Patent Description:
For six decades, antibiotics have been a bulwark against bacterial infectious diseases. This bulwark is failing due to the appearance of resistant bacterial strains. For all major bacterial pathogens, strains resistant to at least one current antibiotic have arisen. For several bacterial pathogens, including tuberculosis, strains resistant to all current antibiotics have arisen.

Bacterial RNA polymerase (RNAP) is a proven target for antibacterial therapy (<NPL>; <NPL>; <NPL>; <NPL>; and <NPL>). The suitability of bacterial RNAP as a target for antibacterial therapy follows from the fact that bacterial RNAP is an essential enzyme (permitting efficacy), the fact that bacterial RNAP subunit sequences are highly conserved (permitting broad-spectrum activity), and the fact that bacterial RNAP-subunit sequences are highly conserved in human RNAP I, RNAP II, and RNAP III (permitting therapeutic selectivity).

The rifamycin antibacterial agents function by binding to and inhibiting bacterial RNAP (<NPL>; <NPL>; <NPL>; and <NPL>). The rifamycins bind to a site on bacterial RNAP adjacent to the RNAP active center and prevent extension of RNA chains beyond a length of <NUM>-<NUM> nt. The rifamycins are in current clinical use in treatment of both Gram-positive and Gram-negative bacterial infections. The rifamycins are of particular importance in treatment of tuberculosis; the rifamycins are first-line anti-tuberculosis agents and are among the few antituberculosis agents able to kill non-replicating tuberculosis bacteria.

The clinical utility of the rifamycin antibacterial agents is threatened by the existence of bacterial strains resistant to rifamycins (<NPL>; <NPL>; <NPL>; and <NPL>). Resistance to rifamycins typically involves substitution of residues in or immediately adjacent to the rifamycin binding site on bacterial RNAP--i.e., substitutions that directly decrease binding of rifamycins.

In view of the public-health threat posed by rifamycin-resistant and multidrug-resistant bacterial infections, there is an urgent need for new antibacterial agents that (i) inhibit bacterial RNAP (and thus have the same biochemical effects as rifamycins), but that (ii) inhibit bacterial RNAP through binding sites that do not overlap the rifamycin binding site (and thus do not share cross-resistance with rifamycins.

A new drug target--the "switch region"--within the structure of bacterial RNAP has been identified (<CIT>; <NPL>; see also <NPL>; <NPL>; <NPL>). The switch region is a structural element that mediates conformational changes required for RNAP to bind and retain the DNA template in transcription. The switch region is located at the base of the RNAP active-center cleft and serves as the hinge that mediates opening of the active-center cleft to permit DNA binding and that mediates closing of the active-center cleft to permit DNA retention. The switch region can serve as a binding site for compounds that inhibit bacterial gene expression and kill bacteria. Since the switch region is highly conserved in bacterial species, compounds that bind to the switch region are active against a broad spectrum of bacterial species. Since the switch region does not overlap the rifamycin binding site, compounds that bind to the switch region are not cross-resistant with rifamycins.

It has been shown that the α-pyrone antibiotic myxopyronin (Myx) functions through interactions with the bacterial RNAP switch region (<CIT>; <NPL>; see also <NPL>; <NPL>; <NPL>). Myx binds to the RNAP switch region, traps the RNAP switch region in a single conformational state, and interferes with formation of a catalytically competent transcription initiation complex. Amino acid substitutions within RNAP that confer resistance to Myx occur only within the RNAP switch region. There is no overlap between amino acid substitutions that confer resistance to Myx and amino acid substitutions that confer resistance to rifamycins and, accordingly, there is no cross-resistance between Myx and rifamycins.

A crystal structure of a non-pathogenic bacterial RNAP, Thermus thermophilus RNAP, in complex with Myx has been determined, and homology models of pathogenic bacterial RNAP, including Mycobacterium tuberculosis RNAP and Staphylococcus aureus RNAP, in complex with Myx have been constructed (<CIT>; <NPL>; see also <NPL>; <NPL>; <NPL>). The crystal structure and homology models define interactions between RNAP and Myx and can be used to understand the roles of the "west" and "east" Myx sidechains as well as the Myx α-pyrone core.

<CIT>,<CIT>,<CIT> and<CIT> relate to pyronin compounds that are reported to possess antibacterial activity. There remains a need for pyronin antibacterial compounds that possess improved metabolic stability, improved in vivo pharmacokinetics, improved in vitro antibacterial activity, and/or improved in vivo antibacterial efficacy.

The invention provides new compositions of matter that inhibit bacterial RNA polymerase and inhibit bacterial growth. The compounds are anticipated to have applications in analysis of RNA polymerase structure and function, control of bacterial gene expression, control of bacterial growth, antibacterial prophylaxis, antibacterial therapy, and drug discovery.

The invention provides new compositions of matter that inhibit bacterial RNA polymerase and inhibit bacterial growth.

Compounds of this invention are structurally related to previously disclosed pyronins with RNA-polymerase-inhibitory and antibacterial activities.

Compounds of this invention differ from previously disclosed pyronins with RNA-polymerase-inhibitory and antibacterial activities by deuteration of the enecarbamate O-alkyl group.

Applicant has discovered--surprisingly--that deuteration of Cβ of the enecarbamate O-alkyl group improves metabolic stability, in vivo bioavailbility, in vitro antibacterial efficacy, and in vivo antibacterial efficacy.

Certain compounds of this invention exhibit higher metabolic stabilities than the corresponding non-deuterated pyronins.

Certain compounds of this invention exhibit superior in vivo pharmacokinetics than the corresponding non-deuterated pyronins.

Certain compounds of this invention exhibit superior in vitro antibacterial efficacies than the corresponding non-deuterated pyronins.

Certain compounds of this invention exhibit superior in vivo antibacterial efficacies than the corresponding non-deuterated pyronins.

An object of this invention is to provide antibacterial compounds that possess one or more of the following: <NUM>) improved metabolic stability, <NUM>) in vivo pharmacokinetics, <NUM>) improved in vitro antibacterial efficacy, and <NUM>) improved in vivo antibacterial efficacy.

The compounds of the invention have utility as inhibitors of bacterial RNAP.

The salts of the invention also have utility as inhibitors of bacterial growth.

A particular object of this invention is to provide compounds and pharmaceutical compositions that have utility in the treatment of bacterial infection in a mammal.

Accordingly, in one embodiment the invention provides a compound of of formula Ia" or Id" as defined in claim <NUM> and described in more detail below. The invention also provides a compound of formula Ia" or Id", or a pharmaceutically acceptable salt thereof for use in medical treatment.

