MACROLIDE COMPOUNDS AND METHODS OF MAKING AND USING THE SAME

RELATED APPLICATIONS

This application incorporates by reference and claims 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 macrolide compounds that are useful as such agents. In particular embodiments the present invention relates to macrolide compounds in which the macrocyclic ring contains a carbamate or other related functionality and wherein the compounds also contain a triazole ring.

BACKGROUND

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

The problem of resistance is not limited to the area of anti-infective agents. Resistance has also been encountered with anti-proliferative agents used in cancer chemotherapy. Therefore, the need exists for new anti-infective and anti-proliferative 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 al, Lancet, vol 357, p. 1179 (2001); Zurenko et al., Proceedings Of The 39 ^th 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 anti- proliferative 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 macrolide compounds in which the macrocyclic ring contains a carbamate or other related functionality having the structure:

or a stereoisomer, pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In the formula, variables G, T, X, R ¹ , R ^2a - R ^2b , R ³ , R ^a , R ^b , R ^c , R ^d and R ^e can be selected from the respective groups of chemical moieties later defined in the detailed description.

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

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

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

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used as 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, antiparasitic and/or anti-viral agents. Further, the present invention provides a family of compounds that can be used without limitation as anti-inflammatory agents, for example, for use in treating chronic inflammatory airway diseases, and/or as prokinetic agents, for example, for use in treating gastrointestinal motility disorders such as gastroesophageal reflux disease, gastroparesis (diabetic and post surgical), irritable bowel syndrome, and constipation. Further, the compounds can be used to treat or prevent a disease state in a mammal caused or mediated by a nonsense or missense mutation. Further, the present invention provides a family of compounds that can be used without limitation as anti-diarrheal agents.

The compounds described herein can have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described

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

1. Definitions

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). The term "carbamate or other related functionality" means a functional group such as a carbamate, -OC(O)NH- or -NHC(O)O-, an N-alkyl carbamate, such as -OC(0)N(alkyl)- or -N(alkyl)C(O)O-, a carbazate, -OC(O)N(NRR)- or N(NRR)C(O)O-, a carbazate with a further imine function, -OC(O)N(N=R)- or -N(N=R)C(O)O-, a lactone -C(O)O- or -OC(O)-, a carbonate, -OC(O)O-, etc. For illustrative purposes of this paragraph, R includes, but is not limited to substituents such as hydrogen, alkyl, acetyl etc. As can be seen from the compounds illustrated in the present invention, a wide variety of compounds can include a carbamate or similar related functionality. Some nonlimiting examples include: compound 206, which is a carbamate, compound 200, which is an N-alkylcarbmate, wherein R as defined in this paragraph is methyl; compound 246, which is a carbazate, where R is — (CH ₂ ) ₃ -S-CH ₃ and H; compound 252, which is a carbamate wherein R is a 2-carbon alkyl group attached back to the core macrolide ring via an imine group to form a further ring; and compound 264, which is a carbamate wherein R is a 2-carbon alkyl group attached back to the core macrolide ring via an amino group to form a further ring. One of skill in the art will appreciate that the term "carbamate or other related functionality" is being used herein to describe a generally common chemical feature of the compounds of the present invention. The various chemical variable substituents, as defined in the present patent application, further illustrate the term "carbamate or other related functionality".

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C- 13 and C- 14.

When any variable (e.g., R ¹¹⁴ ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at

₈ very other occurrence. Thus, for example, if a group is shown to be substituted with one or more R ¹¹⁴ moieties, then the group can optionally be substituted with one, two, three, four, five, or more R ¹¹⁴ moieties, and R ¹¹⁴ at each occurrence is selected independently from the definition of R ¹¹⁴ . Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

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

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent can be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. In cases wherein there are 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 nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N →O) derivative, as appropriate. As used herein, the term "anomeric carbon" means the acetal carbon of a glycoside.

As used herein, the term "glycoside" is a cyclic acetal.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C ₁ _ ₆ alkyl is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C^ alkyl groups. C ₁ _ ₆ alkyl is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n- hexyl, n-heptyl, and n-octyl.

As used herein, "alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that can occur in any stable point along the chain, such as ethenyl and propenyl. C ₂ _ ₆ alkenyl is intended to include C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkenyl groups. C ₂ _ ₈ alkenyl is intended to include C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ alkenyl groups.

As used herein, "alkynyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that can occur in any stable point along the chain, such as ethynyl and propynyl. C ₂ _ ₆ alkynyl is intended to include C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkynyl groups. C ₂ _ ₈ alkynyl is intended to include C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , Cη, and C ₈ alkynyl groups.

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

As used herein, the terms used to describe various carbon-containing moieties, including, for example, "alkyl," "alkenyl," "alkynyl," "phenyl," and any variations thereof, are intended to include univalent, bivalent, or multivalent species. For example, "C _1-6 alkyl- R ³ " is intended to represent a univalent C ₁ . ₆ alkyl group substituted with a R ³ group, and "O- C ₁ _ ₆ alkyl-R ³ " is intended to represent a bivalent C ₁ _ ₆ alkyl group, i.e., an "alkylene" group, substituted with an oxygen atom and a R ³ group.

As used herein, "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C ₃ . ₈ cycloalkyl is intended to include C ₃ , C ₄ , C ₅ , C ₆ , Cη, and C ₈ cycloalkyl groups. As used herein, "unsaturated" refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds.

As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo substituents. "Counterion" is used to mean a positively or negatively charged species present in conjunction with an ion of opposite charge. A nonlimiting example of a counterion is an ion or ions present to counterbalance the charge or charges on an organic compound. Nonlimiting examples of counterions include chloride, bromide, hydroxide, acetate, sulfate, and ammonium. As used herein, "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -C _V F _W wherein v = 1 to 3 and w = 1 to

(2v+l)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

As used herein, "alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C ₁ . ₆ alkoxy, is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkoxy groups. C ₁ _ ₆ alkoxy, is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , Cη, and C ₈ 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 C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkylthio groups. C ₁ . ₆ alkylthio, is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , Cη, and C ₈ 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 , wherein p = 1 or 2). When a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (i.e., a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle can optionally be quaternized. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Spiro and fused rings are also included. As used herein, the term "aromatic heterocycle" or "heteroaryl" is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic (e.g., 2,3- dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O) _P , wherein 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-ό]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 (c) relieving the disease-state, i.e., causing regression of the disease state.

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

As used herein, "mammal" refers to human and non-human patients.

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

All percentages and ratios used herein, unless otherwise indicated, are by weight.

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

2. Compounds of the Invention

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

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

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 C _1-6 alkyl group, (d) a C _2-6 alkenyl group, (e) a C _2-6 alkynyl group, (f) -OH, (g) -OR ⁵ , (h) -NR ⁴ R ⁴ , (i) -C(O)R ⁵ , G) -C(O)OR ⁵ , (k) - C(O)-NR ⁴ R ⁴ , (1) -C(S)R ⁵ , (m) -C(S)OR ⁵ , (n) -C(O)SR ⁵ , (o) -C(S)-NR ⁴ R ⁴ , (p) -N ₃ , (q) -CN, (r) -CF ₃ , (s) -CF ₂ H, (t) -CFH ₂ , (u) -S(O) _P H, (v) -S(O)pR ⁵ , (w) -S(O) _P OH, (x) -S(O) _P OR ⁵ , (y) -S(O)pNR ⁴ R ⁴ , (z) -NR ⁴ C(O)R ⁴ , (aa) a C _3-7 saturated, unsaturated, or aromatic carbocycle, and (bb) a 3-7 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur;

R ^a and R ^b at each occurrence, independently are selected from: (a) H, (b) a C _1-6 alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, (e) -OH, (f) -OR ⁵ , (g) -NR ⁴ R ⁴ , (f) - C(O)R ⁵ , (g) -C(=O)OR ⁵ , (h) -C(O)-NR ⁴ R ⁴ , (i) -S(O)pNR ⁴ R ⁴ , (j) -C(O)SR ⁵ , (k) halogen, (1) -S(O) _p H, or (m) - S(O) _p R ⁵ , (n) -N ₃ , (o) -CN, and (p) -NR ⁴ C(O)R ⁴ , wherein any of (b) -(d) immediately above optionally is substituted with one or more R ⁵ _; alternatively R ^a and R ^b are taken together with the carbon to which they are attached to form (a) -C(O)-, (b) -C(=S)-, (c) -C=NR ⁴ , or (d) -C=NOR ⁵ ; R ^c is selected from: (a) H, (b) a C ₁ ^ alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, (e) OR ⁵ , such that it is not selected from OH, (f) -NR ⁴ R ⁴ , (g) -C(O)R ⁵ , (h) -C(O)OR ⁵ , (i) -C(O)-NR ⁴ R ⁴ , (j) -S(O)pNR ⁴ R ⁴ , (k) -C(O)SR ⁵ , (1) -S(O) ₁₃ H, (m) - S(O) _P R ⁵ , (n) -CF ₃ , (o) -CF ₂ H, and (p) -CFH ₂ , wherein any of (b) -(d) immediately above is optionally substituted with one or more R ⁵ ; R ^d and R ^e at each occurrence, independently are selected from: (a) H, (b) a C _1-6 alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, (e) -OH, (f) OR ⁵ , (g) -NR ⁴ R ⁴ , (f) - C(O)R ⁵ , (g) -C(O)OR ⁵ , (h) -C(O)-NR ⁴ R ⁴ , (i) -S(O) _P NR ⁴ R ⁴ , (j) -C(O)SR ⁵ , (k) halogen, (1) -S(O) _P H, and (m) - S(O) _p R ⁵ , wherein any of (b) -(d) immediately above is optionally substituted with one or more R ⁵ , or alternatively R ^d and R ^e are taken together with the carbon to which they are attached to form (a) -C(O)-, (b) -C(=S)-, (c) -C=NR ⁴ , or (d) -C=NOR ⁵ ; alternatively, R ^c and R ^d or R ^c and R ^e are taken together to form a carbon-carbon double bond between the carbon atoms to which they are attached; alternatively R ^d and X are taken together to form OR ⁵ R ⁵ ; or alternatively R ^d and R ^e are taken together with the carbon to which they are attached to form (a) -C(O)-, (b) -C(=S)-, (c) -C=NR ⁴ , (d) -C=NOR ⁵ , (e) =CH ₂ , or (f) 3-12- membered carbocycle or heterocycle optionally substituted with one or more R ; R ¹ and R ³ at each occurrence, independently are selected from: (a) H, (b) a C _1-6 alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, (e) -C(O)R ⁵ ,

(f) -C(O)OR ⁵ , (g) -C(O)-NR ⁴ R ⁴ , (h) -C(S)R ⁵ , (i) -C(S)OR ⁵ , (j) -C(O)SR ⁵ , and (k) -C(S)- NR ⁴ R ⁴ ; alternatively R ¹ and R ³ are taken together with the oxygen to which R ¹ is attached, the nitrogen to which R ³ is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R ⁵ ;

R ^2a and R ^2b at each occurrence, independently, are selected from hydrogen or -OR ¹² ; 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) immediately above optionally contains one or more carbonyl groups, and wherein each (aa) or (bb) immediately above optionally is substituted with one or more R ¹ ' or R ^{1 la} ; ii) each B" is independently selected from: (aa) -H, (bb) -OH, (CC) -OR ⁹ , (dd) -SH, (ee) -S(O) _p R ⁹ , (ff) halogen, (gg) -CN, (Mi)-N ₃ , (ii) -NO ₂ , (jj) -Si(R ¹³ ) ₃ , (kk) -SO ₃ H, (11) -SO ₃ N(R ⁴ ) ₂ , (mm) -SO ₃ R ⁹ , (nn) -NR ⁶ R ⁶ , (oo) -C(O)R ⁹ , (pp) -C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (qq) - OC(O)(CR ⁶ R ⁶ )tR ⁹ , (rr) -C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (ss) -NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ ,

(tt) -NR ⁶ C(O)(CR ⁶ R ⁶ )tR ⁹ , (uu) -C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (w) - NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (ww) -C(=NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (xx) - C(=NR ⁶ )NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (yy) -NR ⁶ C(=NR ⁶ )NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (zz) - S(O) _p (CR ⁶ R ⁶ )tR ⁹ , (aaa) -SC(O)(CR ⁶ R ⁶ ),R ⁹ , (bbb) - C(=NNR ⁶ R ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (ccc) -C[=NNR ⁶ C(O)R ⁶ ](CR ⁶ R ⁶ ) _t R ⁹ ,

(ddd) -NR ⁶ C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (eee) -OC(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (fff) -

NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (ggg) -NR ⁶ S(O)p(CR ⁶ R ⁶ )tR ⁹ , (hhh) - NR ⁶ C(O)R ⁶ , (iii) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings, (jjj) 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, (kkk) -C ₁ .6 alkyl, (111) -C _2- ^ alkenyl, and (mmm) -C _2- 6

alkynyl; wherein any of (iii) or (jjj) immediately above optionally contains one or more carbonyl groups, and wherein any of (iii) or (jjj) immediately above is optionally substituted with one or more R ¹ ' or R ^{I la} ; wherein each (kkk), (111), or (mmm) is optionally are substituted with one or more R ¹⁴ groups;

(iii) Z is selected from: (a) a single bond, (b) -C ₁ -6 alkyl-, (c) -C _2-6 alkenyl-, (d) -C _2-6 alkynyl-, (e) -O-, (f) -NR ⁴ -, (g) -S(O) _P -, (h) -C(OH (i) -C(O)O-, O) -OC(O)- k) -OC(O)O-, (1) -C(O)NR ⁴ -, (m) - NR ⁴ CO-, (n) -NR ⁴ C(O)NR ⁴ - (o) -C(=NR ⁴ )-, (p) - C(=NR ⁴ )O-, (q) -OC(=NR ⁴ )-, (r) -C(=NR ⁴ )NR ⁴ -, (s) -NR ⁴ C(=NR ⁴ )-, (t) -C(=S}-, (u)

-C(=S)NR ⁴ - (v) -NR ⁴ C(=SK (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) immediately above is optionally replaced with - (C=O)-, -O-, -S-, or -NR ⁴ -, and wherein any of (b), (c), or (d), immediately above optionally is further substituted with -OH, -NR ⁴ -, or halogen; wherein R ¹⁴ is selected from:

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

(r) -C(R ⁸ )(OR ⁸ )(CH ₂ ) _r NR ⁸ R ⁸ , (s) -NR ⁸ R ⁸ , (t) -NR ⁸ OR ⁸ , (u) -NR ⁸ C(O)R ⁸ , (v) -NR ⁸ C(O)OR ⁸ , (w) -NR ⁸ C(O)NR ⁸ R ⁸ , (x) -NR ⁸ S(O) _p R ⁸ , (y) -C(OR ⁸ )(OR ⁸ )R ⁸ , (z) -C(R ⁸ ) ₂ NR ⁸ R ⁸ , (aa) -C(S)NR ⁸ R ⁸ , (bb) -NR ⁸ C(S)R ⁸ , (cc) -OC(S)NR ⁸ R ⁸ , (dd) -NR ⁸ C(S)OR ⁸ , (ee) -NR ⁸ C(S)NR ⁸ R ⁸ , (ff) -SC(O)R ⁸ , (gg) -N ₃ , (hh) -Si(R ¹³ ) ₃ , (ii) a C _1-6 alkyl group, Gj) a C _2-6 alkenyl group,

