Agents for the treatment of non-replicating bacteria

Abstract

In one aspect, the invention relates to compounds useful as hybrid antibiotics, acting as both activators of the ClpP protease and inhibitors of RNA polymerase activity. Also disclosed are methods of using the disclosed compounds in the treatment of infectious diseases such as, for example, biofilm-mediated diseases and infectious diseases due to prosthetic joint infections, intracellular bacteria, and Gram-positive bacteria (e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

AGENTS FOR THE TREATMENT OF NON-REPLICATING BACTERIA CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No.63 / 535,552, filed on August 30, 2023, the contents of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grant numbers AI141193 and AI157081 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention. BACKGROUND

[0003] The spread of antibiotic resistance has substantially diminished the efficacies of multiple clinical antibiotics in recent times owing to the emergence and proliferation of multidrug-resistant (MDR) bacterial pathogens (Aminov (2010) Front / . Microbiol.1: 134; Aslam et al. (2018) Infect. Drug Resist.11: 1645-1658; Annunziato (2019) Int. J. Mol. Sci. 20(23): 5844). Six pathogenic species, collectively designated ESKAPE (Enterococcus faecium, Staphyloccocus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli) were ranked by the World Health Organization (WHO) as high-priority pathogens because of their ability to “escape” multiple antibiotics via resistance mechanisms including enzymatic inactivation, active efflux, and target modification, which can be genetically innate or acquired via horizontal gene transfer (Santajit and Indrawattana (2016) Biomed. Res. Int.2016: 2475067; Mulani et al. (2019) Front. Microbiol.10: 539; Zhen et al. (2019) Antimicrob. Resist. Infect. Control 8(1): 137; de Oliveira et al. (2020) Clin. Microbiol. Revi.33(3): 001811; Cardoso et al. (2021) Biophys. Rev.13: 35-69). While prudent stewardship of antibiotics may mitigate resistance, it remains paramount to expand the library of treatment options to compensate for various antibiotics rendered obsolete over the years. One of the means to revive antibiotic efficacy is through antibiotic combinations between synthetic antibiotics and / or last-resort antibiotics.

[0004] Co-administration of multiple antibiotics has gained increased popularity because the likelihood of pathogens developing resistance against two or more antibiotics concurrently is surmised to be extensively lower than against a single antibiotic administered(Mulani et al. (2019) Front. Microbiol.10: 539). However, antibiotic combination therapy incurs significant administrative and therapeutic monitoring costs as in-vitro synergy might not necessarily translate to the same effect in-vivo owing to a myriad of factors, including non-complementary pharmacodynamic / pharmacokinetic properties, which could have the unintended effect of exacerbating toxicity (Rybap and Mcgrath (1996) Drugs 52: 390-405; Tamma et al. (2012) Clin. Microbiol. Rev.25: 450-470). Furthermore, different antibiotics may be chemically incompatible with one another when mixed.

[0005] One alternative to combination therapy is a dual hybrid antibiotic. The underlying objective behind ligating two antibiotics together via metabolically stable tethers is to construct a singular heterodimeric entity with a fixed pharmacokinetic profile while retaining the antibacterial mechanisms of the constituent pharmacophores. Without wishing to be bound by theory, this could improve on-site targeting, impede bacterial efflux, sterically protect constituent pharmacophores from enzymatic degradation, and reduce toxicity when administered in-vivo (Pokrovskaya and Baasov (2010) J. Med. Chem.52(8): 2243-2254; Theuretzbacher (2020) Nat. Microbiol.5(8): 984-985).

[0006] Despite the significant promise of dual-acting hybrid antibiotics in overcoming bacterial resistance, a number of challenges with this approach remain. For example, the complexity of designing chemical synthetic procedures may affect overall yields and potentially impair the intrinsic activity of the hybrids synthesized (Ma and Lynch (2016) J. Med. Chem.59(14): 6645-6657; Domalaon et al. (2018) Clin. Microbiol. Rev.31(2): e00077; Lungu et al. (2022) J. Antibiot. (Tokyo) 61(10): 595-602). Other obstacles include the meticulous work needed to understand the mode of action and determine the benefits of the hybrid compounds over conventional antibiotics, such as the possibility of delaying the evolution of resistance (Pokrovskaya et al. (2009) J. Med. Chem.52(8): 2243-2254; Shavit et al. (2017) Bioorg. Med. Chem.25(11): 2917-2925; Koh Jing Jie et al. (2022) Pathogens 11(12): 1420). Thus, there remains a significant need for antibiotic compounds that are potent and effective for the treatment of diseases associated with bacterial infection, while also combatting resistant bacterial strains. SUMMARY

[0007] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds useful as hybrid antibiotics, acting as both activators of the ClpP protease and inhibitors of RNA polymeraseactivity. Also disclosed are methods of using the disclosed compounds in the treatment of infectious diseases such as, for example, biofilm-mediated diseases and infectious diseases due to prosthetic joint infections, intracellular bacteria, and Gram-positive bacteria (e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae).

[0008] Disclosed are compounds having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, orNHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0009] Also disclosed are compounds having a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1; wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0010] Also disclosed are compounds having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0011] Also disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] Also disclosed are methods for treating an infectious disease in a subject in need thereof, in the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby treating the infectious disease in the subject.

[0013] Also disclosed are methods for activating ClpP protease in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby activating ClpP protease in the cell.

[0014] Also disclosed are methods for activating ClpP protease in a subject, the methodcomprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby activating ClpP protease in the subject.

[0015] Also disclosed are methods for inhibiting RNA polymerase activity in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby inhibiting RNA polymerase activity in the cell.

[0016] Also disclosed are methods for inhibiting RNA polymerase activity in a subject, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby enhancing RNA polymerase activity in the subject.

[0017] Also disclosed are kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an antimicrobial agent; (b) instructions for treating an infectious disease; and (c) instructions for administering the compound in connection with treating a microbial infection.

[0018] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0019] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

[0021] FIG.1 shows structure of compound 5192.

[0022] FIG.2A-F shows representative data for the mechanism of action of compound 5192.

[0023] FIG.3A and FIG.3B show representative data of stationary phase and intracellular killing.

[0024] FIG.4A-D shows representative data of the in vivo efficacy of compound 5192.

[0025] FIG.5 shows a representative graph illustrating the efficacy of compound 5192 in a peritonitis septicemia model in kidneys.

[0026] FIG.6 shows a representative graph illustrating the effects of compound 5192 in a thigh lesion MRSA model.

[0027] FIG.7 shows a representative graph illustrating the effects of compound 5192 and control antibiotics on MRSA counts in a foreign device biofilm model.

[0028] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. DESCRIPTION

[0029] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0030] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited tospecific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0031] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation. A. DEFINITIONS

[0032] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0033] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0034] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0035] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0036] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0037] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0038] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0039] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0040] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0041] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0042] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0043] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccaladministration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0044] As used herein, the term “imaging” refers to a procedure that can make detailed pictures of areas inside a human body. Imaging procedures use different forms of energy such as x-rays (high-energy radiation), ultrasound (high-energy sound waves), radio waves, and radioactive substances. Imaging procedures can be used to help diagnose disease, to plan treatment, or to determine how well treatment is working. Exemplary imaging procedures include, but are not limited to, computed tomography (CT), mammography, ultrasonography, magnetic resonance imaging (MRI), nuclear medicine tests, positron emission tomography (PET), PET / MRI, and PET / CT.

[0045] The terms “radioactive isotope” and “radioisotope,” as used herein, refers to an isotope whose nuclei is unstable and, as such, the isotope can dissipate excess energy by spontaneously emitting radiation in the form of alpha, beta, and / or gamma rays. Examples of radioisotopes include, but are not limited to,2H,3H,11C,13C,14C,13N,15N,15O,17O,18F,35S,36Cl,82Br,76Br,77Br,123I,124I,125I, and131I.

[0046] As used herein, the phrase “a subject in need of RONS imaging” refers to a subject who has been diagnosed as having, or is otherwise suspected of having, a disorder or disease caused by or otherwise attributable to oxidative stress as detailed elsewhere herein. For example, in various aspects, where a subject is suspected of having a disorder or disease caused by or exacerbated by oxidative stress (e.g., a subject in need of RONS imaging), the subject can undergo an imaging procedure to assess whether they demonstrate an increased signal (e.g., an increased PET signal) in a region of interest. If the imaging procedure reveals that the subject does, indeed, have an increased signal in the region of interest, they would then be identified as being in need of therapeutic treatment.

[0047] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specifictherapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0048] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage form can comprise a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g.,glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0049] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0050] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0051] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active ormore active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0052] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0053] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity,would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0054] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0055] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether themoiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH2)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0056] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0057] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0058] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0059] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0060] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0061] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, asubstituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0062] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. For example, the cycloalkyl group and heterocycloalkyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, −NH2, (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, ether, halogen, −OH, C1-C4 hydroxyalkyl, −NO2, silyl, sulfo-oxo, −SH, and C1-C4 thioalkyl, as described herein.

[0063] The term “polyalkylene group” as used herein is a group having two or more CH2 groups linked to one another. The polyalkylene group can be represented by the formula — (CH2)a—, where “a” is an integer of from 2 to 500.

[0064] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or — OA1—(OA2)a—OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0065] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

[0066] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. For example, the cycloalkenyl group and heterocycloalkenyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl, aryl, heteroaryl, aldehyde, −NH2, (C1- C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, carboxylic acid, ester, ether, halogen, −OH, C1-C4 hydroxyalkyl, ketone, azide, −NO2, silyl, sulfo-oxo, −SH, and C1-C4 thioalkyl, as described herein.

[0067] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0068] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy,ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0069] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0070] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0071] The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” or “CO” is a short hand notation for a carbonyl group, i.e., C=O.

[0072] The terms “amine” or “amino” as used herein are represented by the formula — NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.

[0073] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0074] The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)2where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- ethyl-N-propylamino group and the like.

[0075] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0076] The term “ester” as used herein is represented by the formula —OC(O)A1or — C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula —(A1O(O)C-A2-C(O)O)a— or —(A1O(O)C-A2-OC(O))a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0077] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula —(A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0078] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I. As would be understood by one of skill in the art, isoptically- labeled halogens are also envisioned. The isotopically labeled halogens also include the radioactive isotopes such as ‒18F, ‒76Br, ‒123I, and ‒124I.

[0079] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0080] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, whereinthe nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0081] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0082] The terms “heterocycle” or “heterocyclyl” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4- tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group, which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0083] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.

[0084] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0085] The term “hydroxy” or “hydroxyl” as used herein is represented by the formula — OH.

[0086] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

[0087] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0088] The term “nitro” as used herein is represented by the formula —NO2.

[0089] The term “nitrile” or “cyano” as used herein is represented by the formula —CN or — C≡N.

[0090] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0091] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, — S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0092] The term “thiol” as used herein is represented by the formula —SH.

[0093] “R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0094] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” ornot, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0095] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0096] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R ^; –(CH2)0–4OR ^; -O(CH2)0-4Ro, – O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR ^)2; –(CH2)0–4SR ^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R ^)2; –(CH2)0–4N(R ^)C(O)R ^; –N(R ^)C(S)R ^; – (CH2)0–4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^2; –(CH2)0–4N(R ^)C(O)OR ^; – N(R ^)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^2; -N(R ^)N(R ^)C(O)OR ^; –(CH2)0–4C(O)R ^; – C(S)R ^; –(CH2)0–4C(O)OR ^; –(CH2)0–4C(O)SR ^; -(CH2)0–4C(O)OSiR ^3; –(CH2)0–4OC(O)R ^; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R ^; –(CH2)0–4C(O)NR ^2; –C(S)NR ^2; – C(S)SR°; -(CH2)0–4OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH2C(O)R ^; – C(NOR ^)R ^; -(CH2)0–4SSR ^; –(CH2)0–4S(O)2R ^; –(CH2)0–4S(O)2OR ^; –(CH2)0–4OS(O)2R ^; – S(O)2NR ^2; -(CH2)0–4S(O)R ^; -N(R ^)S(O)2NR ^2; –N(R ^)S(O)2R ^; –N(OR ^)R ^; – C(NH)NR ^2; –P(O)2R ^; -P(O)R ^2; -OP(O)R ^2; –OP(O)(OR ^)2; SiR ^3; –(C1–4 straight or branched alkylene)O–N(R ^)2; or –(C1–4straight or branched alkylene)C(O)O–N(R ^)2, wherein each R ^ may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0097] Suitable monovalent substituents on R ^ (or the ring formed by taking two independent occurrences of R ^ together with their intervening atoms), are independently halogen, – (CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S.

[0098] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0099] Suitable substituents on the aliphatic group of R*include halogen, – R^, -(haloR^), -OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0100] Suitable substituents on a substitutable nitrogen of an “optionally substituted”group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0101] Suitable substituents on the aliphatic group of R†are independently halogen, – R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0102] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0103] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0104] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0105] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure:, regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0106] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0107] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

[0108] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0109] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0110] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the moleculeabout its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0111] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0112] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0113] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson,., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[0114] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N1- unsubstituted, 3-A3and N1-unsubstituted, 5-A3as shown below.Unless stated to the contrary, the invention includes all such possible tautomers.

[0115] It is known that chemical substances form solids, which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0116] In some aspects, a structure of a compound can be represented by a formula: , which is understood to be equivalent to a formula:, wherein n is typically an integer. That is, Rnis understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0117] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0118] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are tobe limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0119] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0120] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result. B.COMPOUNDS

[0121] In one aspect, the invention relates to compounds useful as activators of the ClpP protease. In another aspect, the compounds of the invention are useful as inhibitors for RNA polymerase activity in cells. In one aspect, the compounds of the invention are useful in the treatment of infectious disease, including infectious disease associated with bacterial infections, and other diseases in which activation of the ClpP protease can have therapeutic benefit, as further described herein.

[0122] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1. STRUCTURE

[0123] In one aspect, disclosed are compounds having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, andNHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0124] In one aspect, disclosed are compounds having a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1; wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0125] In various aspects, disclosed are pharmaceutical compositions comprising aneffective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0126] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0127] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0128] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0129] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0130] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0131] In various aspects, the compound has a structure represented by a formula:, wherein L is a linker selected from C1-C8 alkyl and ‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl), or a pharmaceutically acceptable salt thereof.

[0132] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0133] In various aspects, the residue of the rifamycin analog has a structure represented by a formula selected from: ,,wherein R22is selected from C1-C4 alkyl and C1-C4 alkoxy.

[0134] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0135] In various aspects, the compound has a structure represented by a formula:, wherein L is a linker selected from C1-C8 alkyl and ‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl), or a pharmaceutically acceptable salt thereof.