The invention also provides a compound of formula Ia" or Id", or a pharmaceutically acceptable salt thereof for use in the prophylaxis or treatment of a bacterial infection.

The invention also provides a composition suitable for intravenous administration, comprising a compound of formula Ia" or Id", or a pharmaceutically acceptable salt thereof, and water, wherein the composition is free of co-solvents and surfactants.

The invention also provides the use of a compound of the invention as an inhibitor of a bacterial RNA polymerase.

The invention also provides the use of a compound of the invention as an antibacterial agent.

The invention also provides the use of a compound of the invention as a disinfectant, a sterilant, an antispoilant, an antiseptic, or an antiinfective.

The invention also provides the use of a compound of of formula Ia" or Id", or a pharmaceutically acceptable salt thereof for the preparation of a medicament for prophylaxis or treatment of a bacterial infection in a mammal.

The invention also provides a method of inhibiting a bacterial RNA polymerase, comprising contacting a bacterial RNA polymerase with a compound of the invention.

The invention also provides a method of treating a bacterial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of of formula Ia" or Id", or a pharmaceutically acceptable salt thereof.

The following definitions are used, unless otherwise indicated.

The term "halo" means fluoro, chloro, bromo, or iodo.

The term "alkyl" used alone or as part of a larger moiety, includes both straight and branched chains. For example, C<NUM>-C<NUM> alkyl includes both straight and branched chained alkyl groups having from one to ten carbon atoms. The term alkyl also includes cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopently, cyclohexyl, cycloheptyl, and cyclooctyl), as well as (cycloalkyl)alkyl groups (e.g. <NUM>-cyclohexylpropyl, cyclopentylmethyl, <NUM>-cyclohexylethyl, and <NUM>-cyclopropylethyl).

The term "alkenyl" used alone or as part of a larger moiety, includes an alkyl that has one or more double bonds. For example, C<NUM>-C<NUM> alkenyl includes both straight and branched chained groups having from two to ten carbon atoms and one or more (e.g. <NUM>, <NUM>, or <NUM>) double bonds, as well as (cycloalkyl)alkyl groups having one or more double bonds in the cycloalkyl portion or in the alkyl portion of the (cycloalkyl)alkyl.

The term "alkoxy" used alone or as part of a larger moiety is a group alkyl-O-, wherein alkyl has any of the values defined herein.

The term "aryl" denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. For example, aryl can be phenyl, indenyl, or naphthyl.

The term "heteroaryl" encompasses a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (C<NUM>-C<NUM>)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms comprising one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X). For example heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).

The term "heterocycle" or "heterocyclyl" ring as used herein refers to a ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. The ring can be saturated, partially unsaturated, or aromatic. The term includes single (e.g., monocyclic) saturated, partially unsaturated, and aromatic rings (e.g., <NUM>, <NUM>, <NUM>, <NUM> or <NUM>-membered rings) from about <NUM> to <NUM> carbon atoms and from about <NUM> to <NUM> heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. In one embodiment the term includes <NUM>-<NUM> membered saturated, partially unsaturated, and aromatic heterocycles that include <NUM>-<NUM> carbon atoms and <NUM>-<NUM> heteroatoms.

A bond designated <IMG> herein represents a double bond that can optionally be cis, trans, or a mixture thereof.

A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure (i.e., the R and S configurations for each asymmetric center). Therefore, single stereochemical isomers, as well as enantiomeric and diastereomeric mixtures, of the present compounds are within the scope of the invention. Similarly, E- and Z-isomers, or mixtures thereof, of olefins within the structures also are within the scope of the invention.

It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (<NUM>H or D). As a non-limiting example, a -CH<NUM> group may be substituted with -CD<NUM>. When a compound is shown or named as containing a specific isotope, it is understood that the compound is enriched in that isotope above the natural abundance of that isotope. In one embodiment the compound may be enriched by at least <NUM>-times the natural abundance of that isotope. In one embodiment the compound may be enriched by at least <NUM>-times the natural abundance of that isotope. In one embodiment the compound may be enriched by at least <NUM>-times the natural abundance of that isotope. In one embodiment the compound may be enriched by at least <NUM>-times the natural abundance of that isotope.

Compounds of this invention may exist in tautomeric forms, such as keto-enol tautomers. The depiction of a single tautomer is understood to represent the compound in all of its tautomeric forms.

The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.

The term "pharmaceutically acceptable cation" includes sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Particularly acceptable cations are the monovalent catins, including sodium, potassium, lithium, and ammonium, and the like. The term pharmaceutically acceptable cation" also includes cations formed by protonation or alkylation of a pharmaceutically acceptable organic nontoxic bases such as primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. For example, the term "pharmaceutically acceptable cation" includes cations formed from unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(<NUM>-OH-(C<NUM>-C<NUM>)-alkylamine), such as N,N-dimethyl-N-(<NUM>-hydroxyethyl)amine or tri-(<NUM>-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

The invention provides new compositions of matter that highly potently inhibit bacterial RNA polymerase and inhibit bacterial growth. Certain compounds of this invention exhibit potencies higher than the potencies of the natural products myxopyronin A and B and of other known analogs of myxopyronin A and B.

An assay for inhibition of a RNA polymerase comprises contacting a bacterial RNA polymerase with a compound according to general structural formula (Ia''), or (Id").

An assay for antibacterial activity comprises contacting a bacterial RNA polymerase with a compound according to general structural formula (Ia"), or (Id").

A compound according to general structural formula (Ia"), or (Id'') may be used as an inhibitor of a bacterial RNA polymerase.

A compound according to general structural formula (Ia"), or (Id'') may be used as an antibacterial agent.

A compound according to general structural formula (Ia"), or (Id'') may be used as one of a disinfectant, a sterilant, an antispoilant, an antiseptic, or an antiinfective.

The invention relates to a compound of formula Ia" or a compound of formula Id". <CHM>
<CHM>
or a salt thereof, wherein:
each bond designated <IMG> represents a double bond that can optionally be cis, trans, or a mixture thereof.

In a certain embodiment, the invention provides a compound of formula Ia'', or a salt thereof.

In a certain embodiment, the invention provides a compound of formula Id'', or a salt thereof.

In a certain embodiment, R<NUM> is methyl.

In a certain embodiment, R<NUM> is methyl and the compound, or a salt thereof, is a mixture of the R and S stereoisomers.