(kk) a C _2-6 alkynyl group, (11) a C _3-I2 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (ii)-(mm) immediately above optionally is substituted with one or more R ⁵ groups; alternatively two R ¹⁴ groups are taken together to form (a) =O, (b) =S, (c) =NR ⁸ , or (e) =N0R ⁸ ; R ⁴ is selected from:

(a) H, (b) a C _1-6 alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, (e) a C _6-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)-C _1-6 alkyl, (h) -C(O)-C _2-6 alkenyl, (i) -C(O)-C _2-6 alkynyl, (j) -C(O)-C _6-I2 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-C _{1 -6} alkyl, (m) - C(O)O-C _2-6 alkenyl, (n) -C(O)O-C _2-6 alkynyl, (o) -C(O)O-C _6-I2 saturated, unsaturated, or aromatic carbocycle, (p) -C(O)O-

3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and q) - C(O)NR ⁶ R ⁶ , wherein any of (b)-(p) immediately above is optionally substituted with one or more R ⁵ groups, alternatively, NR ⁴ R ⁴ forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R ⁴ groups are bonded, wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R ⁴ groups are bonded, with one or more moieties selected from O, S(0) _p , N, and NR ⁸ ; R ⁵ is selected from:

(a) R ⁷ , (b) a C ₁ - ₆ alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, (e) a C _3-J2 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 R ⁷ groups; or alternatively two R ⁵ groups, when present on the same carbon atom can be taken together with the carbon atom to which they are attached to form a spiro 3-6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of these ring systems formed from two R ⁵ groups optionally is substituted with one or more R ⁷ groups; R ⁶ is selected from:

(a) H, (b) a C ₁ -6 alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, (e) a C _3-12 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) immediately above is optionally 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, (Mi) NO ₂ , (ii) -OR ⁸ ,

Oi) -S(O)pR ⁸ , (ldc) -C(O)R ⁸ , (11) -C(O)OR ⁸ , (mm) -OC(O)R ⁸ , (nn) -C(O)NR ⁸ R ⁸ ,

(oo) -OC(O)NR ⁸ R ⁸ , (pp) -C(=NR ⁸ )R ⁸ , (qq) -C(R ⁸ )(R ⁸ )OR ⁸ , (rr) -C(R ⁸ ) ₂ OC(O)R ⁸ , (ss) -C(R ⁸ )(OR ⁸ )(CH ₂ ) _r NR ⁸ R ⁸ , (tt) -NR ⁸ R ⁸ , (uu) -NR ⁸ OR ⁸ , (w) -NR ⁸ C(O)R ⁸ , (ww) -NR ⁸ C(O)OR ⁸ , (xx) -NR ⁸ C(O)NR ⁸ R ⁸ ,

(yy) -NR ⁸ S(O) _r R ⁸ , (zz) -C(OR ⁸ )(OR ⁸ )R ⁸ ,

(ab) -C(R ⁸ ) ₂ NR ⁸ R ⁸ , (ac) =NR ⁸ , (ad) -C(S)NR ⁸ R ⁸ , (ae) -NR ⁸ C(S)R ⁸ , (af) -OC(S)NR ⁸ R ⁸ , (ag) -NR ⁸ C(S)OR ⁸ , (ah) -NR ⁸ C(S)NR ⁸ R ⁸ , (ai) -SC(O)R ⁸ ,

(aj) a C ₁ _ ₆ alkyl group, (ak) a C _2-6 alkenyl group, (al) a C _2- 6 alkynyl group, (am) a C _1-6 alkoxy group, (an) a Cu alkylthio group, (ao) a C _1-6 acyl group, (ap) -CF ₃ , (aq) -SCF ₃ , (ar) a C _3-I2 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, NR ⁶ R ⁶ forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R ⁶ groups are attached wherein said ring is optionally replaced at a position other than the nitrogen atom to which the R ⁶ groups are bonded, with one or more moieties selected from -O-, -S(O) _P -, -N=, and -NR ⁸ -; alternatively, CR ⁶ R ⁶ forms a carbonyl group; R ⁷ is selected from:

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF ₃ ,

(h) -CN, (i) -N ₃ 0) -NO ₂ , (k) -NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (1) -OR ⁹ , (m) - S(O)pC(R ⁶ R ⁶ )tR ⁹ , (n) -C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (o) -OC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (p) - SC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (q) -C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (r) -NR ⁶ C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (s) - C(O)NR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (t) -C(=NR ⁶ )(CR ⁶ R ⁶ )tR ⁹ , (u) -C(=NNR ⁶ R ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (v) -C(=NNR ⁶ C(O)R ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (w) -C(=NOR ⁹ )(CR ⁶ R ⁶ ) _t R ⁹ , (x) -

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

NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (aa) -NR ⁶ S(O)p(CR ⁶ R ⁶ )tR ⁹ , (bb) - S(O)pNR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (cc) -NR ⁶ S(O)pNR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (dd) -NR ⁶ R ⁶ , (ee) - NR ⁶ (CR ⁶ R ⁶ ), (ff) -OH, (gg) -NR ⁶ R ⁶ , (hh) -OCH ₃ , (ii) -S(O) _p R ⁶ , (jj) - NC(O)R ⁶ , (kk) -Si(R ¹³ ), (11) a C _1-6 alkyl group, (mm) a C _2-6 alkenyl group,

(nn) a C _2-6 alkynyl group, (oo) -C _3-I2 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) immediately above is optionally substituted with one or more R groups; alternatively, two R ⁷ groups can form -O(CH ₂ ) _U O-, =0, or =S; R ⁸ is selected from:

(a) R ⁵ , (b) H, (c) a C ₁ -6 alkyl group, (d) a C _2- 6 alkenyl group, (e) a C _2-6 alkynyl group, (f) a C _3-I2 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)-C ₁ ^ alkyl, (i) -C(O)-C _2-6 alkenyl, G) -C(O)-C _2-6 alkynyl, (k) -C(O)-C _3-I2 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) immediately above is optionally substituted with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO ₂ , (hh) OH, (ii) NH ₂ , (jj) NH(C _1-6 alkyl), (kk) N(C i_ ₆ alkyl) ₂ , (11) a C _1-6 alkoxy group, (mm) an aryl group, (nn) a substituted aryl group, (oo) a heteroaryl group, (pp) a substituted heteroaryl group, and qq) a C _1-6 alkyl group optionally substituted with

one or more moieties selected from an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, F, Cl, Br, I, CN, NO ₂ , CF ₃ , SCF ₃ , and OH; R ⁹ is selected from: (a) R ¹⁰ , (b) a C _w alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2-6 alkynyl group, e) a C ₃ . ₁₂ saturated, unsaturated, or aromatic carbocycle, and f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) immediately above is optionally substituted with one or more R ¹⁰ groups;

R ¹⁰ is selected from:

(a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g) -CF ₃ , (h) -CN, (i) -NO ₂ , (j) - NR ⁶ R ⁶ , (k) -OR ⁶ , (1) -S(O)pR ⁶ , (m) -C(O)R ⁶ , (n) -C(O)OR ⁶ , (o) -OC(O)R ⁶ , (p) NR ⁶ C(O)R ⁶ , (q) -C(O)NR ⁶ R ⁶ , (r) -C(=NR ⁶ )R ⁶ , (s) -NR ⁶ C(O)NR ⁶ R ⁶ , (t) - NR ⁶ S(O)pR ⁶ , (u) -S(O)pNR ⁶ R ⁶ , (v) -NR ⁶ S(O)pNR ⁶ R ⁶ , (w) a C _u alkyl group,

(x) a C _2-6 alkenyl group, (y) a C _2-6 alkynyl group, (z) a C _3-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) immediately above is optionally substituted with one or more moieties selected from R ⁶ , F, Cl, Br, I, -CN, -NO ₂ , - OR ⁶ , -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , a C _1-6 alkoxy group, a C _1-6 alkylthio group, and a C ₁ -6 acyl group; R ⁿ and R ^{l 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)

NO ₂ , (i) OR ⁸ , O) -S(O) _p R ⁸ , (k) -€(O)R ⁸ , (1) -C(O)OR ⁸ , (m) -OC(O)R ⁸ , (n) -C(O)NR ⁸ R ⁸ , (o) -OC(O)NR ⁸ R ⁸ , (p) -C(=NR ⁸ )R ⁸ , (q) -C(R ⁸ )(R ⁸ )OR ⁸ , (r) -C(R ⁸ ) ₂ OC(O)R ⁸ , (s) -C(R ⁸ )(OR ⁸ )(CH ₂ ) _r NR ⁸ R ⁸ , (t) -NR ⁸ R ⁸ , (u) -NR ⁸ OR ⁸ , (v) -NR ⁸ C(O)R ⁸ , (w) -NR ⁸ C(O)OR ⁸ , (x) -NR ⁸ C(O)NR ⁸ R ⁸ , (y) -NR ⁸ S(O) _p R ⁸ ,

(z) -C(OR ⁸ )(OR ⁸ )R ⁸ , (aa) -C(R ⁸ ) ₂ NR ⁸ R ⁸ , (bb) =NR ⁸ , (cc) -C(S)NR ⁸ R ⁸ , (dd) - NR ⁸ C(S)R ⁸ , (ee) -OC(S)NR ⁸ R ⁸ , (ff) -NR ⁸ C(S)OR ⁸ , (gg) -NR ⁸ C(S)NR ⁸ R ⁸ , (hh) -SC(O)R ⁸ , (ii) -N ₃ , (jj) -Si(R ¹³ ) ₃ , (kk) a C _-6 alkyl group, (11) a

C ₂ _ _O alkenyl group, (mm) a C _2-6 alkynyl group, (nn) a C _1-6 alkoxy group, (oo) a C ₁ _ ₆ alkylthio group, (pp) a C ₁ -< _> acyl group, (qq) a C _3-I2 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(OC _{1- 6 alkyl) 2 , (uu) -B(OH)(OC 1-6 alkyl), (w) -B[-OC(CH 3 ) 2 (CH 3 ) 2 CO-], (ww) - P(OH) 2 , (xx) -P(OC 1 _ 6 alkyl) 2 , (yy) -P(OH)(OC 1-6 alkyl), and (zz) - NR ⁸ (C=NR ⁸ )R ⁸ , wherein any of (kk)-(mm) immediately above is optionally substituted with one or more R ⁵ groups; R ¹² is selected from:}

(a) H, (b) a C ₁ _ ₆ alkyl group, (c) a C _2-6 alkenyl group, (d) a C _2- 6 alkynyl group, (e) -C(O)R ⁵ , (f) -C(O)OR ⁵ , (g) -C(O)-NR ⁴ R ⁴ , (h) -C(S)R ⁵ , (i) -C(S)OR ⁵ , (j) -C(O)SR ⁵ , (k) -C(S)-NR ⁴ R ⁴ , (1) a C _3-J2 saturated, unsaturated, or aromatic carbocycle, or (m) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (n) a -(C _1-6 alkyl) -C _3-I2 saturated, unsaturated, or aromatic carbocycle, and (o) a -(C _1-6 alkyl)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(d) or (l)-(o) immediately above is optionally substituted with one or more R ⁵ groups; R ¹³ is selected from (a) -C _1-6 alkyl and (b) -0-(C _1-6 alkyl); p at each occurrence, independently is selected from O, 1, and 2; r at each occurrence, independently is selected from O, 1 , and 2; t at each occurrence, independently is selected from O, 1, and 2; and u at each occurrence, independently is selected from 1, 2, 3, and 4. 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 ¹ ,

_R 2a, _R 2b _{, R} 3 _{, R} a _{, R} b _{, R} c _{, R} d _{, and R} e _{are as described herein}

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

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

_R 2a, _R 2b _{, R} 3 _{, R} a _{, R} b _{, R} c _{, R} d _{, and R} e _{are as described herein}

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

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

_R 2a, _R 2b _{, R} 3 _{, R} a _{, R} b _{, R} c _{, R} d _{, and R} e _{are as described herein}

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from: (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -CN, (g) -CF ₃ , (h) -CF ₂ H, (i) -CFH ₂ , (j) -O(C _1-

₆ alkyl), (k) -N ₃ , (1) -COOH, (m) -COO(C, ^alkyl), (n) -NH ₂ , (o) -NH(C^alkyl), (p) -N(C _{1- 6} alkyl) ₂ , (q) -C(O)NH ₂ , (r) -C(O)NH(C ^alkyl), (s) -C(O)N(C ,^alkyl) ₂ , (t) -NHC(O)H, (u) - NHC(0)(C ₁ ^alkyl), (v) -N(C _t -6alkyl)C(0)H, and (w) -N(C _1-6 alkyl)C(O)N(C _1-6 alkyl) ₂ .

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

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 ^d and R ^e are selected from: (a) Cl, (b) Br, (c) F, (d) H and (e) C^alkyl.

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

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

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

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^a and R ^b are independently selected from: (a) H, (b) Cl, (b) Br, (d) F, (g) -OH, (h) -0(C _1-6 alkyl), (i) -N ₃ , (j) -COOH, (k) -COO(C ₁ ^alkyl), (1) -CN, (m) -NH ₂ , (n) -NH(C _1-6 alkyl), (o) -N(C, _ ₆ alkyl) ₂ , (P)-C(O)NH ₂ , (q) -C(O)NH(C,^alkyl), (r) -C(O)N(C, -ealkyl),, (s) -NHC(O)H, (t) - NHCtOXC-ealkyl), (u) -N(C _1-6 alkyl)C(O)H, (v) (w) -SH, and (x) -S(C _-6 alkyl), or alternatively R ^a and R ^b 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 R ^a and R ^b are independently selected from (a) H, (b) F, (c) -OH, (d) -OCH ₃ , (e) -SH, and (f) -SCH ₃ .

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

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 different.

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

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein one of R ^a or R ^b is H and the remaining R ^a or R ^b is -OCH ₃ .

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

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein one of R ^a or R ^b is H and the remaining R ^a or R ^b is -SCH ₃ .

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein one of R ^a or R ^b is H and the remaining R ^a or R ^b is H. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ¹ is H.

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ^2a and R ^2b are both H. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ³ is C ₁ ^alkyl.

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ³ 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) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3- 12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein any of (a)-(b) immediately above is optionally substituted with one or more R ¹ ' groups.

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

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) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein any of (a)-(b) immediately above optionally is substituted with one or more R ¹¹ groups.

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B" is substituted with R ⁿ , wherein R ¹¹ is selected from -NR ⁸ R ⁸ , -S(O)pR ⁸ , -C _1-6 alkyl, -C(O)NR ⁸ R ⁸ , -C(O)R ⁸ , -C(R ⁸ )(R ⁸ )OR ⁸ , halogen, -CN, and OR ⁸ .

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B" is substituted with R ¹ ', wherein R ¹ ' is selected from -NH ₂ , -SO ₂ CH ₃ , -SCHF ₂ , -SO ₂ CHF ₂ , -CH ₃ , -SO ₂ NH ₂ , -C(O)NH ₂ , -N(CH ₃ ) ₂ , -C(O)CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OH, I, CN, -OCH ₃ .

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B" is substituted with R ¹¹ , wherein R ¹¹ is selected from -NR ⁸ R ⁸ , -S(O) _p R ⁸ , -C _1-6 alkyl, -C(O)NR ⁸ R ⁸ , -C(O)R ⁸ , and C(R ⁸ )(R ⁸ )OR ⁸ and B' is unsubstituted.

