jj) -NC(O)R114, (kk) -COOR114, (11) -N3, (mm) =N-O-R114, (nn) =NR114, (oo) ^N-NR114R114, (pp) =N-NH-C(O)R114, or (qq) =N-NH- C(O)NR114R114; alternatively R106 and R107 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 C3- C7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a C1 -6 alkyl;

R108 is selected from:

(a) C1-6 alkyl, (b) C2-6 alkenyl, and (c) C2-6 alkynyl, wherein any of (a)-(c) optionally is substituted with one or more R114 groups;

R109 is H, C1-6alkyl, or F;

R114, at each occurrence, independently is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 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)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-12 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-C1-6 alkyl, (m) -C(O)O-C2-6 alkenyl, (n) - C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 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)NR116R116, (r) -NR116CO-C1-6 alkyl, (s) - NR116CO-C3-12 saturated, unsaturated, or aromatic carbocycle, (t) -NR116C(O)- 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (u) -(C1-6 alkyl)-O-(C1-6 alkyl), (v) -(C1-6 alkyl)-O-(C1-6 alkyl)-O-(C1-6 alkyl), (w) -OH, (x) -OR115, (y) -NH(C1-6 alkyl), (z) -N(C1-6 alkyl)2, (aa) -(C1-6 alkyl)-S(O)p- (C1-6 alkyl), (bb) -(C1-6 alkyl)- S(O)p-(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (cc) -(C1-6 alkyl)-O-(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (dd) -(C1-6 alkyl)- S(O)p-(C1-6 alkyl)-O-(C1-6 alkyl); and (ee) -NH2; 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 R115 groups, wherein one or more non-terminal carbon moieties of any of (b)-(d) optionally is replaced with oxygen, S(O)p, or-NRU6 ( alternatively, NR114R114 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R114 groups are bonded and optionally one or more moieties selected from O, S(O)p, N, and NR118; R115 is selected from:

(a) R117, (b) C1-6 alkyl, (c) C2-6 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) -OCj-6 alkyl, (h) -OC2-6 alkenyl, and (i) -OC2-6 alkynyl, wherein any of (b)-(f) optionally is substituted with one or more R117 groups; R116, at each occurrence, independently is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-12 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 -NR118, 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) N3, (ii) NO2, (jj) OR118, (kk) -S(O)PR118, (11) -C(O)R118, (mm) - C(O)OR118, (nn) -OC(O)R118, (oo) -C(O)NR118R118, (pp) - OC(O)NR118R118, (qq) -C(=NR118)R118, (rr) -C(R118)(R118)OR118, (ss) - C(R118)2OC(O)R118, (tt) -C(R118)(OR118)(CH2)rNR118R118, (uu) - NR118R118; (w) -NR118OR118, (ww) -NR118C(O)R118, (xx) - NR118C(O)OR118, (yy) -NR118C(O)NR118R118, (zz) -NR118S(O)rR118,

(ab) -C(OR118)(OR118)R118, (ac) -C(R118)2NR118R118, (ad) =NR118, (ae) -C(S)NR118R118, (af) -NR118C(S)R118, (ag) -OC(S)NR118R118, (ah) - NR118C(S)OR118, (ai) -NR118C(S)NR118R118, (aj) -SC(O)R118, (ak) C1-6 alkyl, (al) C2-6 alkenyl, (am) C2-6 alkynyl, (an) C1-8 alkoxy, (ao) C1-6 alkylthio, (ap) C1-6 acyl, (aq) saturated, unsaturated, or aromatic C3-12 carbocycle, and (ar) saturated, unsaturated, or aromatic 3-12 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR116R116 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R116 groups are attached and optionally one or more moieties selected from O, S(O)p, N, and NR118; alternatively, CR116R116 forms a carbonyl group; R117, at each occurrence, is selected from:

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h) (CR116R116)rCN,

(i) (CR116R116)rNO2, Q) (CR116R116)rNR116(CR116R116)tR119, (k) (CR116R116)rOR119,

(1) (CR116R116)rS(O)P(CR116R116)tR119, (m) (CRU6R116)rC(O)( CR116R116)tR119,

(n) (CR116R116)rOC(O)( CR116R116)tR119, (o) (CR116R116)rSC(O)( CR116R116),R119,

(p) (CR116R116)rC(O)O(CR116R116),R119, (q) (CR116R116)rNR116C(O)(CR116R116),R119,

(r) (CR116R116)rC(O)NR116(CR116R116)tR119, (s)

(CR116R116)rC(=NR116)(CR116R116),R119,

(t) (CR116R116)rC(=NNR116R116)(CR116R116)tR119,

(u) (CR116R116)rC(=NNR116C(O)R116)(CR116R116VR119,

(v) (CR116R116)rC(=NOR119)(CR116R116)tR119,

(w) (CR116R116)rNR116C(O)O(CR116R116)tR119,

(x) (CR116R116)rOC(O)NR116(CR116R116)tR119,

(y) (CR116R116)rNR116C(O)NR116(CR116R116)tR119, (z) (CR116R116)rNR1 16S(O)P(CR116R116)tR119,

(aa) (CR116R116)rS(O)PNR116(CR116R116)tR119,

(bb) (CR116R116)rNR1 16S(O)PNR116(CR116R116)tR119, (cc) (CR116R116)rNR116R116,

(dd) C1-6 alkyl, (ee) C2.6 alkenyl, (ft) C2.6 alkynyl, (gg) (CRU6R116)r-C3-i2 saturated, unsaturated, or aromatic carbocycle, (hh) (CR116R116)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(C1 -6alkyl))2, wherein any of (dd)-(hh) optionally is substituted with one or more R119 groups; alternatively, two R117 groups can form -O(CH2)UO-; is selected from:

(a) H, (b) C1-6 alkyl, (c) C2.6 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)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-J2 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) NO2, (hh) OH, (ii) NH2, (jj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2, (11) C1-6 alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C1-6 alkyl, optionally substituted with one or more moieties selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO2, and OH; R119, at each occurrence, independently is selected from:

(a) R120, (b) C1-6 alkyl, (c) C2.6 alkenyl, (d) C2.6 alkynyl, (e) C3-12 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 R114 groups; R120, at each occurrence, independently is selected from: (a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h) (CR116R116)rCN,

(i) (CR116R116)rNO2, (j) (CR116R116)rNR116R116, (k) (CR116R116)rOR114,

(1) (CR116R116)rS(O)13R116, (m) (CR116R116)rC(O)R116, (n) (CR116R116)rC(O)OR116,

(o) (CR116R116)rOC(O)R116, (p) (CR116R116)rNR116C(O)R116,

(q) (CR116R116)rC(O)NR116R116, (r) (CR116R116)rC(=NR116)R116,

(s) (CR116R1^)1NR116C(O)NR116R116, (t) (CR116R116)rNR116S(O)15R116,

(u) (CR116R116)rS(O)15NR116R116, (v) (CR116R116)rNR116S(O)15NR116R116,

(W) C1-6 alkyl, (x) C2^ alkenyl, (y) C2.6 alkynyl, (z) (CR116Rn6)r-C3-i2 saturated, unsaturated, or aromatic carbocycle, and (aa) (CR116R116)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 R116, F, Cl, Br, I, CN, NO2, -OR116, -NH2, -NH(C1-6 alkyl), - N(C1-6 alkyl)2, C1-6 alkoxy, C1-6 alkylthio, and C1-6 acyl; at each occurrence, independently is selected from:

(a) H, (b) -OR118, (c) -O-C1-6 alkyl-OC(O)R118, (d) -O-C1-6 alkyl-OC(O)OR118, (e) -C)-C1-6 alkyl-OC(O)NR118R118, (f) -O-C1-6 ^yI-C(O)NR118R118, (g) -O- C1-6 alkyl-NR118C(O)R118, (h) -O-C1-6 alkyl-NR118C(O)OR118, (i) -O-C1-6 alkyl- NR118C(O)NR118R118, O) -O-C1-6 alkyl-NR118C(=N(H)NR118R118), (k) -O- C1-6 (m) -O-C2-6 alkenyl- OC(O)OR118, (n) -O-C2-6 alkenyl-OC(O)NR118R118, (o) -O-C2-6 alkenyl- C(O)NR118R118, (p) -O-C2-6 alkenyl-NR118C(O)R118, (q) -O-C2-6 alkenyl- NR118C(O)OR118, (r) -O-C2-6 alkenyl-NR118C(O)NR118R118, (s) -O-C2-6 alkenyl- NR118C(=N(H)NR118R118), (t) -O-C2-6 alkenyl-S(O)pR118, (u) -O-C2-6 alkynyl- OC(O)R118, (v) -O-C2-6 alkynyl-OC(O)OR118, (w) -O-C2-6 alkynyl- OC(O)NR118R118, (x) -O-C2-6 alkynyl-CO^NR118R118, (y) -O-C2-6 alkynyl- NR118C(O)R118, (z) -O-C2-6 alkynyl-NR118C(O)OR118, (aa) -O-C2-6 alkynyl- NR118C(O)NR118R118, (bb) -O-C2-6 alkynyl-NR118C(=N(H)NR118R118), (cc) -O- C2-6 alkynyl-S(O)pR118, (dd) -NR118R118, (ee) -C1-6 alkyl-O-C1-6 alkyl, (ff) -C1-6 alkyl-NR114-C1-6 alkyl, (gg) -C1-6 alkyl-S(OVC1.6 alkyl, (hh) -OC(O)NR114(C1-6 alkyl)-NR114-(C1-6 alkyl) -R114, (ii) -OH, (jj) -C1-6 alkyl, (kk) C2-6 alkenyl, (11) C2-6 alkynyl, (mm) -CN, (nn) -CH2S(O)PR137, (oo) -CH2OR137, (pp) - CH2N(OR138)R137, (qq) -CH2NR137R139, (rr) -(CH2)v(C6-10 aryl), and (ss)- (CH2)v(5-10 membered heteroaryl), wherein GJMSS) ^e optionally substituted by 1, 2, or 3 R140 groups; alternatively, two R121 groups taken together form =O, =NOR118, or =NNR118R118; R127 is selected from R114, a monosaccharide or a disaccharide (including amino sugars and halogenated sugar(s)), -S(O)PR148, -(CH2)n-(O-CH2CH2-)m-O(CH2)nCH3, -(CH2)n-(O-CH2CH2-)m-OR148, -(CH2)n-[S(O)p-CH2CH2-]ni-S(O)p(CH2)nCH3 , -(CH2)n-[S(O)p-CH2CH2-]m-OR148, -OCH2-O-(CH2)n-[S(O)p-CH2CH2-]m- S(O)p(CH2)nCH3, -OCH2-O-(CH2)n-[S(O)p-CH2CH2-]m-OR148, -O-[C3-12 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R114, -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 R114, -S(COp-[C3-I2 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R114, and -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 R114; R128 is R114; R129 is R114; alternatively both R128 substituents can be taken together with the carbons to which they are attached to form carbonyl or =NR114, or a saturated or unsaturated C3-6 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 subsituted by one or more R117 groups, alternatively both R129 substituents can be taken together wtih the carbons to which they are attached to form carbonyl or =NR1 14, or a saturated or unsaturated C3-6 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 subsituted by one or more R117 groups, alternatively an R128 and an R129 substituent can be taken together wtih the carbons to which they are attached to form a C3-12 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 substitued by one or more R117 groups, alternatively both R128 groups and both R129 groups can be taken together with the carbons to which they are attached to form an unsaturated bond between the carbon atoms to which R128 and R129 are attached and a C3-12 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 substitued by one or more R117 groups,

R11Ss R114; alternatively, R109 and R110 taken together with the carbons to which they are attached form:

R132, R133, and R134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br,

(e) -OR114, (f) -SR114, (g) -NR114R114, and (h) C1-6 alkyl, wherein (h) optionally is substituted with one or more R115 groups; alternatively, R132 and R133 are taken together to form a carbon-carbon double bond; alternatively, R133 and R134 are taken together to form =O, =S, =NOR114, =NR114, or

=N-NR114R114; alternatively, R105 and R134 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 R114 groups; alternatively when M is a carbon moiety, R134 and M are taken together to form a carbon-carbon double bond;

R137 is independently (a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) -

(CH2)qCR141R142(CH2)nNR143R144, -(CH2)v(C6-C10 aryl), or -(CH2)v(5-10 membered heteroaryl); or where R137 is as -CH2NR137R139, R139 and R137 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 )-, in addition to the nitrogen to which R139 and R137 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 R140 groups; each R138 is independently H or Cr6 alkyl; each R141, R142, R143, and R144 is independently selected from H, Cr6 alkyl, - (CH2)m(C6-C10aryl), and -(CH2)m(5-10 membered heteroaryl), wherein the foregoing R141, R142, R143, and R144 groups, except H, are optionally substituted by 1, 2, or 3 R140 groups; or R141 and R143 are taken together to form -(CH2)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 R143 and R144 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(R137)-, in addition to the nitrogen to which R143 and R144 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 R140 group;

R139 is H, Cr6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the foregoing R139 groups, except H, are optionally substituted by 1, 2, or 3 substituents independently selected from halo and -OR138; each R140 is independently selected from halo, cyano, nitro, trifluoromethyl, azido, -C(O)R145, -C(O)OR145, -OC(O)OR145, -NR146C(O)R147, -NR146R147, OH, Cr6 alkyl, Cr6 alkoxy, -(CH2)v(C6-C10aryl), and -(CH2)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)R145,-C(O)OR145, -OC(O)OR145, -NR146C(O)R147, -C(O)NR146R147, -NR146R147, OH, Cr6alkyl, and Cr6 alkoxy; each R145 is independently selected from H, Cr6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)V(C6-C1OaTyI), and -(CH2)v(5-10 membered heteroaryl); each R146 and R147 is independently H, hydroxyl, Cr6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)v(C6-10 aryl), or -(CH2)v(5-10 membered heteroaryl); R .148 is C1-6 alkyl, C3-12 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further optionally substituted with one or more R114, 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 R114; p, at each occurrence is 0, 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 TAl through TA24:

wherein M, Q, R104, R114, R126, R127, R128, R129, R149, and R150 are as described herein.