In a certain embodiment, R<NUM> is methyl and the compound, or a salt thereof, is predominantly the R stereoisomer, preferably at least <NUM>% of the R isomer.

In a certain embodiment, the compound has formula Ia' or Id':
<CHM>
<CHM>
wherein Y is a pharmaceutically acceptable counter ion.

In a certain embodiment, R<NUM> is methyl that is enriched in deuterium by at least <NUM>-times the natural abundance of deuterium.

In a certain embodiment, the compound is selected from
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
and
<CHM>.

In a certain embodiment, the compound is:
<CHM>.

In a certain embodiment, the invention provides a composition that is suitable for intravenous administration. In a certain embodiment, the pharmaceutically acceptable carrier is water. In a certain embodiment, the composition is substantially free of co-solvents and surfactants. In a certain embodiment, the composition is substantially free of organic co-solvents.

In a certain embodiment, R<NUM> is not a cation (e.g. a pharmaceutically acceptable cation).

Ene-ester-containing precursors for synthesis of the O-alkyl-deuterated compounds of Formulae Ia" or Id" can be prepared, for example, as described for synthesis of the corresponding non-O-alkyl-deuterated pyronins in <CIT>, <CIT>,<CIT> and <CIT>, as in Scheme <NUM>, and as in the Examples.

Starting from said ene-ester-containing precursors, the O-alkyl-deuterated compounds of Formulae Ia" or Id" can be prepared, for example, by converting the ene-ester by into an acyl azide, followed by Curtius rearrangement to yield the isocyanate, followed by addition of deuterated methanol, as in Scheme <NUM> and as in the Examples.

Starting from the resulting O-alkyl-deuterated "free acids" of Formulae Ia" or Id" in which R<NUM> = OH, the corresponding "salts" of Formulae Ia" or Id" in which O-M+, where M+ is a pharmaceutically acceptable cation, can be prepared by contacting with an aqueous solution at a pH of at least about <NUM>-<NUM>, and preferably at least about <NUM>-<NUM>, until solids are dissolved, followed by reversed-phase sold-phase extraction or reversed-phase chromatography, for example, as in the Examples.

The compounds of Formulae Ia" or Id" may be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration (i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes).

Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least <NUM>% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about <NUM> to about <NUM>% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see <CIT>), <CIT>),<CIT>) and <CIT>).

Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see <CIT>.

The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

The compound is conveniently formulated in unit dosage form; for example, containing <NUM> to <NUM>, conveniently <NUM> to <NUM>, most conveniently, <NUM> to <NUM> of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

The following illustrate representative preferred pharmaceutical dosage forms, containing a compound of formula Ia", or Id", or a pharmaceutically acceptable salt thereof, for therapeutic or prophylactic use in humans:.

The invention will now be illustrated by the following non-limiting Examples.

<NUM>-Fluorophenol (Sigma-Aldrich; <NUM>; <NUM> mmol), ethyl <NUM>-bromo-<NUM>-methylthiazole-<NUM>-carboxylate (Ark Pharm; <NUM>; <NUM> mmol), and cesium carbonate (Sigma-Aldrich; <NUM>; <NUM> mmol) were thoroughly mixed in <NUM> anhydrous dimethylsulfoxide, and the resulting slurry stirred vigorously <NUM> at <NUM>. After cooling to <NUM>, the reaction mixture was poured into <NUM> water. Organics were extracted with 4x100 ml ether, and the pooled extracts were washed with <NUM> water, washed with <NUM> brine, dried over anhydrous sodium sulfate, filtered, and concentrated to <NUM> brown solid. NMR showed the desired product, ethyl <NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazole-<NUM>-carboxylate, which was used in the next step without further purification. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (q, <NUM>),) <NUM> (s, <NUM>), <NUM> (t, <NUM>).

Ethyl <NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazole-<NUM>-carboxylate (Example <NUM>; <NUM>; <NUM> mmol) was dissolved in <NUM> anhydrous tetrahydrofuran and cooled to -<NUM>. DIBAH (Sigma-Aldrich; <NUM> <NUM> in hexanes; <NUM> mmol) was added over <NUM>, and the reaction mixture was allowed to stir <NUM> at -<NUM> and <NUM> at <NUM>. The reaction was quenched by dropwise addition of <NUM> water, dropwise addition of <NUM> <NUM>% NaOH, addition of ~<NUM> anhydrous magnesium sulfate, and addition of <NUM> dichloromethane, and then was stirred vigorously <NUM> at <NUM>. The suspension was filtered, and the retentate was washed with <NUM> dichloromethane and filtered. The pooled filtrates were evaporated, and the product was isolated via silica chromatography ethyl acetate/hexanes gradient) on a CombiFlash Companion (Teledyne ISCO). Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>),) <NUM> (s, <NUM>).

To (<NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazol-<NUM>-yl)methanol (Example <NUM>; <NUM>; <NUM> mmol) in <NUM> anhydrous tetrahydrofuran, were added molecular sieves (Sigma-Aldrich; <NUM>Å; <NUM>) and activated manganese dioxide (Sigma-Aldrich; <NUM>; <NUM> mmol), and the reaction mixture was heated for <NUM> at <NUM>. Thin-layer chromatography showed that all starting material was consumed. The reaction mixture was allowed to cool to <NUM> and was filtered through a pad of Celite (Sigma-Aldrich). Yield: <NUM>, <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>).

Lithium diisopropylamide (<NUM> mmol) was freshly prepared according to the following procedure: Diisopropylamine (Sigma-Aldrich; <NUM>; <NUM> mmol) in <NUM> tetrahydrofuran was cooled to -<NUM>; n-butyl-lithium (Sigma-Aldrich; <NUM> <NUM> in hexanes; <NUM> mmol) was added drop-wise over <NUM>. Stiriring was continued for <NUM> at <NUM>, followed by re-cooling to -<NUM>. <NUM>-Ethyl-<NUM>-hydroxy-<NUM>-propionyl-<NUM>-pyran-<NUM>-one (Ark Pharm or prepared according to <NPL>; <NUM>; <NUM> mmol) was dissolved in <NUM> tetrahydrofuran-hexamethylphosphoramide (Sigma-Aldrich; <NUM>:<NUM>, v/v) and added to the freshly-prepared lithium diisopropylamide drop-wise over <NUM> minutes. The reaction mixture was stirred for <NUM> at -<NUM>. <NUM>-Bromobutene (Sigma-Aldrich; <NUM>; <NUM> mmol) was added drop-wise, and the reaction mixture was stirred overnight, allowing the temperature to increase to room temperature. The reaction was quenched with saturated ammonium chloride and extracted with <NUM>-x-<NUM> ethyl acetate, and the ethyl acetate extracts were pooled, washed with <NUM> brine, dried over anhydrous sodium sulfate, and evaporated to an oil. The product was isolated via silica chromatography (ethyl acetate/hexanes gradient) on a CombiFlash Companion. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>).