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 both unsubstituted.

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

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 ¹ , R ^2a> R ^2b , and R ³ are as described herein.

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

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

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

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

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

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R ¹ , R ^2a , R2 ^b and R ³ are as described herein.

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

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

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

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

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

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R ¹ , _R 2a, _R 2b^ _an( j _R 3 _{are ag} d _escr ii _3e( j herein.

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

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

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

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

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

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R ¹ , R ²⁸ ' R ^2b , and R ³ are as described herein.

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

f wherein, B", Z, and R ¹¹ are as described herein and wherein, one of or B" is substituted with R ¹¹ .

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

and B", Z, and R ¹¹ are as described herein.

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

and B", Z, and R ¹¹ are as described herein.

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

wherein B", Z, and R ¹ ' are as described herein and one of or B" is substituted with

R ¹

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

wherein B", Z, and R ¹¹ are as described herein.

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

wherein B", Z, and R ¹ ' are as described herein.

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

/ wherein B", Z, and R ¹¹ are as described herein and one of or B" is substituted with R".

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

wherein B", Z, and R ¹ ' are as described herein.

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

wherein B", Z, and R ¹ ' are as described herein.

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

wherein B", Z, and R ¹ ' are as described herein and one of ^ or B" is substituted with

R ¹¹ .

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

wherein B", Z, and R ¹¹ are as described herein.

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

wherein B", Z, and R ¹¹ are as described herein.

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ¹¹ is selected from -NR ⁸ R ⁸ , -S(O)pR ⁸ , -C _1-6 alkyl, -C(O)NR ⁸ R ⁸ , -C(O)R ⁸ , C(R ⁸ )(R ⁸ )OR ⁸ , halogen, -CN, and -OR ⁸ .

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ¹ ' is selected from -NH ₂ , -SO ₂ CH ₃ , -SCHF ₂ , -SO ₂ CHF ₂ , -CH ₃ , -C(O)NH ₂ , -N(CH ₃ ) ₂ , -C(O)CH ₃ , - CH ₂ OCH ₃ , -CH ₂ OH, I, -CN, and -OCH ₃ . In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R ¹ ' 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 C _1-6 alkyl group, (b) a C _2-6 alkenyl group, (c) a C _2-6 alkynyl group, (d) a C _3-I2 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, G) Cl, (k) Br, (1) I, (m) -CF ₃ , (n) -CN, (o) -N ₃ (p) -NO ₂ , (q) -NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (r) -OR ⁹ , (s) -S(CR ⁶ R ⁶ ) _t R ⁹ , (t) -S(O)(CR ⁶ R ⁶ ) _t R ⁹ ,(u) -S(O) ₂ (CR ⁶ R ⁶ ) _t R ⁹ (v) -

C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (w) -OC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (x) -OC(0)0(CR ⁶ R ⁶ ) _t R ⁹ , (y) -SC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (z) -C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (aa) -NR ⁶ C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (bb) -C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (cc) - C(=NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (dd) -C(=NNR ⁶ R ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (ee) -C[=NNR ⁶ C(O)R ⁶ ](CR ⁶ R ⁶ ) _t R ⁹ , (ff) -NR ⁶ C(O)O(CR ⁶ R ⁶ )tR ⁹ , (gg) -OC(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (hh) -NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (ii) -NR ⁶ S(O)p(CR ⁶ R ⁶ )tR ⁹ , Qj) -S(O)pNR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (kk) -NR ⁶ R ⁶ , (11) -SR ⁹ , (mm) - S(O)R ⁹ , (nn) -S(O) ₂ R ⁹ , (oo) -NR ⁶ C(O)R ⁶ , (pp) -Si(R ¹³ ) ₃ , and (qq) -C(=O)H; wherein t at each occurrence is O, 1, or 2; wherein any of (a)-(e) immediately above is optionally substituted with one or more R ¹⁴ groups; wherein R ¹⁴ at each occurrence is independently selected from:

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

(y) -C(OR ⁸ )(OR ⁸ )R ⁸ , (z) -C(R ⁸ ) ₂ NR ⁸ R ⁸ , (aa) -C(S)NR ⁸ R ⁸ , (bb) -NR ⁸ C(S)R ⁸ , (cc) -OC(S)NR ⁸ R ⁸ , (dd) -NR ⁸ C(S)OR ⁸ , (ee) -NR ⁸ C(S)NR ⁸ R ⁸ , (ff) -SC(O)R ⁸ , (gg) -N ₃ , (hh) -Si(R ¹³ ) ₃ , (ii) a C _1-6 alkyl group, Gj) a C _2-6 alkenyl group, (kk) a C _2- 6 alkynyl group, (11) a C _3-I2 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (ii)-(mm) immediately above is optionally substituted with one or more R groups; alternatively two R ¹⁴ groups are taken together to form (a) =0, (b) =S, (c) =NR ⁸ , or (d) =N0R ⁸ .

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 C _1-6 alkyl group, (b) a C ₂ . ₆ alkenyl group, (c) a C _2-6 alkynyl group, (d) a C _3-I2 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) -CF ₃ , (g) -νR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (h) -OR ⁹ , (i) -S ⁽ CR ⁶ R ⁶ )tR ⁹ , (j) -S(O)<CR ⁶ R ⁶ ) _t R ⁹ ,(k) - S(O) ₂ ⁽ CR ⁶ R ⁶ ) _t R ⁹ (1) -C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (m) -OC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (n) -OC(O)O(CR ⁶ R ⁶ ) _t R ⁹ ,

(0) -SC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (p) -C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (q) -NR ⁶ C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (r) - C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (s) -C(=NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (t) -C(=NNR ⁶ R ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (u) - C[=NNR ⁶ C(O)R ⁶ ](CR ⁶ R ⁶ ) _t R ⁹ , (v) -NR ⁶ C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (w) -OC(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ ,

(x) ->fR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (y) -NR ⁶ S(O)p(CR ⁶ R6) _t R ⁹ , (z) -S(O) _p NR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (aa) - NR ⁶ R ⁶ , (bb) -SR ⁹ , (cc) -S(O)R ⁹ , (dd) -S(O) ₂ R ⁹ , and (ee) -NR ⁶ C(O)R ⁶ , wherein any of (a)-

(e) immediately above is optionally substituted with one or more R ¹⁴ 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 C _1-6 alkyl group, (b) a C _2-6 alkenyl group, (c) a C _2-6 alkynyl group, (d) a C _3-I2 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 any of (a)-(e) immediately above is optionally substituted with one or more

R ¹⁴ 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) -νR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (b) -OR ⁹ , (c) -S ⁽ CR ⁶ R ⁶ ) _t R ⁹ , (d) -S(O) ⁽ CR ⁶ R ⁶ ) _t R ⁹ , (e) -

S(O) ₂ ⁽ CR ⁶ R ⁶ ) _t R ⁹ (f) -C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (g) -OC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (h) -OC(0)0(CR ⁶ R ⁶ ) _t R ⁹ ;

(1) -SC(O)(CR ⁶ R ⁶ ) _t R ⁹ , (j) -€(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (k) -NR ⁶ C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (1) - C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (m) -C(=NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (n) -C(=NNR ⁶ R ⁶ )(CR ⁶ R ⁶ ) _t R ⁹ , (o) -

C[=NNR ⁶ C(O)R ⁶ ](CR ⁶ R ⁶ ) _t R ⁹ , (p) -NR ⁶ C(O)O(CR ⁶ R ⁶ ) _t R ⁹ , (q) -OC(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (r) - NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (s) -NR ⁶ S(O)p(CR ⁶ R6) _t R ⁹ , (t) -S(O)pNR ⁶ (CR ⁶ R ⁶ )tR ⁹ , (u) - NR ⁶ R ⁶ , (v) -NR ⁶ (CR ⁶ R ⁶ ) _t R ⁹ , (w) -SR ⁶ , (x) -S(O)R ⁶ , (y) -S(O) ₂ R ⁶ , and (z) -NR ⁶ C(O)R ⁶ . In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or pro-drug thereof, wherein G is selected

G43 G44

G49 GSO

In other embodiments, the present invention relates to a compound wherein T is:

rmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein:

M is selected from:

( (aa)) --CC((OOHH I (b) -CH(-OR ^π V. ( ^c ) -NR ¹¹⁴ -CH ₂ - (d) -CH ₂ -NR ¹¹⁴ -, (e) -

CH(NR ¹¹⁴ R ¹¹⁴ H (0 -C ₁ =NNR ¹¹⁴ R ¹¹⁴ H (g) -NR ¹¹⁴ -C(O)-, (h) -C(O)NR ¹¹⁴ -, (i) -C(=NR ¹¹⁴ H G) -CR ¹¹⁵ R ¹¹⁵ - and (k) -C(=NOR ¹²⁷ )-; R ¹⁰⁰ is selected from: (a) H, (b) F, (c) Cl, (d) Br, (e) -SR ¹¹⁴ , and (f) C _1-6 alkyl, wherein (f) immediately above is optionally substituted with one or more R » 115 groups;

R ¹⁰¹ is selected from:

(a) H, (b) Cl, (c) F, (d) Br, (e) I, (f) -NR ¹¹⁴ R ¹¹⁴ , (g) -NR ¹¹⁴ C(O)R ¹¹⁴ , (h) - OR ¹¹⁴ , (i) -OC(O)R ¹¹⁴ , G) -OC(O)OR ¹¹⁴ , (k) -OC(O)NR ¹¹⁴ R ¹¹⁴ , (1) -O-C ₁ - C ₆ alkyl, (m) -OC(O)-C ₁ ^ alkyl, (n) -OC(O)O-C _1-6 alkyl, (o) -OC(O)NR ¹¹⁴ - Cι-6 alkyl, (p) C _1-6 alkyl, (q) C _2-6 alkenyl, and (r) C _2-6 alkynyl, wherein any of (1) - (r) immediately above is optionally substituted with one or more R ¹¹⁵ groups;

R ¹⁰² is selected from: (a) H, (b) F, (c) Cl, (d) Br, (e) -SR ¹¹⁴ , and (f) C _1-6 alkyl, wherein (f) immediately above is optionally substituted with one or more R ¹¹⁵ groups; R ¹⁰³ is selected from:

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

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

(h) -OC(O)NR ¹¹⁴ R ¹¹⁴ , (i) -OC(O)NR ¹¹⁴ -C ^alkyl-R ¹¹⁵ , and

alternatively, R ¹⁰² and R ¹⁰³ taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which is optionally substituted with one or more R ¹¹⁴ groups; alternatively, R ¹⁰¹ and R ¹⁰³ taken together are a single bond between the respective carbons to which these two groups are attached thereby creating a double bond between the carbons to which R ¹⁰⁰ and R ¹⁰² are attached; alternatively, R ¹⁰¹ and R ¹⁰³ taken together with the carbons to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring, wherein said 3-7 membered ring is optionally substituted with one or more R ¹¹⁴ groups; alternatively, R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , and R ¹⁰³ taken together with the carbons to which they are attached form a 5 or 6 membered fused carbocyclic or heterocyclic ring, wherein said fused ring is optionally substituted with one or more R ¹¹⁴ groups;

R ¹⁰⁴ is selected from:

(a) H, (b) R ¹¹⁴ , (c) -C(O)R ¹¹⁴ (d) -C(O)OR ¹¹⁴ (e) -C(O)NR ¹¹⁴ R ¹¹⁴ , (f) -C _1-6 alkyl-K-R ¹¹⁴ , (g) -C _2-6 alkenyl-K-R ¹¹⁴ , and (h) -C _2-6 alkynyl-K-R ¹¹⁴ ;

K is selected from:

(a) -C(O)-, (b) -C(O)O-, (c) -C(O)NR .1 ¹ 1 ¹ 4S (d) -C(=NR ¹¹⁴ H (e) - C(=NR ¹¹⁴ )O-,

(f) -C(=NR ¹¹⁴ )NR ¹¹⁴ -, (g) -OC(OH (h) -OC(O)O-, (i) -OC(O)NR ¹¹⁴ -, O) -NR ¹¹⁴ C(O)-, (k) -NR ¹¹⁴ C(O)O-, (1) -NR ¹¹⁴ C(O)NR ¹¹⁴ - (m) -NR ¹¹⁴ C(=NR' ¹⁴ )NR' ¹⁴ -, and (o) -S(0) _p -;

R ¹⁰⁵ and R ¹⁰⁶ taken together with the atoms to which they are attached form a 5-membered ring by attachment to each other through a chemical moiety selected from: (a) -OC(R ¹¹⁵ ) ₂ O-, (b) -OC(O)O-, (c) -OC(O)NR ¹¹⁴ -, (d) -NR ¹¹⁴ C(O)O-, (e) -OC(O)NOR ¹¹⁴ -, (f) -NOR ¹¹⁴ -C(0)0-, (g) -OC(O)N[NR ¹¹⁴ R ¹¹⁴ ] -, (h) - N[NR ¹¹⁴ R ¹¹⁴ J-C(O)O-, (i) -OC(O)C(R ¹¹ V, (j) -C(R ¹¹⁵ ) ₂ C(O)O-, (k) -

OC(S)O-, (1) -OC(S)NR ¹¹⁴ -, (m) -NR ¹¹⁴ C(S)O-, (n) -OC(S)NOR ¹¹⁴ -, (o) - NOR ^{1 I4} -C(S)O-, (p) -OC(S)N[NR ¹¹⁴ R ¹¹⁴ ]-, (q) -N[NR ¹¹⁴ R ¹¹⁴ J-C(S)O-, (r) - OC(S)C(R ¹¹ V, (s) -C(R ¹¹⁵ ^C(S)O-, (t) -OC(O)CR ¹¹⁵ ES(O) _P R ¹¹⁴ ] - (u) - OC(O)CR ¹¹⁵ CNR ¹¹⁴ R ¹¹⁴ ] -, (v) -CR ¹ ^[NR ¹¹⁴ R ¹¹⁴ JC(O)O-, and (w) - CR ¹¹⁵ ES(O) _P R ¹¹⁴ JC(O)O-; alternatively, R ¹⁰⁵ , R ¹⁰⁶ , and R ¹³³ taken together with the atoms to which they are attached form:

alternatively, M, R , ¹ 1"0 ³ 5, and R ¹⁰⁶ taken together with the atoms to which they are attached form:

wherein J ¹ and J ² are selected from hydrogen, Cl, F, Br, I, OH, -C _1-6 alkyl, and -0(C ₁ _ ₆ alkyl) or are taken together to form =O, =S and =NR ¹¹⁴ , =NOR ¹¹⁴ , =NR ¹¹⁴ , and =N-

NR ¹¹⁴ R ¹¹⁴ ,

R ¹⁰⁷ is selected from:

(a) H, (b) -C ₁ .6 alkyl, (c) -C _2-6 alkenyl, which can be further substituted with C _1- O alkyl or one or more halogens, (d) -C _2- 6 alkynyl, which can be further substituted with C ₁ _ ₆ alkyl or one or more halogens, (e) aryl or heteroaryl, which can be further substituted with C _1-6 alkyl or one or more halogens, (f) - C(O)H, (g) -COOH, (h) -CN, (i) -COOR ¹¹⁴ , (j) -C(O)NR ¹¹⁴ R ¹¹⁴ , (k) - C(O)R ¹¹⁴ , and (1) -C(O)SR ¹¹⁴ , wherein (b) immediately above is optionally further substituted with one or more substituents selected from: (aa) -OR ¹¹⁴ , (bb) halogen, (cc) -SR ¹¹⁴ , (dd) C _1-6 alkyl, which can be further substituted with halogen, hydroxyl, C ₁ ^alkoxy, or amino, (ee) -OR ¹¹⁴ , (ff) -SR ¹¹⁴ , (gg) -