In other embodiments the present invention related to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from Tl through T93:

T16 T17 T18

T19 T20

T21 T22

T29

T30

T32 T33

T57

T58

T60

T61

T62

T63

T64

59

T65

T66

T67

T68

T69

T70

T71

T72

T73

T74

T77 T78

T83 T84

T92 md 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 according to 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 a diarrhea 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 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 orally, parentally, otically, ophthalmically, nasally, 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 comprise 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 A, B, C, and D depict exemplary chemistries available for synthesizing the compounds of the invention, In these schemes, the variables n, R, R1, R3, R4, R5, R7, and X are merely illustrative, and not necessarily those used in the claims, and can be selected and defined in accordance with the invention.

In Scheme A, compounds such as, e.g., 3'-N-desmethyl erythromycin (1, R = H) or 3'-N-desmethyl clarithromycin (1, R = CH3), are alkylated with an electrophilic alkyne, 2, to yield 3'-N-alkynyl compounds such as 3. The electrophilic alkyne, 2, can include, e.g., compounds such as chlorides, bromides, iodides, tosylates, and mesylates depending on the selection of X. Cycloaddition of azide compounds, such as 6, with the 3'-N-allkynyl compounds 3 provides two regioisomeric triazole products 7 and 8. The major isomer is the "anti" isomer 7, a 1 ,4 disubstituted triazole. The minor component is the "syn" isomer 8, a 1,5 disubstituted triazole. The cycloaddition reaction can be thermally catalyzed, or a number of catalysts can be used, such as, but not limited to, copper (I) iodide. See, Tornoe, CW. et al. (2002) J. Org. Chem. 67: 3057). It is to be understood that other macrolide compounds such as, but not limited to, azithromycin and telithromycin, can be N-demethylated and used as starting materials for the chemistry exemplified in Scheme A.

7 (1, 4 isomer) 8 (1, 5 isomer)

An alternate approach to compounds such as 7 and 8 is illustrated by Scheme B. Acetylenic alcohols, 9, can be treated with azide compounds such as 6 to yield intermediate alcohols such as 10 (the 1,4 isomer) along with minor amounts of the 1,5, isomer. The alcohol 10 is then converted to the corresponding chloride, bromide, iodide, tosylate, or mesylate (11) using conventional chemical transformations. Compounds such as 11 are then coupled with 3'-N-desmethyl macrolides such as 1, to afford compounds such as 7 (and its isomer 8). Scheme B

10 X = OH

VII X = CI1 Br1 I1 OtS1 ONlS (+ 1,5 isomers)

Base, Solvent

7 (1, 4 isomer) + 8 (1,5 isomer)

The following Scheme C illustrates the synthesis of oxime type macrolides of the present invention. These compounds can be prepared from 3'-N-alknynyl compounds such as 3, which are made from the 3'-N-desmethyl macrolides, 1, as in Scheme A. Compound 3 can either be converted directly to the desired intermediate oxime 4 (by the appropriate choice of R1), or alternatively via a the hydroxyl oxime 5. A cycloaddition reaction of the intermediate oxime 4 and an azide compound 6 provides the final compounds 7 and 8 as a mixture of isomers.

Scheme C

7 (1, 4 isomer) 8 (1, 5 isomer)

The following Scheme D illustrates the synthesis of carbamate type macrolides of the present invention. The synthesis of these compounds generally involves introducing the carbamate functionality after the introduction of the N-alkynyl group. The reaction in Scheme D is illustrated starting with 3 '-N-alkynyl clarithromycin compound (see Scheme A, above). Compound 3 is then converted to the protected acetate 9, using standard acetylation conditions. Reaction of this acetate 9 with a base and carbodiimide (CDI) yields the open chain unsaturated carbamate 10, which is then cyclized to the carbamate 11. Removal of the acetate protecting groups provides 12. This deprotected compound 12 can be reacted with an azide compound 6, to yield the carbamate macrolide compound as a mixture of isomers 13 and 14.

( 11 R' = OAc 12 R7 = OH

13 (1, 4 isomer) 14 (1, 5 isomer)

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 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-turn 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 IC50S 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 (IC50) for inhibiting protein synthesis. Incorporation of 3H leucine or 35S 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 antiproliferative 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 in 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 PD5O 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 II 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, diarrhea, parasitic diseases, 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, otic, ophthalmic, nasal, or parenteral, for example, intravenous, intradermal, inhalation, 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 (B ASF, 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.

1 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, otic, ophthalmic, nasal, 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 otic, ophthalmic, nasal, oral 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, ophthalmically, 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 VIII 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 BRCA2 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" 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 = liter(s); mL = milliliters); Et2O = diethyl ether; THF = tetrahydrofuran; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; Et3N = triethylamine; /-Pr2NEt = diisopropylethylamine; CH2Cl2 = methylene chloride; CHCl3 = chloroform; CDCl3 = deuterated chloroform; CCLj = carbon tetrachloride; MeOH = methanol; CD3OD= deuterated methanol; EtOH = ethanol; DMF = dimethylformamide; BOC = t- butoxycarbonyl; CBZ = benzyloxycarbonyl; TBS = t-butyldimethylsilyl; TBSCl = t- butyldimethylsilyl chloride; TFA = trifluoroacetic acid; DBU = diazabicycloundecene; TBDPSCl = t-butyldiphenylchlorosilane; Hunig's Base= N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; CuI = copper (I) iodide; MsCl = methanesulfonyl chloride; NaN3 = sodium azide; Na2SO4= sodium sulfate; NaHCO3 = sodium bicarbonate; NaOH = sodium hydroxide; MgSO4= magnesium sulfate; K2CO3 = potassium carbonate; KOH = potassium hydroxide; NH4OH = ammonium hydroxide; NH4Cl = ammonium chloride; SiO2 = silica; Pd-C = palladium on carbon; Pd(dppf)Cl2 = dichloro[1,1'- bis(diphenylphosphino)ferrocene] palladium (II).

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

397 558.1*

398 562.1*

399 1122.0

400 1130.1

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 1A-I I, 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 1A 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 1A to give the indicated compound. Below is an exemplary compound of the invention showing variable G:

Below is an exemplary compound of the invention showing G as B'-Z-B":

Below is an exemplary compound of the invention showing variable G as B'-Z-B", where B' is phenyl:

Below is an exemplary compound of the invention showing variable G as B'-Z-B", where B' is phenyl and -Z-B" is the first chemical moiety or fragment from Table 1A:

Examples 1 — 6: Synthesis of 3'-N-desmethyl macrolide 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'-N-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 °C followed by addition of iodine (I2) (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 1N 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 (CH2Cl2ZMeOHZNH4OH 10:1:0.05) after 2 hours showed a single major product (Rf= 0.66). The reaction was cooled to room temperature, poured into H2O (75 mL) containing NH4OH (1.5 mL) and extracted with CHCl3 (3 x 30 mL). The combined organic layers were washed with H2O (30 mL) containing NH4OH (1.5 mL), dried over Na2SO4 and the solvent evaporated to give a white residue. The crude was purified on a silica gel column eluting with CH2Cl2/MeOH/NH4OH 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'-N-desmethyl clarithromycin from clarithromycin

To a mixture of clarithromycin (1.00 g, 1.3 mmol) and ΝaOAc»3H20 (0.885 g, 6.5 mmol) was added MeOH-H2O (20 mL, 4:1), and the mixture heated to 55-60 °C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and the reaction stirred at 55-60 °C for 3 h. The reaction mixture was poured into 50 mL CHCl3 containing 1 mL ammonium hydroxide. It was extracted with CHCl3 (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, CHCl3 :MeOH:NH4OH 100:10:0.1) to afford 3'-N-desmethyl clarithromycin. Yield: 0.9g (92%).

Example 4: Synthesis of 3'-7V-desmethyl roxithromycin from roxithromycin

To a mixture of roxithromycin (850 mg, 0.914 mmol, 90%) and NaOAc (828 mg, 10.000mmol) in a mixture of MeOH (6.0 mL) and water (1.5 mL) at 48 °C was added I2 in four portions (each portion: 63.5 mg) over 30 min, after each portion I2, followed by IN NaOH (400 μL). 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 mL X2), dried with Na2SO4. The residue was separated by FC (6/94/0.2 MeOHZCH2Cl2ZNH4OH), gave 600mg of the 3'-N-desmethyl roxithromycin in 80% yield. LCMS (ESI) m/e 824 (M+H)+.

Example 5: Synthesis of 3'-N-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 °C under argon atmosphere. The mixture was allowed to warm to rt and stirred overnight. CH2Cl2 (250 mL) and 5 % Na2S2O3 (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na2S2O3 (1 X 80 mL), dilute NH4Cl (1 X 80 mL) and dried over Na2SO4. Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 8 % methanolic ammonia (2N NH3) in CH2Cl2 to give 3'-N-desmethyl telithromycin as white solid (1.95 g, 68 %). MS (ESI) MZE; 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-desemthyl 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. This process is shown below in Example 12.

Examples 7-12: Synthesis of N-alkynyl substituted macrolide compounds from 3'-N- desmethyl macrolide compounds

The compounds of the present invention can be made via an N-alkynyl substituted macrolide intermediate. The following Examples 7-12 illustrate the preparation of such compounds. In these examples, the 3'-N-(but-3-ynyl) compounds are illustrated, but other corresponding alkynyl compounds are readily prepared by varying the alkynyl starting material.

Example 7: Synthesis of S'-W-(but-3-ynyl) erythromycin

A mixture of 3'-N-desmethyl erythromycin and the tosylate of 1-butyn-4-ol in Hunig's base and THF was stirred. The reaction mixture was diluted to EtOAc and washed with NaHCO3(aq) and with brine. The organic layer was dried over K2CO3 and the solvent was evaporated to give product. The crude product was purified on silica gel column to give the N-alkynyl substituted erythromycin as a white solid.

Example 8: Synthesis of 3'-N-(but-3-ynyl) azithromycin

A mixture of 3'-N-desmethyl azithromycin and the tosylate of 1-butyn-4-ol in Hunig's base was stirred. The reaction mixture was diluted to EtOAc and washed with ΝaHCO3(aq) and with brine. The organic layer was dried over K2CO3 and the solvent was evaporated to give product. The crude product was purified on silica gel column to give the N-alkynyl substituted azithromycin as a white solid. Example 9: Synthesis of 3'-N-(but-3-ynyl) clarithromycin

A mixture of S'-N-desmethyl-clarithromycin and the tosylate of 1,2-butyn-4-ol in anhydrous THF and Hunig's base was stirred. The reaction was poured into CH2Cl2, extracted with 2% aqueous NH4OH and saturated brine. The organic layer was dried over Na2SO4 and the solvent was evaporated away. The crude material was purified on a silica gel column to give the N-alkynyl substituted clarithromycin.