[0136] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof. In a further aspect, the residue of the rifamycin analog has a structure represented by a formula selected from:,,wherein R22is selected from C1-C4 alkyl and C1-C4 alkoxy.

[0137] In various aspects, the compound has a structure represented by a formula:,or a pharmaceutically acceptable salt thereof.

[0138] In various aspects, The compound of claim 1, wherein the compound has a structure represented by a formula:, wherein L is a linker selected from C1-C8 alkyl and ‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl), or a pharmaceutically acceptable salt thereof. In a further aspect, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof. In a still further aspect, the residue of the rifamycin analog has a structure represented by a formula selected from:,wherein R22is selected from C1-C4 alkyl and C1-C4 alkoxy.

[0139] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0140] In various aspects, the compound is selected from:. or a pharmaceutically acceptable salt thereof.

[0141] In various aspects, the compound is selected from:,,,H,NOF O F O O NHO N HO HO OHHOO O O,,,,,,,,,F, or a pharmaceutically acceptable salt thereof.

[0142] In one aspect, q is selected from 0 and 1. In a further aspect, q is 0. In a further aspect, q is 1. a. L GROUPS

[0143] In one aspect, L is a linker. Examples of linkers include, but are not limited to, alkyl linkers, cycloalkyl linkers, heterocycloalkyl linkers (e.g., piperazine linkers, piperidine linkers), alkyl ether linkers, and alkyl substituted 1,2,3-triazoles linkers. Thus, in various aspects, the linker is selected from C1-C8 alkyl, C4-C7 cycloalkyl, ‒(C1-C4 alkyl)‒ O‒(C1-C4 alkyl)‒, and a structure represented by a formula: .

[0144] In various aspects, L is a linker selected from C1-C8 alkyl and ‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl).

[0145] In various aspects, L is a linker and is a structure represented by a formula:.

[0146] In a further aspect, L is a linker selected from: ,b. Q GROUPS

[0147] In one aspect, Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒ (cyclopropyl)‒. In a further aspect, Q is selected from─CH2─, ─CH2CH2─, and ─CH=CH─. In a still further aspect, Q is selected from─CH2─ and─CH2CH2─. In yet a further aspect, Q is─CH2─. In an even further aspect, Q is─CH2CH2─. In a still further aspect, Q is─CH=CH─. In a still further aspect, Q is─(cyclopropyl)─. c. X GROUPS

[0148] In one aspect, X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒.

[0149] In various aspects, X is ‒O‒.

[0150] In various aspects, X is ‒N(R10)‒. In a further aspect, X is ‒N(C1-C4 alkyl)‒. In a still further aspect, X is ‒N(CH3)‒. In yet a further aspect, X is ‒NH‒.

[0151] In various aspects, X is ‒CH(R10). In a further aspect, X is ‒CH(C1-C4 alkyl)‒. In a still further aspect, X is ‒CH(CH3)‒. In an even further aspect, X is ‒CH2‒.d. Y GROUPS

[0152] In one aspect, Y is selected from R80and –NH–(Q)q–Ar2. In a further aspect, Y is selected from R80and –NH–Q–Ar2. In a still further aspect, Y is selected from R80and – NHAr2.

[0153] In various aspects, Y is selected from R80and a structure represented by a formula:.

[0154] In various aspects, Y is R80.

[0155] In various aspects, Y is a structure represented by a formula:. e. R1A, R1B, AND R1CGROUPS

[0156] In one aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy. In a further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, ‒CF3, ‒CHF2, ‒CH2F, ‒CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CH(F)CH3, ‒CH(CH3)CF3, ‒CH(CH3)CHF2, ‒CH(CH3)CH2F, ‒CH2CH2CF3, ‒ CH2CH2CHF2, ‒CH2CH2CF3, ‒CH2CH(F)CH3, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒ CH2CHCl2, ‒CH2CH2Cl, ‒CH(Cl)CH3, ‒CH(CH3)CCl3, ‒CH(CH3)CHCl2, ‒CH(CH3)CH2Cl, ‒CH2CH2CCl3, ‒CH2CH2CHCl2, ‒CH2CH2CCl3, ‒CH2CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒ OCH(CH3)2, ‒OCH2CH2CH3, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒OCH2CF3, ‒OCH2CHF2, ‒ OCH2CH2F, ‒OCH(F)CH3, ‒OCH(CH3)CF3, ‒OCH(CH3)CHF2, ‒OCH(CH3)CH2F, ‒ OCH2CH2CF3, ‒OCH2CH2CHF2, ‒OCH2CH2CF3, ‒OCH2CH(F)CH3, ‒OCCl3, ‒OCHCl2, ‒ OCH2Cl, ‒OCH2CCl3, ‒OCH2CHCl2, ‒OCH2CH2Cl, ‒OCH(Cl)CH3, ‒OCH(CH3)CCl3, ‒ OCH(CH3)CHCl2, ‒OCH(CH3)CH2Cl, ‒OCH2CH2CCl3, ‒OCH2CH2CHCl2, ‒ OCH2CH2CCl3, and ‒OCH2CH(Cl)CH3. In yet a further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, methyl, ethyl, ‒CF3, ‒CHF2, ‒CH2F, ‒ CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒CH2CHCl2, ‒CH2CH2Cl, ‒CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒OCH(CH3)2, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒ OCH2CF3, ‒OCH2CHF2, ‒OCH2CH2F, ‒OCH(F)CH3, ‒OCCl3, ‒OCHCl2, ‒OCH2Cl, ‒ OCH2CCl3, ‒OCH2CHCl2, ‒OCH2CH2Cl, and ‒OCH(Cl)CH3. In an even further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, methyl, ‒CF3, ‒ CHF2, ‒CH2F, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒OCH3, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒OCCl3, ‒ OCHCl2, and ‒OCH2Cl.

[0157] In various aspects, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy. In a further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, methyl, ethyl, n-propyl, isopropyl, ‒CF3, ‒CHF2, ‒CH2F, ‒CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CH(F)CH3, ‒CH(CH3)CF3, ‒CH(CH3)CHF2, ‒CH(CH3)CH2F, ‒CH2CH2CF3, ‒ CH2CH2CHF2, ‒CH2CH2CF3, ‒CH2CH(F)CH3, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒ CH2CHCl2, ‒CH2CH2Cl, ‒CH(Cl)CH3, ‒CH(CH3)CCl3, ‒CH(CH3)CHCl2, ‒CH(CH3)CH2Cl, ‒CH2CH2CCl3, ‒CH2CH2CHCl2, ‒CH2CH2CCl3, ‒CH2CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒ OCH(CH3)2, ‒OCH2CH2CH3, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒OCH2CF3, ‒OCH2CHF2, ‒ OCH2CH2F, ‒OCH(F)CH3, ‒OCH(CH3)CF3, ‒OCH(CH3)CHF2, ‒OCH(CH3)CH2F, ‒ OCH2CH2CF3, ‒OCH2CH2CHF2, ‒OCH2CH2CF3, ‒OCH2CH(F)CH3, ‒OCCl3, ‒OCHCl2, ‒ OCH2Cl, ‒OCH2CCl3, ‒OCH2CHCl2, ‒OCH2CH2Cl, ‒OCH(Cl)CH3, ‒OCH(CH3)CCl3, ‒ OCH(CH3)CHCl2, ‒OCH(CH3)CH2Cl, ‒OCH2CH2CCl3, ‒OCH2CH2CHCl2, ‒ OCH2CH2CCl3, and ‒OCH2CH(Cl)CH3. In yet a further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, methyl, ethyl, ‒CF3, ‒CHF2, ‒CH2F, ‒ CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒CH2CHCl2, ‒ CH2CH2Cl, ‒CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒OCH(CH3)2, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒ OCH2CF3, ‒OCH2CHF2, ‒OCH2CH2F, ‒OCH(F)CH3, ‒OCCl3, ‒OCHCl2, ‒OCH2Cl, ‒ OCH2CCl3, ‒OCH2CHCl2, ‒OCH2CH2Cl, and ‒OCH(Cl)CH3. In an even further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, methyl, ‒CF3, ‒ CHF2, ‒CH2F, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒OCH3, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒OCCl3, ‒ OCHCl2, and ‒OCH2Cl.

[0158] In various aspects, each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, and C1-C4 alkyl. In a further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, methyl, and ethyl. In an even further aspect, each of R1a, R1b, and R1cisindependently selected from hydrogen, halogen, and methyl.

[0159] In various aspects, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, and C1-C4 alkyl. In a further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, methyl, and ethyl. In an even further aspect, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, and methyl.

[0160] In various aspects, each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, and methyl.

[0161] In various aspects, R1bis hydrogen and each of R1aand R1cis independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy. In a further aspect, R1bis hydrogen and each of R1aand R1cis independently selected from ‒ F, ‒Cl, methyl, ethyl, n-propyl, isopropyl, ‒CF3, ‒CHF2, ‒CH2F, ‒CH2CF3, ‒CH2CHF2, ‒ CH2CH2F, ‒CH(F)CH3, ‒CH(CH3)CF3, ‒CH(CH3)CHF2, ‒CH(CH3)CH2F, ‒CH2CH2CF3, ‒ CH2CH2CHF2, ‒CH2CH2CF3, ‒CH2CH(F)CH3, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒ CH2CHCl2, ‒CH2CH2Cl, ‒CH(Cl)CH3, ‒CH(CH3)CCl3, ‒CH(CH3)CHCl2, ‒CH(CH3)CH2Cl, ‒CH2CH2CCl3, ‒CH2CH2CHCl2, ‒CH2CH2CCl3, ‒CH2CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒ OCH(CH3)2, ‒OCH2CH2CH3, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒OCH2CF3, ‒OCH2CHF2, ‒ OCH2CH2F, ‒OCH(F)CH3, ‒OCH(CH3)CF3, ‒OCH(CH3)CHF2, ‒OCH(CH3)CH2F, ‒ OCH2CH2CF3, ‒OCH2CH2CHF2, ‒OCH2CH2CF3, ‒OCH2CH(F)CH3, ‒OCCl3, ‒OCHCl2, ‒ OCH2Cl, ‒OCH2CCl3, ‒OCH2CHCl2, ‒OCH2CH2Cl, ‒OCH(Cl)CH3, ‒OCH(CH3)CCl3, ‒ OCH(CH3)CHCl2, ‒OCH(CH3)CH2Cl, ‒OCH2CH2CCl3, ‒OCH2CH2CHCl2, ‒ OCH2CH2CCl3, and ‒OCH2CH(Cl)CH3. In yet a further aspect, R1bis hydrogen and each of R1aand R1cis independently selected from ‒F, ‒Cl, methyl, ethyl, ‒CF3, ‒CHF2, ‒CH2F, ‒ CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒CH2CHCl2, ‒ CH2CH2Cl, ‒CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒OCH(CH3)2, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒ OCH2CF3, ‒OCH2CHF2, ‒OCH2CH2F, ‒OCH(F)CH3, ‒OCCl3, ‒OCHCl2, ‒OCH2Cl, ‒ OCH2CCl3, ‒OCH2CHCl2, ‒OCH2CH2Cl, and ‒OCH(Cl)CH3. In an even further aspect, R1bis hydrogen and each of R1aand R1cis independently selected from ‒F, ‒Cl, methyl, ‒CF3, ‒ CHF2, ‒CH2F, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒OCH3, ‒OCF3, ‒OCHF2, ‒OCH2F, ‒OCCl3, ‒ OCHCl2, and ‒OCH2Cl.

[0162] In various aspects, R1bis hydrogen and each of R1aand R1cis independently selected from hydrogen, ‒F, ‒Cl and C1-C4 alkyl. In a further aspect, R1bis hydrogen andeach of R1aand R1cis independently selected from ‒F, ‒Cl, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, R1bis hydrogen and each of R1aand R1cis independently selected from ‒F, ‒Cl, methyl, and ethyl. In an even further aspect, R1bis hydrogen and each of R1aand R1cis independently selected from ‒F, ‒Cl, and methyl.

[0163] In various aspects, R1bis hydrogen and each of R1aand R1cis independently selected from hydrogen, ‒F, and methyl. f. R2AAND R2BGROUPS

[0001] In one aspect, each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1- C4 aminoalkyl. In yet a further aspect, each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl, ‒NH2, ‒OH, ‒NO2, ‒CN, methyl, ethyl, n-propyl, isopropyl, ‒CF3, ‒ CHF2, ‒CH2F, ‒CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CH(F)CH3, ‒CH(CH3)CF3, ‒ CH(CH3)CHF2, ‒CH(CH3)CH2F, ‒CH2CH2CF3, ‒CH2CH2CHF2, ‒CH2CH2CF3, ‒ CH2CH(F)CH3, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒CH2CHCl2, ‒CH2CH2Cl, ‒ CH(Cl)CH3, ‒CH(CH3)CCl3, ‒CH(CH3)CHCl2, ‒CH(CH3)CH2Cl, ‒CH2CH2CCl3, ‒ CH2CH2CHCl2, ‒CH2CH2CCl3, ‒CH2CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒OCH(CH3)2, ‒ OCH2CH2CH3, ‒NHCH3, ‒NHCH2CH3, ‒NHCH(CH3)2, ‒NHCH2CH2CH3, ‒N(CH3)2, ‒ N(CH3)CH2CH3, ‒N(CH2CH3)CH(CH3)2, ‒N(CH3)CH2CH2CH3, ‒CH2NH2, ‒CH2CH2NH2, ‒ CH(CH3)CH2NH2, and ‒CH2CH2CH2NH2. In an even further aspect, each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl, ‒NH2, ‒OH, ‒NO2, ‒CN, methyl, ethyl, ‒ CF3, ‒CHF2, ‒CH2F, ‒CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CH(F)CH3, ‒CCl3, ‒CHCl2, ‒ CH2Cl, ‒CH2CCl3, ‒CH2CHCl2, ‒CH2CH2Cl, ‒CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒NHCH3, ‒ NHCH2CH3, ‒N(CH3)2, ‒N(CH3)CH2CH3, ‒CH2NH2, and ‒CH2CH2NH2. In a still further aspect, each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl, ‒NH2, ‒OH, ‒ NO2, ‒CN, methyl, ‒CF3, ‒CHF2, ‒CH2F, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒OCH3, ‒NHCH3, ‒ N(CH3)2, and CH2NH2.