NR , 1 ¹ M ¹⁴ nRI"l ₄ ", (hh) -CN, (U)-NO ₂ , (jj) -NC(O)R 1 14, (kk) -COOR , 1"14 ⁴ , (11) -N ₃ ,

(mm) =N-O-R . 1"14 ⁴ , (nn) =NR , 1"14 ⁴ , (oo) =N-NR 1"14 ⁴ TR> 1"14 ⁴ , (pp) =N-NH-C(0)R . 1 H and (qq) =N-NH-C(0)NR 1'1 '4 ⁴ rR, 114.

alternatively R ¹⁰⁶ and R ¹⁰⁷ are taken together with the atom to which they are attached to form an epoxide, a carbonyl, an exocyclic olefin, or a substituted exocyclic olefin, or a C ₃ - C ₇ carbocyclic carbonate or carbocyclic carbamate, wherein the nitrogen of said carbamate can be further substituted with a C 1-6 alkyl; R ¹⁰⁸ is selected from:

(a) C _1-6 alkyl, (b) C _2-6 alkenyl, and (c) C _2-6 alkynyl, wherein any of (a)-(c) immediately above is optionally substituted with one or more R ¹¹⁴ groups; R ¹⁰⁹ is selected from: (a) H, (b) C _1-6 alkyl, and (c) F; R ¹¹⁴ , at each occurrence, independently is selected from:

(a) H, (b) C ₁ -6 alkyl, (c) C _2-6 alkenyl, (d) C _2-6 alkynyl, (e) C _3-I2 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-C _{1 -6} alkyl, (h) -C(O)-C _2-6 alkenyl, (i) -C(O)-C _2-6 alkynyl, (j) -C(O)-C _3-I2 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-C _1-6 alkyl, (m) -C(O)O-C _2-6 alkenyl, (n) - C(O)O-C _2-6 alkynyl, (o) -C(O)O-C _3-I2 saturated, unsaturated, or aromatic carbocycle, (p) -C(O)O-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (q) -C(O)NR ¹¹⁶ R ¹¹⁶ , (r) -NR ¹¹⁶ CO-C _1-6 alkyl, (s) - NR ¹¹⁶ CO-C _3-I2 saturated, unsaturated, or aromatic carbocycle, (t) -NR ¹¹⁶ C(O)- 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (u) -(C _1-6

3UCyI)-O-(C _1-6 alkyl), (v) -(C _1-6 alkyl)-O-(C _1-6 alkyl)-O-(C ₁ _ ₆ alkyl), (w) -OH, (x) -OR ¹¹⁵ , (y) -NH(C _1-6 alkyl), (z) -N(C _-6 alkyl) ₂ , (aa) -(C _1-6 alkyl)-S(O) _p - (C _1-6 alkyl), (bb) -(C _1-6 alkyl)- S(OV(C _1-6 3UCyI)-S(OV(C ₁ ^ alkyl), (cc) -(C ₆ alkyl)-O-(C _1-6 alkyl), (dd) -(C _1-6 alkyl)- S(OV(C _1-6 alkyl)-O-(C _1-6 alkyl); and (ee) -NH ₂ ; wherein the terminal alkyl group in any of (u)-(v) or (aa)-(dd) immediately above includes cycloalkyl,

wherein any of (b)-{v) or (aa)-(dd) optionally is substituted with one or more R ¹¹⁵ groups, wherein one or more non-terminal carbon moieties of any of (b)-(d) immediately above optionally is replaced with oxygen, S(O) _p , or -NR ¹¹⁶ alternatively, NR ¹¹⁴ R ¹¹⁴ forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R ¹⁴ groups are bonded and optionally one or more moieties selected from O, S(O) _P , N, and NR ¹¹⁸ ;

R ¹¹⁵ , at each occurrence, independently is selected from:

(a) R ¹¹⁷ , (b) C _1-6 alkyl, (c) C _2-6 alkenyl, (d) C _2-6 alkynyl, (e) C _3-I2 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) -OC ₁ _ ₆ alkyl, (h) -OC _2-6 alkenyl, and (i) - OC _2-6 alkynyl, wherein any of (b)-(f) immediately above is optionally substituted with one or more R ¹¹⁷ groups;

R ¹¹⁶ , at each occurrence, independently is selected from:

(a) H, (b) C _1-6 alkyl, (c) C _2-6 alkenyl, (d) C _2-6 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) immediately above optionally is replaced with oxygen, S(O) _P , or - NR ¹¹⁸ , wherein any of (b)- (f) immediately above optionally is substituted with one or more moieties selected from: (aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg)

CN, (Mi) N ₃ , (U)NO ₂ , (jj) OR ¹¹⁸ , (kk) -S(O)pR ¹¹⁸ , (11) - C(O)R ¹¹⁸ , (mm) -C(O)OR ¹¹⁸ , (nn) -OC(O)R ¹¹⁸ , (00) - C(O)NR ¹¹⁸ R ¹¹⁸ , (pp) -OC(O)NR ¹¹⁸ R ¹¹⁸ , (qq) -C(=NR ¹¹⁸ )R' ¹⁸ , (rr) -C(R ¹¹⁸ )(R ¹¹⁸ )OR ¹¹⁸ , (ss) -C(R ¹¹ ^ ₂ OC(O)R ¹¹⁸ , (tt) - C(R ¹¹⁸ XOR ¹¹⁸ XCH ₂ ) _r NR ¹¹⁸ R ¹¹⁸ , (uu) -NR ¹¹⁸ R ¹¹⁸ ; (w) -

NR ¹¹⁸ OR ¹¹⁸ , (ww) -NR ¹¹⁸ C(O)R ¹¹⁸ , (xx) -NR ¹¹⁸ C(O)OR ¹¹⁸ , (yy) -NR ¹¹⁸ C(O)NR ¹¹⁸ R ¹¹⁸ , (zz) -NR ¹¹⁸ S(O) _r R ¹¹⁸ , (ab) - C(OR ¹¹⁸ XOR ¹¹⁸ )R ¹¹⁸ , (ac) -C(R ¹¹⁸ ) ₂ NR ¹¹⁸ R ¹¹⁸ , (ad) =NR ¹¹⁸ ,

(ae) -C(S)NR ¹¹⁸ R ¹¹⁸ , (af) -NR ¹¹⁸ C(S)R ¹¹⁸ , (ag) -

OC(S)NR ¹¹⁸ R ¹¹⁸ , (ah) -NR ¹¹⁸ C(S)OR ¹¹⁸ , (ai) - NR ¹¹⁸ C(S)NR ¹¹⁸ R ¹¹⁸ , (aj) -SC(O)R ¹¹⁸ , (ak) C _1-6 alkyl, (al) C _2-6 alkenyl, (am) C ₂ -< _> alkynyl, (an) C 1-5 alkoxy, (ao) C _1-6 alkylthio, (ap) C _1- ^ acyl, (aq) saturated, unsaturated, or aromatic C _3-I2 carbocycle, and (ar) saturated, unsaturated, or aromatic

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

(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR ¹¹⁶ R ¹¹⁶ ) _r CF ₃ , (h) (CR ¹¹⁶ R ¹¹⁶ ) _r CN, (i) (CR ^{l l6} R ¹¹⁶ ) _r NO ₂ , Q) (CR ¹¹⁶ R ¹¹⁶ ^NR ¹¹ ^CR ¹¹⁶ R ¹¹⁶ ^R ¹¹⁹ , (k) (CR ¹¹⁶ R ¹¹⁶ ) _r OR ¹¹⁹ , (1) (CR ¹¹⁶ R ¹¹⁶ ) _r S(O) _p (CR' ¹⁶ R ¹¹⁶ ^R ¹¹⁹ ,

(m) (CR ¹¹⁶ R ¹¹⁶ ) _r C(O)( CR ¹¹⁶ R ¹¹⁶ ),R ¹¹⁹ , (n) (CR ¹¹⁶ R ¹¹⁶ ) _r OC(O)( CR ^{l l6} R ¹¹⁶ ) _t R ¹¹⁹ , (o) (CR ¹¹⁶ R ¹¹⁶ ) _r SC(O)( CR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ , (p) (CR ¹¹⁶ R ¹¹⁶ ) _r C(O)O(CR ¹¹⁶ R ¹¹⁶ ^R ¹¹⁹ , (q) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ C(O)( CR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ , (r) (CR ¹¹⁶ R ¹¹⁶ ) _r C(O)NR ¹¹ ^CR ¹¹⁶ R ¹¹⁶ ),R ¹¹⁹ , (s) (CR ¹¹⁶ R ¹¹⁶ ) _r C ₁ =NR ¹¹⁶ X CR ¹¹⁶ R ¹¹⁶ ),R ¹¹⁹ ,

(t) (CR ¹¹⁶ R ¹¹⁶ ) _r C ₁ =NNR ¹¹⁶ R ¹¹⁶ )(CR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ , (u) (CR ¹¹⁶ R ¹¹⁶ ) _r C ₁ =NNR ¹¹⁶ C(O)R ¹¹⁶ )( CR ¹¹⁶ R ¹¹⁶ ),R ¹¹⁹ , (v) (CR ¹¹⁶ R ¹¹⁶ ) _r C ₁ =NOR ¹¹⁹ )( CR ¹¹⁶ R ¹¹⁶ ),R ¹¹⁹ , (w) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ C(O)O(CR ¹¹⁶ R ¹¹⁶ ),R' ¹⁹ , (x) (CR ¹¹⁶ R ¹¹⁶ ) _r OC(O)NR ¹ "XCR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ ,

(y) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ C(O)NR ¹¹⁶ (CR* ¹⁶ R ¹¹⁶ XR ¹¹⁹ , (z) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ S(O)p(CR' ¹⁶ R ¹¹⁶ XR ¹¹⁹ , (aa) (CR ¹¹⁶ R ¹¹⁶ ) _r S(O) _P NR ¹¹⁶ (CR ¹¹⁶ R ¹¹⁶ XR ¹¹⁹ , (bb) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ S(O) _P NR ¹¹⁶ (CR' ¹⁶ R ¹¹⁶ ) _t R' ¹⁹ , (cc) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ R ¹¹⁶ , (dd) C ₁ ^ alkyl, (ee) C _2-6 alkenyl, (ff) C _2-6 alkynyl,

(gg) (CR ¹¹⁶ R ¹¹⁶ ) _r -C _3-I2 saturated, unsaturated, or aromatic carbocycle, (hh) (CR ¹¹⁶ R ¹¹⁶ ) _r -3-12 membered saturated, unsaturated, or aromatic heterocycle

containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and (ii) -P(O)(O(C i_ ₆ alkyl)) ₂ , wherein any of (dd)-(hh) immediately above is optionally substituted with one or more R ¹¹⁹ groups; alternatively, two R ¹¹⁷ groups form -O(CH ₂ ) _U O-;

R ¹¹⁸ , at each occurrence, independently is selected from:

(a) H, (b) C _1-6 alkyl, (c) C _2-6 alkenyl, (d) C _2-6 alkynyl, (e) C _3- I ₂ saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-C _1-6 alkyl, (h) -C(O)-C _2-6 alkenyl,

(i) -C(O)-C _2-6 alkynyl, (j) -C(O)-C _3-I2 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) immediately above optionally is substituted with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO ₂ , (hh) OH, (ii) NH ₂ , (jj) NH(C _1-6 alkyl), (kk) N(C _1-6 alkyl) ₂ , (11) C _1-6 alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C _1-6 alkyl, optionally substituted with one or more moieties selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO ₂ , and OH; R ¹¹⁹ , at each occurrence, independently is selected from:

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

(a) H, (b) =0, (c) F, (d) Cl, (e) Br, (f) I, (g) (CR ¹¹⁶ R ¹¹⁶ ) _r CF ₃ . OO (CR ^{I 16} R ¹¹⁶ ) _r CN, (i) (CR ¹¹⁶ R ¹¹⁶ ) _r NO ₂ , (j) (CR ¹¹⁶ R ¹¹⁶ J ₁ NR ¹¹⁶ R ¹¹⁶ , (k) (CR ¹¹⁶ R ¹¹⁶ ) _r OR ¹¹⁴ , (1) (CR ¹¹⁶ R ¹¹⁶ ) _r S(O) ₁₃ R ¹¹⁶ , (m) (CR ¹¹⁶ R ^{1 I6} ) _r C(O)R ¹¹⁶ ,

(n) (CR ¹¹⁶ R ¹¹⁶ ) _r C(O)OR' ¹⁶ , (o) (CR ^U6 R ¹¹⁶ ) _r OC(O)R ¹¹⁶ , (p) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ C(O)R ¹¹⁶ , (q) (CR ¹¹⁶ R ¹¹⁶ ) _r C(O)NR ¹¹⁶ R ¹¹⁶ , (r) (CR ¹¹⁶ R ^{l l6} ) _r C(=NR ¹¹⁶ )R ¹¹⁶ , (s) (CR ¹¹⁶ R ¹¹ ^-NR ¹¹⁶ C(O)NR ¹¹⁶ R ¹¹⁶ , (t) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ S(O) ₁₃ R ¹¹⁶ , (u) (CR ¹¹⁶ R ¹¹⁶ ) _r S(O) _P NR ¹¹⁶ R ¹¹⁶ , (v) (CR ¹¹⁶ R ¹¹⁶ ) _r NR ¹¹⁶ S(O) ₁₃ NR ¹¹⁶ R ¹¹⁶ , (w) C _1-6 alkyl, (x) C _2-6 alkenyl, (y)

C _2-6 alkynyl, (z) (CR ¹¹⁶ R ¹ ^)--C _3- I ₂ saturated, unsaturated, or aromatic carbocycle, and (aa) (CR ¹¹⁶ R ¹¹⁶ ) _r -3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (w)-(aa) immediately above is optionally substituted with one or more moieties selected from R ¹¹⁶ , F, Cl, Br, I, CN, NO ₂ , - OR ¹¹⁶ , -NH ₂ , -NH(C _1-6 alkyl), -N(C _-6 alkyl) ₂ , C _-6 alkoxy, C ₁ _ ₆ alkylthio, and C _1-6 acyl; each occurrence, independently is selected from: (a) H, (b) -OR ¹¹⁸ , (c) -O-C _1-6 alkyl-OC(O)R' ¹⁸ , (d) -C)-C _1-6 alkyl-

OC(O)OR ¹¹⁸ , (e) -O-C _1-6 311CyI-OC(O)NR ¹¹⁸ R ¹¹⁸ , (f) -O-C _1-6 alkyl- C(O)NR ¹¹⁸ R ¹¹⁸ , (g) -O-C _-6 alkyl-NR ¹¹⁸ C(O)R ¹¹⁸ , (h) -O-C _1-6 alkyl- NR ¹¹⁸ C(O)OR ¹¹⁸ , (i) -O-C _1-6 alkyl-NR ¹¹⁸ C(O)NR ¹¹⁸ R ¹¹⁸ , O) -O-C _1-6 alkyl- NR ¹¹⁸ C(^N(H)NR ¹¹⁸ R ¹¹⁸ ), (k) -O-C _{1 -6} alkyl-S(O)pR ¹¹⁸ , (1) -O-C _2-6 alkenyl- OC(O)R ¹¹⁸ , (m) -O-C _2-6 alkenyl-OC(O)OR' ¹⁸ , (n) -O-C _2-6 alkenyl-