Example 10: Synthesis of 3'-N-(but-3-ynyl) roxithromycin

A mixture of 3'-N-desmethyl roxithromycin (500 mg, 0.608 mmol) and the tosylate of l-butyn-4-ol in a mixture solvents of THF (5.4 mL) and Hunig's base (1.6 mL) was refluxed for 48 hr. The reaction mixture was concentrated, then, EtOAc (100 mL) was added. The organic layer was washed with Sat. NaHCO3 (20 mL), and brine (50 mL). The N-alkynyl substituted roxithromycin was isolated by FC (3/100/0.2 eOH/CH2Cl2/NH4OH), gave 316mg in 59% yield. LCMS (ESI) m/e 876 (M+H)+.

Example 11: Synthesis of 3'-N-(but-3-ynyl) telithromycin:

Two alternative procedures are used for the synthesis of 3'-N-(but-3-ynyl) telithromycin.

Protocol A: A mixture of 3'-N-desmethyl telithromycin (0.66 g, 0.83 mmol) and the tosylate of 1-butyn-4-ol (0.33 g, 1.49 mmol) in THF (15 mL) and Hunig's base (3 mL) was heated at 90 °C for 5 days. The solvent was evaporated; the residue was dissolved in 1N HCl (50 mL) and kept stirring at room temperature for about Ih. CH2Cl2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 X 30 mL) and basified with NaOH (IN) to form a whitish-suspension. The suspension was extracted with CH2Cl2 (3 X 30 mL) and the organic layer was dried over Na2SO4. Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 6 % methanolic ammonia (2N NH3) in CH2Cl2 to give 3'-N-(but-3-ynyl) telithromycin as white solid (0.12 g, 17 %). MS (ESI) m/e 850.8 (M+H)+.

Protocol B: A mixture of 3'-N-desmethyl telithromycin (0.66 g, 0.83 mmol), and the tosylate of 1-butyn-4-ol (0.40 g, 1.84 mmol) in acetonitrile (10 mL) and Hunig's base (0.18 mL, 1.0 mmol) was microwave heated to 90 °C within 10 min and maintained at 90 °C for 1.5h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in 1N HCl (60 mL) and kept stirring at room temperature for about 2h. CH2Cl2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 X 30 mL) and basified with 50 % KOH to form a whitish-suspension. The suspension was extracted with CH2Cl2 (3 X 30 mL) and the organic layer was dried over Na2SO4. The solvent was evaporated and the crude was purified by preparative TLC (2000 micron plate) eluting with CH2Cl2/methanolic ammonia (2N NH3) 12:1 to give 3'-N-(but-3-ynyl) telithromycin as white solid (0.19 g, 27 %). MS (ESI) m/e 850.8 (M+H)+.

Example 12: Synthesis of 3'-N-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring.

3'-N-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring are prepared by introducing the oxime function typically after the 3'-Ν-but-3-ynyl (or other desired alkynyl group) has been introduced. Example 12.1 provides a method for making the oxime of 3'-N'(but-3-ynyl) clarithromycin. Examples 12.2 to 12.6 provide procedures for making more complex oximes.

Example 12.1 Oxime of 3'-N'-(but-3-ynyl) clarithromycin

To a mixture of 3'-N-(butyl-3-ynyl) clarithromycin alkyne (3.0 g, 3.8 mmol) and hydroxylamine hydrochloride (7.9g, 114.3 mmol) was added pyridine (30 mL) and was heated to 60-65 °C for 12h. The solution was evaporated to dryness and the crude material was partitioned between CH2Cl2 (150 mL) and saturated NaHCO3 solution (100 mL). The pH of the solution was adjusted to 10 using 1N NaOH solution. Organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layer was washed with brine (2 x 200 mL) and dried over anhydrous sodium sulphate. The solution was filtered, concentrated and co-evaporated with dry toluene (3 x 100 mL). The crude material thus obtained was purified by flash chromatography over silica gel (15: 1 = CH2Cl2: 2N NH3- MeOH). Yield = 2.2 g (73%).

Examples 12.2 to 12.6

The following scheme shows two exemplary oxime compounds (a piperidinyl oxime and a pyrrolidinyl oxime) and also the 3'-N-(but-3-ynyl) ketolide (see Example 6). The N- alkynyl oxime macrolides were prepared from 3'-N-(but-3-ynyl) clarithromycin (see Example 9). Below is a Scheme for Examples 12.2 to 12.6 for preparing 3'-N-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring:

Descladinose derivative Acetate derivative

EDC

3'-N'(but-3-ynyl) clarithromycin DMSO pyrH+CF3CO2-

Example 12.2: Descladinose Derivative

To 3'-N'(but-3-ynyl) clarithromycin (0.700 g) was added 10 mL 0.9 N HCl and the mixture was stirred for 4 h at room temperature. The reaction mixture was saturated with sodium chloride and was adjusted to pH 8 using aqueous NH4OH solution. The solution was extracted with ethyl acetate (3 x 30 mL), dried (with Na2SO4), and concentrated under reduced pressure. Purification of the crude reaction mixture by flash chromatography (silica gel, 60% ethyl acetate in hexane) afforded 0.200 g (35% yield) of the descladinose derivative. Data for the descladinose derivative: 1HNMR (300 MHz, CDCl3, partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.25 (dd, 1H), 3.55 (m, 2H), 3.70 (s, 1H), 3.85 (s, 1H), 3.95 (s, 1H), 4.40 (d, 1H), 5.15 (dd, 1H). Example 12.3: Acetate Derivative

To a solution of the descladinose derivative (0.200 g, 0.32 mmol) in acetone (2 mL) was added acetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with saturated sodium bicarbonate (3 x 50 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 50% ethyl acetate in hexane) to yield 0.100 g (50% yield) of acetate derivative. Data for acetate derivative: 1HNMR(S00 MHz, CDCl3, partial): δ 0.84 (t, 3H), 2.00 (s, 3H), 2.20 (s, 3H), 2.90 (s, 3H), 3.00 (q, 1H), 3.25 (s, 1H, 3.47 (m, 2H), 3.70 (bs, 1H), 3.82 (bs, 1H), 3.97 (s, 1H), 4.60 (d, 1H), 4.77 (dd, 1H), 5.15 (dd, 1H). Example 12.4: 3'-N-(but-3-ynyl) ketolide

To a solution of the acetate derivative (0.090 g, 0.134 mmol), EDC-HCl (0.172 g, 0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH2Cl2 (1.5 mL) was added dropwise a solution of pyridinium trifluoroacetate (0.174 g, 0.90 mmol) in CH2Cl2 (1 mL) at 15 °C. The reaction mixture was slowly warmed up to room temperature and stirred for 3 h. The reaction was quenched with water (2 mL), and allowed to stir for 30 min. The mixture was then poured into CHCl3 (50 mL), and the organic layer was washed with water (2 x 50 mL), dried (over anhydrous Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.070g (78%) of the 3'-N-(but-3-ynyl) ketolide. Data for the 3'-N-(but-3-ynyl) ketolide: MS (ESI) m/e 668 (M+H)+; 1HNMR (300 MHz, CDCl3, partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (s, 3H), 2.70 (s, 3H), 2.95-3.10 (m, 1H), 3.15-3.05 (m, 1H), 3.45-3.65 (m, 1H), 3.80 (q, 1H), 3.90 (s, 1H), 4.28 (d, 1H), 4.40 (d, 1H), 4.76 (dd, 1H), 5.10 (dd, 1H). Example 12.5: Piperidinyl oxime

To a solution of the 3'-N-(but-3-ynyl) ketolide (2.0 g, 2.9 mmol) in MeOH (10 mL) was added (R)-N-Piperidin-3-yl-hydroxylamine hydrobromide (1.26 g, 4.4 mmol). The reaction mixture was stirred at it for 14h. The mixture was then poured into (50 mL) and water (50 mL) the pH was adjusted to 11 by addition 0fNH4OH and the organic layer was separated and washed with brine (50 mL), dried (over anhydrous Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 12:1 CH2Cl2 and 2M methanolic ammonia) to yield 2g (78%) of the piperidinyl oxime as a 1:1 mixture of E/Z isomers. Data for the piperidinyl oxime: MS (ESI) m/e 724.7 (M+H)+. Example 12.6: Pyrollidinyl oxime

The pyrollidinyl oxime was synthesized from the 3'-N-(but-3-ynyl) ketolide and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of piperidinyl oxime. Data for the pyrrolidinyl: MS (ESI) m/e 710.6 (M+H)+. Example 13: Synthesis of 3'-N-(but-3-ynyl) carbamate macrolide compounds

3'-N-(but-3-ynyl) macrolides having a carbamate substituent on the macrolide ring can be prepared by introducing the carbamate ring after the 3'-N-but-3-ynyl (or other desired alkynyl group) has been introduced. Note that a scheme for a direct preparation was given above for 3'-N-(but-3-ynyl) telithromycin (see Example 11). The following scheme shows an exemplary carbamate compound prepared by an intramolecular cyclization reaction. By using various substituted amines, hydrazine, or substituted hydrazines, other compounds are prepared. Also, other macrolides, rather than the ketolide shown below can be used.

Below is a scheme for Example 13 for preparing 3'-Ν-(but-3-ynyl) macrolides having a carbamate substituent on the macrolide ring:

Acylimidazole ,, ., ,. , „ ,. - .

3 -N-(but-3-ynyl) Carbamate

A solution of the acylimidazole (0.74 g, 1.0 mmol) in acetonitrile (20 mL) and H2O (3 mL) was treated with a primary amine (e.g. R-NH2, wherein R can be a large range of desired substituents) (10 mmol) and stirred at 50 °C for about 3 h. The reaction mixture was evaporated to yellow foam and redissolved in methanol (50 mL) and heated to reflux for 20 h. Solvent was evaporated purification by flash chromatography (SiO2, 50-100% ethyl acetate/hexanes) provides the 3'-N-(but-3-ynyl) carbamate (0.50 g, 0.75 mmol) as a white powder.

Example 14: Synthesis of Compounds of the present invention via a cyclization reaction of a 3'-N-(but-3-ynyl) macrolide with an azide.

The various compounds of the present invention are generally made by a cyclization reaction of an azide with the corresponding 3'-N-(but-3-ynyl) macrolide compound. Other N-alkynyl compounds can alternatively be used. The time required for each reaction to proceed to completion was variable and was dependent upon several factors including: the specific substrates; the amount of Cu(I) salt used; the presence or absence of Hunig's base; and the concentration of the reactants. Reactions were monitored for the disappearance of the starting materials by TLC and/or LCMS and were typically allowed to run for between about 2h to about 72h. Reactions were stopped when analysis demonstrated that the starting alkyne substrate had been substantially consumed. The workup and purification protocols are typical of those used previously. Slight modifications to the described workup procedures may have been used (such modifications include the use of different aqueous wash solutions, different organic solvents for extraction, the use of other anhydrous salts for the drying of organic extracts, and the employment of different solvent mixtures for the chromatographic purification of the compounds). In all cases, the methods used for the workup of the reaction mixtures, the extraction of products, the drying of organic extracts, and for the isolation and purification of the title compounds were typical of procedures familiar to those trained in the art of organic synthesis. There were no specific or unusual protocols employed in the isolation and purification of the reaction products that were found to be critical in these processes. For compounds produced from 3'-N-bu -3-ynyl clarithromycin and the from the carbamates, the use of conditions that do not include the step of degassing the reaction mixture, resulted in the formation of iodinated side-products and generally lower yields. Additionally, reduction of the amount of copper salt used in the reaction to 0.5 molar equivalents or less resulted in reduced formation of iodinated by-products.

The following scheme is a general scheme for preparing the compounds:

For the synthesis of the compounds, various substituents such as, e.g., "G" can either be present in the azide compound indicated above, or alternatively G can be constructed in a subsequent reaction. Example 15: Synthesis of azides of the compounds of the present invention

The azides compounds used in preparing the compounds of the present invention can be readily synthesized by methods known from the literature. Exemplary azide syntheses are presented below. The remaining azides can be synthesized in analogous fashion from appropriate commercial starting materials. When possible, azides were produced from the corresponding substituted alkyl bromides by direct displacement with azide ion. When the required alkyl bromides were not readily available, the compounds were derived from substituted alkanols: to accomplish this, the alcohols were first activated as their sulfonyl ester derivatives and then substituted with azide ion. If neither the required bromides nor alkanols were commercially available, the azides were synthesized from the corresponding carboxylic acids by reduction with borohydride to the corresponding alcohols. The resulting alkanols were then treated as above to yield the azides. Finally, some azides of were synthesized from the corresponding substituted alkyl amines by reaction with triflic azide. In a few cases, azides were synthesized by modification of other azides that had been synthesized according to the methodologies above. The following are exemplary schemes for preparing azides.