[0164] In various aspects, each of R2aand R2bis independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, each of R2aandR2bis independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, each of R2aand R2bis independently selected from ‒F, ‒ Cl, ‒NH2, ‒OH, ‒NO2, ‒CN, methyl, ethyl, n-propyl, isopropyl, ‒CF3, ‒CHF2, ‒CH2F, ‒ CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CH(F)CH3, ‒CH(CH3)CF3, ‒CH(CH3)CHF2, ‒ CH(CH3)CH2F, ‒CH2CH2CF3, ‒CH2CH2CHF2, ‒CH2CH2CF3, ‒CH2CH(F)CH3, ‒CCl3, ‒ CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒CH2CHCl2, ‒CH2CH2Cl, ‒CH(Cl)CH3, ‒CH(CH3)CCl3, ‒ CH(CH3)CHCl2, ‒CH(CH3)CH2Cl, ‒CH2CH2CCl3, ‒CH2CH2CHCl2, ‒CH2CH2CCl3, ‒ CH2CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒OCH(CH3)2, ‒OCH2CH2CH3, ‒NHCH3, ‒ NHCH2CH3, ‒NHCH(CH3)2, ‒NHCH2CH2CH3, ‒N(CH3)2, ‒N(CH3)CH2CH3, ‒ N(CH2CH3)CH(CH3)2, ‒N(CH3)CH2CH2CH3, ‒CH2NH2, ‒CH2CH2NH2, ‒CH(CH3)CH2NH2, and ‒CH2CH2CH2NH2. In an even further aspect, each of R2aand R2bis independently selected from ‒F, ‒Cl, ‒NH2, ‒OH, ‒NO2, ‒CN, methyl, ethyl, ‒CF3, ‒CHF2, ‒CH2F, ‒ CH2CF3, ‒CH2CHF2, ‒CH2CH2F, ‒CH(F)CH3, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒CH2CCl3, ‒ CH2CHCl2, ‒CH2CH2Cl, ‒CH(Cl)CH3, ‒OCH3, ‒OCH2CH3, ‒NHCH3, ‒NHCH2CH3, ‒ N(CH3)2, ‒N(CH3)CH2CH3, ‒CH2NH2, and ‒CH2CH2NH2. In a still further aspect, each of R2aand R2bis independently selected from ‒F, ‒Cl, ‒NH2, ‒OH, ‒NO2, ‒CN, methyl, ‒CF3, ‒ CHF2, ‒CH2F, ‒CCl3, ‒CHCl2, ‒CH2Cl, ‒OCH3, ‒NHCH3, ‒N(CH3)2, and CH2NH2.

[0165] In various aspects, each of R2aand R2bis independently selected from hydrogen, halogen, and C1-C6 alkyl. In a further aspect, each of R2aand R2bis independently selected from hydrogen, halogen, and C1-C4 alkyl. In a still further aspect, each of R2aand R2bis independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, each of R2aand R2bis independently selected from hydrogen, halogen, methyl, and ethyl. In an even further aspect, each of R2aand R2bis independently selected from hydrogen, halogen, and ethyl. In a still further aspect, each of R2aand R2bis independently selected from hydrogen, halogen, and methyl.

[0166] In various aspects, each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl, and C1-C6 alkyl. In a further aspect, each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl, and C1-C4 alkyl. In a still further aspect, each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl, methyl, and ethyl. In an even further aspect, each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl, and ethyl. In a still further aspect, each of R2aand R2bisindependently selected from hydrogen, ‒F, ‒Cl, and methyl.

[0167] In various aspects, each of R2aand R2bis independently selected from halogen and C1-C6 alkyl. In a further aspect, each of R2aand R2bis independently selected from halogen and C1-C4 alkyl. In a still further aspect, each of R2aand R2bis independently selected from halogen, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, each of R2aand R2bis independently selected from halogen, methyl, and ethyl. In an even further aspect, each of R2aand R2bis independently selected from halogen and ethyl. In a still further aspect, each of R2aand R2bis independently selected from halogen and methyl.

[0168] In various aspects, each of R2aand R2bis independently selected from ‒F and methyl.

[0169] In various aspects, each of R2aand R2bis hydrogen. g. R3GROUPS

[0170] In one aspect, R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒ NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21. In a further aspect, R3is selected from hydrogen, ‒OH, ‒OC(O)‒(C1-C8 alkyl)‒R21, ‒OC(O)‒(C4-C7 cycloalkyl)‒R21, ‒OC(O)‒ (C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NH2, ‒NH‒(C1-C8 alkyl)‒R21, ‒NH‒(C4-C7 cycloalkyl)‒R21, ‒NH‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NHC(O)‒(C1-C8 alkyl)‒R21, ‒ NHC(O)‒(C4-C7 cycloalkyl)‒R21, and ‒NHC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In a still further aspect, R3is selected from hydrogen, ‒OH, ‒OC(O)‒(C1-C8 alkyl)‒R21, ‒ OC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NH2, ‒NH‒(C1-C8 alkyl)‒R21, ‒NH‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NHC(O)‒(C1-C8 alkyl)‒R21, and ‒NHC(O)‒(C1-C4 alkyl)‒ O‒(C1-C4 alkyl)‒R21. In yet a further aspect, R3is selected from hydrogen, ‒OH, ‒OC(O)‒ (C1-C8 alkyl)‒R21, ‒NH2, ‒NH‒(C1-C8 alkyl)‒R21, and ‒NHC(O)‒(C1-C8 alkyl)‒R21.

[0171] In various aspects, R3is selected from ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒ R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21. In a further aspect, R3is selected from ‒OH, ‒ OC(O)‒(C1-C8 alkyl)‒R21, ‒OC(O)‒(C4-C7 cycloalkyl)‒R21, ‒OC(O)‒(C1-C4 alkyl)‒O‒ (C1-C4 alkyl)‒R21, ‒NH2, ‒NH‒(C1-C8 alkyl)‒R21, ‒NH‒(C4-C7 cycloalkyl)‒R21, ‒NH‒ (C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NHC(O)‒(C1-C8 alkyl)‒R21, ‒NHC(O)‒(C4-C7 cycloalkyl)‒R21, and ‒NHC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In a still further aspect, R3is selected from ‒OH, ‒OC(O)‒(C1-C8 alkyl)‒R21, ‒OC(O)‒(C1-C4 alkyl)‒O‒ (C1-C4 alkyl)‒R21, ‒NH2, ‒NH‒(C1-C8 alkyl)‒R21, ‒NH‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒ R21, ‒NHC(O)‒(C1-C8 alkyl)‒R21, and ‒NHC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. Inyet a further aspect, R3is selected from ‒OH, ‒OC(O)‒(C1-C8 alkyl)‒R21, ‒NH2, ‒NH‒(C1- C8 alkyl)‒R21, and ‒NHC(O)‒(C1-C8 alkyl)‒R21.

[0172] In various aspects, R3is selected from ‒OH and ‒OC(O)‒L‒R21. In a further aspect, R3is selected from ‒OH, ‒OC(O)‒(C1-C8 alkyl)‒R21, ‒OC(O)‒(C4-C7 cycloalkyl)‒ R21, and ‒OC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In a still further aspect, R3is selected from ‒OH, ‒OC(O)‒(C1-C8 alkyl)‒R21, and ‒OC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In yet a further aspect, R3is selected from ‒OH, and ‒OC(O)‒(C1-C8 alkyl)‒R21.

[0173] In various aspects, R3is selected from ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21. In a further aspect, R3is selected from ‒NH2, ‒NH‒(C1-C8 alkyl)‒R21, ‒ NH‒(C4-C7 cycloalkyl)‒R21, ‒NH‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NHC(O)‒(C1-C8 alkyl)‒R21, ‒NHC(O)‒(C4-C7 cycloalkyl)‒R21, and ‒NHC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In a still further aspect, R3is selected from ‒NH2, ‒NH‒(C1-C8 alkyl)‒R21, ‒ NH‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NHC(O)‒(C1-C8 alkyl)‒R21, and ‒NHC(O)‒(C1- C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In yet a further aspect, R3is selected from ‒NH2, ‒NH‒ (C1-C8 alkyl)‒R21, and ‒NHC(O)‒(C1-C8 alkyl)‒R21.

[0174] In various aspects, R3is selected from hydrogen, ‒OH, and ‒NH2. In a further aspect, R3is selected from hydrogen and ‒OH. In a still further aspect, R3is selected from hydrogen and ‒NH2.

[0175] In various aspects, R3is selected from ‒OH and ‒NH2. In a further aspect, R3is ‒OH. In a still further aspect, R3is ‒NH2.

[0176] In various aspects, R3is selected from ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒ C(O)‒R21, and NHC(O)‒L‒R21. In a further aspect, R3is selected from ‒OC(O)‒(C1-C8 alkyl)‒R21, ‒OC(O)‒(C4-C7 cycloalkyl)‒R21, ‒OC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NH‒(C1-C8 alkyl)‒R21, ‒NH‒(C4-C7 cycloalkyl)‒R21, ‒NH‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NHC(O)‒(C1-C8 alkyl)‒R21, ‒NHC(O)‒(C4-C7 cycloalkyl)‒R21, and ‒ NHC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In a still further aspect, R3is selected from ‒ OC(O)‒(C1-C8 alkyl)‒R21, ‒OC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NH‒(C1-C8 alkyl)‒R21, ‒NH‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21, ‒NHC(O)‒(C1-C8 alkyl)‒R21, and ‒ NHC(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In yet a further aspect, R3is selected from ‒ OC(O)‒(C1-C8 alkyl)‒R21, ‒NH‒(C1-C8 alkyl)‒R21, and ‒NHC(O)‒(C1-C8 alkyl)‒R21.

[0177] In various aspects, R3is selected from ‒OC(O)‒L‒R21‒L‒C(O)‒R21, and ‒ NHC(O)‒L‒R21. In a further aspect, R3is selected from ‒OC(O)‒L‒R21and NHC(O)‒L‒R21. In a still further aspect, R3is selected from ‒L‒C(O)‒R21and NHC(O)‒L‒R21. In yet afurther aspect, R3is selected from ‒OC(O)‒L‒R21and NHC(O)‒L‒R21. In an even further aspect, R3is ‒OC(O)‒L‒R21. In an even still further aspect, R3is ‒L‒C(O)‒R21. In yet an even further aspect, R3is ‒NHC(O)‒L‒R21.

[0178] In various aspects, R3is selected from ‒L‒C(O)‒R21and NHC(O)‒L‒R21. In a further aspect, R3is ‒L‒C(O)‒R21. In a still further aspect, R3is NHC(O)‒L‒R21. h. R4GROUPS

[0179] In one aspect, R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH. In a further aspect, R4is selected from hydrogen and ‒OH. In a still further aspect, R4is selected from hydrogen and ‒CH2OH.

[0180] In various aspects, R4is selected from ‒OH and ‒CH2OH. In a further aspect, R4is ‒OH. In a still further aspect, R4is ‒CH2OH.

[0181] In various aspects, R4is selected from hydrogen and C1-C4 alkyl. In a further aspect, R4is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, R4is selected from hydrogen, methyl and ethyl. In yet a further aspect, R4is selected from hydrogen and methyl.

[0182] In various aspects, R4is a C1-C4 alkyl. In a further aspect, R4is selected from methyl, ethyl, propyl, and isopropyl. In a still further aspect, R4is selected from methyl and ethyl. In yet a further aspect, R4is methyl.

[0183] In various aspects, R4is hydrogen. i. R10GROUPS

[0184] In one aspect, R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒ C(O)‒L‒R21. In a further aspect, R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, ‒ C(O)‒(C1-C8 alkyl)‒R21, ‒C(O)‒(C4-C7 cycloalkyl)‒R21, and ‒C(O)‒(C1-C4 alkyl)‒O‒(C1- C4 alkyl)‒R21. In a further aspect, R10is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, ‒C(O)R20, ‒C(O)‒(C1-C8 alkyl)‒R21, ‒C(O)‒(C4-C7 cycloalkyl)‒R21, and ‒C(O)‒ (C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In a still further aspect, R10is selected from hydrogen, methyl, ethyl, ‒C(O)R20, ‒C(O)‒(C1-C8 alkyl)‒R21, and ‒C(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In yet a further aspect, R10is selected from hydrogen, methyl, ‒C(O)R20, and ‒ C(O)‒(C1-C8 alkyl)‒R21.

[0185] In various aspects, R10is selected from hydrogen, C1-C4 alkyl, and ‒C(O)R20. In a further aspect, R10is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and ‒C(O)R20. In a still further aspect, R10is selected from hydrogen, methyl, ethyl, and ‒ C(O)R20. In yet a further aspect, R10is selected from hydrogen, methyl, and ‒C(O)R20.

[0186] In various aspects, R10is ‒C(O)‒L‒R21. In a further aspect, R10is selected from ‒C(O)‒(C1-C8 alkyl)‒R21, ‒C(O)‒(C4-C7 cycloalkyl)‒R21, and ‒C(O)‒(C1-C4 alkyl)‒ O‒(C1-C4 alkyl)‒R21. In a further aspect, R10is selected from ‒C(O)‒(C1-C8 alkyl)‒R21and ‒C(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In a still further aspect, R10is ‒C(O)‒(C1-C8 alkyl)‒R21. In yet a further aspect, R10is ‒C(O)‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl)‒R21. In an even further aspect, R10is ‒C(O)‒(C4-C7 cycloalkyl)‒R21.

[0187] In various aspects, R10is selected from hydrogen and C1-C4 alkyl. In a further aspect, R10is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R10is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R10is selected from hydrogen and ethyl. In an even further aspect, R10is selected from hydrogen and methyl.

[0188] In various aspects, R10is C1-C4 alkyl. In a further aspect, R10is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R10is selected from methyl and ethyl. In yet a further aspect, R10is ethyl. In an even further aspect, R10is methyl.

[0189] In various aspects, R10is hydrogen. j. R20GROUPS

[0190] In one aspect, R20is selected from C1-C4 alkyl and Ar1. In a further aspect, R20is selected from methyl, ethyl, n-propyl, isopropyl, and Ar1. In a still further aspect, R20is selected from methyl, ethyl, n-propyl, isopropyl, and Ar1. In yet a further aspect, R20is selected from methyl, ethyl, and Ar1. In an even further aspect, R20is selected from ethyl and Ar1. In a still further aspect, R20is selected from methyl and Ar1.

[0191] In various aspects, R20is C1-C4 alkyl. In a further aspect, R20is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R20is selected from methyl and ethyl. In yet a further aspect, R20is ethyl. In a still further aspect, R20is methyl.

[0192] In various aspects, R20is Ar1. k. R21GROUPS

[0193] In one aspect, R21is a residue of a rifamycin analog (e.g., a rifamycin analog minus a proton). In a further aspect, the residue of the rifamycin analog has a structure represented by a formula selected from:,

[0194] In a still further aspect, the residue of the rifamycin analog has a structure represented by a formula selected from:wherein R22is selected from C1-C4 alkyl and C1-C4 alkoxy.

[0195] In various aspects, the residue of the rifamycin analog has a structure:.