OC(O)NR ¹¹⁸ R ¹¹⁸ , (o) -O-C _2-6 alkenyl-C(O)NR ¹¹⁸ R ¹¹⁸ , (p) -O-C _2-6 alkenyl- NR ¹¹⁸ C(O)R ¹¹⁸ , (q) -O-C _2-6 alkenyl-NR ¹¹⁸ C(O)OR ¹¹⁸ , (r) -O-C _2-6 alkenyl- NR ¹¹⁸ C(O)NR ¹¹⁸ R ¹¹⁸ , (s) -O-C _2-6 alkenyl-NR ¹¹⁸ C(=N(H)NR ^{I 18} R ¹¹⁸ ), (t) -O- C _2-6 (u) -O-C _2-6 alkynyl-OC(O)R ¹¹⁸ , (v) -O-C _2-6 alkynyl- OC(O)OR ¹¹⁸ , (w) -O-C _2-6 alkynyl-OC(O)NR' ¹⁸ R ¹¹⁸ , (x) -C)-C _2-6 alkynyl-

C(O)NR ¹¹⁸ R ¹¹⁸ , (y) -O-C ₂ _6 alkynyl-NR ¹¹⁸ C(O)R ¹¹⁸ , (z) -O-C _2-6 alkynyl- NR ¹¹⁸ C(O)OR ¹¹⁸ , (aa) -O-C _2-6 alkynyl-NR ¹¹⁸ C(O)NR ¹¹⁸ R ¹¹⁸ , (bb) -C ⁾ -C _2-6 alkynyl-NR ¹¹⁸ C(=N(H)NR' ¹⁸ R ¹¹⁸ ), (cc) -O-C _2-6 alkynyl- S(O)pR ¹¹⁸ , (dd) -NR ¹¹⁸ R ¹¹⁸ , (ee) -C _1-6 alkyl-O-C _1-6 alkyl, (ff) -C^alkyl- NR ¹ "-C _-6 alkyl, (gg) -C ₁ ^ alkyl-S(O) _p -C^ alkyl, (hh) -OC(O)NR ¹¹⁴ (C _1-6 alkyl)-NR ¹¹⁴ -(C ₁ ^ alkyl) -R ¹¹⁴ , (ii) -OH, Gj) -C ₁ _ ₆ alkyl, (kk) C _2-6 alkenyl, (11) C _2-6 alkynyl, (mm) -CN, (nn) -CH ₂ S(O) _P R ¹³⁷ , (00) -CH ₂ OR ¹³⁷ , (pp) - CH ₂ N(OR ¹³⁸ )R ¹³⁷ , (qq) -CH ₂ NR ¹³⁷ R ¹³⁹ , (rr) -(CH ₂ ) _v (C _6-10 aryl), and (ss>-

(CH ₂ )v(5-10 membered heteroaryl), wherein (jj)-(ss) ^are optionally substituted by 1, 2, or 3 R ¹⁴⁰ groups _; alternatively, two R ¹²¹ groups taken together form =O, =NOR ¹¹⁸ , or =NNR ¹¹⁸ R ¹¹⁸ ; R ¹²⁷ is selected from (a) R ¹¹⁴ , (b) a monosaccharide or a disaccharide (including amino sugars and halogenated sugar(s)), (c) -S(O)pR ¹⁴⁸ , (d) -(CH ₂ ) _n -(O-CH ₂ CH ₂ _) _m -

O(CH ₂ ) _n CH ₃ , (e) -<CH ₂ )n-(O-CH ₂ CH ₂ _) _m -OR ¹⁴⁸ , (f) -(CH ₂ ) _n -[S(O) _p -CH ₂ CH ₂ _] _m - S(O)p(CH ₂ ) _n CH ₃ , (g) -(CH ₂ ) _n -[S(O) _p -CH ₂ CH ₂ _] _m -OR ¹⁴⁸ , (h) -OCH ₂ -O-(CH ₂ ) _n - [S(O)p-CH ₂ CH ₂ _] _m -S(O)p(CH ₂ ) _n CH _3> (i) -OCH ₂ _O-(CH ₂ ) _n -[S(O) _p -CH ₂ CH ₂ _] _m -OR ¹⁴⁸ , (j) -0-[C _3-I2 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R ¹¹⁴ , (k) -O-[3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur], wherein said heterocycle is further optionally substituted with one or more R ¹¹⁴ , (1) -S(O) _p -[C ₃ -i ₂ saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R ¹¹⁴ , and (m) -S(O) _p -[3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur], wherein said heterocycle is further optionally substituted with one or more R ¹¹⁴ ; R ¹²⁸ is R ¹¹⁴ ; R ¹²⁹ is R ¹¹⁴ ; alternatively both R ¹²⁸ substituents can be taken together with the carbons to which they are attached to form carbonyl or =NR ¹¹⁴ , or a saturated or unsaturated C _3-6 spiro ring or a 3-6 membered saturated or unsaturated heterospiro ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R ^{1 π} groups, alternatively both R ¹²⁹ substituents can be taken together with the carbons to which they are attached to form carbonyl or =NR ¹¹⁴ , or a saturated or unsaturated C _3-6 spiro ring or a 3-6 membered saturated or unsaturated heterospiro ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R ¹¹⁷ groups, alternatively an R ¹²⁸ and an R ¹²⁹ substituent can be taken together with the carbons to which they are attached to form a C _3-I2 saturated or unsaturated ring or saturated or unsaturated bicyclic ring, or a 3-12 membered saturated or unsaturated heterocyclic ring or saturated or unsaturated heterobicyclic ring containing one or more nitrogens,

oxygens, or sulfurs, said rings further being optionally substituted by one or more R ¹¹⁷ groups, alternatively one R ¹²⁸ group and one R ¹²⁹ group may be taken together with the carbons to which they are attached to form a double bond, and the other R ¹²⁸ group and the other R ¹²⁹ group are as defined herein or can form (a) a C _3-I2 ring which may be further unsaturated or aromatic, (b) a C _7-I2 bicyclic ring which may be further unsaturated or aromatic, (c) a 3-12 membered heterocyclic ring containing one or more nitrogens, oxygens, or sulfurs, which may be further unsaturated or aromatic, or (d) a 7-12 membered heterobicyclic ring containing one or more nitrogens, oxygens, or sulfurs, which may be further unsaturated or aromatic, said rings described in (a),

(b), (c) and (d) further being optionally substituted by one or more R ¹¹⁷ groups,

R ¹¹⁰ is R ¹¹⁴ : alternatively, R ¹⁰⁹ and R ¹¹⁰ , taken together with the carbons to which they are attached form:

R ¹³² , R ¹³³ , and R ¹³⁴ at each occurrence, independently are selected from: (a) H, (b) F, (c) Cl, (d) Br, (e) -OR ¹¹⁴ , (f) -SR ¹¹⁴ , (g) -NR ¹¹⁴ R ¹¹⁴ , and (h) C _1-6 alkyl, wherein (h) immediately above is optionally substituted with one or more R ¹¹⁵ groups; alternatively, R ¹³² and R ¹³³ are taken together to form a carbon-carbon double bond; alternatively, R ¹³³ and R ¹³⁴ are taken together to form =0, =S, =NOR' ¹⁴ , =NR ¹¹⁴ , or

=N-NR ¹¹⁴ R ¹¹⁴ ; alternatively, R ¹⁰⁵ and R ¹³⁴ are taken together with the carbons to which they are attached to form a 3 -membered ring, said ring optionally containing an oxygen or nitrogen atom, and said ring being optionally substituted with one or more R ¹¹⁴ groups; alternatively when M is a carbon moiety, R ¹³⁴ and M are taken together to form a carbon-carbon double bond;

R ¹³⁷ at each occurrence, independently is selected from: (a) H, (b) C _1-6 alkyl, (c) C _2-6 alkenyl, (d) C _2-6 alkynyl, (e) -(CH ₂ ) _q CR ¹⁴¹ R ¹⁴² (CH ₂ ) _n NR ¹⁴³ R ¹⁴⁴ , -(CH ₂ ) _v (C ₆ -C ₁₀ aryl), and -(CH ₂ ) _V (5- 10 membered heteroaryl); or wherein R ¹³⁷ is as -CH ₂ NR ¹³⁷ R ¹³⁹ , R ¹³⁹ and R ¹³⁷ may be taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered

heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S, and -N(R ¹³⁷ )-, in addition to the nitrogen to which R ¹³⁹ and R ¹³⁷ are attached, said saturated ring optionally includes 1 or 2 carbon- carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1, 2, or 3 R ¹⁴⁰ groups;

R ¹³⁸ at each occurrence, independently is selected from (a) H and (b) Cr ₆ alkyl; R ¹⁴¹ , R ¹⁴² , R ¹⁴³ , and R ¹⁴⁴ at each occurrence, independently is selected from (a) H, (b) C ₁ -6 alkyl, (c) -(CH ₂ ) _m (C ₆ -C ₁₀ aryl), and (d) -(CH ₂ V(S-IO membered heteroaryl), wherein the foregoing R ¹⁴¹ , R ¹⁴² , R ¹⁴³ , and R ¹⁴⁴ groups, except H, are optionally substituted by 1, 2, or 3 R ¹⁴⁰ groups; or R ¹⁴¹ and R ¹⁴³ are taken together to form -(CH ₂ ) ₀ - wherein o, at each occurrence is 0, 1, 2, or 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds; or R ¹⁴³ and R ¹⁴⁴ are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and - N(R ¹³⁷ )-, in addition to the nitrogen to which R ¹⁴³ and R ¹⁴⁴ are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1, 2, or 3 R ¹⁴⁰ group;

R ¹³⁹ at each occurrence, independently is selected from: (a) H, (b) C ₁ _ ₆ alkyl, (c) C ₂ _C ₆ alkenyl, and (d) C ₂ -C ₆ alkynyl, wherein the foregoing R ¹³⁹ groups, except H, are optionally substituted by 1, 2, or 3 substituents independently selected from halogen and -OR ¹³⁸ ; R ¹⁴⁰ at each occurrence, independently is selected from (a) halogen, (b) cyano,

(c) nitro, (d) trifluoromethyl, (e) azido, (f) -C(O)R ¹⁴⁵ , (g) -C(O)OR ¹⁴⁵ , (h) - OC(O)OR ¹⁴⁵ , (i) -NR ¹⁴⁶ C(O)R ¹⁴⁷ , (j) -NR ¹⁴⁶ R ¹⁴⁷ , (k) -OH, (1) C,_ ₆ alkyl, (m) Cr ₆ alkoxy, (n) -(CH ₂ ) _V (C ₆ -C ₁ oaryl), and (o) -(CH ₂ ) _v (5-10 membered heteroaryl), wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from: (a) halogen, (b) cyano, (c) nitro, (d) trifluoromethyl, (e) azido, (f) -C(O)R ¹⁴⁵ , (g) -C(O)OR ¹⁴⁵ , (h) -OC(O)OR ¹⁴⁵ , (i) -NR ¹⁴⁶ C(O)R ¹⁴⁷ , (j) - C(O)NR ¹⁴⁶ R ¹⁴⁷ , (k) -NR ¹⁴⁶ R ¹⁴⁷ , (1) OH, (m) d-ealkyl, and (n) C ₁ _ ₆ alkoxy;

R ¹⁴⁵ at each occurrence, independently is selected from: (a) H, (b) -C ₁ ^alkyl, (c) -C ₂ _C ₂ alkenyl, (d) -C ₂ _C ₂ alkynyl, (e) -(CH ₂ ) _v (C ₆ -C ₁₀ aryl), and (f) -(CH ₂ ) _v (5-10 membered heteroaryl);

R ¹⁴⁶ and R ¹⁴⁷ at each occurrence, independently is selected from: (a) H, (b) hydroxyl, (c) C ₁ _ ₆ alkoxy, (d) C _1-6 alkyl, (e) C ₂ _ ₆ alkenyl, (f) C ₂ _ ₆ alkynyl, (g) - (CH ₂ )v(C ₆ -io aryl), and (h) -(CH ₂ ) _v (5-10 membered heteroaryl); R ¹⁴⁸ at each occurrence, independently is selected from: (a) C ₁ -ealkyl, (b) C _3-I2 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further optionally substituted with one or more R ¹¹⁴ , and (c) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said heterocycle is further optionally substituted with one or more R ¹¹⁴ ; p, at each occurrence is 0, 1, or 2; k, at each occurrence, independently is selected from 0, 1, and 2; m, at each occurrence, independently is selected from 0, 1, 2, 3, 4, and 5; n, at each occurrence, independently is selected from 1, 2, and 3; r, at each occurrence, independently is selected from 0, 1, and 2; t, at each occurrence, independently is selected from 0, 1, and 2; v, at each occurrence, independently is selected from 0, 1, 2, 3, and 4; q 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, wherein T is:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁷ , R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹¹⁴ , R ¹³² , R ¹³³ , and R ¹³⁴ are as described herein. In other embodiments, the present invention relates to a compound, wherein T is:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, R 100

R , 1 ¹ 0 ^U 1 ¹ , τ R> 1 ^W 02 ^δ , τ R> 1 ¹ 0 ^U 3 ^J , „ R1 ¹ 0 ^W 4, _D R1 ⁱ 0 ^υ 7 ^/ , τ R> 1 ¹ 0 ^U 8 ^δ , _D R1 ⁱ 0 ^υ 9 ^y , τ R> 1 ^l 1 ⁱ 0 ^υ , τ R> 1"14 ⁴ , _D R1 ¹ 3"2, R 1 ^U 33 ^J , and R » 1 ¹ 3 ^J 4 ⁴ a. re as described herein In other embodiments, the present invention relates to a compound, wherein T is:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁷ , R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹¹⁷ , R ¹³² , R ¹³³ , and R ¹³⁴ are as described herein. In other embodiments, the present invention relates to a compound, wherein T is:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁷ , R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹²⁸ , R ¹²⁹ , R ¹³² , R ¹³³ , k, and R ¹³⁴ are as described herein.

In other embodiments, the present invention relates to a compound, wherein T is:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁷ , R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹¹⁴ , R ¹²⁸ , R ¹²⁹ , R ¹³² , R ¹³³ , k, and R ¹³⁴ are as described herein.

In other embodiments, the present invention relates to a compound, wherein T is:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁷ , R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹²⁸ , R ¹²⁹ , R ¹³² , R ¹³³ , and R ¹³⁴ are as described herein.

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

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, R ¹⁰⁰ , R ¹⁰¹ , R ¹⁰² , R ¹⁰³ , R ¹⁰⁴ , R ¹⁰⁷ , R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹¹⁴ , R ¹²⁸ , R ¹²⁹ , R ¹³² , R ¹³³ , and R ¹³⁴ are as described herein.

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

wherein R ¹⁰⁴ , R ¹¹⁴ , R ¹¹⁷ , R ¹²⁸ , R ¹²⁹ , and k are as described herein.

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is selected from Tl, T2, T3, T4, T7, TlA, T2A, T3A, T4A, T5A, T6A, and T7A.

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

In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is selected from T8-T113.