To <NUM>-(hex-<NUM>-en-<NUM>-yl)-<NUM>-hydroxy-<NUM>-propionyl-<NUM>-pyran-<NUM>-one (Example <NUM>; <NUM>; <NUM>) and methyl crotonate (Sigma-Aldrich; <NUM>; <NUM> mmol) in <NUM> anhydrous dichloromethane, was added Hoveyda-Grubbs Catalyst II (Sigma-Aldrich; <NUM>; <NUM> mmol), and the reaction mixture was heated <NUM> at <NUM>. The solvent was evaporated, and the product was isolated via silica chromatography (ethyl acetate/hexanes gradient) on a CombiFlash Companion. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (q, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>).

Methyl (E)-<NUM>-(<NUM>-hydroxy-<NUM>-oxo-<NUM>-propionyl-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoate (Example <NUM>; <NUM>; <NUM> mmol) and <NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazole-<NUM>-carbaldehyde (Example <NUM>; <NUM>; <NUM> mmol) were mixed in <NUM> isopropanol in a sealed vial, warmed until the solids went into solution, and allowed to cool to <NUM>. Piperidine (Sigma-Aldrich; <NUM>µl; <NUM> mmol) was added, and the reaction mixture was heated <NUM> at <NUM> with vigorous stirring. The reaction mixture was evaporated to an oil, re-dissolved in <NUM> dichloromethane, shaken vigorously with <NUM> <NUM> HCl in a separatory funnel, and re-extracted with <NUM>×<NUM> dichloromethane. The combined dichloromethane extracts were washed with <NUM> water and <NUM> brine, dried over anhydrous sodium sulfate, and evaporated to an oil. The product was isolated via silica chromatography (ethyl acetate/hexanes gradient) on a CombiFlash Companion to give give <NUM> of a ~<NUM>:<NUM> mixture of the desired product, (E)-<NUM>-(<NUM>-((E)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazol-<NUM>-yl)-<NUM>-methylacryloyl)-<NUM>-hydroxy-<NUM>-oxo-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoate, and <NUM>-methyl-<NUM>-(piperidin-<NUM>-yl)thiazole-<NUM>-carbaldehyde (unwanted side product removed in next step). Yield:<NUM>; <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

To crude methyl (E)-<NUM>-(<NUM>-((E)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazol-<NUM>-yl)-<NUM>-methylacryloyl)-<NUM>-hydroxy-<NUM>-oxo-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoate (Example <NUM>; <NUM>) in <NUM> t-butanol and <NUM> water, was added <NUM> <NUM> LiOH. The mixture was microwaved (Biotage Initiator, Biotage) <NUM> at <NUM>. Upon cooling to <NUM>, the reaction mixture was evaporated to dryness, re-dissolved in <NUM> ethyl acetate and <NUM> <NUM> HCl, adjusted to pH ~ <NUM>, and extracted with 3x10 ml ethyl acetate. The pooled extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated to an oil. The crude sample was purified via semi-preparative reversed-phase HPLC (<NUM> x <NUM> Phenomenx Jupiter C18 column, <NUM>Å, <NUM>µ; A = <NUM>% acetic acid; B = <NUM>% acetic acid in acetonitrile; gradient = <NUM>% B to <NUM>% B at <NUM>; flow rate = <NUM>/min). Yield: <NUM> ;<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>):. δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

Example <NUM> was obtained by conversion of (E)-<NUM>-(<NUM>-((E)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazol-<NUM>-yl)-<NUM>-methylacryloyl)-<NUM>-hydroxy-<NUM>-oxo-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoic acid (Example <NUM>) into the acyl azide, followed by Curtius rearrangement under thermal conditions to yield the isocyanate, followed by addition of deuterated methanol.

To (E)-<NUM>-(<NUM>-((E)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazol-<NUM>-yl)-<NUM>-methylacryloyl)-<NUM>-hydroxy-<NUM>-oxo-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoic acid (Example <NUM>; <NUM>, <NUM> mmol) and diisopropylamine (Sigma-Aldrich; <NUM>µl; <NUM> mmol) in anhydrous acetone (<NUM>) under argon at <NUM>, was added ethyl chloroformate (Sigma-Aldrich; <NUM>µl; <NUM> mmol), and the reaction was stirred <NUM> at <NUM>. Sodium azide (<NUM>; <NUM> mmol) in <NUM> water was addded, the reaction mixture was allowed to stir <NUM> at <NUM>, and the reaction was quenched by addition of <NUM> water. The pH of the mixture was adjusted to ~<NUM> by addition of <NUM> N HCL. Organics were extracted with 3x20 ml ethyl acetate, and the combined extracts were washed with <NUM> brine, dried over anhydrous sodium sulfate, evaporated to an oil, and trace water was removed by azeotropic evaporation of added anhydrous toluene (3x10 ml). The crude azide was further dried <NUM> under high vacuum, then re-dissolved in anhydrous toluene (<NUM>) and heated for <NUM> at <NUM>. The reaction mixture was allowed to cool to <NUM>, <NUM> anhydrous methanol was added, and heating was continued for <NUM> at <NUM>. The reaction mixture was allowed to cool to room temperature and then evaporated to dryness. The crude sample was purified via semi-preparative reversed-phase HPLC (<NUM> x <NUM> Phenomenx Jupiter C18 column, <NUM>Å, <NUM>µ; A = <NUM>% acetic acid; B = <NUM>% acetic acid in acetonitrile; gradient = <NUM>% B to <NUM>% B at <NUM>; flow rate = <NUM>/min).

Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>, <NUM> (M+Na).

<NUM>-Fluorophenol (Sigma-Aldrich; <NUM>; <NUM> mmol) and potassium carbonate (<NUM>; <NUM> mmol) were mixed in <NUM> anhydrous DMF, and the resulting slurry was stirred vigorously <NUM> at <NUM>. After allowing the reaction mixture to cool to <NUM>, <NUM>-bromothiazole (Sigma-Aldrich; <NUM>; <NUM> mmol) in <NUM> DMF was added drop-wise over <NUM>, and the reaction mixture was heated <NUM> at <NUM>. After cooling to <NUM>, <NUM> water was added, and the reaction mixture was extracted with 3x50 ml ethyl acetate. The extracts were pooled and washed with 3x25 ml <NUM>% NaOH, <NUM> water, and <NUM> brine, and were dried over anhydrous sodium sulfate and concentrated to a brown oil. The product was isolated via silica chromatography (ethyl acetate/hexanes gradient) on a CombiFlash Companion. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>).