Below is a scheme for preparing an azide compound:

Florfenicol

Florfenicol amine Florfenicol azide

A solution of florfenicol (0.090 g, 0.25 mmol) in acetic acid (3.0 mL) was treated with sulfuric acid (10%, 15 mL) and heated to 110 °C for 12 h. The reaction mixture was cooled to room temperature, treated with 10 M aqueous sodium hydroxide to adjust the pH to 14, extracted with dichloromethane (3 x 30 mL), dried (Na2SO4), and evaporated to provide florfenicol amine (65 mg, 0.25 mmol) as a yellow oil.

A solution of florfenicol amine (0.90 g, 3.6 mmol) in H2O (10 mL) and methanol (30 mL) was treated with triethylamine (1.5 mL, 10.8 mmol) and trifluoromethanesulfonyl azide (13.4 mmol dissolved in 20 mL of dichloromethane; solution prepared according to method described in J. Am. Chem. Soc. 2002, 124, 10773), and stirred at 0 °C 3 h and then warmed to 23 °C for 1 h. The reaction mixture was diluted with H2O (30 mL), extracted with dichloromethane (30 mL) and evaporated. Flash chromatography (SiO2, 50-100% ethyl acetate/hexanes) provided the florfenicol azide (0.65 g, 2.4 mmol) as a yellow solid. Below is a scheme for preparing an azide compound:

A solution of D-(-)-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol (0.42 g, 2.0 mmol) in H2O (5 mL) and methanol (17 mL) was treated with triethylamine (0.84 mL, 6.0 mmol) and trifluoromethanesulfonyl azide (3.0 mmol dissolved in 5 mL of dichloromethane; solution prepared according to method described in J. Am. Chem. Soc. 2002, 124, 10773), and stirred at 23 °C for 3 h. The reaction mixture was diluted with H2O (30 mL), extracted with dichloromethane (30 mL) and evaporated. Flash chromatography (SiO2, 50-100% ethyl acetate/hexanes) provided the azide (0.28 g, 1.2 mmol) as a yellow solid.

Below is a scheme for preparing an azide compound:

Azide compound

To a stirred 0 °C solution of 4-nitrophenylalanine (4.6g, 20 mmol) and NaBH4 (3.2g, 84 mmol) in THF (50 mL) was added BF3 OEt (14.8 mL, 106 mmol). The reaction was warmed to rt and stirred for 24h. The mixture was cooled to 0 °C and quenched with methanol. The reaction mixture was filtered and the filtrate concentrated to give a solid residue. 10% of this residue was dissolved in water (5 mL), methanol (20 mL) and triethyl amine (0.9 mL). Triflic azide solution (3.5 mmol dissolved in 7 mL of dichloromethane; solution prepared according to method described in J. Am. Chem. Soc. 2002, 124, 10773) was added and the mixture was stirred at RT for 14 h. The reaction mixture was diluted with dichloromethane (30 mL) washed with saturated NaHCO3, and with brine. The organic extract was dried, filtered and concentrated to give the azide compound as a white solid (150mg) The foregoing azide compound is useful for preparing a wide variety of macrolide compounds of the present invention. The free nitro functional group in the macrolide compound can be later transformed to an azide via an amino group. This azide can be used for further cyclization reactions.

Below are Schemes 15.4a-c for preparing an azide compound: a.

Bromo compound

A solution of florfenicol (0.494 g, 1.38 mmol) in acetonitrile (15.0 mL) was treated with carbontetrabromide (0.594 g, 1.66 mmol) and triphenylphosphine (0.434 g, 1.66 mmol), and stirred at 23 °C for 12 h. The reaction mixture evaporated to a yellow residue and purified by flash chromatography (SiO2, 10% ethyl acetate/dichloromethane) to provide the bromo compound (0.28 g, 0.67 mmol) as a white powder, b.

Bromo compound Debrominated Compound

A solution of the bromo compound (0.20 g, 0.41 mmol) in methanol (5.0 mL) was treated with 10% palladium on charcoal (20 mg) and stirred at 23 °C for 2 h under a balloon of hydrogen. The reaction mixture was filtered, evaporated and purified by preparative thin- layer chromatography (SiO2, 10% ethyl acetate/dichloromethane) to afford the debrominated compound (90 mg, 0.26 mmol) as a white film, c.

Debrominated compound Amine Azide

A solution of the debrominated compound (90 mg, 0.26 mmol) in acetic acid (3.0 mmol) was treated with 10% sulfuric acid (15 mL) and heated to 110 °C for 12 h. The reaction mixture was cooled to room temperature, treated with 10 M aqueous sodium hydroxide to adjust the pH to 14, extracted with dichloromethane (3 x 30 mL), dried (Na2SO4), and evaporated to provide crude amine as a yellow oil. A solution of this crude amine (83 mg) in methanol (3.6 mL) and dichloromethane (3.0 mL) was cooled to 0 °C and treated with triethylamine (0.14 mL, 1 mmol) and triflic azide (1.2 mL of a 0.3 M solution in dichloromethane) and allowed to warm to 23 °C. After 2 h, the reaction mixture was evaporated and purified by preparative thin-layer chromatography (SiO2, 10% ethyl acetate/dichloromethane) to afford the azide (60 mg, 0.23 mmol) as a colorless oil.

Below is a scheme for fluorinating an azide compound:

azide compound fluorinated azide compound

To a stirred -78 °C solution of azide compound (111 mg, 0.5 mmol) in CH2Cl2 was added (diethylamino)sulfur trifluoride (DAST) (0.1 mL, 0.82 mmol). The reaction was stirred at -78 °C for 2h, then allowed to warm to RTand stirred for 14 h. The reaction mixture was poured into water and extracted with CH2Cl2. The organic extracts were dried, filtered, and concentrated to give the fluorinated azide compound as a solid (36 mg, 0.16 mmol). Below is a scheme for oxidizing a thioether chain in an azide compound

Thioether Sulfone

To a solution of the thioether (0.27 g, 1.1 mmol) in CH2Cl2 (15 mL) was added mCPBA (1.10 g, 4.5 mmol) and the mixture was stirred at room temperature overnight. Solvent was evaporated and the crude was purified on silica gel eluting with CH2Cl2/MeOH 20:1 to 15:1 to 12:1 to give the sulfone as colorless paste that solidified on standing (0.26 g, 87 %).

Example 16: Synthesis of more complex azide compounds

More complex organic azide compounds used in the synthesis of the compounds of the present invention are generally prepared from the iodo compound 2 or the boronic acid ester compound 3. Typically, the iodo or boronic acid functional groups provide a means for preparing a wide range of compounds using methods available to one skilled in the art.

Ester Compound, 3

Idodo Compound, 2

Further chemical transformations Further chemical transformations

Azide Compound

The iodo compound 2, is prepared according to the following scheme from commercially available (lR,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. The boronic acid ester compound 3 is prepared from the iodo compound 2.

The following reaction scheme illustrates various azide compounds that can be made from iodo compound 2. Ra, Rb, Rc, and Rd represent various alkyl, substituted alkyl, aryl, and substituted aryl groups.

General Scheme for Synthesis of Various Azide Compounds from lodo Compound 2

Ra, Rb, Rc, and Rd represent various alkyl, substitued alkyl, aryl, substituted aryl, etc.

Additionally, the iodo azide compound 2 can be coupled with aromatic systems using standard chemical processes to provide a biaryl type azide compounds.

The Following Table 2 exemplifies azide compounds useful in the synthesis of compounds of the present invention

574 682

575 683

576 684

577 685

578 686

579 687

Examples 17-19

The following Examples further exemplify methods for making compounds of the present invention.

Example 17 Synthesis of Compound 372

A mixture of 5-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (0.4 g, 1.791 mmol), 1-(2-azido-3-fluoro-1-methoxy-propyl)-4-iodo-benzene (0.5 g, 1.4925 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium (II) chloride 1 :1 complex with dichloromethane (61 mg, 0.075 mmol), potassium carbonate (621 mg, 4.5 mmol), dioxane (6 ml), ethanol (2 ml) and water (2 ml) was degassed and heated at 85 °C for 5 h under argon atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (30 ml, twice) and brine (20 ml). The ethyl acetate solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica, gradient from 0% to 80% ethyl acetate in hexane) to afford the aminopyrimidinyl azide compound (250 mg, 56%). M/Z: 303 [M+H]+.

A mixture of the aminopyrimidinyl azide compound (100 mg, 0.331 mmol), 3'-N- (but-3-ynyl) clarithromycin (260 mg, 0.331 mmol), CuI (69 mg, 0.363 mmol), in THF (5 ml) was degassed. Hunig's base (0.3 ml) was added to the degassed mixture and stirred at room temperature under argon atmosphere for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 ml) and extracted with dichloromethane (30 ml, twice). The extract was washed with brine (25 ml) and dried over MgSO4, filtered and concentrated. The crude product was purified by Preparative TLC (silica gel, 6% 2N ammonia methanol in dichloromethane) to afford the macrolide final product (280 mg, 78%). M/Z: 1089, [M+H]+; 545, [M/2+H]+.

Example 18: Synthesis of Compound 439

A mixture of 1-(2-azido-3-fluoro-1-methoxy-propyl)-4-iodo-benzene (6.7 g, 20 mmol), bis(pinaclato)diboron (5.59 g, 22 mmol), palladium (II) acetate (224 mg, 1 mmol), potassium acetate (5.88 g, 60 mmol) and DMF (30 ml) was degassed and heated at 80 °C for 16h under argon atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (100 ml, twice) and brine (50 ml). The ethyl acetate solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 8% ethyl acetate in hexane) to afford the boronate (5.40 g, 80.6%).

HoJLj A mixture of the boronate (5.4 g, 16.119 mmol), 5-bromo-2-hydromethylpyridine (3.165 g, 16.925 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium (II) chloride 1 :1 complex with dichloromethane (658 mg, 0.806 mmol), potassium carbonate (6.67 g, 48.357 mmol), dioxane (60 ml), ethanol (20 ml) and water (20 ml) was degassed and heated at 85 °C for 4 h under argon atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (200 ml, twice) and brine (100 ml). The ethyl acetate solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, gradient from 10% to 65% ethyl acetate in hexane) to afford the indicated product (3.83 g, 75%). M/Z: 317 [M+H]+.

3-Chloroperoxybenzoic acid (3.94 g, 22.837 mmol) was added to a solution of the compound from the previous step (5.1 g, 15.224 mmol) in dichloromethane (50 ml). The resulted solution was stirred at room temperature for 1 h, diluted with dichloromethane (200 ml), washed with sodium bicarbonate solution (saturated, 200 ml), water (200 ml) and brine (50 ml), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, gradient from 0% to 10% methanol in dichloromethane) to afford the indicated N-oxide azide compound (3.45 g, 68%). M/Z: 333 [M+H]+.

To a mixture of 3'-N-(but-3-ynyl) clarithromycin (3.0 g, 3.8 mmol) and hydroxylamine hydrochloride (7.9g, 114.3 mmol) was added pyridine (30 mL) and was heated to 60-650C for 12h. The solution was evaporated to dryness and the crude material was partitioned between CH2Cl2 (150 mL) and saturated NaHCO3 solution (100 mL). pH of the solution was adjusted to 10 using 1N NaOH solution. Organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layer was washed with brine (2 x 200 mL) and dried over anhydrous sodium sulphate. The solution was filtered, concentrated and co-evaporated with dry toluene ( 3 x 100 mL). The crude material thus obtained was purified by flash chromatography over silica gel (15: 1 = CH2Cl2: 2N NH3- MeOH) to yield 3'-N-(but-3-ynyl) clarithromycin oxime. Yield = 2.2 g (73%).

An aqueous solution of KOH (50%, 120 ml) was added to a mixture of 3'-N-(but-3- ynyl) clarithromycin oxime compound shown above, 4.0g, 5.0 mmol), tetrabutylammonium bromide (322 mg, 1 mmol), chloromethyl methyl ether (1.2 ml, 15 mmol) and dichloromethane (160 ml) at 0 °C. The resulted solution was stirred at room temperature for 2 h before diluted with dichloromethane (200 ml), washed with water (200 ml, twice) and brine (100 ml), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, gradient from 30% to 80% ethyl acetate in hexane) to afford the indicated 3'-N-(but-3-ynyl) clarithromycin mom-oxime compound (3.80 g, 90%). M/Z: 845.8 [M+H]+.