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

In other embodiments, the present invention relates to a method for treating or preventing a disease state in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 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, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

In other embodiments, the present invention relates to the use of a compound of the invention, 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

In other embodiments, the present invention relates to a method of treating or preventing a microbial infection in a mammal comprising administering to the mammal an

effective amount of a compound of the invention, 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 (uSSTI)s 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 or preventing a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

In other embodiments, the present invention relates to a method of treating or preventing a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

In other embodiments, the present invention relates to a method of treating or preventing a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In other embodiments, the present invention relates to a method of treating or preventing a viral infection in a mammal comprising administering to the mammal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

In other embodiments, the present invention relates to a method of treating or preventing an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

In other embodiments, the present invention relates to a method of treating or preventing a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In other embodiments, the present invention relates to a method of treating or preventing diarrhea in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

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, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, 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, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered otically, ophthalmically, nasally, orally, parentally, or topically. In other embodiments, the present invention relates to a method of synthesizing a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In other embodiments, the present invention relates to a medical device containing a compound of the present invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

In other embodiments, the present invention relates to a medical device, wherein the device is a stent. As is seen from the foregoing, the compounds of the present invention can include a wide range of structures. Examples of such macrolide components and their syntheses are provided in the following documents, all of which are incorporated by reference in their entirety: PCT Application No. WO 2007/025284, published March 1, 2007, to Rib-X Pharmaceuticals, Inc.; PCT Application No. WO 2007/025098, published March 1, 2007, to Rib-X Pharmaceuticals, Inc.; PCT Application No. WO 2007/ 025089, published March 1 , 2007, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/118610, published December 15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/085266, published September 15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO

2005/049632, published June 2, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No.

WO 2005/042554, published May 12, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2004/078770, published September 16, 2004, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2004/029066, published April 8, 2004, to Rib-X Pharmaceuticals, Inc.; 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; 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; PCT WO 98/54197, published December 3, 1998, to Abbott Laboratories; and PCT 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, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁷ , 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 = CH ₃ ), 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 where 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).

Scheme A

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

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. 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

The following Scheme C illustrates the synthesis of oxime type macrolides of the present invention. These compounds can be 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 R ¹ ), 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.

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. 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.

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 ran 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 IC ₈ os and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore. This is generally the smaller molecule in the system (in this case, the compound of interest). The sample mixture, containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured. Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-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 IC ₈ os and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions. (3) Protein Synthesis. It is contemplated that, in addition to characterization by the foregoing biochemical assays, the compound of interest can also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.

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

protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis. A decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.

(4) Antimicrobial assays and other evaluations Furthermore, the compounds can be assayed for 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 (MIC ₈ ) are determined by the microdilution method, typically in a final volume of 100 microliters, according to protocols outlined by The Clinical and Laboratory Standards Institute [CLSI; formerly the National Committee for Clinical Laboratory Standards (NCCLS)]. See CLSI: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. Wayne, PA: NCCLS; 2000. The assays can be also be performed in microtiter trays according to conventional methodologies as published by the CLSI. See CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition. CLSI Document M7-A7 [ISBN 1-56238-587-9] CLSI, 940 West Valley Road, Suite 1400, Wayne Pennsylvania 19087-1898 USA, 2006).

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

To further assess a compound's drug-like properties, measurements of inhibition of cytochrome P450 enzymes and phase 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 (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

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

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

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

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

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

The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Furthermore, administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag). Where adhesion to a tissue surface is desired the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound then can be painted, sprayed or otherwise applied to the desired tissue surface. Alternatively, the drugs can be formulated for otic, ophthalmic, nasal, parenteral or oral administration to humans or other mammals, for example, in therapeutically effective amounts, e.g., amounts that provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect.

Where the active compound is to be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of tissue or organ from the donor. The compound can be provided to the donor host. Alternatively or, in addition, once removed from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue, as by injection to the tissue, or it can be provided systemically, e.g., by 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 otically, ophthalmically, nasally, orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective.

Generally, an effective amount of dosage of active component will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg of body weight/day. The amount administered will also likely depend on such variables as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage can be smaller than the optimum and the daily dosage can be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times per day.

Various disease states or conditions in humans and other mammals are found to be caused by or mediated by nonsense or missense mutations. These mutations cause or mediate the disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking and/or function. Examples of disease states or conditions in which an appreciable percentage of the disease or condition is believed to result from nonsense or missense mutations include hemophilia (factor VTII gene), neurofibromatosis (NFl and NF2 genes), retinitis pigmentosa (human USH2A gene), bullous skin diseases like Epidermolysis bullosa pruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosis transmembrane regulator gene), breast and ovarian cancer (BRCAl and 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); Et ₂ O = diethyl ether; THF = tetrahydrofuran; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; Et ₃ N = triethylamine; /-Pr ₂ NEt or DIPEA = diisopropylethylamine; CH ₂ Cl ₂ = methylene chloride; CHCl ₃ = chloroform; CDCl ₃ = deuterated chloroform; CCl ₄ = carbon tetrachloride; MeOH = methanol; CD ₃ OD= deuterated methanol; EtOH = ethanol; DMF = dimethylformamide; BOC = t- butoxycarbonyl; CBZ = benzyloxycarbonyl; TBS = f-butyldimethylsilyl; TBSCl = t- butyldimethylsilyl chloride; TFA = trifluoroacetic acid; DBU = diazabicycloundecene; TBDPSCl = f-butyldiphenylchlorosilane; Hunig's Base= N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; CuI = copper (I) iodide; MsCl = methanesulfonyl chloride; NaN ₃ = sodium azide; Na ₂ SO ₄ = sodium sulfate; NaHCO ₃ = sodium bicarbonate; NaOH = sodium hydroxide; MgSO ₄ = magnesium sulfate; K ₂ CO ₃ = potassium carbonate; KOH = potassium hydroxide; NH ₄ OH = ammonium hydroxide; NH ₄ Cl = ammonium chloride; SiO ₂ = silica; Pd-C = palladium on carbon; Pd(dppf)Cl ₂ = dichloro[l,l '- bis(diphenylphosphino)ferrocene] palladium (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] ⁺ .

205 610.2*

206 1106.0

207 629.4*

208

1144.0

225 1200.1

226 603.2*

227

615.6*

228 1232.3

229

230 617.3*

235 1172.1

236

1202.0

245 601.1*

246 1169.90

119

250 1113.00

251

592.00

252 1138.00

253

1123.00

254 1123.00

255

571.00*

256 563.00*

257 563.00*

258 547.00*

259

548.00*

262

482.00*

263 468.00

264 468.00*

265

1109.00

266 570.00*

267 953.80

268 969.00

269

640.30*

270 572.60*

271 611.00*

272 1213.40

273

619.00*

274 562.00

275 569.00*

278

564.50*

279

580.60*

280 565.00*

281 569.00*

284 622.00*

285

593.00*

286 579.00*

287

597.20*

290 579.00*

291

589.30*

292 584.20*

293 593.30*

303 611.40*

304 1319.40

305

1312.00

306 656.90*

307

638.50*

311 566.20*

312 566.20*

319 618.10*

320 617.20*

323

607.00*

324 651.00*

325 601.60*

326

606.00*

329 613.00*

330 659.00*

333

680.70*

334

599.00*

337

591.00*

338

1212.00

339 615.20*

340 657.90*

341

598.10*

342

614.30*

345

606.40*

346

606.70*

349

590.00*

350 577.40*

351 650.70*

352

606.60*

355

651.50*

356

614.10*

357 614.40*

358

614.00*

359 623.20*

360 606.00*

363 662.90*

364

661.90*

365 617.10*

366 607.2*

369 654.60*

370

606.60*

371 614.10*

372 622.50*

373 621.30*

374 628.00*

375 570.10*

376 625.60*

377 634.70*

378 605.30*

379 606.20*

380 1198.90

381 614.70*

382 613.10*

385 602.50*

386 586.50*

389 622.60*

390 574.60*

395 1241.00

396 591.10*

397

398

401 1227.00

402 591.60*

415 592.90*

416 642.00*

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

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

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

Exemplary macrolide compound of the present invention showing variable G.

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

Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B", wherein B ¹ is phenyl.

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

Examples 1 - 6: Synthesis of 3'-N-desmethyl macrolide 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'-7V-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 (I ₂ ) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes, however, stirring was continued for 2 hours. TLC (CH ₂ Cl ₂ /MeOH/NH ₄ OH 10: 1 :0.05) after 2 hours showed a single major product (Rf= 0.66). The reaction was cooled to room temperature, poured into H ₂ O (75 mL) containing NH ₄ OH (1.5 mL) and extracted with CHCI ₃ (3 x 30 mL). The combined organic layers were washed with H ₂ O (30 mL) containing NH ₄ OH (1.5 mL), dried over Na ₂ SO ₄ and the solvent evaporated to give a white

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

Example 3: Synthesis of 3'-N-desmethyl clarithromycin from clarithromycin To a mixture of clarithromycin (1.00 g, 1.3 mmol) and νaOAc●3H ₂ 0 (0.885 g, 6.5 mmol) was added MeOH-H ₂ O (20 mL, 4:1), and the mixture heated to 55-60 °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 CHCl ₃ containing 1 mL ammonium hydroxide. It was extracted with CHCI ₃ (4 x 50 mL), washed with water (70 mL) containing 5 mL ammonium hydroxide, dried (anhydrous Na ₂ SO ₄ ), concentrated, and purified by flash chromatography (silica gel, CHCl ₃ :MeOH:NH ₄ OH 100:10:0.1) to afford 3'-N-desmethyl clarithromycin. Yield: 0.9g (92%).

Example 4: Synthesis of 3'-N-desmethyl roxithromycin from roxithromycin

To a mixture of roxithromycin (850 mg, 0.914 mmol, 90%) and NaOAc (828 mg, 10.000 mmol) in a mixture of MeOH (6.0 mL) and water (1.5 mL) at 48 "C was added I ₂ in four portions (each portion: 63.5 mg) over 30 min, after each portion I ₂ , followed by IN NaOH (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 X 2), dried with Na ₂ SO ₄ . The residue was separated by FC (6/94/0.2 MeOH/CH ₂ Cl ₂ /NH ₄ OH), gave 600 mg 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 room temperature and stirred overnight. CH ₂ Cl ₂ (250 mL) and 5 % Na ₂ S ₂ O ₃ (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na ₂ S ₂ O ₃ (1 X 80 mL), dilute NH ₄ Cl (1 X 80 mL) and dried over Na ₂ SO ₄ . Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 8 % methanolic ammonia (2N NH ₃ ) in CH ₂ Cl ₂ to give 3'-N- desmethyl telithromycin as white solid (1.95 g, 68 %). MS (ESI) M/E; M+H ⁺ 798.6.

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

Most of the 3'-N-desmethyl ketolide intermediates are not made directly. Instead, the ketolide function, i.e. the 1,3-diketone, is introduced after the 3'-N-desmethyl functionality has been further transformed to an N-alkynyl intermediate. In an exemplary process, clarithromycin is converted to 3'-N-desmethyl clarithromycin. This compound is then alkylated to form an alkynyl intermediate. The cladinose sugar is then cleaved from this intermediate and the resulting free hydroxyl group is oxidized to the ketone. This process is shown below in Example 12.

Examples 7-11: 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 7-11 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 3'-N-(but-3-ynyl) erythromycin

A mixture of 3'-N-desmethyl erythromycin and the tosylate of l-butyn-4-ol in Hunig's base and THF was stirred. The reaction mixture was diluted to EtOAc and washed with νaHC03(aq) and with brine. The organic layer was dried over K ₂ CO ₃ 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'-iV-desmethyl azithromycin and the tosylate of l-butyn-4-ol in Hunig's base was stirred. The reaction mixture was diluted to EtOAc and washed with NaHCO ₃ (aq) and with brine. The organic layer was dried over K ₂ CO ₃ 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 3'-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 CH ₂ Cl ₂ , extracted with 2% aqueous NH ₄ OH and saturated brine. The organic layer was dried over

Na ₂ SO ₄ 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'-iV-(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. NaHCO ₃ (20 mL), and brine (50 mL). The N-alkynyl substituted roxithromycin was isolated by FC (3/100/0.2 eOH/CH ₂ Cl ₂ /NH4θH), gave 316 mg in 59% yield. LCMS (ESI) m/e 876 (M+H) ⁺ .

Example 11: Synthesis of 3'-iV-(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'-ν-desmethyl telithromycin (0.66 g, 0.83 mmol) and the tosylate of l-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 IN HCl (50 mL) and kept stirring at room temperature for about Ih. CH ₂ Cl ₂ (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 X 30 mL) and basified with NaOH (IN) to form a whitish-suspension. The suspension was extracted with CH ₂ Cl ₂ (3 X 30 mL) and the organic layer was dried over Na ₂ SO ₄ . Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 6 % methanolic ammonia (2N NH ₃ ) in CH ₂ Cl ₂ 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'-ν-desmethyl telithromycin (0.66 g, 0.83 mmol), and the tosylate of l-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 1.5 h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in IN HCl (60 mL) and kept stirring at room temperature for about 2h. CH ₂ Cl ₂ (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 X 30 mL) and basified with 50 % KOH to form a whitish-suspension. The suspension was extracted with CH ₂ Cl ₂ (3 X 30 mL) and the organic layer was dried over Na ₂ SO ₄ . The solvent was evaporated and the crude was purified by preparative TLC (2000 micron plate) eluting

with CH ₂ Cl ₂ /methanolic ammonia (2N NH ₃ ) 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'-7V-(but-3-ynyl) carbamate macrolide compounds

3'-iV-(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.

Scheme for Example 12 for preparing 3'-N-(but-3-ynyl) macrolides having a carbamate substituent on the macrolide ring.

Acylimidazole „ _tl . , . _1% _ .

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

A solution of the acylimidazole (0.74 g, 1.0 mmol) in acetonitrile (20 mL) and H ₂ O (3 mL) was treated with a primary amine (e.g. R-NH ₂ , 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 (SiO ₂ , 50-100% ethyl acetate/hexanes) provides the 3'-N-(but-3-ynyl) carbamate (0.50 g, 0.75 mmol) as a white powder.

Example 13. Synthesis of the Compounds of the Present Invention

Compounds of the present invention can be made, for example, via a cycloaddition reaction of an alkynyl macrolide with an azide compound. In this cycloaddition reaction, the triazole functional group of the resulting compound is formed. Other compounds of the present invention are made by further chemically modifying the resulting compound from the cycloaddition reaction.

The cycloaddition reaction is generally run in the presence of a copper (I) salt such as copper iodide (CuI). A base can also be optionally used, such as Hunig's base (N ₁ N- diisopropylethylamine). The following general reaction scheme outlines the cycloaddition reaction of the alkynyl macrolide and the azide compound.

The time required for the reaction to proceed to completion is variable and is dependent upon several factors including: the specific alkynyl macrolide and azide compounds and their concentrations; the amount of Cu(I) salt used; and the presence or absence of base, such as Hunig's Base(N,N-diisopropylethylamine). Reactions are monitored for the disappearance of the starting materials by TLC and/or LCMS and are typically allowed to run for between about 2 hours to about 72 hours. Reactions are generally stopped when analysis demonstrates that the starting alkynyl macrolide has been substantially consumed. The workup and purification protocols are standard. Modifications to the described workup procedures can be used. Such modifications can 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. 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 compounds of the present invention are typical of procedures familiar to those trained in the art of organic synthesis.