[0196] In various aspects, the residue of the rifamycin analog has a structure:.

[0197] In various aspects, the residue of the rifamycin analog has a structure:.

[0198] In various aspects, the residue of the rifamycin analog has a structure:.

[0199] In various aspects, the residue of the rifamycin analog has a structure:. l. R22GROUPS

[0001] In one aspect, R22is selected from C1-C4 alkyl and C1-C4 alkoxy. In a further aspect, R22is selected from methyl, ethyl, n-propyl, isopropyl, ‒OCH3, ‒OCH2CH3, ‒ OCH(CH3)2, and ‒OCH2CH2CH3. In a further aspect, R22is selected from methyl, ethyl, ‒ OCH3, and ‒OCH2CH3. In a still further aspect, R22is selected from methyl and ‒OCH3.

[0002] In various aspects, R22is C1-C4 alkyl. In a further aspect, R22is selected from methyl, ethyl, n-propyl, and isopropyl. In a further aspect, R22is selected from methyl and ethyl. In a still further aspect, R22is methyl.

[0003] In various aspects, R22is C1-C4 alkoxy. In a further aspect, R22is selected from ‒ OCH3, ‒OCH2CH3, ‒OCH(CH3)2, and ‒OCH2CH2CH3. In a further aspect, R22is selected from ‒OCH3and ‒OCH2CH3. In a still further aspect, R22is ‒OCH3. m. R80GROUPS

[0200] In one aspect, R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl.

[0201] In various aspects, R80is selected from a C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl. In a further aspect, R80is selected from a C4-C8 alkyl, C4-C8 alkenyl, and C4-C8 alkynyl.

[0202] In various aspects, R80is a C2-C8 alkenyl. In a further aspect, R80has a structure represented by a formula selected from:, , ,,.

[0203] In a further aspect, R80has a structure represented by a formula:.

[0204] In a further aspect, R80has a structure represented by a formula selected from:.

[0205] In a further aspect, R80has a structure represented by a formula selected from:.

[0206] In a further aspect, R80is a C1-C8 alkyl. In a still further aspect, R80is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, tert- pentyl, 3,3-dimethylbutan-2-yl, or 2,3-dimethylbutan-2-yl. In a yet further aspect, R80is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, or tert-butyl. In an even further aspect, R80is methyl, ethyl, propyl, or isopropyl. n. AR1GROUPS

[0207] In one aspect, Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, Ar1is C6 aryl substituted with 1 or 2 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a still further aspect, Ar1is C6 aryl monosubstituted with a group selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. o. AR2GROUPS

[0208] In one aspect, Ar2is selected from C6 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, Ar2is selected from C6 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a still further aspect, Ar2is selected from C6 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In yet a further aspect, Ar2is selected from C6 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In an even further aspect, Ar2is selected from C6 aryl and C2-C9 heteroaryl, and is unsubstituted.

[0209] In various aspects, Ar2is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, Ar2is C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a still further aspect, Ar2is C6 aryl substituted with 0 or 1 group selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In yet a further aspect,Ar2is C6 aryl monosubstituted with a group selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In an even further aspect, Ar2is unsubstituted C6 aryl.

[0210] In various aspects, Ar2is C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. Examples of C2-C9 heteroaryls include, but are not limited to, pyridinyl, pyrimidinyl, indolinyl, indolyl, oxazolyl, thiazolyl, isoxazolyl, and pyrazolyl. In a further aspect, Ar2is C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a still further aspect, Ar2is C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ‒NH2, ‒OH, ‒ NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1- C6) dialkylamino, and C1-C6 aminoalkyl. In yet a further aspect, Ar2is C2-C9 heteroaryl monosubstituted with a group selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1- C6 aminoalkyl. In an even further aspect, Ar2is unsubstituted C2-C9 heteroaryl.

[0211] In various aspects, Ar2is a structure represented by a formula:. 2.EXEMPLARY COMPOUNDS

[0212] In one aspect, a compound can be present as one or more of the following structures:,,,,N O F O O F ONHO O O N N N H N HN H F N O O O O N,O NH HO HO OH OHOOOO O,,,,,,,,,, or a pharmaceutically acceptable salt thereof.

[0213] In one aspect, a compound can be present as one or more of the following structures:, or a pharmaceutically acceptable salt thereof. 3. PROPHETICEXEMPLARYCOMPOUNDS

[0214] The following and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be active as activators of ClpA protease, and such activity can be determined using the assay methods described herein below.

[0215] Thus, in one aspect, a compound is:. or a pharmaceutically acceptable salt thereof.

[0216] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[0217] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[0218] It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like. C. METHODS OF MAKING THE COMPOUNDS

[0219] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents areallowed under the definitions disclosed herein.

[0220] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-III, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1. ROUTE I

[0221] In one aspect, the disclosed compounds can be prepared as shown below. SCHEME 1A.

[0222] Compounds are represented in generic form, wherein PG is an amine protecting group and wherein L’ and R21’generally correspond to L and R21groups, as described elsewhere herein. As would be appreciated by one of ordinary skill in the art, however, the boundaries of which portion of the compound correspond to L / L’ and which correspond to R21 / R21’may differ slightly. Thus, while R21can include an imine group, as drawn above R21’does not. Other substituents are as noted in compound descriptions elsewhere herein. A specific non-limiting example of the synthesis shown in Scheme 1A is provided below. SCHEME 1B.

[0223] In one aspect, compounds of type 1.12, and similar compounds, can be prepared according to reaction Scheme 1B above. Thus, compounds of type 1.9 can be prepared by a coupling reaction between an appropriate alcohol, e.g.1.7 as shown above, and an appropriate carboxylic acid, e.g., 1.8 as shown above. Appropriate alcohols and appropriate carboxylic acids are commercially available or prepared by methods known to one of skill in the art. The coupling reaction is carried out in the presence of an appropriate coupling agent, e.g., 2,4,6-trichlorobenzyl chloride, an appropriate activating agent, e.g., 4- dimethylaminopyridine (DMAP), and an appropriate base, e.g., triethylamine (TEA), in an appropriate solvent, e.g., diisopropylethylamine (DIPEA). Compounds of type 1.10 can be prepared by deprotection of an appropriate amine, e.g., 1.9 as shown above. The deprotectioncan be carried out in the presence of an appropriate deprotecting agent, e.g., hydrogen gas with 10% palladium on carbon, in an appropriate solvent, e.g., methanol. Compounds of type 1.12 can be prepared by a condensation reaction between an appropriate amine, e.g., 1.10 as shown above, and an appropriate aldehyde, e.g., 1.11 as shown above. Appropriate aldehydes are commercially available or prepared by methods known to one of skill in the art. The condensation reaction can be carried out in the presence of an appropriate acid, e.g., 2N acetic acid (AcOH), in an appropriate protic solvent, e.g., methanol. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 1.1, 1.2, 1.3, 1.4, and 1.5) can be substituted in the reaction to provide compounds similar to Formula 1.6. 2. ROUTE II

[0224] In one aspect, the disclosed compounds can be prepared as shown below. SCHEME2A.

[0225] Compounds are represented in generic form, wherein PG is an amine protecting group and wherein L’ and R21’generally correspond to L and R21groups, as described elsewhere herein. As would be appreciated by one of ordinary skill in the art, however, the boundaries of which portion of the compound correspond to L / L’ and which correspond to R21 / R21’may differ slightly. Thus, while R21can include an imine group, as drawn above R21’does not. Other substituents are as noted in compound descriptions elsewhere herein. A specific non-limiting example of the synthesis shown in Scheme 2A is provided below. SCHEME 2B.

[0226] In one aspect, compounds of type 2.12, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 1.9 can be prepared by a coupling reaction between an appropriate amine, e.g.2.7 as shown above, and an appropriate carboxylic acid, e.g., 2.8 as shown above. Appropriate amines and appropriate carboxylic acids are commercially available or prepared by methods known to one of skill in the art. The coupling reaction is carried out in the presence of an appropriate coupling agent, e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), and an appropriate base, e.g., N,N-diisopropylethylamine (DIEA), in an appropriate solvent, e.g., dimethylformamide (DMF). Compounds of type 2.10 can be prepared by deprotection of an appropriate amine, e.g., 2.9 as shown above. The deprotection can be carried out in the presence of an appropriate deprotecting agent, e.g., hydrogen gas with 10% palladium on carbon, in an appropriate solvent, e.g., methanol. Compounds of type 2.12 can be prepared by a condensation reaction between an appropriate amine, e.g., 2.10 as shown above, and an appropriate aldehyde, e.g., 2.11 as shown above. Appropriate aldehydes are commercially available or prepared by methods known to one of skill in the art. The condensation reaction can be carried out in the presence of an appropriate acid, e.g., 2N acetic acid (AcOH), in anappropriate protic solvent, e.g., methanol. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 2.1, 2.2, 2.3, 2.4, and 2.5) can be substituted in the reaction to provide compounds similar to Formula 2.6. 3.ROUTEIII

[0227] In one aspect, the disclosed compounds can be prepared as shown below. SCHEME 3A.

[0228] Compounds are represented in generic form, wherein PG is an amine protecting group and wherein L’ and R21’generally correspond to L and R21groups, as described elsewhere herein. As would be appreciated by one of ordinary skill in the art, however, the boundaries of which portion of the compound correspond to L / L’ and which correspond to R21 / R21’may differ slightly. Thus, while R21can include an imine group, as drawn above R21’does not. Other substituents are as noted in compound descriptions elsewhere herein. A specific non-limiting example of the synthesis shown in Scheme 3A is provided below. SCHEME 3B.

[0229] In one aspect, compounds of type 3.14, and similar compounds, can be prepared according to reaction Scheme 3B above. Thus, compounds of type 3.10 can be prepared by a coupling reaction between an appropriate amine, e.g.3.8 as shown above, and an appropriate carboxylic acid, e.g., 3.9 as shown above. Appropriate amines and appropriate carboxylic acids are commercially available or prepared by methods known to one of skill in the art. The coupling reaction is carried out in the presence of an appropriate coupling agent, e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), and an appropriate base, e.g., N,N-diisopropylethylamine (DIEA), in an appropriate solvent, e.g., dimethylformamide (DMF). Compounds of type 3.13 can be prepared by a condensation reaction between an appropriate aldehyde, e.g., 3.11 as shown above, and an appropriate hydrazine, e.g., 3.12 as shown above. Appropriate aldehydes and appropriate hydrazines are commercially available or prepared by methods known to one of skill in the art. The condensation reaction can be carried out in the presence of an appropriate acid, e.g., 2N acetic acid (AcOH), in an appropriate protic solvent, e.g., methanol. Compounds of type 3.14 can be prepared by click chemistry of an appropriate alkyne, e.g., 3.10 as shown above, and an appropriate azide, e.g., 3.13 as shown above. The click chemistry reaction is carried out in the presence of an appropriate catalyst, e.g., copper sulfate, and an appropriate scavenger, e.g., sodium ascorbate, in an appropriate solvent, e.g., water in tetrahydrofuran, at an appropriate temperature, e.g., room temperature. As can be appreciated by one skilled in the art the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactions above (compounds similar to 3.1, 3.2, 3.3, 3.4, 3.5, and 3.6) can be substituted in the reaction to provide compounds similar to Formula 3.7. D. PHARMACEUTICAL COMPOSITIONS

[0230] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, useful in treating infectious diseases such as, for example, biofilm-mediated diseases and infectious diseases due to prosthetic joint infections, intracellular bacteria, and Gram-positive bacteria (e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus,Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae). Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0231] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1; wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0232] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0233] In various aspects, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0234] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., intravenous, topical, or oral administration.

[0235] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many ofwhich are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0236] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0237] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0238] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0239] In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques

[0240] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0241] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0242] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0243] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectablesolutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably 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 (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0244] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0245] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0246] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[0247] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[0248] In a further aspect, the pharmaceutical composition is used to treat an infectious disease. Examples of infectious diseases include, but are not limited to, biofilm- mediated diseases (e.g., bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, an urinary tract infection (UTI), periodontitis, a wound infection, a diabetic foot ulcer, a catheter-associated bloodstream infection, an implant-associated infection, ventilator-associated pneumonia, osteomyelitis), infectious diseases due to a prosthetic joint infection, infectious diseases due to intracellular bacteria, infectious diseases due to a Gram-positive bacterial infection (e.g., methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, an enterococcal infection, a vancomycin-resistant enterococci (VRE) infection, anthrax, toxic shock).

[0249] In various aspects, the pharmaceutical composition is used to treat an infectious disease due to a Gram-positive bacterial infection. In a further aspect, the Gram- positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp.. In a still further aspect, Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE). In yet a further aspect, the Gram-positive bacterial infection is due to a Gram- positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. In an even further aspect, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes. In a still further aspect, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).

[0250] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. E. METHODS OF TREATING AN INFECTIOUS DISEASE

[0251] In one aspect, disclosed are methods for treating an infectious disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby treating theinfectious disease in the subject. Thus, in various aspects, disclosed are methods for treating an infectious disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0252] In various aspects, the compound has a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1; wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0253] In various aspects, the compound has a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0254] In various aspects, the compound has a structure represented by a formula:,wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0255] In various aspects, the subject is a mammal. In a further aspect, the subject is a human.

[0256] In various aspects, the effective amount is a therapeutically effective amount. In a further aspect, the effective amount is a prophylactically effective amount.

[0257] In various aspects, the infectious disease is a biofilm-mediated disease. Examples of biofilm-mediated diseases include, but are not limited to, bacterial endocarditis, bacteremia, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, a wound infection, a diabetic foot ulcer, a catheter-associated bloodstream infection, an implant-associated infection, ventilator-associated pneumonia, and osteomyelitis.

[0258] In various aspects, the infectious disease is due to a prosthetic joint infection.

[0259] In various aspects, the infectious disease is due to or complicated by the presence of intracellular bacteria.

[0260] In various aspects, the infectious disease is due to a Gram-positive bacterial infection. Examples of Gram-positive bacterial infections include, but are not limited to, methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, an enterococcal infection, a vancomycin-resistant enterococci (VRE) infection, anthrax, and toxic shock. In a further aspect, the Gram-positive bacterial infection is methicillin-resistantStaphylococcus aureus (MRSA).

[0261] In various aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp. In a further aspect, Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE).

[0262] In various aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. In a further aspect, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes. In a still further aspect, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).