A mixture of the indicated N-oxide azide compound, 240 mg, 0.723 mmol), 3'-N- (but-3-ynyl) clarithromycin oxime alkyne (611 mg, 0.723 mmol), CuI (28 mg, 0.145 mmol), and THF (10 ml) was degassed. Hunig's base (0.3 ml) was added to the above reaction mixture and stirred at room temperature under argon atmosphere for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 ml) and extracted with ethyl acetate (40 ml, twice). The extract was washed with brine (25 ml) and dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica, gradient from 0% to 6% 2N ammonia methanol in dichloromethane) to afford the oxime macrolide final product (700 mg, 82%). M/Z: 1178.2 [M+H]+.

Example 19 Synthesis of Compound 440

60-65°C

To a mixture of tributyl tin pyrazine (920 mg, 2.5 mmol), 1-(2-azido-3-fluoro-1- methoxy-propyl)-4-iodo-benzene (900 mg, 2.6 mmol), Pd (Ph3P)4 (290 mg, 0.25 mmol), CuI (95.5 mg, 0.5 mmol) and CsF (760 mg, 5 mmol) was added DMF in a sealed tube and purged with inert gas and heated to 60-65 °C for 4h. Then the solution was stirred at ambient temperature overnight and was diluted with ethyl acetate (100 mL). The whole solution was filtered through a small celite bed and washed with ethyl acetate (2 x 25 mL). The combined organic fraction was stirred with saturated KF solution (150 mL) for 30 min. The organic layer was separated and washed with brine (3 x 100 mL). It was dried over anhydrous Na2SO4, concentrated and purified by preparative TLC (50% ethyl acetate-heptane) to provide the indicated pyrazine azide compound. Yield: 500 mg (70%).

HOD-190-031 440

A mixture of the pyridine azide compound (102 mg, 0.3554 mmol), and the indicated 3'-N-(but-3-ynyl) clarithromycin carbamate compound (324 mg, 0.3554 mmol), CuI (34 mg, 0.18 mmol), in THF (5 ml) was degassed. Hunig's base (0.3 ml) was added to this degassed reaction mixture and stirred at room temperature under argon atmosphere for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 ml) and extracted with dichloromethane (30 ml, twice). The extract was washed with brine (25 ml) and dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica, gradient from 0% to 6% 2N ammonia methanol in dichloromethane) to afford the carbamate macrolide final product (350 mg, 82.1%). M/Z: 1201.1, [M+H]+; 601.1, [M+2H]+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.

Table 3

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.

What is claimed is:

1. A compound having the structure:

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

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 C1-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2-6 alkynyl group, (f) -OH, (g) -OR5, (h) -NR4R4, (i) -C(O)R5, G) -C(O)OR5, (k) - C(O)-NR4R4, (1) -C(S)R5, (m) -C(S)OR5, (n) -C(O)SR5, (o) -C(S)-NR4R4, (p) -N3, (q) -CN, (r) -CF3, (S) -CF2H, (t) -CFH2, (u) -S(O)PH, (v) -S(O)PR5, (w) -S(O)POH, (x) -S(O)POR5, (y) -S(O)pNR4R4, (z) a C3-12 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;

Ra and Rb independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(=O)R5, (i) - C(=O)OR5, (j) -C(=O}-NR4R4, (k) -S(O)PNR4 R4, (1) -C(O)SR5, (m) halogen, (n) -S(O)PH, and (o) - S(O)pR5, wherein (b) -(d) are further optionally substituted with one or more R5; alternatively Ra and Rb are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, or (d) -C=NOR5;

Rc is selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OR5, provided that R5 is not H, (f) -NR4R4, (g) -C(=O)R5, (h) - C(=O)OR5, (i) -C(=O)-NR4R4, (j) -S(O)PNR4 R4, (k) -C(O)SR5, (1) -S(O)PH, and (m) - S(O)pR5, wherein (b) -(d) are further optionally substituted with one or more R5;

Rd and Re independently are selected from: (a) H, (b) a Q-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OH, (f) -OR3, (g) -NR 44rR»44, (h) -C(=O)R3, (i) - C(=O)OR5, (j) -C(=O)-NR4R4, (k) -S(O)PNR4 R4, (1) -C(O)SR5, (m) halogen, (n) -S(O)PH, and (o) - S(O)PR5, wherein (b) -(d) are further optionally substituted with one or more R5, or alternatively Rd and Re are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, or (d) -C=NOR5; alternatively, Rc and Rd or Rc and Re are taken together to form a carbon-carbon double bond between the carbon atoms to which they are attached; alternatively Rd and X are taken together to form =CR5R5; or alternatively Rd and Re are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, (d) -C=NOR5, (e) =CH2, or (f) 3-12- membered carbocycle or heterocycle optionally substituted with one or more R5;

R1 and R3 independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -C(O)R5, (f) -C(O)OR5, (g) -C(O)-NR4R4, (h) - C(S)R5, (i) -C(S)OR5, O) -C(O)SR5, and (k) -C(S)-NR4R4; alternatively R1 and R3 are taken together with the oxygen to which R1 is attached, the nitrogen to which R3 is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R5 groups; R2 is hydrogen or -OR12; 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 R11 Or R113; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) - OR9, (dd) -SH, (ee) -S(O)15R9, (ff) halogen, (gg) -CN, (hh) -N3, (ii) -NO2, (jj) -Si(R13)3, (kk) -SO3H, (11) -SO3N(R4)2, (mm) -SO3R9, (nn) -NR6R6, (oo) -C(O)R9, (pp) -C(O)(CR6R6)tR9, (qq) - OC(O)(CR6R6)tR9, (rr) -C(O)O(CR6R6)tR9, (ss) - NR6(CR6R6)tR9,(tt) -NR6C(O)(CR6R6)tR9, (uu) - C(O)NR6(CR6R6)tR9, (w) -NR6C(O)NR6(CR6R6)tR9, (ww) - C(=NR6)(CR6R6)tR9, (xx) -C(=NR6)NR6)(CR6R6)tR9, (yy) - NR6C(=NR6)NR6)(CR6R6)tR9, (zz) -S(CR^tR9, (aaa) - S(O)p(CR6R6)tR9, (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) -C1-6 alkyl, (eee) -C2-6 alkenyl, and (fff) a C2-6 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 R11 or Rl la; wherein each (ddd), (eee), or (fff) is optionally are substituted with one or more R14 groups; (iii) Z is selected from (a) a single bond, (b) -C1-6 alkyl-, (c) -C2-6 alkenyl-, (d) -C2-6 alkynyl-, (e) -O-, (f) -NR4-, (g) -S(O)1,-, (h) - C(O)-, (i) -C(O)O-, O) -OC(O)- (k) -OC(O)O-, (1) -C(O)NR4-, (m) -NR4CO-, (n) -NR4C(O)NR4- , (o) -C(=NR4)-, (p) - C(=NR4)O-, (q) - OC(=NR4)-, (r) -C(=NR4)NR4-, (s) - NR4C(^NR4K (t) -C(=S)-, (u) -C(=S)NR4-, (v) -NR4C(=S)-, (w) -C(O)S-, (x) -SC(O)-, (y) -OC(=SK and (z) -C(=S)-O-, wherein any of the aliphatic carbons atoms in (b), (c), or (d) are optionally replaced with -(C=O)-, -O-, -S-, or -NR4-, and wherein any of (b), (c), or (d), are optionally further substituted with -OH, -NR4-, or halogen; R4, at each occurrence, independently is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-I2 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 sulfur, (g) -C(O)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-12 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-C1-6 alkyl, (m) - C(O)O-C2-6 alkenyl, (n) -C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 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)NR6R6, wherein any of (b)-(p) optionally is substituted with one or more R5 groups, alternatively, NR4R4 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R4 groups are bonded, wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R4 groups are bonded, with one or more moieties selected from O, S(O)P, N, and NR8; R5 is selected from:

(a) R7, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-12 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; wherein any of (b)-(f) immediately above optionally is substituted with one or more R7 groups; alternatively two R5 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 these ring systems formed from two R5 groups optionally is substituted with one or more R7 groups; R6, at each occurrence, independently is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-12 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, wherein any of (b)-(f) optionally is substituted with one or more moieties selected from:

(aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br, (fit) I, (gg) CN, (hh) NO2, (ii) -OR8, (jj) -S(O)pR8, (kk) -C(O)R8, (11) - C(O)OR8, (mm) -OC(O)R8, (nn) -C(O)NR8R8, (oo) -OC(O)NR8R8, (PP) -C(=NR8)R8, (qq) -C(R8)(R8)OR8, (rr) -C(R8)2OC(O)R8, (ss) - C(R8)(OR8)(CH2)rNR8R8, (tt) -NR8R8, (uu) -NR8OR8, (w) - NR8C(O)R8, (ww) -NR8C(O)OR8, (xx) -NR8C(O)NR8R8, (yy) - NR8S(O)rR8, (zz) -C(OR8)(OR8)R8, (ab) -C(R8)2NR8R8, (ac) =NR8, (ad) -C(S)NR8R8, (ae) -NR8C(S)R8, (af) -OC(S)NR8R8, (ag) - NR8C(S)OR8, (ah) -NR8C(S)NR8R8, (ai) -SC(O)R8, (aj) a C1-6 alkyl group, (ak) a C2-6 alkenyl group, (al) a C2-6 alkynyl group, (am) a C1-6 alkoxy group, (an) a C1-6 alkylthio group, (ao) a C)-6 acyl group, (ap) -CF3, (aq) -SCF3, (ar) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (as) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR6R6 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R6 groups are attached wherein said ring is optionally replaced at a position other than the nitrogen atom to which the R6 groups are bonded, with one or more moieties selected from -O-, -S(O)P-, -N=, and -NR8-; alternatively, CR6R6 forms a carbonyl group; R7, at each occurrence, is selected from:

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -N3 (j) -NO2,

(k) -NR6(CR6R6)tR9, (1) -OR9, (m) -S(O)pC(R6R6)tR9, (n) -C(O)(CR6R6)tR9,

(o) -OC(O)(CR6R6)tR9, (p) -SC(O)(CR6R6)tR9, (q) -C(O)O(CR6R6)tR9,

(r) -NR6C(O)(CR6R6)tR9, (s) -C(O)NR6(CR6R6)tR9, (t) -C(=NR6)(CR6R6)tR9,

(u) -C(=NNR6R6)(CR6R6)tR9, (v) -C(=NNR6C(O)R6)(CR6R6)tR9,

(w) -C(=NOR9)(CR6R6)tR9, (x) -NR6C(O)O(CR6R6)tR9,

(y) -OC(O)NR6(CR6R6)tR9, (z) -NR6C(O)NR6(CR6R6)tR9,

(aa) -NR6S(O)p(CR6R6)tR9, (bb) -S(O)pNR6(CR6R6)tR9, (cc) -NR6S(O)pNR6(CR6R6)tR9, (dd) -NR6R6, (ee) -NR6(CR6R6), (ff) -OH, (gg) -NR6R6, (hh) -OCH3, (ii) -S(O)pR6, (jj) -NC(O)R6, (kk) (-Si(R13)3, (ll)a Cj_6 alkyl group, (mm) a C2.6 alkenyl group, (nn) a C2.6 alkynyl group, (oo) -C3-12 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 (11)— (pp) optionally is substituted with one or more R9 groups; alternatively, two R7 groups can form -O(CH2)UO-, =O, or =S;

R8 is selected from: (a) R5, (b) H, (c) a C1-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2.6 alkynyl group, (f) a C3-12 saturated, unsaturated, or aromatic carbocycle, (g) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (h) -C(O)-C1-6 alkyl, (i) -C(O)-C2-6 alkenyl, Q) -C(O)-C2-6 alkynyl, (k) -C(O)-C3-12 saturated, unsaturated, or aromatic carbocycle, and (1) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (c)-(l) optionally is substituted with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, Oj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2, (11) a C1-6 alkoxy group, (mm) an aryl group, (nn) a substituted aryl group, (oo) a heteroaryl group, (pp) a substituted heteroaryl group, and (qq) a C1-6 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, NO2, CF3, SCF3, and OH; R9, at each occurrence, independently is selected from:

(a) R10, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-12 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, wherein any of (b)-(f) optionally is substituted with one or more R10 groups; R10, at each occurrence, independently is selected from:

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -NO2, Q) -NR6R6, (k) -OR6, (1) -S(O)pR6, (m) -C(O)R6, (n) -C(O)OR6, (o) -OC(O)R6, (p) NR6C(O)R6, (q) -C(O)NR6R6, (r) -C(=NR6)R6, (s) -NR6C(O)NR6R6, (t) -NR6S(O)pR6, (u) -S(O)pNR6R6, (v) -NR6S(O)pNR6R6, (w) a C1-6 alkyl group, (x) a C2-6 alkenyl group, (y) a C2-6 alkynyl group, (z) a C3-12 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 R6, F, Cl, Br, I, CN, NO2, -OR6, -NH2, -NH(C1-6 alkyl), - N(C1-6 alkyl)2, a C1-6 alkoxy group, a C1-6 alkylthio group, and a C1-6 acyl group;

R11 and Rl la at each occurrence, independently is selected from:

(a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h) NO2, (i) OR8, 0) -S(O)pR8, (k) -C(O)R8, (1) -€(O)OR8, (m) -OC(O)R8, (n) -C(O)NR8R8, (o) -OC(O)NR8R8, (p) -C(=NR8)R8, (q) -C(R8)(R8)OR8, (r) -C(R8)2OC(O)R8, (s) -C(R8)(OR8)(CH2)rNR8R8, (t) -NR8R8, (u) -NR8OR8, (v) -NR8C(O)R8, (w) -NR8C(O)OR8, (x) -NR8C(O)NR8R8, (y) -NR8S(O)pR8, (z) -C(OR8)(OR8)R8, (aa) -C(R8)2NR8R8, (bb) =NR8, (cc) -C(S)NR8R8, (dd) -NR8C(S)R8, (ee) -OC(S)NR8R8, (ff) -NR8C(S)OR8, (gg) - NR8C(S)NR8R8, (hh) -SC(O)R8, (ii) -N3, (jj) -Si(R13)3, (kk) a C1-6 alkyl group, (11) a C2-6 alkenyl group, (mm) a C2-6 alkynyl group, (nn) a C1-6 alkoxy group, (oo) a C1-6 alkylthio group, (pp) a Cj-6 acyl group, (qq) a C3-12 saturated, unsaturated, or aromatic carbocycle, (rr) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (ss) -B(OH)2, (tt) -B(OC1-6 alkyl)2, (uu) -B(OH)(OC1-6 alkyl), (vv) -B[-OC(CH3)2(CH3)2CO-], (ww) -P(OH)2, (xx) -P(OC1-6 alkyl)2, (yy) -P(OH)(OC1-6 alkyl), and (zz) -NR8(C=NR8)R8, wherein (kk)-(mm) optionally are substituted with one or more R5 groups;

R12 is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -C(O)R5, (f) -C(O)OR5, (g) -C(O)-NR4R4, (h) -C(S)R5, (i) -C(S)OR5, O) -C(O)SR5, (k) -C(S)-NR4R4, (1) a C3-12 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 -(C1-6 alkyl) -C3-12 saturated, unsaturated, or aromatic carbocycle, and (o) a -(C1-6 alkyl)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (b)-(d) and (l)-(o) optionally are substituted with one or more R5 groups; each R13 is independently selected from (a) -C1-6 alkyl and (b) -O-(C1-6 alkyl): wherein R14 at each occurrence is independently selected from:

(a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)PR8, Q) - C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8, (o) -C(=NR8)R8, (p) -C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) -C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) -NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)pR8, (y) -C(OR8)(OR8)R8, (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -OC(S)NR8R8, (dd) -NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) -N3, (hh) -Si(R13)3, (ii) a C1-6 alkyl group, (jj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl group, (U) a C3-12 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 R5 groups; p at each occurrence is O, 1, or 2; r 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.

2. A compound according to claim 1, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.

3. A compound according to claim 2, having the structure: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.

4. A compound according to claim 2, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, R3, Ra, Rb, Re, Rd, and Re are as described in claim 1.

5. A compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -CN, (g) -CF3, (h) -CF2H, (i) -CFH2, (j) -O(C1-6 alkyl), (k) -N3, (1) -COOH,

(m) -COO(C1-6 alkyl), (n) -NH2, (o) -NH(C1-6 alkyl), (p) -N(C1-6 alkyl)2, (q) -C(O)NH2, (r) -C(O)NH(C1-6 alkyl), (s) -C(O)N(C1-6 alkyl)2, (t) -NHC(O)H, (u) -NHC(O)(C1-6 alkyl), (v) -N(C1-6 alkyl)C(O)H, and (w) -N(C1-6 alkyl)C(O)N(C1-6 alkyl)2.

6. A compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from F and OH.

7. A compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is F.

8. A compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH.

9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are selected from (a) Cl, (b) Br, (c) F, (d) H and (e) C1-6 alkyl.

10. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are H.

11. A compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rc is selected from (a) H, (b) C1-6 alkyl, (c) -CF3, (d) -CF2H, and (e) -CFH2.

12. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rc is H.

13. A compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra and Rb are independently selected from (a) H, (b) Cl, (C) Br, (d) F, (e) -OH, (f) -O(C1-6 alkyl), (g) -N3, (h) -COOH, (i) -COO(C1-6 alkyl), (j) -CN, (k) -NH2, (1) -NH(C1-6 alkyl), (m) -N(C1-6 alkyl)2, (n)-C(O)NH2,

(o) -C(O)NH(C1-6 alkyl), (p) -C(O)N(C1-6 alkyl)2, (q) -NHC(O)H, (r) -NHC(O)(C1-6 alkyl), (s) -N(C1-6 alkyl)C(O)H, (t) -N(C1-6 alkyl)C(O)N(C1-6 alkyl)2, (u) -SH, and (v) -S(C1-6 alkyl), or alternatively Ra and Rb are taken together with the carbon to which they are attached to form (aa) -C(=O)- or (bb) -C(=S)-.

14. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein Ra and Rb are independently selected from -H, -F, -OH, -OCH3, -SH, and -SCH3.

15. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein Ra is H and Rb is F.

16. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -OH.

17. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -OCH3.

18. A compound according to any one of claims 1 - 14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -SH.

19. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -SCH3.

20. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is H.

21. A compound according to any one of claims 1 -20, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 is H.

22. A compound according to any one of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R2 is H.

23. A compound according to any one of claims 1-22, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is C1-6alkyl.

24. A compound according to any one of claims 1-22, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is methyl.

25. A compound according to any one of claims 1-24, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is B'.

26. A compound according to any one of claims 1-25, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is selected from: (a) a heterocyclic group, (b) an aryl group, (c) a heteroaryl group, (d) a biaryl group, and (e) a fused bicyclic or tricyclic unsaturated or aromatic ring system optionally containing one or more carbonyl groups and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (a)-(e) optionally is substituted with one or more R 11 groups

27. A compound according to any one of claims 1-26, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is -B'-Z-B".

28. A compound according to claim 27, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein B' and B" are independently selected from: (a) a heterocyclic group, (b)an aryl group, (c) a heteroaryl group, (d) a biaryl group, and (e) a fused bicyclic or tricyclic unsaturated or aromatic ring system optionally containing one or more carbonyl groups and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (a)-(e) optionally is substituted with one or more R1 ' groups, and Z is selected from (aa) a single bond, (bb) -O-, (cc) -NR4-, (dd) -C(O)-, (ee) -C(S)-, (ff) -S(O)P-,

(gg) -S(O)p(C1-6 alkyl)-, and (hh) a C1-6 alkyl.

29. A compound according to claim 3, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.

30. A compound according to claim 3, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described in claim 1.

31. A compound according to claim 3, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.

32. A compound according to claim 3, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described in claim 1.

33. A compound according to claim 3, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.

34. A compound according to claim 3, having the structure: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R .1 , τ R»2 , and R3 are as described in claim 1.

35. A compound according to claim 3, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.

36. A compound according to claim 3, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described in claim 1.

37. A compound according to claim 3, having the structure: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.

38. A compound according to claim 3, having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described in claim 1.

39. A compound according to any of claims 1-38, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:

where B", Z, and R1 ! are as described in claim 1.

40. A compound according to any of claims 1-38, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:

, where B", Z, and R11 are as described in claim 1.

41. A compound according to any of claims 1-38, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:

where B", Z, and R11 are as described in claim 1.

42. A compound according to any of claims 1-38, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:

where B", Z, and R are as described in claim 1.

43. A compound according to any of claims 39-42, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 ' is selected from H and F.

44. A compound according to any of claims 39-42, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is H.

45. A compound according to any of claims 39-42, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is F.

46. A compound according to any of claims 39-45, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1-6 alkyl group, (b) a C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) H, (g) -OH (h) -SH, (i) F, (j) Cl, (k) Br,

(1) I, (m) -CF3, (n) -CN, (o) -N3 (p) -NO2, (q) -NR6(CR6R6)tR9, (r) -OR9, (s) -S(CR6R6)tR9, (t) -S(O)(CR6R6)tR9, (u) -S(O)2(CR6R6)tR9 (v) -C(O)(CR6R6)tR9, (w) -OC(O)(CR6R6)tR9, (x) -OC(O)O(CR6R6)tR9, (y) -SC(O)(CR6R6)tR9, (z) -C(O)O(CR6R6)tR9, (aa) -NR6C(O)(CR6R6)tR9, (bb) -C(O)NR6(CR6R6)tR9, (cc) -C(=NR6)(CR6R6)tR9, (dd) -C(=NNR6R6)(CR6R6)tR9, (ee) -C[=NNR6C(O)R6](CR6R6)tR9,

(ff) -NR6C(O)O(CR6R6)tR9, (gg) -OC(O)NR6(CR6R6)tR9, (hh) -NR6C(O)NR6(CR6R6)tR9,

(ii) -NR6S(O)p(CR6R6)tR9, (jj) -S(O)pNR6(CR^tR9, (kk) -NR6R6, (11) -NR6(CR6R6)tR9,

(mm) -SR6, (nn) -S(O)R6, (oo) -S(O)2R6, (pp) -NR6C(O)R6, (qq) -Si(R13)3, and (rr) -

C(=O)H; wherein t at each occurrence is O, 1, or 2; wherein (a)-(e) optionally are substituted with one or more R14 groups; wherein R14 at each occurrence is independently selected from:

(a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)PR8, (j) -C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8, (o) -C(=NR8)R8, (p) -C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) -C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) -NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)13R8, (y) -C(OR8)(OR8)R8, (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -OC(S)NR8R8, (dd) -NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) -N3, (hh) -Si(R13)3, (ii) a C1-6 alkyl group, (jj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl group, (11) a C3-12 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 R5 groups; alternatively two R14 groups are taken together to form (a) =O, (b) =S, (c) =NR8, or

(e) =NOR8.

47. A compound according to claim 46, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1-6 alkyl group, (b) a C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) -CF3, (g) -NR6(CR6R6)tR9, (h) -OR9, (i) -S(CR6R6)tR9, O) -S(O)(CR6R6)tR9, (k) -S(O)2(C 6R6)tR9 (1) -C(O)(CR6R6)tR9, (m) -OC(O)(CR6R6)tR9, (n) -OC(O)O(CR6R6)tR9, (o) -SC(O)(CR6R6)tR9, (p) -C(O)O(CR6R6)tR9, (q) -NR6C(O)(CR6R6)tR9, (r) -C(O)NR6(CR6R6)tR9, (s) -C(=NR6)(CR6R6)tR9, (t) -C(=NNR6R6)(CR6R6)tR9, (u) -C[=NNR6C(O)R6](CR6R6)tR9, (v) -NR6C(O)O(CR6R6)tR9, (w) -OC(O)NR6(CR6R6)tR9, (x) -NR6C(O)NR6(CR6R6)tR9,

(y) -NR6S(O)p(CR6R6)tR9, (z) -S(O)pNR6(CR^tR9, (aa) -NR6R6, (bb) -NR6(CR6R6)tR9, (cc) -SR6, (dd) -S(O)R6, (ee) -S(O)2R6, and (ff) -NR6C(O)R6, wherein (a)-(e) optionally are substituted with one or more R14 groups.

48. A compound according to claim 47, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1_6 alkyl group, (b) a

C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, wherein (a)-(e) optionally are substituted with one or more R14 groups.