Most compounds of the present invention can be prepared from the desired alkynyl macrolide and azide compound under one of several similar reaction conditions as exemplified by Conditions A, B, C, and D below. Use of Conditions A and C, which do not include the step of degassing the reaction mixture, tend to result in the formation of iodinated side-products in addition to the desired product and thereby generally produced lower isolated yields. Additionally, reduction of the amount of copper iodide used in the reaction to 0.5 molar equivalents or less as in conditions B and D also tends to result in reduced formation of iodinated by-products. As demonstrated in Condition D, the presence of Hunig's base is not essential for the success of the triazole formation step; however, it is found preferable that the base be included since it often results in a higher rate of reaction and correspondingly shorter reaction times.

Condition A:

To a stirred solution of the alkynyl macrolide (0.04 mmol), the azide compound (0.07 mmol) and Hunig's base (10 μL) in 0.5 mL tetrahydrofuran (THF) is added CuI (5 mg, 0.03 mmol). The mixture is stirred at ambient temperature for 16 hours then diluted with CH ₂ Cl ₂ (10 mL) and washed with a 3:1 mixture of saturated aqueous NH ₄ Cl and 28% aqueous NH ₄ OH (10 mL) and with brine (10 mL) the aqueous washes are back-extracted with CH ₂ Cl ₂ (2 x 10 mL). The combined organic extracts are dried over K ₂ CO ₃ , filtered, and concentrated to afford 52 mg of crude product which is purified by chromatography on silica gel (elution with 40:1 2M NH ₃ in MeOH and CH ₂ Cl ₂ ) to give the desired compound.

Condition B:

A solution of alkynyl compound (0.10 mmol) and azide compound (0.12 mmol) and Hunig's base in 0.4 mL THF are thoroughly degassed by alternately evacuating the reaction vessel and purging with dry argon. CuI is then added (2 mg, 0.01 mmol) and the mixture is further degassed. The mixture is stirred under argon for 6h then diluted with CH ₂ Cl ₂ (20 mL) and washed with a 3:1 mixture of saturated aqueous NH ₄ Cl and 28% aqueous NH ₄ OH (10 mL) and with brine (10 mL) the aqueous washes are back-extracted with CH ₂ Cl ₂ (2 x 15 mL). The combined organic extracts were dried over K ₂ CO ₃ , filtered, and concentrated to afford 115 mg of crude product which is purified by chromatography on silica gel (eluted with 2M NH ₃ in MeOH (2.5%) and CH ₂ Cl ₂ (97.5%), to give the desired compound.

Condition C:

To a stirred solution of alkynyl compound (0.10 mmol) and Hunig's base (0.2 mL) in 3 mL THF is added the azide compound (0.50 mmol) and CuI (20 mg, 0.10 mmol). The reaction mixture is stirred under argon for 60 hours then poured into saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ . The organic extracts are dried over Na ₂ SO ₄ , filtered, and concentrated to afford a crude residue which is purified by silica gel chromatography (eluted with 25:1:0.1 CH ₂ Cl ₂ :MeOH:NH4θH) and then by preparative TLC (elution with 25:1:0.1 CH ₂ Cl ₂ MeOH=NH ₄ OH) to afford the desired compound.

Condition D

A solution of alkynyl compound (0.15 mmol) and the azide compound (0.25 mmol) in 2.7 mL THF are thoroughly degassed by alternately evacuating the reaction vessel and purging with dry argon. CuI is then added (10 mg, 0.05 mmol) and the mixture is further degassed. The mixture is stirred under argon for 4h then concentrated in vacuo, dissolved in CH ₂ Cl ₂ (1 mL), and placed directly on a silica gel column. Elution with 2 molar (M) NH ₃ in MeOH (3%) and CH ₂ Cl ₂ (97%) gives the desired compound.

Akvnyl Macrolide Compounds

The alkynyl macrolide compounds that can be used in the synthesis of the compounds of the present invention are shown in the following Table 2. It is appreciated by one of skill in the art that these alkynyl macrolide compounds, M1 to M43, are non-limiting examples and that a wide variety of additional alkynyl macrolides can be used to prepare other compounds of the present invention. In particular, macrolide moieties, M2, M6, M7, M8, M15, M19, M26, M29, M30, M31, M32, M33, M34, M35, M36, M37, M38, M39, M40, M41, M42, and M43, are illustrative of various carbamate moieties.

M15

M16

M17

NH ₂

M18

M19

M20

M21

M22

M23

M24

M25

M26

M27

M28

Example 13.1 Synthesis of Alkynyl Macrolides

The alkynyl macrolide compounds, such as alkynyl macrolide compounds Ml to M43, are generally made by the alkynylation (i.e. the addition of an alkynyl group) to a monomethyl amine macrolide compound. The monomethyl amine macrolide is generally made by the desmethylation of the corresponding macrolide compound. Depending on the macrolide compound and functional groups present, the desmethylation process can involve several steps, including various protection and deprotection steps. The desmethyl macrolide compound is alkynylated with the corresponding alkynyl compound, which is generally an alkynyl halide, tosylate, or mesylate. For the compounds of the present invention, 4-bromo- 1-butyne, 4-iodo-1-butyne, or the tosylate or mesylate of l-butyn-4-ol are generally used. Examples of synthetic procedures for preparing alkynyl macrolides are found in PCT Application No. WO 2005/085266, published September 15, 2005, to Rib-X Pharmaceuticals, Inc. The following general reaction scheme outlines this alkynylation process.

Macrolide, Desmethyl Macrolide

R ³ is generally Methyl

Desmethyl Macrolide Alkynyl Macrolide

The following procedures outline the synthesis of various alkynyl macrolide compounds of the present invention.

Example 13.1a Synthesis of Alkynyl Macrolide Ml

Alkynyl macrolide M1 is made by selective demethylation of azithromycin 1 to produce 3'-N-desmethylazithromycin 2. This compound 2 is selectively alkylated with alkynyl tosylate 11 to produce alkynyl macrolide M1.

Synthesis of S'-N-desmethylazithromycin 2

Azithromycin 1 (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 (I ₂ ) (0.272 g, 1.07 mmol) in three batches within 3 minutes.

The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes. Stirring was continued for 2 hours. TLC (CH ₂ Cl ₂ /MeOH/NH ₄ OH 10:1 :0.05) after 2 hours showed a single major product (Rf= 0.66). The reaction was cooled to room temperature, poured into H ₂ O (75 mL) containing NH ₄ OH (1.5 mL) and extracted with CHCI ₃ (3 x 30 mL). The combined organic layers were washed with H ₂ O (30 mL) containing NH ₄ OH (1.5 mL), dried over Na ₂ SO ₄ and the solvent evaporated to give a white residue. The crude was purified on a silica gel column eluting with CH ₂ Cl ₂ /MeOH/NH ₄ OH 18:1:0.05 to 10:1:0.05 to provide compound 2 (0.41 g, 55%).

Synthesis of alkynyl macrolide M1

A mixture of 3'-N-desmethylazithromycin 2 and tosylate 11 in Hunig's base was stirred. The reaction mixture was diluted to EtOAc and washed with νaHCO ₃ (aq) and with brine. The organic layer was dried over K ₂ CO ₃ and the solvent was evaporated to give product. The crude product was purified on silica gel column to give Ml as a white solid.

Example 13.1b Synthesis of alkynyl macrolide M3.

Synthesis of β'-iV-desmethyl-clarithroinycin 21

To a mixture of clarithromycin (1.00 g, 1.3 mmol) and NaOAc ^» 3H ₂ 0 (0.885 g, 6.5 mmol) was added MeOH-H ₂ O (20 mL, 4:1), and the mixture heated to 55-60 °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 CHCl ₃ containing 1 mL ammonium hydroxide. It was extracted with CHCl ₃ (4 x 50 mL), washed with water (70 mL) containing 5 mL ammonium hydroxide, dried (anhydrous Na ₂ SO ₄ ), concentrated, and purified by flash chromatography (silica gel, CHCl ₃ MeO^NH ₄ OH 100:10:0.1) to afford 21. Yield: 0.9g (92%).

Synthesis of Alkynyl Macrolide M3

A mixture of S'-N-desmethyl-clarithromycin 21 and tosylate 11 in anhydrous THF and Hunig's base was stirred. The reaction was poured into CH ₂ Cl ₂ , extracted with 2% aqueous NH ₄ OH and saturated brine. The organic layer was dried over Na ₂ SO ₄ and the solvent was evaporated away. The crude was purified on a silica gel column to give M3.

Example 13.1c Synthesis of Alkvnyl Macrolide M14

Alkynyl macrolide M14 is made using a procedure analogous to that for making M3, starting from erythromycin A. The 3'-N-desmethyl-erythromycin A intermediate is made using a procedure described in U.S. Patent No. 3,725,385, to Freiberg, issued April 3, 1973. Alkynyl macrolide M14 can further be used to prepare a variety of macrolides analogous to those already depicted for the clarithromycin core.

A mixture of 3'-N-desmethyl-erythromycin (1.0 g, 1.4 mmol) and the tosylate of 1- butyn-4-ol (1.25 g, 5.6 mmol) in anhydrous THF (15 mL) and Hunig's base (2.2 mL, 11.9 mmol) was kept stirring at 55 °C for 48 hours. The reaction was poured into CH ₂ Cl ₂ (50 mL), extracted with 2% aqueous NH ₄ OH (3 x 30 mL) and saturated brine (1 x 30 mL). The organic layer was dried over Na ₂ SO ₄ and the solvent was evaporated away. The crude was purified on a silica gel column eluting with CH ₂ Cl ₂ /Me0H 10: 1 to give alkynyl macrolide 14 (0.35 g, 32%).

Example 13.1d Synthesis of Alkynyl Macrolides M4. M5. M9. MlO. Mil and M12

The synthesis of alkynyl macrolides M4, M9, M1O, Mil and M12 are depicted in the scheme below. Alkynyl macrolide M9 is prepared from the removal of the cladinose sugar of alkynyl macrolide M3 under acidic conditions. Alkynyl macrolide M1O is made by the acetylation of macrolide M9. Macrolide M4 is made by the oxidation of the hydroxyl group of macrolide M1O. Alkynyl macrolides Mil and M12 are made by converting a keto group of alkynyl macrolide M4 to the desired oximes. The oxime functionality of alkynyl macrolides of precursors with substituted oxime functionality at the 9-position of the macrocyclic ring were prepared from alkyne M3 and as shown below.

Synthesis of alkynyl macrolide M9

To the alkynyl macrolide M3 (0.700 g) was added 10 mL 0.9N 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 NH ₄ OH solution. The solution was extracted with ethyl acetate (3 x 30 mL), dried (with Na ₂ SO ₄ ), 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 alkynyl macrolide M9. Data for M9: ¹ HNMR (300 MHz, CDCl ₃ , 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).

Synthesis of Alkynyl Macrolide M5

A solution of alkynyl macrolide M4 (Ig, 1.5 mmol) in MeOH (30 mL) was refluxed for 12h. The solution was concentrated and the crude material was purified by flash chromatography over silica gel (50% ethyl acetate in hexane). Yield: 0.5g of M5 (53%).

Synthesis of alkynyl macrolide M1O

To a solution of alkynyl macrolide M9 (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 Na ₂ SO ₄ ), 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 functionalized alkynyl macrolide M1O. Data for M1O: ¹ HNMR(SOO MHz, CDCl ₃ , 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).

Synthesis of alkynyl macrolide M4

To a solution of alkynyl macrolide M1O (0.090 g, 0.134 mmol), EDCηC1 (0.172 g, 0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH ₂ Cl ₂ (1.5 mL) was added dropwise a solution of pyridinium trifluoroacetate (0.174 g, 0.90 mmol) in CH ₂ Cl ₂ (1 mL) at 15 ⁰ 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 CHCl ₃ (50 mL), and the organic layer was washed with water (2 x 50 mL), dried (over anhydrous Na ₂ SO ₄ ), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.07Og (78%) of the alkynyl macrolide M4 (also commonly referred to as a ketolide). Data for M4:M4 MS (ESI) m/e 668 (M+H) ⁺ ; ¹ HNMR (300 MHz, CDCl ₃ , 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).

Synthesis of alkynyl macrolide M11

To a solution of M4 (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 rt for 14h. The mixture was then poured into (50 mL) and water (50 mL) the pH was adjusted to 11 by addition OfNH ₄ OH and the organic layer was separated and washed with brine (50 mL), dried (over anhydrous Na ₂ SO ₄ ), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 12:1 CH ₂ Cl ₂ and 2M methanolic ammonia) to yield 2g (78%) of the oxime functionalized alkynyl macrolide Mil as a 1:1 mixture of E/Z isomers. Data for Mil: MS (ESI) m/e 724.7 (M+H) ⁺ .

Synthesis of Alkynyl Macrolide M12

Alkynyl macrolide M12 was synthesized from alkynyl macrolide M4 and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of alkynyl macrolide Mil. Data for M12: MS (ESI) m/e 710.6 (M+H) ⁺ .

Example 13.1e Synthesis of Alkvnyl Macrolides M13. M16. M17. and M18

Alkynyl macrolides M13, M16, and M17 are also synthesized from alkynyl macrolide M4 . Alkynyl macrolide M18 is synthesized from alkynyl macrolide M17. The syntheses are outlined in the following reaction scheme.

Synthesis of alkynyl macrolide M13

Alkynyl macrolide Ml 3 was synthesized from alkynyl macrolide M4 and N-[2- dimethtylaminoethyl]-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M13: MS (ESI) m/e 726.5 (M+H) ⁺ .

Synthesis of alkynyl macrolide M16

Alkynyl macrolide Ml 6 was synthesized from alkyne M4 and N-Piperidin-4-yl- hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M16: MS (ESI) m/e 724.6 (M+H) ⁺ .

Synthesis of alkynyl macrolide M17

Alkynyl macrolide Ml 7 was synthesized from alkyne M4 and cis-4- aminocylcohexyl-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M17: MS (ESI) m/e 738.7 (M+H) ⁺ .

Synthesis of alkynyl macrolide M18

To a solution of alkynyl macrolide M17 (20 mg, 0.02 mmol) in CHCl ₃ (0.2 mL) was added formaldehyde (5 mg of 37% aqueous solution, 0.06 mmol) and formic acid (6 mg, 0.12 mmol). The mixture was heated at 50 °C in a sealed tube for 12h. The reaction mixture was partitioned between aqueous NaHCO ₃ (10 mL) and chloroform (10 mL) the organic fraction was dried on K ₂ CO ₃ , filtered and concentrated to give alkynyl macrolide M18 as a white solid (18 mg). Data for M18: MS (ESI) m/e 766.7 (M+H) ⁺ .

Example 13. If Synthesis of Alkynyl Macrolide M15 Telithromycin was selectively N-demethylated and then alkylated with the tosylate of l-butyn-4-ol as described for azithromycin, erythromycin and clarithromycin above.

Synthesis of 3'-iV-Desmethyl telithromycin 30

To a solution of telithromycin 29 (3.0 g, 3.60 mmol) in anhydrous acetonitrile (70 mL) was added ν-iodosuccinimide (νIS) (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. CH ₂ Cl ₂ (250 mL) and 5 % Na ₂ S ₂ O ₃ (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na ₂ S ₂ O ₃ (1 X 80 mL), dilute NH ₄ Cl (1 X 80 mL) and dried over Na ₂ SO ₄ . Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 8 % methanolic ammonia (2N NH ₃ ) in CH ₂ Cl ₂ to give compound 30 as white solid (1.95 g, 68 %). MS (ESI) M/E; M+H ⁺ 798.6.