Freshly prepared lithium diisopropylamide (<NUM> mmol in <NUM> tetrahydrofuran; see Example <NUM>) was cannulated into a solution of <NUM>-(<NUM>-fluorophenoxy)thiazole (Example <NUM>; <NUM>; <NUM> mmol) in <NUM> anhydrous tetrahydrofuran at -<NUM> (dry ice bath) over <NUM>. The reaction mixture was stirred <NUM>, <NUM> anhydrous DMF added drop-wise over <NUM>, and stirring was continued for <NUM>. The dry ice bath was removed, and the reaction mixture was stirred for <NUM>. The reaction was quenched with <NUM> saturated ammonium chloride and extracted with 3x50 ml ethyl acetate, and the pooled organic extracts were dried with brine and anhydrous sodium sulfate and evaporated to a brown solid. The product was isolated via silica chromatography (ethyl acetate/hexanes gradient) on a CombiFlash Companion.

Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>).

The compound was prepared from methyl (E)-<NUM>-(<NUM>-hydroxy-<NUM>-oxo-<NUM>-propionyl-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoate (Example <NUM>; <NUM>; <NUM> mmol) and <NUM>-(<NUM>-fluorophenoxy)thiazole-<NUM>-carbaldehyde (Example <NUM>; <NUM>; <NUM> mmol) and piperidine (<NUM>µl, <NUM> mmol)according to the procedures in Example <NUM>. Yield: <NUM> (<NUM>%).

<NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The compound was prepared from methyl (E)-<NUM>-(<NUM>-((E)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)thiazol-<NUM>-yl)-<NUM>-methylacryloyl)-<NUM>-hydroxy-<NUM>-oxo-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoate (Example <NUM>), according to the procedures in Example <NUM>. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>) MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The compound was prepared from (E)-<NUM>-(<NUM>-((E)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)thiazol-<NUM>-yl)-<NUM>-methylacryloyl)-<NUM>-hydroxy-<NUM>-oxo-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoic acid (Example <NUM>), according to the procedures in Example <NUM>. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad m, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>, <NUM> (M+Na).

The compound was prepared by reacting <NUM>-hydroxy-<NUM>-methyl-<NUM>-pyran-<NUM>-one (Sigma-Aldrich) with lithium diisopropylamide (<NUM> mole equivalentsLDA to pyrone), followed by addition of <NUM>-bromobutene, according to the procedures in Example <NUM>.

Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS (API-ESI): calculated: m/z <NUM> (MH+); found: <NUM>.

N,N'-Diisopropylcarbodiimide (Sigma-Aldrich; <NUM>,;<NUM> mmol), <NUM>-(dimethylamino)pyridine (Sigma-Aldrich; <NUM>, <NUM> mmol), propionic acid (Sigma-Aldrich; <NUM>, <NUM> mmol), and <NUM>-hydroxy-<NUM>-(pent-<NUM>-en-<NUM>-yl)-<NUM>-pyran-<NUM>-one (Example <NUM>; <NUM>; <NUM> mmol) were dissolved in <NUM> toluene and heated <NUM> at <NUM> under argon. Upon cooling to <NUM>, the reaction mixture was filtered, and the filtrate was washed with <NUM> <NUM> HCl, <NUM> water, and <NUM> brine, and dried over anhydrous sodium sulfate. The product was isolated via silica chromatography (ethyl acetate/hexanes gradient) on a CombiFlash Companion. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, <NUM>), <NUM> (t, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (t, <NUM>).

The compound was prepared from <NUM>-hydroxy-<NUM>-(pent-<NUM>-en-<NUM>-yl)-<NUM>-propionyl-<NUM>-pyran-<NUM>-one (Example <NUM>, according to the procedures in Example <NUM>. Yield: <NUM> (<NUM> %).

<NUM>H NMR (<NUM>, CDCl<NUM>):<NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (q, <NUM>), <NUM> (t, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (t, <NUM>).

The compound was prepared from methyl (E)-<NUM>-(<NUM>-hydroxy-<NUM>-oxo-<NUM>-propionyl-<NUM>-pyran-<NUM>-yl)hex-<NUM>-enoate (Example <NUM>) and <NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazole-<NUM>-carbaldehyde (Example <NUM>), according to the procedures in Example <NUM>. Yield: <NUM> (<NUM>%).

<NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The compound was prepared from methyl (E)-<NUM>-(<NUM>-((E)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazol-<NUM>-yl)-<NUM>-methylacryloyl)-<NUM>-hydroxy-<NUM>-oxo-<NUM>-pyran-<NUM>-yl)hex-<NUM>-enoate (Example <NUM>), according to the procedures in Example <NUM>. Yield:<NUM> (<NUM>%).

<NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The compound was prepared from (E)-<NUM>-(<NUM>-((E)-<NUM>-(<NUM>-(<NUM>-fluorophenoxy)-<NUM>-methylthiazol-<NUM>-yl)-<NUM>-methylacryloyl)-<NUM>-hydroxy-<NUM>-oxo-<NUM>-pyran-<NUM>-yl)hex-<NUM>-enoic acid (Example <NUM>), according to the procedures in Example <NUM>. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The title compound was prepared as described for Example <NUM>, but using deuterated methanol (methanol-d4, <NUM> atom % D; Sigma-Aldrich) in place of methanol in the last step of the synthesis. Deuterated methanol was recovered for future use by distillation. Yield: <NUM> (<NUM>%) <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>) MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>, <NUM> (M+Na).