[0263] In various aspects, the compound kills intracellular pathogens such as, for example, S. aureus with a 2-log decrease in intracellular colony counts after 24 hours of exposure. In various further aspects, the compound kills intracellular pathogens such as, for example, S. aureus with a 1.5-log decrease in intracellular colony counts after 24 hours of exposure. In various further aspects, the compound kills intracellular pathogens such as, for example, S. aureus with a 1.0-log decrease in intracellular colony counts after 24 hours of exposure. In various further aspects, the compound kills intracellular pathogens such as, for example, S. aureus with a 2.5-log decrease in intracellular colony counts after 24 hours of exposure.

[0264] In various aspects, the subject has been diagnosed with a need for treatment of the infectious disease prior to the administering step. In a further aspect, the method further comprises the step of identifying a subject in need of treatment of the infectious disease.

[0265] In various aspects, the method further comprises administering to the subject an effective amount of an antibacterial agent. Examples of antibacterial agents include, but are not limited to, amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin,carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin.

[0266] In various aspects, the compound and the antibacterial agent are administered simultaneously. In a further aspect, the compound and the antibacterial agent are administered sequentially.

[0267] In various aspects, the compound and the antibacterial agent are co-formulated. In a further aspect, the compound and the antibacterial agent are co-administered. F. METHODS OF ACTIVATING CLPP PROTEASE IN CELLS

[0268] In one aspect, disclosed are methods for activating ClpP proteasein a cell, the method comprising the step of contacting the cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt. Thus, in various aspects, disclosed are methods for activating ClpP proteasein a cell, the method comprising the step of contacting the cell with an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0269] In various aspects, the compound has a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1;wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0270] In various aspects, the compound has a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0271] In various aspects, the compound has a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptablecarrier.

[0272] In one aspect, the cell is a bacterial cell. In a further aspect, the cell is a Gram- positive bacterial cell. In a still further aspect, the cell is a Gram-negative bacterial cell. In an even further aspect, the cell is a fungus. In a still further aspect, the cell has been isolated from a subject prior to the contacting step. In a yet further aspect, contacting the cell is via administration of the compound to a subject. In an even further aspect, the cell is a bacterial cell, and is infecting a subject.

[0273] In a further aspect, the subject has been diagnosed with a need for treatment of an infectious disease prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject in need of activating ClpP protease prior to the administering step. In a yet further aspect, activating ClpP protease treats an infectious disease in a subject. In a yet further aspect, the subject has been diagnosed with a need for activating ClpP protease prior to the administering step.

[0274] In a further aspect, the subject has been diagnosed with a need for treatment of a biofilm mediated disease prior to the administering step. In a yet further aspect, activating ClpP protease treats a biofilm-mediated disease in a subject. In a still further aspect, the biofilm-mediated disease is due to a prosthetic joint infection. In a still further aspect, the biofilm-mediated disease is due to a Gram-positive bacterial infection. In a yet further aspect, the method further comprises the step of identifying a subject in need of treatment of the biofilm mediated disease with a low potential for resistance development.

[0275] In a further aspect, contacting the cell treats an infectious disease. In a still further aspect, the infectious disease is selected from is selected from bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, and osteomyelitis.

[0276] In a further aspect, the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, and toxic shock. In a still further aspect, the Gram-positive bacterial infection is methicillin-resistant Staphylococcus aureus (MRSA). In a still further aspect, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp. In a yet further aspect, Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE). In various aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani,Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, and Streptococcus pyogenes. In further aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes. In still further aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).

[0277] In a further aspect, the method further comprises contacting the cell with an effective amount of an antibacterial agent. In various aspects, the method further comprises contacting the cell with the compound and at least one antibacterial agent. In a still further aspect, the compound and the antibacterial agent are administered simultaneously. In a yet further aspect, the compound and the antibacterial agent are co-formulated. In an even further aspect, the compound and the antibacterial agent are administered sequentially.

[0278] In a further aspect, the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim,troleandomycin, trovafloxacin, and vancomycin. G. METHODS OF ACTIVATING CLPP PROTEASE IN A SUBJECT

[0279] In one aspect, disclosed are methods for activating ClpP protease in a subject, the method comprising the step administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, thereby activating ClpP protease in the subject. Thus, in various aspects, disclosed are methods for activating ClpP protease in a subject, the method comprising the step of administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0280] In various aspects, the compound has a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1; wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0281] In various aspects, the compound has a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0282] In various aspects, the compound has a structure represented by a formula:,wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0283] In a further aspect, the compound administered is a product of a disclosed method of making a compound. In a still further aspect, an effective amount is a therapeutically effective amount. In a yet further aspect, an effective amount is a prophylactically effective amount.

[0284] In one aspect, the subject is a mammal. In a further aspect, the subject is a human.

[0285] In a further aspect, the subject has been diagnosed with a need for activating ClpP protease prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject in need of activating ClpP protease prior to the administering step. In a yet further aspect, activating ClpP protease treats an infectious disease in a subject. In a yet further aspect, the subject has been diagnosed with a need for activating ClpP protease prior to the administering step.

[0286] In a further aspect, the subject has been diagnosed with a need for treatment of a biofilm mediated disease prior to the administering step. In a yet further aspect, activating ClpP protease treats a biofilm-mediated disease in a subject. In a still further aspect, the biofilm-mediated disease is due to a prosthetic joint infection. In a still further aspect, the biofilm-mediated disease is due to a Gram-positive bacterial infection. In a yet further aspect, the method further comprises the step of identifying a subject in need of treatment of the biofilm mediated disease.

[0287] In a further aspect, activating ClpP protease in a subject treats an infectious disease. In a still further aspect, the infectious disease is selected from is selected from bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, and osteomyelitis.

[0288] In a further aspect, the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, and toxic shock. In a still further aspect, the Gram-positive bacterial infection is methicillin-resistant Staphylococcus aureus (MRSA). In a still further aspect, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp. In a yet further aspect, Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE). In various aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, and Streptococcus pyogenes. In further aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes. In still further aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).

[0289] In a further aspect, the method further comprises administering to the subject an effective amount of an antibacterial agent. In various aspects, the method further comprises administering to the subject an effective amount of the compound and at least one antibacterial agent. In a still further aspect, the compound and the antibacterial agent are administered simultaneously. In a yet further aspect, the compound and the antibacterial agent are co-formulated. In an even further aspect, wherein the compound and the antibacterial agent are administered sequentially.

[0290] In a further aspect, the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil,cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin.

[0291] In a yet further aspect, the administration in a substantially simultaneous manner comprises a single dose form containing a fixed ratio of the compound and the antibacterial agent. In an even further aspect, the single dose form is a capsule or a tablet. In a still further aspect, the single dose form is an ampule for a single intravenous administration. In a yet further aspect, the co-administration is administration in a substantially sequential manner. H. METHODS OF INHIBITING RNA POLYMERASE ACTIVITY IN CELLS

[0292] In one aspect, disclosed are methods for inhibiting RNA polymerase activity in a cell, the method comprising the step of contacting the cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt. Thus, in various aspects, disclosed are methods for inhibiting RNA polymerase activity in a cell, the method comprising the step of contacting the cell with an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0293] In various aspects, the compound has a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1;wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0294] In various aspects, the compound has a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0295] In various aspects, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or Xis ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0296] In one aspect, the cell is a bacterial cell. In a further aspect, the cell is a Gram- positive bacterial cell. In a still further aspect, the cell is a Gram-negative bacterial cell. In an even further aspect, the cell is a fungus. In a still further aspect, the cell has been isolated from a subject prior to the contacting step. In a yet further aspect, contacting the cell is via administration of the compound to a subject. In an even further aspect, the cell is a bacterial cell, and is infecting a subject.

[0297] In a further aspect, the subject has been diagnosed with a need for treatment of an infectious disease prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject in need of inhibiting RNA polymerase activity prior to the administering step. In a yet further aspect, inhibiting RNA polymerase activity treats an infectious disease in a subject. In a yet further aspect, the subject has been diagnosed with a need for inhibiting RNA polymerase activity prior to the administering step.

[0298] In a further aspect, the subject has been diagnosed with a need for treatment of a biofilm-mediated disease prior to the administering step. In a yet further aspect, inhibiting RNA polymerase activity treats a biofilm-mediated disease in a subject. In a still further aspect, the biofilm-mediated disease is due to a prosthetic joint infection. In a still further aspect, the biofilm-mediated disease is due to a Gram-positive bacterial infection. In a yet further aspect, the method further comprises the step of identifying a subject in need of treatment of the biofilm mediated disease.

[0299] In a further aspect, contacting the cell treats an infectious disease. In a still further aspect, the infectious disease is selected from is selected from bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, and osteomyelitis.

[0300] In a further aspect, the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, and toxic shock. In a still further aspect, the Gram-positive bacterial infection is methicillin-resistant Staphylococcus aureus (MRSA). In a still further aspect, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp. In a yet further aspect, Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE). In various aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillusanthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, and Streptococcus pyogenes. In further aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes. In still further aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).

[0301] In a further aspect, the method further comprises contacting the cell with an effective amount of an antibacterial agent. In various aspects, the method further comprises contacting the cell with the compound and at least one antibacterial agent. In a still further aspect, the compound and the antibacterial agent are administered simultaneously. In a yet further aspect, the compound and the antibacterial agent are co-formulated. In an even further aspect, the compound and the antibacterial agent are administered sequentially.

[0302] In a further aspect, the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone,thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin. I. METHODS OF INHIBITING RNA POLYMERASE ACTIVITY IN A SUBJECT

[0303] In one aspect, disclosed are methods for inhibiting RNA polymerase activity in a subject, the method comprising the step administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, thereby inhibiting RNA polymerase activity in the subject. Thus, in various aspects, disclosed are methods for inhibiting RNA polymerase activity in a subject, the method comprising the step of administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, orNHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0304] In various aspects, the compound has a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1; wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0305] In various aspects, the compound has a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0306] In various aspects, the compound has a structure represented by a formula:,wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0307] In a further aspect, the compound administered is a product of a disclosed method of making a compound. In a still further aspect, an effective amount is a therapeutically effective amount. In a yet further aspect, an effective amount is a prophylactically effective amount.

[0308] In one aspect, the subject is a mammal. In a further aspect, the subject is a human.

[0309] In a further aspect, the subject has been diagnosed with a need for inhibiting RNA polymerase activity prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject in need of inhibiting RNA polymerase activity prior to the administering step. In a yet further aspect, inhibiting RNA polymerase activity treats an infectious disease in a subject. In a yet further aspect, the subject has been diagnosed with a need for inhibiting RNA polymerase activity prior to the administering step.

[0310] In a further aspect, the subject has been diagnosed with a need for treatment of a biofilm-mediated disease prior to the administering step. In a yet further aspect, inhibiting RNA polymerase activity treats a biofilm-mediated disease in a subject. In a still further aspect, the biofilm-mediated disease is due to a prosthetic joint infection. In a still further aspect, the biofilm-mediated disease is due to a Gram-positive bacterial infection. In a yet further aspect, the method further comprises the step of identifying a subject in need of treatment of the biofilm mediated disease.

[0311] In a further aspect, inhibiting RNA polymerase activity in a subject treats an infectious disease. In a still further aspect, the infectious disease is selected from is selected from bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, and osteomyelitis.

[0312] In a further aspect, the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, and toxic shock. In a still further aspect, the Gram-positive bacterial infection is methicillin-resistant Staphylococcus aureus (MRSA). In a still further aspect, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp. In a yet further aspect, Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE). In various aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, and Streptococcus pyogenes. In further aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes. In still further aspects, the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).

[0313] In a further aspect, the method further comprises administering to the subject an effective amount of an antibacterial agent. In various aspects, the method further comprises administering to the subject an effective amount of the compound and at least one antibacterial agent. In a still further aspect, the compound and the antibacterial agent are administered simultaneously. In a yet further aspect, the compound and the antibacterial agent are co-formulated. In an even further aspect, wherein the compound and the antibacterial agent are administered sequentially.

[0314] In a further aspect, the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil,cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin.

[0315] In a yet further aspect, the administration in a substantially simultaneous manner comprises a single dose form containing a fixed ratio of the compound and the antibacterial agent. In an even further aspect, the single dose form is a capsule or a tablet. In a still further aspect, the single dose form is an ampule for a single intravenous administration. In a yet further aspect, the co-administration is administration in a substantially sequential manner. J. METHODS OF USING THE COMPOUNDS AND COMPOSITIONS

[0316] Provided herein are methods of using a disclosed compound or composition as a medicament. In one aspect, the method of use is directed to the treatment of an infectious disease. In a further aspect, the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy can also beadministered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent.

[0317] In one aspect, the compounds can be co-administered with an antibacterial agent. In a further aspect, the compounds can be co-administered with an antibacterial agent selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin, or combinations thereof.

[0318] In a further aspect, the compounds can be administered in combination with one or more antibacterial agents, and salts thereof and combinations thereof. In a still further aspect, the compounds can be administered in combination with an antibacterial agent selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid,kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin, or combinations thereof.

[0319] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein, which are usually applied in the treatment of the above mentioned pathological conditions. 1.MANUFACTURE OF A MEDICAMENT

[0320] In one aspect, the invention relates to a method for the manufacture of a medicament comprising one or more disclosed compounds, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for treating an infectious disease. In a further aspect, the one or more compounds is a product of a disclosed method of making.

[0004] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in treatment of an infectious disease, such as, for example, biofilm-mediated diseases and infectious diseases due to prosthetic joint infections, intracellular bacteria, and Gram-positive bacteria (e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae) as further disclosed herein. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time- frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severityand stage of the disease or disorder.

[0321] In various aspect, the invention relates methods for the manufacture of a medicament for enhancing the activity of ClpP protease (e.g., treatment of one or more infectious diseases) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, with a pharmaceutically acceptable carrier. It is understood that the disclosed methods can be performed with the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed methods can be employed in connection with the disclosed methods of using. 2. USE OF COMPOUNDS AND COMPOSITIONS

[0322] Also provided are uses of the disclosed compounds, compositions, and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt thereof for treating an infectious disease in a subject. In a further aspect, the compound used is a product of a disclosed method of making.

[0323] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0324] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[0005] In various aspects, the use relates to a treatment of an infectious disease in a subject. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the infectious disease is a biofilm-mediated disease or an infectious disease due to a prosthetic joint infection, an intracellular bacteria, or a Gram-positive bacteria (e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus,Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae).

[0325] In a further aspect, the use relates to the manufacture of a medicament for the treatment of a disease or disorder due to oxidative stress in a subject.

[0326] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for treating an infectious disease in a mammal. In a still further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disease or disorder due to oxidative stress in a mammal. 3. SUBJECTS

[0327] In various aspects, the subject of the disclosed methods is a vertebrate, e.g., a mammal. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0328] In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for treatment of an infectious disease prior to the administering step. some aspects of the disclosed methods, the subject has been identified with a need for treatment prior to the administering step. In one aspect, a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere. a. DOSAGE

[0329] Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LD50(the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50.