49. A compound according to claim 48, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein -ZB" is selected from (a) -ΝR6(CR6R6)tR9, (b) -OR9, (c) -S(CR6R6)tR9, (d) -S(O)(CR6R6)tR9, (e) -S(O)2(CR6R6)tR9 (f) -C(O)(CR6R6)tR9,

(g) -OC(O)(CR6R6)tR9, (h) -OC(O)O(CR6R6)tR9, (i) -SC(O)(CR6R6)tR9,

(j) -C(O)O(CR6R6)tR9, (k) -NR6C(O)(CR6R6)tR9, (1) -C(O)NR6(CR6R6)tR9,

(m) -C(=NR6)(CR6R6)tR9, (n) -C(=NNR6R6)(CR6R6)tR9, (o) -C[=NNR6C(O)R6](CR6R6)tR9,

(p) -NR6C(O)O(CR6R6)tR9, (q) -OC(O)NR6(CR6R6)tR9, (r) -NR6C(O)NR6(CR6R6)tR9,

(s) -NR6S(O)p(CR6R6)tR9, (t) -S(O)pNR6(CR6R6)tR9, (u) -NR6R6, (v) -NR6(CR6R6)tR9,

(w) -SR6, (x) -S(O)R6, (y) -S(O)2R6, and (z) -NR6C(O)R6.

50. A compound according to any one of claims 1-49, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug, thereof, wherein T is:

wherein:

M is selected from:

(a) -C(O)-, (b) -CH(-ORll4)-, (c) -NR114-CH2- (d) -CH2-NR114-,

(e) -CH(NR114R11V, (f) -C(=NNR114R114)-, (g) -NR114-C(O)-,

(h) -C(O)NR114- (i) -C(=NR114)-, G) -CR115R115- and (k) -C(=NOR127)-;

R100 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR114, and (f) C1-6 alkyl, wherein

(f) optionally is substituted with one or more R115 groups;

R101 is selected from:

(a) H, (b) Cl, (C) F, (d) Br, (e) I, (f) -NR114R114, (g) -NR114C(O)R114,

(h) -OR114, (i) -OC(O)R114, O) -OC(O)OR114, (k) -OC(O)NR114R114, (1) -O-

C1-C6 alkyl, (m) -OC(O)-C1-6 alkyl, (n) -OC(O)O-C1-6 alkyl,

(o) -OC(O)NR114-C1-6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2- 6 alkynyl, wherein any of (1) - (r) optionally is substituted with one or more R115 groups;

R102 is (a) H, (b) F, (c) Cl, (d) Br, (e) -SR114, (f) C1-6 alkyl, wherein (f) optionally is substituted with one or more R115 groups;

R103 is selected from:

(a) H, (b) -OR114, (c) -O-C1-6 alkyl-R115, (d) -OC(O)R114, (e) -OC(O)-C1- 6 alkyl-R115, (f) -OC(O)OR114, (g) -OC(O)O-C1-6 alkyl-R115, (h) -OC(O)NR114R114, (i) -OC(O)NR114-C1-6 alkyl-R115, and

alternatively, R and R taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-12 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more

R114 groups; alternatively, R101 and R103 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 and R taken together with the carbons to which they are attached form a 3-12 membered carbocyclic or heterocyclic ring, wherein said 5-12 membered ring can optionally be substituted with one or more R114 groups; alternatively, R100, R101, R102, and R103 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 R114 groups;

R104 is selected from:

(a) H, (b) R114, (c) -C(O)R114 (d) -C(O)OR114 (e) -C(O)NR114R114, (f) -C1-6 alkyl-K-R114, (g) -C2-6 alkenyl-K-R114, and (h) -C2-6 alkynyl-K-R114; K is selected from:

(a) -C(O)-, (b) -C(O)O-, (C) -C(O)NR114- (d) -C(=NR114)-, (e) - C(=NR114)O-, (f) -C(=NRU4)NR114-, (g) -OC(O)-, (h) -OC(O)O-, (i) - OC(O)NR114-, G) -NR114C(O)-, (k) -NR114C(O)O-, (1) -NR114C(O)NR114- (m) -NR114C(=NR114)NR114-, and (n) -S(O)p-; alternatively R103 and R104, taken together with the atoms to which they are bonded, form:

wherein R'" and R'JD are selected from (a) hydrogen, (b) C]-6 alkyl, (c) C2-6 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 oxygen, nitrogen, or sulfur atoms, (g) F, (h) Br, (i) I, (j) OH, (k) -N3, wherein (b) through (f) are optionally substituted with one or more R117; or alternatively, R135 and R136 are taken together to form =O, =S, =NR114, =NOR114, =NRm, or =N-NR114Rm, wherein V is selected from (a) -(Cϊ-4-alkyl)-, (b)-(C2-4-alkenyl)-, (c) O, (d) S, and (e) NR114, wherein (a) and (b) are optionally further substituted with one or more R117; R 5 is selected from:

(a) R114, (b) -OR114, (c) -NR114R114, (d) -C)-C1-6 alkyl-R115, (e) -C(O)-R114, (f) -C(O)-C1-6 alkyl-R115, (g) -OC(O)-R114, (h) -OC(O)-C1-6 alkyl-R115, (i) -OC(O)O-R114, O) -OC(O)O-C1-6 alkyl-R115, (k) -OC(O)NR114R114, (1) -OC(O)NR114-C1-6 alkyl-R115, (m) -C(O)-C2-6 alkenyl-R115, and (n) -C(O)-C2-6 alkynyl-R115; alternatively, R104 and R105, taken together with the atoms to which they are bonded, form

, w .herei .n

Q is CH or N, and R126 is -OR114, -NR114 or R114; alternatively, R104 and R105, taken together with the atoms to which they are bonded, form:

, wherein i) R149 is selected from: (a) H, Qo) Cl, (c) F, (d) Br, (e) I, (f) -NR114R114, (g) -NR114C(O)R114, (h) -OR114, (i) -OC(O)R114, O) -OC(O)OR114, (k) -OC(O)NR114R114, (1) -O- C1-6 alkyl, (m) -OC(O)-C1-6 alkyl, (n) -OC(O)O-C1-6 alkyl, (o) -OC(O)NR114-C1-6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2- 6 alkynyl, wherein any of (1) - (r) optionally is substituted with one or more R115 groups; ii) R150 is H, C1-6 alkyl, or F; iii) alternately, R149 and R150 can be taken together with the carbon to which they are attached to form a carbonyl group; iv) alternately, R149 and R150 can be taken together to form the group -O(CR116R116)UO-; v) alternatively, R104 and R105, 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) R130 is -OH, or R114,

R , 1M31 ϋ) 1 is -OH, or R 114 iii) alternately, R130 and R131 together with the carbons to which they are attached form a 3-12 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups; iv) alternatively, R130 and the carbon to which it is attached or R131 and the carbon to which it is attached are each independently -C(=O)-; alternatively, R105, R132 and M, taken together with the atoms to which they are attached, form:

where

R106 is selected from:

(a) -OR114, (b) -C1-6 alkoxy-R115, (c) -C(O)R114, (d) -OC(O)R114, (e) -OC(O)OR114, (f) -OC(O)NR114R114, and (g) -NR114R114, alternatively, R105 and R106 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(R115)2O-, (b) -OC(O)O-, (c) -OC(O)NR114-, (d) -NR114C(O)O-, (e) -OC(O)NOR114-, (f) -NORU4-C(O)O-, (g) -OC(O)N[NR114R114] -, (h) -N[NR114R114]-C(O)O-, (i) -OC(O)C(R115)2- (j) -C(R115)2C(O)O-, (k) -OC(S)O-, (1) -OC(S)NR114- (m) -NR114C(S)O-, (n) -OC(S)NOR114- (o) -NOR114-C(S)O-, (p) -OC(S)N[NR114R114]-, (q) -N[NR114R114]-C(S)O-, (r) -OC(S)C(R11V, (s) -C(RU5)2C(S)O-, (t) -OC(O)CR115[S(O)pR114] - (u) -OC(O)CR115[NR114R114] - (v) -CR1 ^[NR114R114JC(O)O-, and (w) -CR115[S(O)PR114]C(O)O-;

alternatively, R105, R106, and R133 taken together with the atoms to which they are attached form:

alternatively, M, R105, and R106 taken together with the atoms to which they are attached form:

wherein J1 and J2 are selected from hydrogen, Cl, F, Br, I, OH, -C1-6 alkyl, and -O(C1-6 alkyl) or are taken together to form =O, =S, =NR114, =NOR114, =NR114, or =N-NRU4R114, alternatively, M and R104 taken together with the atoms to which they are attached form:

wherein U is selected from (a) -(C1-4-alkyl)- and (b)-(C2-4-alkenyl)-, wherein (a) and (b) are optionally further substituted with one or more R117; alternatively, M and R105 are taken together with the atoms to which they are attached to form:

R 107 is selected from

(a) H, (b) -Cj-6 alkyl, (c) -C2-6 alkenyl, which can be further substituted with C1-6 alkyl or one or more halogens, (d) -C2-6 alkynyl, which can be further substituted with C1-6 alkyl or one or more halogens, (e) aryl which can be further substituted with C1-6 alkyl or one or more halogens, (f) heteroaryl, which can be further substituted with C1-6 alkyl or one or more halogens, (g) -C(O)H, (h) -COOH, (i) -CN, (j) -COOR114, (k) -C(O)NR114R114, (1) -C(O)R114, and (m) -C(O)SR114, wherein (b) is further substituted with one or more substituents selected from (aa) -OR114, (bb) halogen, (cc) -SR114, (dd) C1-6 alkyl, which can be further substituted with halogen, hydroxyl, C1-6 alkoxy, or amino, (ee) -OR114, (fϊ) -SR114, (gg) -NR114R114, (hh) -CN,

(ii) -NO2, (jj) -NC(O)R , 111144, (kk) -COOR 1"144, (11) -N3, (mm) =N-O-R , 114 (nn) =NR114, (oo) =N-NR114R114, (pp) =N-NH-C(O)R114, or (qq) =N-NH- C(O)NR114R114; alternatively R106 and R107 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 C3- C7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a Cr6 alkyl;

R is selected from:

(a) C1-6 alkyl, (b) C2-6 alkenyl, and (c) C2-6 alkynyl, wherein any of (a)-(c) optionally is substituted with one or more R114 groups;

R109 is H, C1-6 alkyl, or F;

R114, at each occurrence, independently is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 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)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-12 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-C1-6 alkyl, (m) -C(O)O-C2-6 alkenyl, (n) -C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 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)NR116R116, (r) -NR116CO-C1-6 alkyl, (s) -NR116CO-C3-12 saturated, unsaturated, or aromatic carbocycle, (t) -NR116C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (u) -(C1-6 alkyl)-O-(C1 -6 alkyl), (v) -(C1-6 alkyl)-O-(C1-6 alkyl)-O-(C1-6 alkyl), (w) -OH, (x) -OR115, (y) -NH(C1-6 alkyl), (z) -N(C1-6 alkyl)2, (aa) -(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (bb) -(C1-6 alkyl)- S(O)p-(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (cc) -(C1-6 alkyl)-O-(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (dd) -(C1-6 alkyl)- S(O)p-(C1-6 alkyl)-O-(C1-6 alkyl); and (ee) -NH2; 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 R115 groups, wherein one or more non-terminal carbon moieties of any of (b)-(d) optionally is replaced with oxygen, S(O)P, or -NR116, alternatively, NR114R114 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R114 groups are bonded and optionally one or more moieties selected from O, S(O)P, N, and NR118; R115 is selected from:

(a) R117, (b) C1-6 alkyl, (c) C2-6 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) -OC1-6 alkyl, (h) -OC2-6 alkenyl, and (i) -OC2-6 alkynyl, wherein any of (b)-(f) optionally is substituted with one or more R117 groups; R116, at each occurrence, independently is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-12 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 -NR118, wherein any of (by- (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) N3, (ii) NO2, Oj) OR118, (kk) -S(O)PR118,

(11) -C(O)R118, (mm) -C(O)OR118, (nn) -OC(O)R118,

(oo) -C(O)NR118R118, (pp) -OC(O)NR118R118,

(qq) -C(=NR1 18)R118, (rr) -C(R118)(R118)OR118,

(ss) -C(R118)2OC(O)R118, (tt) -C(R118)(OR1 ^(CH^NR118R118,

(uu) -NR118R118; (w) -NR118OR118, (ww) -NR118C(O)R118,

(XX) -NR118C(O)OR118, (yy) -NR1 18C(O)NR118R118, (zz) -NR118S(COrR118, (ab) -C(OR118)(OR118)R118, (ac) -C(R118)2NR118R118, (ad) =NR118, (ae) -C(S)NR118R118, (af) -NR118C(S)R118, (ag) -OC(S)NR118R118, (ah) -NR118C(S)OR118, (ai) -NR118C(S)NR118R118, (aj) -SC(O)R118, (ak) C1-6 alkyl, (al) C2-6 alkenyl, (am) C2-6 alkynyl, (an) C1-6 alkoxy, (ao) C1-6 alkylthio, (ap) C1-6 acyl, (aq) saturated, unsaturated, or aromatic C3-12 carbocycle, and (ar) saturated, unsaturated, or aromatic 3-12 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR116R116 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R116 groups are attached and optionally one or more moieties selected from O, S(O)P, N, and NR118; alternatively, CR116R116 forms a carbonyl group; R117, at each occurrence, is selected from:

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3,

(h) (CR116R116)rCN, (i) (CR116R116)rNO2,

(j) (CR116R116)rNR116(CR116R116)tR119, (k) (CR116R116)rOR119,

(1) (CR116R116)rS(O)P(CR116R116)tR119, (m) (CR116R116)rC(O)( CR116R116)tR119,

(n) (CR116R116)rOC(O)(CR116R116),R119,

(o) (CR116R116)rSC(O)(CR116R116)tR119,

(p) (CR116R116)rC(O)O(CR116R116)tR119,

((0 (CR116R116)rNR116C(O)(CR116R116)tR119,

(r) (CR116R116)rC(O)NR116(CR116R116),R119,

(s) (CR116R116)rC(=NR116)(CR116R116)tR119,

(t) (CR116R116)rC(=NNR116R116)(CR116R116)tR119,

(u) (CR116R116)rC(=NNR116C(O)R116)(CR116R116)tR119,

(v) (CR116R116)rC(=NOR119XCR116R116)tR119,

(W) (CR116R116)rNR116C(O)O(CR116R116)tR119,

(X) (CR116R116)rOC(O)NR116(CR116R116),R119,

(y) (CR116R116)rNR116C(O)NR116(CR116R116)tR119,

(Z) (CR116R116)rNR116S(O)P(CR116R116)tR119,

(aa) (CR116R116)rS(O)PNR116(CR116R116)tR119, (bb) (CR116R116)rNR116S(O)pNR1 16(CR116R116)tR119,

(cc) (CR116R116)rNR116R116, (dd) C1.6 alkyl, (ee) C2.6 alkenyl, (ff) C2.6 alkynyl, (gg) (CR116R116)r-C3-12 saturated, unsaturated, or aromatic carbocycle, (hh) (CR116R116)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(C1-6 alkyl))2, wherein any of (dd)-(hh) optionally is substituted with one or more R119 groups; alternatively, two R117 groups can form -O(CH2)UO-; R118 is selected from:

(a) H, (b) C1-6 alkyl, (c) C2.6 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)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-12 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) NO2, (hh) OH, (ii) NH2, Oj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2, (11) C1-6 alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C1-6 alkyl, optionally substituted with one or more moieties selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO2, and OH; R119, at each occurrence, independently is selected from:

(a) R120, (b) C1-6 alkyl, (c) C2.6 alkenyl, (d) C2.6 alkynyl, (e) C3-12 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 R114 groups; R120, at each occurrence, independently is selected from:

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R1 ]6)rCF3,

(h) (CR116R116)rCN, (i) (CR116R116)rNO2, (j) (CR116R116(1NR116R116,

(k) (CR116R116)rOR114, (1) (CR116R116)rS(O)pR116, (m) (CR116R116)rC(O)R116,

(n) (CR116R116)rC(O)OR116, (o) (CR116R116)rOC(O)R116,

(p) (CR116R116)rNR116C(O)R116, (q) (CR116R116)rC(O)NR116R116,

(r) (CR116R116)rC(=NR116)R116, (s) (CR116R116(nNR116C(O)NR116R116,

(t) (CR116R116(1NR116S(O)PR116, (u) (CR116R116)rS(O)PNR116R116,

(v) (CR116R1^)1NR116S(O)PNR116R116, (w) C1-6 alkyl, (x) C2.6 alkenyl,

(y) C2.6 alkynyl, (z) (CR116R116)r-C3-12 saturated, unsaturated, or aromatic carbocycle, and (aa) (CR116R116)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 R116, F, Cl, Br, I, CN, NO2, -OR116, -NH2, - NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkoxy, C1-6 alkylthio, and C1-6 acyl; R121, at each occurrence, independently is selected from:

(a) H, (b) -OR118, (c) -O-C1-6 alkyl-OC(O)R118, (d) -C)-C1-6 alkyl- OC(O)OR118, (e) -O-C1-6 alkyl-OC(O)NR118R118, (f) -O-C1-6 alkyl- C(O)NR118R118, (g) -O-C1-6 alkyl-NR118C(O)R118, (h) -O-C1-6 alkyl- NR118C(O)OR118, (i) -O-C1-6 alkyl-NR118C(O)NR118R118, O) -O-C1-6 alkyl- NR118C(=N(H)NR118R118), (k) -O-C1-6 alkyl-S(O)pR118, (1) -O-C2-6 alkenyl- OC(O)R118, (m) -O-C2-6 alkenyl-OC(OpR118, (n) -O-C2-6 alkenyl- OC(O)NR118R118, (o) -O-C2-6 alkenyl-C(O)NR118R118, (p) -O-C2^ alkenyl- NR118C(O)R118, (q) -O-C2-6 alkenyl-NR118C(O)OR118, (r) -O-C2-6 alkenyl- NR118C(O)NR118R118, (s) -O-C2-6 alkenyl-NR118C(=N(H)NR118R118), (t) -O- C2-6 alkenyl-S(O)pR118, (u) -O-C2-6 alkynyl-OC(O^118, (v) -O-C2-6 alkynyl- OC(O)OR118, (w) -O-C2-6 alkynyl-OC(O)NR118R118, (x) -O-C2-6 alkynyl- C(O)NR118R118, (y) -O-C2-6 alkynyl-NR118C(O)R118, (z) -O-C2-6 alkynyl- NR118C(O)OR118, (aa) -C)-C2-6 alkynyl-NR118C(O)NR118R118, (bb) -O- C2-6 alkynyl-NR118C(=N(H)NR118R118), (cc) -O-C2-6 alkynyl-S(O)pR118, (dd) -NR118R118, (ee) -C1-6 alkyl-O-C1-6 alkyl, (ff) -C1-6 alkyl-NR114-C1-6 alkyl, (gg) -C1-6 alkyl-S(O)p-C1-6 alkyl, (hh) -OC(O)NR114(C1-6 alkyl)-NR114- (C1-6 alkyl) -R114, (ii) -OH, (jj) -C^alkyl, (kk) C2-6 alkenyl, (11) C2-6 alkynyl, (mm) -CN, (nn) -CH2S(O)PR137, (oo) -CH2OR137, (pp) -CH2N(OR138)R137, (qq) -CH2NR137R139, (rr) -(CH2)v(C6-10 aryl), and (ss)-(CH2)v(5-10 membered heteroaryl), wherein (jj)-(ss) are optionally substituted by 1, 2, or 3 R140 groups; alternatively, two R121 groups taken together form =O, =NOR118, or =NNR118R118; R127 is selected from R114, a monosaccharide or a disaccharide (including amino sugars and halogenated sugar(s)), -S(O)pR148, -(CH2)n-(O-CH2CH2-)m-O(CH2)nCH3, -(CH2)n-(O-CH2CH2-)m-OR148, -(CH2)n-[S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3 , -(CH2)n-[S(O)p-CH2CH2-]m-OR148, -OCH2-O-(CH2)n-[S(O)p-CH2CH2-]m- S(O)p(CH2)nCH3, -OCH2-O-(CH2)n-[S(O)p-CH2CH2-]m-OR148, -O-[C3-12 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R114, -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 R114, -S(O)P-[C3-12 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R114, and -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 R114; R128 is R114; R129 is R114; alternatively two R128 substituents can be taken together with the carbons to which they are attached to form carbonyl or =NR114, or a saturated or unsaturated C3-6 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 subsituted by one or more R117 groups, alternatively two R substituents can be taken together wtih the carbons to which they are attached to form carbonyl or =NR114, or a saturated or unsaturated C3-6 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 subsituted by one or more R117 groups, alternatively an R128 and an R129 substituent can be taken together wtih the carbons to which they are attached to form a C3-12 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 substitued by one or more R117 groups, alternatively two R128 groups and two R129 groups can be taken together with the carbons to which they are attached to form an unsaturated bond between the carbon atoms to which R128 and R129 are attached and a C3-12 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 substitued by one or more R117 groups,

R110 is R114; alternatively, R109 and R110 taken together with the carbons to which they are attached form:

R132, R133, and R134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br,

(e) -OR114, (f) -SR114, (g) -NR114R114, and (h) C1-6 alkyl, wherein (h) optionally is substituted with one or more R115 groups; alternatively, R132 and R133 are taken together to form a carbon-carbon double bond; alternatively, R133 and R134 are taken together to form =O, =S, =NOR114, =NR114, or

=N-NR114R114; alternatively, R105 and R134 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 R114 groups; alternatively when M is a carbon moiety, R134 and M are taken together to form a carbon-carbon double bond; R137 is independently (a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) - (CH^CR^R^CH^NR^R144, -(CH2)V(C6-CI O aryl), or -(CH2)v(5-10 membered heteroaryl); or where R137 IS-CH2NR137R139, R139 and R137 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(R137)-, in addition to the nitrogen to which R139 and R137 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 R140 groups; each R138 is independently H or Q-6 alkyl; each R141, R142, R143, and R144 is independently selected from H, C1-6 alkyl, - (CH2)m(C6-C10aryl), and -(CH2)m(5-10 membered heteroaryl), wherein the foregoing R141, R142, R143, and R144 groups, except H, are optionally substituted by 1, 2, or 3 R140 groups; or R141 and R143 are taken together to form -(CH2)O- 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 R143 and R144 are taken together to form a 3-12 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(R137)-, in addition to the nitrogen to which R143 and R144 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 R140 groups;

R139 is H, C1-6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the foregoing R139 groups, except H, are optionally substituted by 1, 2, or 3 substituents independently selected from halo and -OR138; each R is independently selected from halo, cyano, nitro, trifluoromethyl, azido, -C(O)R145, -C(O)OR145, -OC(O)OR145, -NR146C(O)R147, -NR146R147, OH, Cr6 alkyl, C1-6 alkoxy, -(CH2)V(C6-C1OaTyI), and -(CH2)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)R145,-C(O)OR145, -OC(O)OR145, -NR146C(O)R147, -C(O)NR146R147, -NR146R147, OH, C1-6alkyl, and Cr6 alkoxy; each R145 is independently selected from H, C1-O alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)V(C6-C1 oaryl), and -(CH2)v(5-10 membered heteroaryl); each R146 and R147 is independently H, hydroxyl, Q-όalkoxy, C1-O alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)v(C6-10 aryl), or -(CH2)v(5-10 membered heteroaryl);

R148 is C1-O alkyl, C3-J2 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further optionally substituted with one or more R114, 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 R114; p, at each occurrence is 0, 1, or 2; k, at each occurrence is 0, 1 , or 2; m, at each occurrence is O, 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 O, 1, or 2; v, at each occurrence is O, 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.

51. A compound according to any one of claims 1 -50, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from TAl through TA24:

wherein M, Q, R104, R114, R126, R127, R128, R129, R149, and R15Ve as described in claim 50.

52. A compound according to any one of claims 1 -51 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from Tl through T93:

T16 T17 T18

T19 T20

T21 T22

T29

T30

T32 T33

T57

T58

T59

T60

T61

T62

T63

T64

T65

T66

T67

T68

T69

T70

T71

T72

T73

T74

T77 T78

T89 T90 T91

T92 and T93

53. 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.

54. A pharmaceutical composition comprising a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, and a pharmaceutically acceptable carrier.

55. 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 according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

56. A method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

57. The use of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, in the manufacture of a medicament for treating a microbial infection in a mammal.

58. A method of treating or preventing a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, 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 atrioventricular 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.

59. A method of treating or preventing a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

60. A method of treating or preventing a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

61. A method of treating a or preventing proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

62. A method of treating or preventing a viral infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

63. A method of treating or preventing an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

64. A method of treating or preventing a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

65. A method of treating or preventing diarrhea in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

66. 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 according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, to suppress expression of the nonsense or missense mutation.

67. The method or use according to any one of claims 55-66 wherein the compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered orally, otically, ophthalmically, nasally, parentally, or topically.

68. A method of synthesizing a compound according to any of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

69. A medical device containing a compound according to any one of claims 1-53, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

70. The medical device according to claim 69, wherein the device is a stent.

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