Scheme 105 Synthesis of alkynyl macrolide M15.

Synthesis of 3'-iV-(but-3-ynyl) telithromycin, M15

Protocol A: A mixture of amine 30 (0.66 g, 0.83 mmol) and tosylate 11 (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 IN HCl (50 mL) and kept stirring at room temperature for about Ih. CH ₂ Cl ₂ (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 X 30 mL) and basified with NaOH (IN) to form a whitish-suspension. The suspension was extracted with CH ₂ Cl ₂ (3 X 30 mL) and the organic layer was dried over Na ₂ SO ₄ . Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 6 % methanolic ammonia (2N NH ₃ ) in CH ₂ Cl ₂ to give compound M15 as white solid (0.12 g, 17 %). MS (ESI) m/e 850.8 (M+H) ⁺ .

Synthesis of 3'-iV-(but-3-ynyl) telithromycin, M15

Protocol B: A mixture of amine 30 (0.66 g, 0.83 mmol), and tosylate 11 (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 1.5 h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in IN HCl (60 mL) and kept stirring at room temperature for about 2h. CH ₂ Cl ₂ (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 X 30 mL) and basified with 50 % KOH to form a whitish-suspension. The suspension was extracted with CH ₂ Cl ₂ (3 X 30 mL) and the organic layer was dried over Na ₂ SO ₄ . The solvent was evaporated and the crude was purified by preparative TLC (2000 micron plate) eluting with CH ₂ Cl ₂ /methanolic ammonia (2N NH ₃ ) 12:1 to give compound M15 as white solid (0.19 g, 27 %). MS (ESI) m/e 850.8 (M+H) ⁺ .

Example 13.1g Synthesis of Alkvnyl Macrolide M19.

Desmethyl telithromycin 30 was treated according to the procedures of US Patent No. 6,124,269 to afford the 2-fluoro amine 30a. This was then alkylated with the tosylate of 1- butyn-4-ol under the conditions for making M15 to afford the fluorinated alkynyl macrolide M19. The reactions are outlined in the following scheme.

Example 13.1h Synthesis of Alkynyl Macrolides M20, M21, M22, and M23

Alkynyl macrolides M21, M22, and M23 are prepared according to the following reaction scheme from alkynyl macrolide M20. Alkynyl macrolide M20 is in turn made from alkynyl macrolide M14.

Synthesis of alkynyl macrolide M20 To a mixture of alkynyl macrolide M14 (Ig, 1.3 mmol) and hydroxylamine hydrochloride (0.4g, 6.4 mmol) was added methanol (15 mL) and triethylamine (3.2 mmol). The solution was refluxed for 72h. Cooled to ambient temperature, poured into water (50 mL) and adjusted pH to 11. The resulting solution was extracted with dichloromethane (4x 50 mL), dried and concentrated. The crude material was purified by flash chromatography over silica gel to yield M20 (C ₂ C1 ₂ :2N NH ₃ -MeOH = 10:1). Yield: 0.6g (60%).

M14 M20

Synthesis of Alkynyl Macrolide M21

To a solution of alkynyl macrolide M20 (2.00 g, 2.54 mmol) in THF (17 mL) at 0 °C was added Et ₃ N (1.50 mL, 10.67 mmol), followed by addition of acetic anhydride (946 μL, 9.91 mmol), then, DMAP (34 mg, 0.25 mmol). The mixture was stirred at 0 °C for 3h, then, Et ₃ N (15 OμL, 1.07 mmol) and acetic anhydride (95 μL, 0.99 mmol) were added. The mixture was stirred for 3h, then, MeOH (2.0 ml) was added. The reaction mixture was concentrated and EtOAc (100 mL) was added, washed with saturated NaHCO ₃ (30.0 mL), then, brine (30.0 mL), dried with Na ₂ SO ₄ , gave 2.28g of alkynyl macrolide M21. The residue was used for the next step without further purification. MS (ESI) m/e 913 (M + H) ⁺ .

Synthesis of Alkynyl Macrolide M22

To a solution of triacetate alkynyl M21 (913 mg, 1.00 mmol, crude), 2-methylene- 1,3-propane-[bis-(tert-butyl)carbonate] (865 mg, 3.00 mmol) and 1,4- bis(diphenylphosphino)-butane (dppb) (305 mg, 0.70 mmol) in THF (10 mL, degassed) was added Pd ₂ (dba) ₃ (92 mg, 0.10 mmol) at room temperature. The mixture was refluxed for 12h , then, the reaction mixture was concentrated and EtOAc (100 mL) was added. Washed with saturated NaHCO ₃ (30 mL), brine (30 mL), dried with Na ₂ SO ₄ , The residue was isolated by silica gel chromatography (CH ₂ Cl ₂ to 2% MeOH in CH ₂ Cl ₂ containing 0.2% NH ₄ OH), gave 340 mg of alkynyl macrolide M22 in 35% yield for two steps. MS (ESI) m/e 966 (M + H) ⁺ .

Synthesis of Alkynyl Macrolide M23

Alkynyl macrolide M22 (330 mg, 0.34 mmol) in MeOH (6 mL), was refluxed for 5 days. The residue was isolated by FC (CH ₂ Cl ₂ to 2% MeOH in CH ₂ Cl ₂ containing 0.2% NH ₄ OH), gave 143 mg of alkynyl macrolide M23 in 50% yield.

MS (ESI) m/e 839 (M + H) ⁴

Example 13. Ii Synthesis of Alkynyl Macrolide M24

To a solution of alkynyl macrolide M4 (6.4g, 9.6 mmol) in pyridine (25 mL) was added methanesulfonic anhydride (4.Og, 22.9 mmol) at 10 ⁰ C. The reaction was stirred at ambient temperature for 24h. The solution was concentrated and portioned between ethyl acetate (150 mL) and saturated NaHCO ₃ solution (150 mL). Organic layer was separated and the aqueous layer was back extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (2 x 150 mL), dried and concentrated. The crude material was purified by flash chromatography over silica gel (50% ethyl acetate in hexane) to give 5.9g of M24 (83%).

Example 13. Ii Synthesis of Alkynyl Macrolide M25

To a solution of alkynyl macrolide M24 (5.9 g, 7.9 mmol) in acetone (25 mL) was added diazabicycloundecene (DBU) (1.4 mL, 9.5 mmol) at ambient temperature. After stirring for 48h, the reaction was diluted with methylene chloride, washed with water, dried and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (40% ethyl acetate in hexanes). Yield 3.6 g M25 (70%).

Example 13.1k Synthesis of Alkvnyl Macrolide M26

To a solution of M25 (3.3 g, 5.0 mmol) in methylene chloride (30 mL) was added DBU (1.0 mL, 6.5 mmol) at O ⁰ C. Then was added carbonyldiimidazole (l.Og, 6.1 mmol) at once. After stirring for 3h, the reaction was diluted with methylene chloride, washed with water, dried and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (70% ethyl acetate in hexanes). Yield 3.4 g M26 (89%).

Example 13.11 Synthesis of Alkvnyl Macrolide M27

Alkynyl macrolide M27 is made from alkynyl macrolide M23 by reduction of the oxime to the imine followed by acetylation of the compound, which is then oxidized to give the bridged ketone. The cladinose sugar is then hydrolyzed by treatment with dilute hydrochloric acid.

Example 13.1m Synthesis of Alkynyl Macrolide M28

Alkynyl macrolide M28 is made by refluxing alkynyl macrolide M27 with the following hydroxyl amine compound in methanol.

Example 13. In Synthesis of Alkynyl Macrolide M2

A mixture of M26 (1.48 g, 2.0 mmol) and hydrazine (0.65 mL, 20 mmol) in acetonitrile (40 mL) and water (6 mL) was heated to 50 ⁰ C. After 5h the solution was concentrated and refluxed with MeOH (100 mL) for 2Oh. The solution was concentrated and the crude material was purified by flash chromatography over silica gel (60% ethyl acetate in hexane). Yield: 0.8g M2 (60%).

Example 13.1o Synthesis of Alkynyl Macrolides M6, M7, and M8

Alkynyl macrolides M6, M7, and M8 are made from M26 (using a procedure analogous to that for making M2, in which the hydrazine is replaced with methyl amine, ammonium hydroxide, and ethanol amine respectively.

Example 13.1p Synthesis of Alkynyl Macrolides M29, M30, M31, and M32

Alkynyl macrolides such as M29, M30, M31, and M32 are made from M26 using the following general procedure and the corresponding diamino compound. For compound M29, to a solution of compound M26 (6.25g, 6.6 mmol) in CH ₃ CN

(35 mL) was added ethylene diamine (4.5 mL, 66.0 mmol) and stirred for 16h. The solution was evaporated to dryness under reduced pressure. The crude product was dissolved in anhydrous EtOH (50 mL). Then acetic acid (AcOH, 1.1 mL, 3.0 mmol) was added and heated to 65 ⁰ C for 30h. The solution was cooled and IN LiOH was added and heated to 50 ⁰ C for 5h. The solution was partitioned between ethyl acetate (150 mL) and brine (150 mL). Organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was concentrated and the crude material was purified by flash chromatography over silica gel (EtOAc: Heptane: TEA - 35:55:10) to yield 4.5g (81%) of the compound product M29. Compounds M30, M31, and M32 are made using the foregoing procedure using cis-

3,4-diamino tetrahydrofuran, cis-1,2-diaminocyclohexane, and 1,2-diamino-2-methylpropane

(i.e. 1,1 -dimethyl ethylenediamine), respectively. Other compounds analogous to compounds M29, M30, M31 and, M32 can be made by selecting other diamino compounds.

The following is a further scheme showing a synthesis that can be followed to prepare compounds of the present invention, e.g., Compound 252, from starting compounds such as compound 1, see, M. Kshimura et al., "Synthesis and Antibacterial Activity of the Tricyclic Kektolides TE-802 and Its Analogs", The Journal of antibiotics, vol 54, no. 8, pp. 664-678, August 2001.

Example 14: 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.

Scheme 14.1 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 * 30 mL), dried (Na ₂ SO ₄ ), 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 H ₂ O (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 H ₂ O (30 mL), extracted with dichloromethane (30 mL) and evaporated. Flash chromatography (SiO ₂ , 50-100% ethyl acetate/hexanes) provided the flofenicol azide (0.65 g, 2.4 mmol) as a yellow solid.

Scheme 14.2 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 H ₂ O (5 mL) and methanol (17 mL) was treated with triethylamine (0.84 mL, 6.0 mmol) and trifiuoromethanesulfonyl 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 H ₂ O (30 mL), extracted with dichloromethane (30 mL) and evaporated. Flash chromatography (SiO ₂ , 50-100% ethyl acetate/hexanes) provided the azide (0.28 g, 1.2 mmol) as a yellow solid.

Scheme 14.3 for preparing an azide compound

Azide compound

To a stirred 0 °C solution of 4-nitrophenylalanine (4.6g, 20 mmol) and NaBH ₄ (3.2g, 84 mmol) in THF (50 mL) was added BF ₃ 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 14h. The reaction mixture was diluted with dichloromethane (30 mL) washed with saturated NaHCO ₃ , and with brine. The organic extract was dried, filtered and concentrated to give the azide compound as a white solid (150 mg).

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.

Schemes 14.4a-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 (SiO ₂ , 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 (SiO ₂ , 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 (Na ₂ SO ₄ ), 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 (SiO ₂ , 10% ethyl acetate/dichloromethane) to afford the azide (60 mg, 0.23 mmol) as a colorless oil.

Scheme 14.7 for fluorinating an azide compound

The fluoro azide compound was prepared from the azide compound as shown.

azide compound fluorinated azide compound

To a stirred -78 °C solution of azide compound (111 mg, 0.5 mmol) in CH ₂ Cl ₂ 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 rt and stirred for 14h. The reaction mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic extracts were dried, filtered, and concentrated to give the fluorinated azide compound as a solid (36 mg, 0.16 mmol).

Scheme 14.6 for oxidizing a thioether chain in an azide compound

Thioether Sulfone

To a solution of the thioether (0.27 g, 1.1 mmol) in CH ₂ Cl ₂ (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 CH ₂ Cl ₂ /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 15: 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.

p

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. R ^a , R ^b , R ^c , and R ^d represent various alkyl, substituted alkyl, aryl, and substituted aryl groups.

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

R*. R", R ^c , and R ^d 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 2A exemplifies azide compounds useful in the synthesis of compounds of the present invention.

Example 17 further exemplifies methods for making compounds of the present invention.

Example 16 Synthesis of Compound 222

To a mixture of tributyl tin pyrazine (920 mg, 2.5 mmol), l-(2-azido-3-fluoro-1- methoxy-propyl)-4-iodo-benzene (900 mg, 2.6 mmol), Pd (Ph ₃ P) ₄ (290 mg, 0.25 mmol), CuI (95.5 mg, 0.5 mmol) and C ₈ F (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 Na ₂ SO ₄ , concentrated and purified by preparative TLC (50% ethyl acetate-heptane) to provide the indicated pyrazine azide compound. Yield: 500 mg (70%).

222

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 MgSO ₄ , 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 02Jl 016) and Streptococcus pyogenes (wild type strain SS 1542) using a standard microdilution assay to determine minimum inhibitory concentrations (MIC ₈ ). 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.

Streptococcus Streptococcus pneumoniae pyogenes

200 + + 201 + + 202 + + 203 + N/A 204 + N/A 205 + + 206 + + 207 + + 208 + + 209 + + 210 + + 211 + + 212 + + 213 + + 214 + + 215 + + 216 + + 217 + + 218 + + 219 + + 220 + + 221 + + 222 + + 223 + + 224 + + 225 + + 226 + + 227 + + 228 + + 229 + + 230 + + 231 + + 232 + + 233 + + 234 + + 235 + + 236 + + 237 + + 238 + + 239 + + 240 + + 241 + + 242 + + 243 + + 244 + + 245 + + 246 + +

247 + + 248 + + 249 + + 250 + + 251 + + 252 + + 253 + + 254 + + 255 + + 256 + + 257 + + 258 + + 259 + + 260 + + 261 + + 262 + + 263 + + 264 + + 265 + + 266 + + 267 + + 268 + + 269 + + 270 + + 271 + + 272 + + 273 + + 274 + + 275 + + 276 + + 277 + + 278 + + 279 + + 280 + + 281 + + 282 + + 283 + + 284 + + 285 + + 286 + + 287 + + 288 + + 289 + + 290 + + 291 + + 292 + + 293 + + 294 + + 295 + + 296 + + 297 + + 298 + + 299 + + 300 + +

301 + + 302 + + 303 + + 304 + + 305 + + 306 + + 307 + + 308 + + 309 + + 310 + + 311 + + 312 + + 313 + + 314 + + 315 + + 316 + + 317 + + 318 + + 319 + + 320 + + 321 + + 322 + + 323 + + 324 + + 325 + + 326 + + 327 + + 328 + + 329 + + 330 + + 331 + + 332 + + 333 + + 334 + + 335 + + 336 + + 337 + + 338 + + 339 + + 340 + + 341 + + 342 + + 343 + + 344 345 + + 346 + + 347 + + 348 + + 349 + + 350 + + 351 + + 352 + + 353 + + 354 + +

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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.