[0330] Data obtained from cell culture assays and further animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity, and with little or no adverse effect on a human's ability to hear. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any agents used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (that is, the concentration of the test compound which achieves a half- maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Exemplary dosage amounts of a differentiation agent are at least from about 0.01 to 3000 mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day, or more.

[0331] The formulations and routes of administration can be tailored to the disease or disorder being treated, and for the specific human being treated. For example, a subject can receive a dose of the agent once or twice or more daily for one week, one month, six months, one year, or more. The treatment can continue indefinitely, such as throughout the lifetime of the human. Treatment can be administered at regular or irregular intervals (once every other day or twice per week), and the dosage and timing of the administration can be adjusted throughout the course of the treatment. The dosage can remain constant over the course of the treatment regimen, or it can be decreased or increased over the course of the treatment.

[0332] In various aspects, the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation, or allergic response. Although individual needs may vary, the determination of optimal ranges for effective amounts of formulations is within the skill of the art. Human doses can readily be extrapolated from animal studies (Katocs et al., (1990) Chapter 27 in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA). In general, the dosage required to provide an effective amount of a formulation, which can be adjusted by one skilled in the art, will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman's ThePharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, NY). b.ROUTES OF ADMINISTRATION

[0333] Also provided are routes of administering the disclosed compounds and compositions. The compounds and compositions of the present invention can be administered by direct therapy using systemic administration and / or local administration. In various aspects, the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient. In various aspects, an individual patient's therapy may be customized, e.g., the type of agent used, the routes of administration, and the frequency of administration can be personalized. Alternatively, therapy may be performed using a standard course of treatment, e.g., using pre-selected agents and pre-selected routes of administration and frequency of administration.

[0334] Systemic routes of administration can include, but are not limited to, parenteral routes of administration, e.g., intravenous injection, intramuscular injection, and intraperitoneal injection; enteral routes of administration e.g., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g., ear drops), syrups, suspensions and emulsions; rectal administration, e.g., a rectal suppository or enema; a vaginal suppository; a urethral suppository; transdermal routes of administration; and inhalation (e.g., nasal sprays).

[0335] In various aspects, the modes of administration described above can be combined in any order. 4. KITS

[0336] In one aspect, disclosed are kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an antimicrobial agent; (b) instructions for treating an infectious disease; and (3) instructions for administering the compound in connection with treating an infectious disease. Thus, in various aspects, disclosed are kits comprising a compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0337] In various aspects, the compound has a structure represented by a formula:, wherein Y is selected from R80and –NH–(Q)q–Ar2; wherein q is selected from 0 and 1;wherein Q is selected from ‒CH2‒, ‒CH2CH2‒, ‒CH=CH‒, and ‒(cyclopropyl)‒; wherein R80is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ─(C1-C8 alkyl)─(C3-C8 cycloalkyl), ─(C1-C8 alkyl)─(C3-C8 cycloalkenyl), ─(C2-C8 alkenyl)─(C3-C8 cycloalkyl), and ─(C2-C8 alkenyl)─(C3-C8 cycloalkenyl; wherein Ar2is selected from C6 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒ C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒ CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒ R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

[0338] In various aspsects, the compound has a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH; and wherein R5is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and one or more selected from: (a) an antimicrobial agent; (b) instructions for treating an infectious disease; and (3) instructions for administering the compound in connection with treating an infectious disease.

[0339] In various aspects, the compound has a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, and NHC(O)‒L‒R21; and wherein R4is selected from hydrogen, ‒OH, and ‒CH2OH, or a pharmaceutically acceptablesalt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, or NHC(O)‒L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21, and a pharmaceutically acceptable carrier.

[0340] In various aspects, the antimicrobial agent is selected from an antibacterial agent, an antiviral agent, an antifungal agent, and an antiparasitic agent.

[0341] In various aspects, the antimicrobial agent is an antibacterial agent. Examples of antibacterial agents include, but are not limited to, amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin.

[0342] In various aspects, the antimicrobial agent is an antiviral agent. Examples of antiviral agents include, but are not limited to, acyclovir, oseltamivir, cidofovir, lamivudine, nitazoxanide, ribavirin, famciclovir, foscarnet, vidarabine, and fomibirsen.

[0343] In various aspects, the antimicrobial agent is an antifungal agent. Examples of antifungal agents include, but are not limited to, clotrimazole, econazole, micronazole, terbinafine, fluconazole, ketoconazole, nystatin, and amphotericin.

[0344] In various aspects, the antimicrobial agent is an antiparasitic agent. Examples of antiparasitic agents include, but are not limited to, metronidazole, furazolidone, tinidazole, albendazole, pyrantel pamoate, ivermectin, chloroquine, quinine, mefloquine, primaquine, sulfadozine-pyrimethamine, doxycycline, atovaquone-proguanil, and artemetherlumefantrine.

[0345] In various aspects, the compound and the antimicrobial agent are co-packaged. In a further aspect, the compound and the antimicrobial agent are co-formulated.

[0346] The kits can also comprise compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0347] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using. K.EXAMPLES

[0348] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0349] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. CHEMISTRYMETHODSa. EXEMPLARY COMPOUNDS

[0350] A complete list of exemplary compounds prepared using the synthetic methods described herein is shown in Table 1 below. TABLE 1.b. SYNTHESIS OF COMPOUND 4206(1) GENERATION OF(2):TERT-BUTYL(2S,4R)-2-(2-(((S)-1- (BENZYLOXY)-1-OXOPROPAN-2-YL) CARBAMOYL)-4-METHYLPIPERAZINE- 1-CARBONYL)-4-HYDROXYPYRROLIDINE-1-CARBOXYLATE

[0351] To the solution of (S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (5 g, 21.71 mmol) in THF (50 mL) were added formaldehyde solution (3.52 mL, 43.4 mmol) and formic acid (1.83 mL, 43.4 mmol). The mixture was heated under reflux overnight and then the solvent was removed under reduced pressure. The residue was dissolved in DMF (30 mL) and N-methylmorpholine (13.50 mL, 123 mmol). To the solution were added L-Alanine benzyl ester hydrochloride (4.41 g, 20.47 mmol), EDC.HCl (4.51 g, 23.54 mmol) and HOBT.H2O (3.45 g, 22.51) at 0 °C. The reaction mixture was stirred overnight, taken up with EtOAc, and then washed with sat. NaHCO3solution and brine. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure after filtration; nuclear magnetic resonance (NMR) (500 MHz, CDCl3) δ 1.45 (d, J = 7.3 Hz, 3H), 1.50 (s, 9H), 1.94 – 2.03 (m, 1H), 2.11 (dd, J = 11.7, 4.3 Hz, 1H), 2.29 (s, 3H), 2.68 – 2.78 (m, 1H), 2.99 – 3.23 (m, 2H), 3.36 (d, J = 11.7 Hz, 1H), 4.69 (p, J = 7.2 Hz, 1H), 5.12 – 5.24 (m, 2H), 7.13 (br.s, 1H), 7.34-7.41 (m, 5H); ESI-MS: [m / z+H+] = 406.41. The solution of above residue in 4N HCl in dioxane (30 mL) was stirred at room temperature and then the solvent was removed under reduced pressure to give a brownish liquid; Electrospray ionization mass spectrometry (ESI-MS): [m / z+H+] = 306.41. To the above residue in DMF (30 mL) were added Boc-Hyp-OH (5.72 g, 24.72 mmol), HATU (9.40 g, 24.72 mmol) and DIEA (11.92 mL, 68.5 mmol) at 0 °C. The reaction mixture was stirred overnight, taken up with ethyl acetate (EtOAc), and then washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4and the solvent was removed under reduced pressure after filtration. The residue was chromatographed in hexane:EtOAc 1:4 to give compound 2,a light brownish foam solid (5.9 g, 59.8%); NMR (500 MHz, CDCl3) δ 1.34 (s, 9H), 1.44 (d, J = 7.5 Hz, 2H), 1.89 – 2.06 (m, 3H), 2.29 (s, 3H), 2.79 (d, J = 10.8 Hz, 1H), 2.83 – 2.91 (m, 1H), 3.40 (d, J = 11.4 Hz, 1H), 3.62 – 3.70 (m, 1H), 3.73 (d, J = 11.4 Hz, 1H), 4.38 (s, 1H), 4.49 (s, 1H), 4.51 – 4.62 (m, 2H), 4.65 (t, J = 7.7 Hz, 1H), 5.00 – 5.17 (m, 3H), 7.23 – 7.36 (m, 5H), 8.01 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H); ESI-MS: [m / z+H+] = 519.32. (2) GENERATION OF(3): (1-((2S,4R)-1-(TERT- BUTOXYCARBONYL)-4-HYDROXYPYRROLIDINE-2-CARBONYL)-4- METHYLPIPERAZINE-2-CARBONYL)-L-ALANINE.

[0352] A mixture of compound 2 (4 g, 7.71 mmol) and 10% Pd-C (0.8 g) in methanol (50 mL) was hydrogenated under hydrogen ballon for 2.5 hours. The mixture was filtered through celite, and the pad was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give compound 3, which was used directly for the next reaction. ESI-MS: [m / z+H+] = 429.46. (3) GENERATION OF (5): 2-OXO-2-PHENYLETHYL ((BENZYLOXY)CARBONYL)-L-ALLOTHREONINATE.

[0353] Compound 4, H-allo-Thr-OH (1 g, 8.39 mmol) was dissolved in saturated aqueous NaHCO3 (50 mL) and THF (20 mL) and the whole was cooled to 0 °C. To this solution, a solution of benzyl chloroformate (1.58 g, 9.23 mmol) in THF (20mL) was added at 0 °C and the mixture was stirred for 1.5 h at 0 °C. After quenching with 3N aqueous HCl, the separated organic layer was washed with 3N aqueous HCl and brine and dried over Na2SO4. The organic solvent was evaporated, and the residue was used in the next step reaction without purification. To the above residue in EtOAc (25 mL) were added 2-bromo-1- phenylethanone (1.833 g, 9.21 mmol) and triethylamine (Et3N) (1.30 ml, 10.05 mmol) in an ice-bath, then the clear mixture was stirred overnight. After overnight reaction, white salt was precipitated from the mixture.50 mL of EtOAc was added to the reaction, and then washed with saturated NaHCO3, 1N HCl, saturated NaCl and distilled water. The organic layer was dried with anhydrous Na2SO4, filtered and removed under reduced pressure. The residue was chromatographed in hexane:EtOAc 3:2 to give target compound 5, a white solid (2.2 g, 71%); 1H NMR (400 MHz, Chloroform-d) δ 1.42 (d, J = 6.5 Hz, 3H), 3.60 (d, J = 8.7 Hz, 1H), 4.44 - 4.52 (m, 1H), 5.14 (s, 2H), 5.51 (s, 2H), 5.72 (d, J = 8.4 Hz, 1H), 7.31-7.37 (m, 5H), 7.50- 7.53 (m, 2H), 7.63-7.68 (m, 1H), 7.92 (d, J = 7.3 Hz, 2H); ESI-MS: [m / z+H+] = 372.33.(4) GENERATION OF (6): 2-((2S,3S)-3-(((BENZYLOXY)CARBONYL) AMINO)-4-OXO-4-(2-OXO-2-PHENYLETHOXY)BUTAN-2-YL) 1-(TERT- BUTYL) (2S,4R)-4-METHYLPYRROLIDINE-1,2-DICARBOXYLATE.

[0354] N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl, 0.29 g, 1.84 mmol) was added to a stirring solution of 5 (0.8 g, 2.154 mmol), (2S,4R)-1-Boc- 4-methylpyrrolidine-2-carboxylic acid (0.593g, 2.58 mmol) and DMAP (53 mg, 0.431 mmol) in dichloromethane (CH2Cl2) (20 mL) at 0 °C. The mixture was slowly warmed to room temperature, stirred overnight, diluted with EtOAc, and washed successively with 1 N HCl, saturated NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure after filtration. The resulting oil was chromatographed in hexane:EtOAc 3:7 to give a colorless oil (1.04 g, 83%); 1H NMR (400 MHz, Chloroform-d) δ 1.00 - 1.08 (m, 3H), 1.41 (d, J = 3.6 Hz, 9H), 1.48 (dd, J = 14.7, 6.7 Hz, 3H), 1.54 - 1.67 (m, 1H), 2.08 - 2.25 (m, 1H), 2.28- 2.37 (m, 1H), 2.89- 2.99 (m, 1H), 3.61 (dd, J = 10.2, 7.5 Hz, 0.52H), 3.69 - 3.77 (m, 0.58H), 4.14 (t, J = 8.3 Hz, 0.51H), 4.19 - 4.25 (m, 0.53H), 4.77 (dd, J = 9.3, 2.9 Hz, 0.48H), 4.87 (dd, J = 8.5, 2.7 Hz, 0.42H), 5.05 - 5.19 (m, 2H), 5.30 (dd, J = 16.2, 11.4 Hz, 1H), 5.40- 5.44 (m, 1H), 5.53- 5.60 (m, 1H), 6.13 (d, J = 9.2 Hz, 0.45H), 7.28 - 7.39 (m, 5H), 7.50 (t, J = 7.1 Hz, 2H), 7.61- 7.64 (m, 1H), 7.84 - 7.95 (m, 2H); ESI-MS: [m / z+Na+] = 605.39. The above colorless oil was treated with 4 N HCl in dioxane for 2 hours at room temperature and then the solvent was removed under reduced pressure to give compound 6, a white foam solid. Compound 6 was used in the next step of the reaction without purification. (5) GENERATION OF (7): TERT-BUTYL (2S,4R)-2-((S)-2-(((S)-1- ((2S,4R)-2-((((2S,3S)-3-(((BENZYLOXY)CARBONYL)AMINO)-4-OXO-4- (2-OXO-2-PHENYLETHOXY)BUTAN-2-YL)OXY)CARBONYL)-4- METHYLPYRROLIDIN-1-YL)-1-OXOPROPAN-2-YL)CARBAMOYL)-4- METHYLPIPERAZINE-1-CARBONYL)-4-HYDROXYPYRROLIDINE-1- CARBOXYLATE.