The title compound was prepared as described for Example <NUM>, but using deuterated methanol (methanol-d4, <NUM> atom % D; Sigma-Aldrich) in place of methanol in the last step of the synthesis. Deuterated methanol was recovered for future use by distillation Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The title compound was prepared as described for Example <NUM>, but using methyl (E)-<NUM>-(<NUM>-hydroxy-<NUM>-oxo-<NUM>-propionyl-<NUM>-pyran-<NUM>-yl)hex-<NUM>-enoate (Example <NUM>) in place of methyl (E)-<NUM>-(<NUM>-hydroxy-<NUM>-oxo-<NUM>-propionyl-<NUM>-pyran-<NUM>-yl)hept-<NUM>-enoate. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The title compound was prepared as described for Example <NUM>, but using deuterated methanol (methanol-d4, <NUM>. 8atom % D; Sigma-Aldrich) in place of methanol in the last step of the synthesis. Deuterated methanol was recovered for future use by distillation. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The title compound was prepared as described for Example <NUM>, but using deuterated methanol (methanol-d4, <NUM>. 8atom % D; Sigma-Aldrich) in place of methanol in the last step of the synthesis. Deuterated methanol was recovered for future use by distillation. Yield: <NUM> (<NUM> %). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

Example <NUM> (<NUM>, <NUM> mmol) was suspended in <NUM> <NUM> sodium carbonate, and the suspension was stirred <NUM> at <NUM> until all solids dissolved. Aliquots (<NUM> each) of the resulting solution were applied to <NUM> HF Mega BE-C18 reversed-phase cartridges (Agilent; prepared for use by one cycle of filling to rim with acetonitrile and draining and two cycles of filling to rim with water and draining), washed with 2x50 ml degassed water, and eluted with 5x20 ml <NUM>% methanol, monitoring elution by monitoring yellow color. Pooled factions containing APY281 (first two <NUM>% methanol fractions). were evaporated to yield a yellow crystalline solid. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CD<NUM>OD): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>),<NUM> (t, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (M+Na+); found: <NUM>.

(±)Myxopyronin B was prepared as described in <CIT>.

The title compound was prepared as in <CIT>.

The title compound was prepared as described for (±)myxopyronin B in <CIT>, but using deuterated methanol (methanol-d4, <NUM> atom % D; Sigma-Aldrich) in place of methanol in the last step of the synthesis. MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The title compound was prepared as described for PY62 in <CIT>, but using deuterated methanol (methanol-d4, <NUM> atom % D; Sigma-Aldrich) in place of methanol in the last step of the synthesis. Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (d, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (m, <NUM>),<NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The title compound was prepared as described for Example <NUM>, but using <NUM>-chloro-<NUM>-fluorophenol (Sigma-Aldrich) in place of <NUM>-fluorophenol (see Example <NUM>). Yield (last reaction step): <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>, <NUM>.

The compound of Example <NUM> (<NUM>; <NUM>µmol) was suspended in <NUM> <NUM> sodium carbonate and stirred for <NUM> at <NUM>. The resulting solution was applied to a <NUM> HF Mega BE-C18 reversed-phase cartridge (Agilent; prepared for use by one cycle of filling to rim with acetonitrile and draining and two cycles of filling to rim with water and draining), washed with 2x50 ml degassed water, and eluted with 1x10 mL <NUM>% methanol, 1x10 mL <NUM>% methanol, and 1x10 mL <NUM>% methanol, monitoring elution by monitoring yellow color. Pooled factions containing the title compound (first two fractions) were evaporated to yield a yellow crystalline solid. Yield: <NUM> (<NUM>%).

The title compound was prepared as described for Example <NUM>, but using <NUM>-phenylphenol (Sigma-Aldrich) in place of <NUM>-fluorophenol (see Example <NUM>). Yield (last reaction step): <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>, <NUM> (MNa+).

The compound of Example <NUM> (<NUM>; <NUM>µmol) was suspended in <NUM> <NUM> sodium carbonate and stirred for <NUM> at <NUM>. The resulting solution was applied to a <NUM> HF Mega BE-C18 reversed-phase cartridge (Agilent; prepared for use by one cycle of filling to rim with acetonitrile and draining and two cycles of filling to rim with water and draining), washed with 2x50 ml degassed water, and eluted with 1x10 mL <NUM>% methanol, 1x10 mL <NUM>% methanol, and 1x10 mL <NUM>% methanol, monitoring elution by monitoring yellow color. Pooled factions containing the title compound (last two fractions) were evaporated to yield a yellow crystalline solid. Yield: <NUM> (<NUM>%).

The title compound was prepared as described for Example <NUM>, but using <NUM>-bromo-<NUM>-fluorophenol (Sigma-Aldrich) in place of <NUM>-fluorophenol (see Example <NUM>). Yield (last reaction step): <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>, <NUM>, <NUM>, <NUM>.

The title compound was prepared from the compound of Example <NUM> through a Suzuki-Miyaura cross-coupling transformation with phenylboronic acid. , as in the following scheme:
<CHM>.

A suspension of the compound of Example <NUM> (<NUM>; <NUM>µmol), phenylboronic acid (<NUM>; <NUM>µmol; Sigma-Aldrich), potassium carbonate (<NUM>; <NUM>µmol), palladium acetate (<NUM>; <NUM>µmol; Sigma-Aldrich), and RuPhos (<NUM>; <NUM>µmol; Sigma-Aldrich) in <NUM> toluene:water (<NUM>:<NUM>) was heated <NUM> at <NUM> in a sealed vial. The reaction was allowed to room temperature, was quenched with <NUM> water, and was extracted with 3x5 ml ethyl acetate. The ethyl acetate extracts were pooled, filtered, and evaporated to an oily residue, the oily residue was re-suspended in <NUM> water pre-adjusted to pH <NUM> (with <NUM> HCl), and the suspension was re-extracted with 3x5 mL ethyl acetate. The resulting extracts were pooled, dried with brine and anhydrous sodium sulfate, evaporated, and purified by use of chromatography on silica (<NUM>). Fractions containing the the product were pooled to yield <NUM> of crude product, which was further purified by use of semi-preparative reversed-phase HPLC (<NUM> x <NUM> Phenomenex Jupiter C18 column, <NUM>Å, <NUM>µ; A = <NUM>% acetic acid; B = <NUM>% acetic acid in acetonitrile; gradient = <NUM>% B to <NUM>% B at <NUM>; flow rate = <NUM>/min). Yield: <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>.

The title compound was prepared as described for Example <NUM>, but using <NUM>,<NUM>-difluorophenol (VWR) in place of <NUM>-fluorophenol, and using methyl <NUM>-bromothiazole-<NUM>-carboxylate (Frontier Scientific) in place of ethyl <NUM>-bromo-<NUM>-thiazole-<NUM>-carboxylate (see Example <NUM>). Yield (last reaction step): <NUM> (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (broad t, <NUM>), <NUM>-<NUM> (broad d, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS (MALDI): calculated: m/z <NUM> (MH+); found: <NUM>, <NUM> (MNa+).

Test compounds were incubated with mouse liver microsomes (CD-<NUM>; male and female pooled; <NUM>/ml) or human liver microsomes (male; <NUM>/ml) in <NUM> potassium phosphate, pH <NUM>, and and <NUM> NADPH at <NUM>. Aliquots were removed at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and amounts of test compounds remaining were determined by LC-MS/MS. Half lives (t0. <NUM>) were calculated as t0. <NUM> = -<NUM>/k, where k is the slope of the linear regression of the natural logarithms of percentages of test compounds remaining vs. time. Data for representative compounds are shown in Table <NUM>.

Test compounds (<NUM>/kg; <NUM> of <NUM>/ml solution in <NUM>% dimethylacetamide and <NUM>% Cremophor EL in <NUM> sodium phosphate, pH <NUM>) were administered to mice (CD-<NUM>; <NUM>-<NUM>; n = <NUM>) by intravenous injection into a tail vein at t = <NUM>. Blood samples were collected by tail-vein bleed (CB <NUM> K2E tubes; Sarstedt) at t = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>, and plasma concentrations of test compounds were determined by LC-MS/MS. Data for representative compounds are shown in Table <NUM>.

Fluorescence-detected RNA polymerase assays with E. coli RNA polymerase were performed by a modification of the procedure of Kuhlman et al. , <NUM> [<NPL>]. Reaction mixtures contained (<NUM>µl): <NUM>-<NUM> test compound, <NUM> E. coli RNA polymerase σ<NUM> holoenzyme, <NUM> <NUM> bp DNA fragment containing the bacteriophage T4 N25 promoter, <NUM> ATP, <NUM> GTP, <NUM> UTP, <NUM> CTP, <NUM> Tris-HCl, pH <NUM>, <NUM> KCl, <NUM> MgCl<NUM>, <NUM> DTT, <NUM>µg/ml bovine serum albumin, and <NUM>% glycerol. Reaction components other than DNA and NTPs were pre-incubated for <NUM> at <NUM>. Reactions were carried out by addition of DNA and incubation for <NUM> at <NUM>, followed by addition of NTPs and incubation for <NUM> at <NUM>. DNA was removed by addition of <NUM>µl <NUM> CaCl<NUM> and <NUM> U DNaseI (Ambion, Inc. ), followed by incubation for <NUM> at <NUM>. RNA was quantified by addition of <NUM>µl RiboGreen RNA Quantitation Reagent (Invitrogen, Inc. ; <NUM>:<NUM> dilution in Tris-HCl, pH <NUM>, <NUM> EDTA), followed by incubation for <NUM> at <NUM>, followed by measurement of fluorescence intensity [excitation wavelength = <NUM> and emission wavelength = <NUM>; QuantaMaster QM1 spectrofluorometer (PTI, Inc. IC50 is defined as the concentration of inhibitor resulting in <NUM>% inhibition of RNA polymerase activity. Data for representative compounds are shown in Table <NUM>.

Minimum inhibitory concentrations (MICs) for Staphylococcus aureus ATCC 12600were quantified using spiral gradient endpoint assays, essentially as described [<NPL>; <NPL>; <NPL>]. Assays employed exponential-gradient plates containing <NUM> x <NUM> Mueller-Hinton II cation-adjusted agar and <NUM>-<NUM>µg/ml of test compound. Plates were prepared using an Autoplate <NUM> spiral plater (Spiral Biotech, Inc. Saturated overnight cultures were swabbed radially onto plates, and plates were incubated for <NUM> at <NUM>. For each culture, the streak length was measured using a clear plastic template (Spiral Biotech, Inc. ), the test-compound concentration at the streak endpoint was calculated using the program SGE (Spiral Biotech, Inc. ), and the MIC was defined as the calculated test-compound concentration at the streak endpoint.

MICs for Mycobacterium tuberculosis H37Rv were quantified using microplate Alamar Blue assays as described [<NPL>].

Data for representative compounds from the assay of Example <NUM> are shown in Table <NUM>.

Female Swiss Webster mice (<NUM>-<NUM>) were experimentally infected by intraperitoneal administration of <NUM> x <NUM><NUM> colony forming units of methicillin-resistant Staphylococcus aureus (MRSA) strain BAA-<NUM> (USA-<NUM>, MW2) in <NUM>% hog gastric mucin. Test compounds in vehicle (<NUM>% dextrose in <NUM> sodium phosphate, pH <NUM>, for Example <NUM>; <NUM>% dimethylacetamide and <NUM>% Cremophor EL in <NUM> sodium phosphate, pH <NUM>, for other compounds), positive control in vehicle (linezolid at <NUM>/kg), and negative control (vehicle only), were administered by intravenous injection into a tail vein (<NUM>µl) <NUM> post-infection to provide single intravenous doses of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg or by oral gavage (<NUM>µl) <NUM> pre-infection to provide single oral doses of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg. Survival was monitored for <NUM> post-infection. Identities of test salts and controls were blinded from personnel performing injections and monitoring survival. The effective dose <NUM> (ED50) was defined as the test-compound dose resulting in <NUM>% survival at <NUM> (calculated using the probit method).

Data from the assay of Example <NUM> are provided in Tables <NUM> and <NUM>.

Female Swiss Webster mice (<NUM>-<NUM>) were rendered immunosuppressed by oral gavage for <NUM> days with cyclophosphamide and were infected by intranasal administration of <NUM> x <NUM><NUM> colony forming units of methicillin-resistant Staphylococcus aureus (MRSA) strain BAA-<NUM> (USA-<NUM>, MW2). Test compounds in vehicle (<NUM>% dextrose in <NUM> sodium phosphate, pH <NUM>), positive control in vehicle (vancomycin at <NUM>/kg), and negative control (vehicle only), were administered by intravenous injection into a tail vein (<NUM>µl) <NUM> post-infection to provide single intravenous doses of <NUM>, <NUM>, amd <NUM>/kg or by oral gavage (<NUM>µl) <NUM> post-infection to provide oral doses of <NUM>, <NUM>, and <NUM>/kg. Mice were euthanized and lungs were harvested and homogenized <NUM> post-infection; and viable bacteria were quantified. The effective dose (ED(2log)) was defined as the minimum test-compound dose resulting in ≥<NUM> log reduction in bacterial burden.