[0355] To the solution of compound 6 (8.26 g, 17.11 mmol) and tripeptide 3 (11 g, 25.7 mmol) in dichloromethane (30 mL) at 0 °C under nitrogen were added TPTU (6.10 g, 20.54 mmol), HOBT (3.67 g, 23.96 mmol), and DIEA (7.92 mL, 47.9 mmol). The reaction mixture was stirred overnight with slow warming to room temperature and then concentrated. The residue was taken up with EtOAc, extracted by shaking with 10% NaHCO3 solution andbrine. The organic layer was dried over anhydrous Na2SO4 and removed under reduced pressure after filtration. The product was chromatographed in EtOAc:methanol 9:1 to give 7,a white foam solid (12.57 g, 82%);1H NMR (500 MHz, CDCl3) δ 1.07 (t, J = 6.8 Hz, 3H), 1.32 – 1.55 (m, 15H), 1.93 – 2.00 (m, 1H), 2.00 – 2.11 (m, 1H), 2.12 – 2.25 (m, 2H), 2.30-2.34 (m, 4H), 2.55 (m, 1H), 2.80 – 2.95 (m, 2H), 3.34 – 3.50 (m, 2H), 3.55 (d, J = 11.9 Hz, 1H), 3.64 – 3.80 (m, 3H), 4.41 – 4.59 (m, 3H), 4.60 – 4.67 (m, 1H), 4.82 – 4.96 (m, 2H), 5.06 – 5.20 (m, 3H), 5.30 (dd, J = 15.9, 3.1 Hz, 1H), 5.37 – 5.48 (m, 2H), 5.55 – 5.67 (m, 2H), 5.71 (t, J = 6.9 Hz, 1H), 7.31 – 7.42 (m, 5H), 7.49 – 7.56 (m, 2H), 7.62 – 7.69 (m, 1H), 7.91 (d, J = 7.8 Hz, 2H), 8.10 (br.s, 1H), 8.68 (d, J = 5.8 Hz, 1H); ESI-MS: [m / z+H+] = 893.97. (6) GENERATION OF(8): BENZYL((6AS,8R,12S,13S,15AS,17R,21S,23AS)-8-HYDROXY-2,13,17,21- TETRAMETHYL-6,11,15,20,23-PENTAOXOOCTADECAHYDRO- 2H,6H,11H,15H-PYRAZINO[2,1-I]DIPYRROLO[2,1-C:2',1'- L][1]OXA[4,7,10,13]TETRAAZACYCLOHEXADECIN-12-YL)CARBAMATE.

[0356] To the solution of compound 7 (15.5 g, 17.36 mmol) in 90 % aqueous acetic acid (20 mL) was added (7.94 g, 122 mmol) zinc powder. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered off through kieselguhr and washed with methanol. The organic solvent was concentrated in vacuo, and the residue taken up with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4and removed under reduced pressure after filtration to give a foam like solid; ESI-MS: [m / z+H+] = 775.75. The above foam solid and pentafluorophenol (12.78 g, 69.4 mmol) were dissolved in CH2Cl2 and cooled to -20 °C under nitrogen, after which EDC.HCl (5.99 g, 31.2 mmol) was added. The reaction mixture was stirred overnight with slow warming room temperature. The reaction solution was concentrated to dryness; ESI-MS: [m / z+H+] = 941.66. To the residue, 4N hydrochloride solution in dioxane (30 mL) was added. The mixture was stirred at room temperature for 1 hour and the solvent was subsequently removed under reduced pressure; ESI-MS: [m / z+H+] = 841.65. The residue was dissolved in DCM (300 mL) and slowly added dropwise to a vigorously stirred two-phase mixture of 1 N aqueous NaHCO3 solution (800 mL) and DCM (500 mL). The reaction mixture was stirred at room temperature for 2 hours. After the phases were separated, the aqueous phase was extracted with DCM and the combined organic phases was dried over Na2SO4 and removed under reduced pressure after filtration. The residue was purified by reverse chromatography (water:ACN 2:3) to give compound 8,a white foam solid (5.9 g, 51.8 % over four steps);1H NMR (500 MHz, CDCl3) δ 1.09 (d, J = 6.6 Hz, 3H), 1.27 (d, J = 6.6 Hz, 3H), 1.45 (d, J = 6.6 Hz, 3H), 1.80 – 1.95 (m, 4H), 2.08 – 2.17 (m, 3H), 2.28 (s, 3H), 2.36 – 2.48 (m, 2H), 2.73 (d, J = 12.2 Hz, 1H), 2.85 – 2.93 (m, 1H), 3.20 (dd, J = 12.0, 8.6 Hz, 1H), 3.65 – 3.82 (m, 4H), 4.36 (d, J = 9.6 Hz, 1H), 4.42 (d, J = 13.4 Hz, 1H), 4.52 – 4.59 (m, 2H), 4.63 (s, 1H), 5.03 (dd, J = 9.9, 6.7 Hz, 1H), 5.05 – 5.16 (m, 3H), 5.53 (t, J = 7.4 Hz, 1H), 5.60 (d, J = 9.6 Hz, 1H), 7.30 – 7.42 (m, 5H), 8.36 (d, J = 9.6 Hz, 1H); ESI-MS: [m / z+H+] = 657.34. (7) GENERATION OF(9)TERT-BUTYL((S)-3-(3,5- DIFLUOROPHENYL)-1-(((6AS,8R,12S,13S,15AS,17R,21S,23AS)-8- HYDROXY-2,13,17,21-TETRAMETHYL-6,11,15,20,23- PENTAOXOOCTADECAHYDRO-2H,6H,11H,15H-PYRAZINO[2,1- I]DIPYRROLO[2,1-C:2',1'- L][1]OXA[4,7,10,13]TETRAAZACYCLOHEXADECIN-12-YL)AMINO)-1- OXOPROPAN-2-YL)CARBAMATE.

[0357] To the solution of 10% Pd / C (240 mg) in methanol (20 mL) under nitrogen were added compound 8 (1.2 g, 1.83 mmol) and 1 N HCL solution (1 mL). The mixture was under hydrogen ballon at room temperature overnight. The reaction solution was filtered off through kieselguhr, which was washed with methanol and then the solvent was removed in vacuo. The residue was dissolved in DMF (15 mL). To the solution were added Boc-L-(3,5- diF) Phe-OH (0.55 g, 1.83 mmol), HATU (0.90 g, 2.38 mmol), and DIEA (1.15 mL, 6.58 mmol) at 0 °C. The reaction mixture was stirred overnight, taken up with EtOAc, and then washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4and removed under reduced pressure after filtration. The product was purified by reverse phase chromatography (water: ACN 2:3) as a white solid (1.1 g, 74.7% over two steps);1H NMR (400 MHz, Chloroform-d) δ 1.09 (d, J = 6.4 Hz, 3H), 1.23 (d, J = 5.9 Hz, 3H), 1.45 (d, J = 6.6 Hz, 3H), 1.80 – 1.96 (m, 4H), 2.07 – 2.15 (m, 2H), 2.27 (s, 3H), 2.35– 2.42 (m, 2H), 2.75 (d, J = 11.1 Hz, 1H), 2.80 – 2.90 (m, 1H), 2.97 (t, J = 12.8 Hz, 1H), 3.06 – 3.18 (m, 2H), 3.62 – 3.80 (m, 3H), 3.81 – 3.90 (m, 1H), 4.23 – 4.34 (m, 1H), 4.50 – 4.69 (m, 5H), 4.94 – 5.05 (m, 1H), 5.10 – 5.20 (m, 1H), 5.41 (t, J = 7.2 Hz, 1H), 5.88 (d, J = 9.3 Hz, 1H), 6.66 (t, J = 8.9 Hz, 1H), 6.76 (d, J = 7.5 Hz, 2H), 6.85 (d, J = 10.1 Hz, 1H), 8.60 (d, J = 9.8 Hz, 1H); ESI-MS: [m / z+H+] = 806.35. (8) GENERATION OF 4206: (S)-3-(3,5-DIFLUOROPHENYL)-2-(3-(2-FLUORO-4-METHYLPHENYL)UREIDO)-N- ((6AS,8R,12S,13S,15AS,17R,21S,23AS)-8-HYDROXY-2,13,17,21- TETRAMETHYL-6,11,15,20,23-PENTAOXOOCTADECAHYDRO- 2H,6H,11H,15H-PYRAZINO[2,1-I]DIPYRROLO[2,1-C:2',1'- L][1]OXA[4,7,10,13]TETRAAZACYCLOHEXADECIN-12- YL)PROPANAMIDE

[0358] The solution of compound 8 (2.52 g, 3.13 mmol) in 4N HCl solution in dioxane (10 mL) was stirred at room temperature and then the solvent was removed under reduced pressure to give a white solid; ESI-MS: [m / z+H+] = 640.74. The above residue was dissolved in DCM (20 mL) and DIEA (1.71 mL, 12.51 mmol). To the mixture was added 2- fluoro-1-isocyanato-4-methylbenzene (0.43 mmL, 3.13 mmol) and the resulting solution was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure and the residue was chromatographed with EtOAc: methanol 95:5 to give 4206 as a white solid;1H NMR (500 MHz, CDCl3) δ 1.00 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.81 – 1.97 (m, 3H), 2.06 – 2.13 (m, 1H), 2.14 – 2.20 (m, 1H), 2.30 (s, 3H), 2.31 (s, 3H), 2.33 – 2.40 (m, 1H), 2.40 – 2.47 (m, 1H), 2.77 (d, J = 11.4 Hz, 1H), 2.90 – 3.04 (m, 3H), 3.21 (dd, J = 12.1, 8.4 Hz, 1H), 3.58 (dd, J = 12.1, 9.2 Hz, 1H), 3.71 – 3.85 (m, 3H), 4.51 – 4.59 (m, 3H), 4.63 – 4.69 (m, 2H), 4.73 (dd, J = 9.8, 2.0 Hz, 1H), 4.99 – 5.07 (m, 1H), 5.16 – 5.22 (m, 1H), 5.38 – 5.44 (m, 1H), 6.16 (d, J = 7.8 Hz, 1H), 6.66 – 6.71 (m, 1H), 6.72 – 6.78 (m, 2H), 6.85 – 6.96 (m, 3H), 7.83 (d, J = 2.9 Hz, 1H), 7.98 (t, J = 8.5 Hz, 1H), 8.48 (d, J = 9.8 Hz, 1H); ESI-MS: [m / z+H+] = 857.86. c. SYNTHESIS OF COMPOUND 5192

[0359] To synthesize the target compound, DIEA (595 uL, 3.41 mmol), DMAP (43.4 mg, 0.36 mmol) and 2,4,6-trichlorobenzoyl chloride (or benzoyl chloride) (266 uL, 1.71 mmol) were added to a mixture of compound 4206 (1.22g, 1.42 mmol) and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid (0.5 g, 1.71 mmol) in THF. The resulting solution was stirred at room temperature for one hour. The solvent was removed and the residue was purified by flash silica gel chromatography with ethyl acetate:MeOH 95:5 as eluent. Combined product fractions were concentrated to give compound A as a white solid (1.28 g, 80%);1H NMR (500 MHz, MeOD) δ 0.96 (d, J = 6.7 Hz, 3H), 1.28 (d, J = 6.6 Hz, 3H), 1.41 (d, J = 6.6 Hz, 3H), 1.83 – 1.92 (m, 1H), 1.93 – 2.01 (m, 1H), 2.05 – 2.15 (m, 2H), 2.26 – 2.31 (m, 5H), 2.39 – 2.49 (m, 1H), 2.69 – 2.76 (m, 4H), 2.78 – 2.87 (m, 4H), 2.90 – 3.01 (m, 2H), 3.03 – 3.14 (m, 2H), 3.31 (d, J = 2.6 Hz, 1H), 3.56 (dd, J = 11.9, 9.0 Hz, 1H), 3.71 (d, J = 11.6 Hz, 1H), 3.74 – 3.85 (m, 2H), 4.50 (d, J = 8.2 Hz, 1H), 4.56 (d, J = 12.1 Hz, 1H), 4.60 – 4.66 (m, 1H), 4.72 (d, J = 2.0 Hz, 2H), 5.03 (q, J = 6.7 Hz, 1H), 5.11 (s, 2H), 5.13 – 5.19 (m, 1H), 5.42 – 5.47 (m, 1H), 5.50 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 8.1 Hz, 1H), 6.75 – 6.81 (m, 1H), 6.84 – 6.97 (m, 4H), 7.28 – 7.39 (m, 4H), 7.79 (t, J = 8.5 Hz, 1H); ESI- MS: [m / z+H+] = 1132.87.

[0360] A mixture of compound A (0.52 g, 0.46 mmol) and 10% Pd-C (0.1 g) in methanol (20 mL) was hydrogenated under hydrogen balloon for 2.5 hours. The mixture was filtered through celite and the pad washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give crude (0.45 g, 98%) that was used directly for the next reaction. To the above residue in 5 mL methanol, 0.57 ml of acetic acid and 3-formyl rifamycin SV (252 mg, 0.347 mmol) were added. The mixture was then stirred at room temperature for one hour until the reaction completed as monitored by HPLC. The solventwas removed under reduced pressure and the brick red residue was purified through Waters PrepLC System with water (0.1% formic acid) and methanol (0.1% formic acid) as an eluent to give compound 5192 as a bright brick red solid (340 mg, 57.5%);1H NMR (500 MHz, CDCl3) δ -0.30 (d, J = 7.0 Hz, 3H), 0.60 (d, J = 7.0 Hz, 3H), 0.87 – 0.82 (m, 4H), 0.92 – 0.99 (m, 3H), 1.02 (d, J = 7.0 Hz, 3H), 1.19 (d, J = 6.7 Hz, 3H), 1.30 – 1.38 (m, 2H), 1.42 (d, J = 6.6 Hz, 3H), 1.44 – 1.49 (m, 1H), 1.50 – 1.57 (m, 1H), 1.68 – 1.75 (m, 1H), 1.79 (s, 3H), 1.90 – 2.02 (m, 2H), 2.06 (s, 3H), 2.08 (s, 3H), 2.17 (s, 3H), 2.23 (s, 3H), 2.28 (s, 3H), 2.32 (s, 3H), 2.34 – 2.43 (m, 2H), 2.48 – 2.57 (m, 1H), 2.79 – 2.83 (m, 3H), 2.86 – 2.95 (m, 2H), 2.97 – 3.03 (m, 2H), 3.04 (s, 3H), 3.09 – 3.23 (m, 4H), 3.26 – 3.38 (m, 2H), 3.44 – 3.50 (m, 1H), 3.56 (dd, J = 12.1, 9.2 Hz, 1H), 3.73 – 3.86 (m, 3H), 3.91 (dd, J = 13.2, 5.1 Hz, 1H), 4.22 – 4.30 (m, 1H), 4.46 – 4.56 (m, 3H), 4.61 – 4.72 (m, 2H), 4.95 (d, J = 10.7 Hz, 1H), 4.97 – 5.05 (m, 1H), 5.10 (dd, J = 12.7, 6.7 Hz, 2H), 5.35 – 5.46 (m, 2H), 5.92 (dd, J = 15.6, 5.2 Hz, 1H), 6.13 – 6.22 (m, 2H), 6.38 (d, J = 11.1 Hz, 1H), 6.57 (dd, J = 17.1, 11.1 Hz, 1H), 6.62 – 6.69 (m, 1H), 6.69 – 6.76 (m, 2H), 6.82 – 6.92 (m, 2H), 7.50 (d, J = 10.1 Hz, 1H), 7.83 (d, J = 2.9 Hz, 1H), 7.95 (t, J = 8.5 Hz, 1H), 8.01 (br.s, 2H), 8.09 (s, 1H), 8.30 (s, 1H), 8.55 (d, J = 9.6 Hz, 1H), 12.04 (s, 1H), 13.09 (s, 1H), 13.21 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.59, 8.50, 8.95, 10.90, 11.11, 12.97, 14.06, 17.85, 18.43, 22.98, 23.99, 29.00, 29.67, 30.96, 33.36, 36.84, 37.46, 38.45, 38.78, 38.91, 39.37, 39.48, 40.55, 45.81, 47.80, 49.98, 51.40, 52.00, 52.80, 53.98, 54.42, 55.27, 55.69, 56.19, 57.02, 57.14, 58.06, 60.09, 67.80, 69.85, 70.74, 72.10, 74.40, 102.46, 104.63, 106.39, 108.82, 110.60, 112.41, 112.60, 113.09, 115.24, 118.00, 118.58, 120.48, 120.94, 123.25, 129.51, 132.87, 134.24, 135.11, 138.58, 139.96, 142.68, 148.20, 151.46, 153.38, 154.81, 162.00, 163.51, 163.87, 166.01, 166.45, 168.04, 169.03, 169.19, 169.69, 170.29, 170.94, 171.98, 172.09, 174.58, 195.63; HRMS (ESI) m / z: [M+H]+calcd for C85H107F3N12O221705.7653; found 1705.7422.