Female BALB/c mice (<NUM>-<NUM>) were experimentally infected by topical administration under isfluurane anesthesia of <NUM> × <NUM><NUM> colony forming units of methicillin-resistant Staphylococcus aureus (MRSA) strain BAA-<NUM> (USA-<NUM>, MW2) to a <NUM> × <NUM> dorsal surface prepared by depiliation (<NUM> pre-infection; isoflurane anesthesia) and removal of epidermis by tape stripping (immediately pre-infection; isoflurane anesthesia; seven applications and removals of <NUM> Nexcare surgical tape). Test compounds in vehicle (<NUM>% dextrose in <NUM> sodium phosphate, pH <NUM>), positive control in vehicle (linezolid at <NUM>/kg), and negative control (vehicle only), were administered by intravenous injection into a tail vein (<NUM>µl) <NUM> post-infection to provide single intravenous doses of <NUM>, <NUM>, <NUM>, and <NUM>/kg. Mice were euthanized and a <NUM> x <NUM> skin segment was harvested and homogenized <NUM> post-infection; and viable bacteria were quantified. Identities of test salts and controls were blinded from personnel performing injections and quantifying bacteria. The effective dose (ED(2log)) was defined as the minimum test-compound dose resulting in ≥<NUM> log reduction in bacterial burden.

Data from the assay of Example <NUM> are provided in Table <NUM>.

Female Balb/c mice (<NUM>-<NUM> weeks old) were infected by aerosol administration of <NUM>-<NUM> colony forming units of Mycobacterium tuberculosis Erdman. Test compounds in vehicle (<NUM>% dextrose in <NUM> sodium phosphate, pH <NUM>), positive control in vehicle (rifampi at <NUM> and <NUM>/kg), and negative control (vehicle only), were administered by oral gavage (<NUM>µl) starting <NUM> days post-infection and continuing for <NUM> days to provide <NUM> daily oral doses of <NUM> and <NUM>/kg. Mice were euthanized and lungs and spleens were harvested and homogenized <NUM> days post-infection; and viable bacteria were quantified. The effective dose (ED(2log)) was defined as the minimum test-compound dose resulting in ≥<NUM> log reduction in bacterial burden.

Screening data for representative deuterated compounds of the invention and for corresponding undeuterated compounds are presented in Tables <NUM>-<NUM>:.

The data in Table <NUM> show that certain deuterated compounds of this invention (compounds with underlined data) exhibit higher metabolic half-lives than the corresponding undeuterated compounds.

The data in Table <NUM> show that certain deuterated compounds of this invention (compounds with underlined data) exhibit higher plasma half-lives upon intravenous administration to mice than the corresponding undeuterated compounds.

The data in Table <NUM> show that certain deuterated compounds of this invention (compounds with underlined data) exhibit higher in vitro RNA polymerase inhibitory potencies than the corresponding undeuterated compounds.

The data in Table <NUM> show that certain deuterated compounds of this invention (compounds with underlined data) exhibit higher in vitro antibacterial potencies than the corresponding undeuterated compounds.

The data in Table <NUM> show that certain deuterated compounds of this invention (compounds with underlined data) exhibit higher in vivo antibacterial potencies than the corresponding undeuterated compounds.

The data in Tables <NUM>-<NUM> further show that certain compounds of this invention potently treat infection and prevent death in a mammal. Table <NUM> presents data for survival from experiments with mice with systemic infections of methicillin-resistant Staphylococcus aureus (MRSA) and compounds administered intravenously. Table <NUM> presents data for survival from experiments with mice with systemic infections of methicillin-resistant Staphylococcus aureus (MRSA) and a compound administered intravenously or orally.

The data in Tables <NUM>-<NUM> indicate that certain compounds of this invention potently treat infections and reduce bacterial burdens in a mammal. Tables <NUM> and <NUM> presents data for reductions in plasma bacterial burdens from experiments with mice with lung infections of methicillin-resistant Staphylococcus aureus (MRSA) and a compound administered intravenously or orally. Table <NUM> presents data for reductions in bacterial burdens from experiments with mice with dermal infections of methicillin-resistant Staphylococcus aureus (MRSA) and a compound administered intravenously. Table <NUM> presents data for reductions in bacterial burdens from experiments with mice with aerosol acute infections of Mycobacterium tuberculosis and a compound administered orally.

Claim 1:
A compound of formula Ia" or formula Id''
<CHM>
<CHM>
or a salt thereof, wherein:
each bond designated <IMG> represents a double bond that can optionally be cis, trans, or a mixture thereof
W is sulfur, oxygen, or nitrogen;
X, Y, and Z are individually carbon, or nitrogen, wherein at least two of X, Y, and Z are carbon;
one of R<NUM> and R<NUM> is C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkenyl, C<NUM>-C<NUM> alkoxy, or aryloxy, wherein any C<NUM>-C<NUM> alkyl, or C<NUM>-C<NUM> alkoxy, is optionally substituted by at least one of halogen, hydroxy, or C<NUM>-C<NUM> alkoxy, and wherein any aryloxy is optionally substituted by at least one of halogen, or aryl, ; or one of R<NUM> and R<NUM> is a <NUM>-<NUM>-membered saturated heterocycle and the other of R<NUM> and R<NUM> is absent;
R<NUM> is absent, or is one of H, C<NUM>-C<NUM> alkyl, or halogen-substituted C<NUM>-C<NUM> alkyl;
R<NUM> is absent, or is one of H, halogen, C<NUM>-C<NUM> alkyl, or halogen-substituted C<NUM>-C<NUM> alkyl;
R<NUM> is H or M+, where M+ is a pharmaceutically acceptable cation;
R<NUM> is H, halogen, or methyl that is optionally substituted with halogen;
R<NUM> is C<NUM>-C<NUM> alkyl or C<NUM>-C<NUM> alkenyl, wherein any C<NUM>-C<NUM> alkyl or C<NUM>-C<NUM> alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NRaRb;
R<NUM> is methyl that is substituted with <NUM>, <NUM>, or <NUM> deuterium atoms;
one of R<NUM> and R<NUM> is hydrogen or C<NUM>-C<NUM> straight alkyl, and the other of R<NUM> and R<NUM> is C<NUM>-C<NUM> straight or branched alkyl, wherein an alkyl moiety of R<NUM> and R<NUM> optionally is substituted with <NUM>-<NUM> groups independently selected from halo
each Ra is C<NUM>-C<NUM> alkyl that is optionally substituted by at least one of halogen, hydroxy, or C<NUM>-C<NUM> alkoxy; and
each Rb is H or C<NUM>-C<NUM> alkyl that is optionally substituted by at least one of halogen, hydroxy, or C<NUM>-C<NUM> alkoxy.