[0361] To a mixture of compound 4518 (90 mg, 0.107 mmol) and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid (37.6 mg, 0.128 mmol) in DMF (5 mL), HATU (52.8 mg, 0.139 mmol) and DIEA (67.1 uL, 0.384 mmol) were added at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated NaHCO3 solution, followed by brine. The organic layer was separated and dried over anhydrous Na2SO4. After filtered through celite, the filtrate was dried under reduced pressure and the residue was purified by flash silica gel chromatography with EtOAc:MeOH 95:5 as eluent. Combined product fractions gave the intermediate mixed with compound 4518 as a white solid (65 mg); ESI- MS: [m / z+H+] = 1118.36. The impure intermediate was used in the next step without further purification. A mixture of the previous intermediate (65 mg) and 10% Pd-C (13 mg) in methanol (5 mL) was hydrogenated under hydrogen balloon for 2.5 hours. The mixture was filtered through celite and the pad washed with methanol (5 mL). The filtrate was concentrated under reduced pressure to give crude that was used directly for the next reaction; ESI-MS: [m / z+H+] = 984.71.0.57 ml of acetic acid and 3-formyl rifamycin SV (36.9 mg, 0.051 mmol) were added to the above residue in 5 mL methanol. The mixture was then stirred at room temperature until the completion of reaction by monitored with HPLC. The solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography with ethyl acetate:MeOH 95:5 as eluent. Combined product fractions were concentrated to give compound 5200 as a bright brick red solid (60 mg, 69.8 %).1H NMR (500 MHz, CDCl3) δ -0.28 (d, J = 6.9 Hz, 3H), 0.63 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 6.7 Hz, 3H), 1.29 (d, J = 8.2 Hz, 3H), 1.33 – 1.41 (m, 2H), 1.52 – 1.59 (m, 1H), 1.70 – 1.77 (m, 1H), 1.78 – 1.86 (m, 3H), 2.09 (s, 3H), 2.20 (s, 3H), 2.26 (s, 3H), 2.31 (s, 3H), 2.35 – 2.47 (m, 2H), 2.56(t, J = 12.1 Hz, 1H), 2.74 (br.s, 2H), 2.95 – 3.01 (m, 2H), 3.04 – 3.01 (m, 5H), 3.23 (d, J = 8.5 Hz, 2H), 3.34 (q, J = 11.4 Hz, 1H), 3.50 (d, J = 6.7 Hz, 1H), 3.58 (t, J = 10.5 Hz, 1H), 3.76 – 3.81 m, 2H), 4.43 (d, J = 7.8 Hz, 1H), 4.57 – 4.78 (m, 5H), 4.89 – 4.97 (m, 2H), 5.03 – 5.21 (m, 3H), 5.39 – 5.45 (m, 1H), 5.92 – 5.99 (m, 1H), 6.12 (d, J = 7.5 Hz, 1H), 6.23 (d, J = 12.5 Hz, 1H), 6.42 (d, J = 10.7 Hz, 1H), 6.58 – 6.77 (m, 4H), 6.85 – 6.96 (m, 2H), 7.80 (s, 1H), 7.94 (t, J = 8.4 Hz, 1H), 8.30 (s, 1H), 8.73 (d, J = 9.5 Hz, 1H), 12.04 (s, 1H), 13.23 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.60, 8.50, 8.96, 10.89, 13.18, 17.90, 18.39, 20.74, 21.49, 29.27, 29.69, 31.76, 33.40, 37.49, 38.56, 38.79, 39.34, 39.50, 40.90, 47.94, 50.37, 51.98, 52.81, 53.78, 54.40, 54.91, 55.83, 57.12, 57.26, 60.03, 60.31, 69.22, 69.57, 70.13, 70.63, 74.41, 102.43, 104.66, 106.26, 108.84, 110.82, 112.53, 112.72, 112.96, 115.45, 117.97, 118.72, 120.52, 121.14, 123.22, 124.67, 124.85, 129.26, 133.07, 134.76, 135.32, 138.58, 139.88, 142.73, 148.07, 151.59, 153.51, 154.67, 161.93, 163.80, 165.83, 167.42, 168.52, 169.18, 169.63, 169.82, 171.72, 171.93, 172.03, 172.19, 174.55, 195.56; HRMS (ESI) m / z: [M+H]+calcd for C84H105F3N12O221691.7497; found 1691.7310. e. SYNTHESIS OF COMPOUND 5201

[0362] Compound 5201 was synthesized from compound 4206 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for compound 5192 as a bright brick red solid (55 mg, 48.9%);1H NMR (500 MHz, CDCl3) δ - 0.44 (d, J = 7.0 Hz, 3H), 0.46 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H), 1.11 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H), 1.36 – 1.43 (m, 2H), 1.47 – 1.53 (m, 2H), 1.66 (s, 3H), 1.68 – 1.81 (m, 3H), 1.92 (s, 3H), 1.94 (s, 3H), 2.03 (s, 6H), 2.09 (s, 3H), 2.13 (s, 3H), 2.15 (s, 3H), 2.17 – 2.22 (m, 3H), 2.23 – 2.37 (m, 4H), 2.41 – 2.51 (m, 3H), 2.63 (d, J = 12.5 Hz, 1H), 2.79 – 2.86 (m, 2H), 2.90 (s, 3H), 2.93 – 2.97 (m, 2H), 3.00 – 3.08 (m, 2H), 3.18 (dd, J = 17.2, 9.0 Hz, 1H), 3.33 (d, J = 7.2 Hz, 1H), 3.38 – 3.44 (m, 1H), 3.57 – 3.66 (m, 2H), 3.75 (dd, J = 13.0, 5.1 Hz, 1H), 4.26 – 4.37 (m, 2H), 4.41 (d, J = 8.2 Hz, 1H), 4.46 – 4.56 (m, 2H), 4.80 (d, J = 11.1 Hz, 1H), 4.87 (dd, J = 9.9, 6.6 Hz, 1H), 4.92 – 5.00 (m, 2H), 5.17 – 5.27 (m, 2H), 5.79 (dd, J = 15.5, 5.1 Hz, 1H), 5.98 – 6.10 (m, 2H), 6.24 (d, J = 11.1 Hz, 1H), 6.44 (dd, J = 16.3, 10.4 Hz, 1H), 6.50 – 6.57 (m, 1H), 6.57 – 6.64 (m, 2H), 6.68 – 6.78 (m, 2H), 7.63 (d, J = 2.9 Hz, 1H), 7.82(t, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.33 (d, J = 9.8 Hz, 1H), 11.88 (s, 1H), 13.04 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.59, 8.49, 8.97, 13.02, 17.86, 18.11, 18.39, 20.72, 21.49, 22.54, 26.14, 29.67, 30.96, 31.76, 33.40, 33.82, 36.92, 37.48, 38.55, 38.81, 39.20, 39.52, 40.86, 46.19, 47.73, 50.17, 51.78, 51.99, 52.80, 53.79, 54.38, 55.39, 55.64, 56.65, 57.12, 57.31, 57.53, 69.54, 69.76, 70.59, 71.58, 74.41, 102.51, 104.64, 106.26, 108.83, 110.83, 112.42, 112.97, 115.38, 117.97, 118.63, 120.52, 120.75, 123.23, 124.86, 129.33, 132.72, 135.21, 138.60, 139.88, 142.75, 148.06, 151.37, 153.30, 154.62, 162.05, 163.92, 165.89, 168.32, 169.23, 169.68, 170.29, 171.16, 171.80, 172.08, 172.16, 172.72, 174.55, 195.54; HRMS (ESI) m / z: [M+H]+calcd for C88H113F3N12O221747.8122; found 1747.8174. f. SYNTHESIS OFCOMPOUND5202

[0363] Compound 5202 was synthesized from compound 3349 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described forcompound 5912 as a bright brick red solid (45 mg, 53.2%);1H NMR (500 MHz, CDCl3) δ - 0.37 (d, J = 6.9 Hz, 3H), 0.53 (d, J = 7.0 Hz, 3H), 0.80 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 3.4 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.27 – 1.41 (m, 2H), 1.43 – 1.53 (m, 3H), 1.54 – 1.65 (m, 3H), 1.67 – 1.82 (m, 3H), 1.99 (s, 3H), 2.10 (s, 3H), 2.16 (s, 3H), 2.27 (s, 3H), 2.35 – 2.44 (m, 2H), 2.52 – 2.70 (m, 6H), 2.79 – 2.86 (m, 1H), 2.98 (s, 3H), 3.01 – 3.17 (m, 4H), 3.21 – 3.29 (m, 1H), 3.39 – 3.49 (m, 2H), 3.62 – 3.72 (m, 2H), 3.78 – 3.84 (m, 1H), 4.20 – 4.28 (m, 1H), 4.43 (d, J = 8.2 Hz, 1H), 4.54 – 4.69 (m, 3H), 4.88 (d, J = 11.4 Hz, 1H), 4.92 – 5.09 (m, 3H), 5.24 – 5.36 (m, 2H), 5.86 (dd, J = 15.6, 5.1 Hz, 1H), 6.11 – 6.20 (m, 2H), 6.36 (dd, J = 36.1, 10.5 Hz, 2H), 6.47 – 6.55 (m, 1H), 6.87 – 6.90 (m, 2H), 6.95 – 7.04 (m, 3H), 7.12 (t, J = 7.5 Hz, 1H), 7.96 (d, J = 3.2 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.23 (s, 1H), 8.60 (d, J = 9.8 Hz, 1H), 11.97 (s, 1H), 13.08 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.63, 8.50, 8.97, 10.91, 13.04, 17.83, 18.02, 18.38, 20.76, 21.26, 21.48, 22.51, 24.92, 28.39, 29.28, 29.69, 30.96, 31.75, 33.40, 33.77, 36.66, 37.47, 38.54, 38.85, 39.51, 40.13, 41.50, 47.87, 49.97, 51.61, 51.99, 52.67, 53.78, 54.34, 55.45, 56.74, 57.13, 57.30, 57.42, 60.31, 69.55, 69.90, 70.60, 71.63, 74.41, 104.64, 106.31, 108.83, 110.74, 113.02, 115.50, 117.98, 118.61, 120.51, 121.18, 123.23, 124.55, 126.38, 127.81, 128.73, 129.35, 129.97, 135.88, 138.60, 142.81, 148.12, 150.85, 152.80, 154.32, 165.59, 169.08, 169.22, 169.66, 170.43, 171.17, 171.90, 172.17, 172.54, 172.69, 174.56, 195.58; HRMS (ESI) m / z: [M+H]+calcd for C88H113ClFN11O221730.7812; found 1730.7815. g. SYNTHESIS OFCOMPOUND5203

[0364] Compound 5203 was synthesized from compound 2 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid in the presence of benzoyl chloride as a bright brick red solid (48 mg, 48.0%) following the method described for compound 5192;1H NMR (500 MHz, CDCl3) δ -0.37 (d, J = 7.0 Hz, 2H), 0.53 (d, J = 6.9 Hz, 2H), 0.80 (d, J = 7.2 Hz, 2H), 0.89 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 7.0 Hz, 2H), 1.13 (d, J = 6.6 Hz, 2H), 1.33 (d, J = 6.6 Hz, 3H), 1.41 – 1.49 (m, 2H), 1.52 – 1.60 (m, 2H), 1.61 – 1.71 (m, 5H), 1.73 (s, 3H), 1.97 (d, J = 5.3 Hz, 1H), 1.99 (s, 2H), 2.01 (s, 2H), 2.10 (s, 2H), 2.16 (s, 2H), 2.22 (s, 3H), 2.25 – 2.33 (m, 4H), 2.83 – 2.96 (m, 3H), 2.98 (s, 4H), 3.05 – 3.16 (m, 3H), 3.37 – 3.43 (m, 1H), 3.47 (dd, J = 12.1, 9.0 Hz, 1H), 3.57 (d, J = 5.2 Hz, 1H), 3.65 – 3.73 (m, 2H), 3.84 (dd, J = 13.0, 5.2 Hz, 1H), 4.32 – 4.42 (m, 2H), 4.47 (s, 1H), 4.59 (d, J = 10.1 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H), 4.85 – 4.93 (m, 2H), 4.96 – 5.08 (m, 2H), 5.23 – 5.35 (m, 2H), 5.86 (dd, J = 15.6, 5.0 Hz, 1H), 6.05 (d, J = 7.9 Hz, 1H), 6.12 – 6.17 (m, 1H), 6.31 (d, J = 11.1 Hz, 1H), 6.51 (dd, J = 17.2, 11.2 Hz, 1H), 6.59 – 6.72 (m, 3H), 6.77 – 6.86 (m, 2H), 7.33 – 7.45(m, 4H), 7.67 (d, J = 2.9 Hz, 1H), 7.88 (t, J = 8.5 Hz, 1H), 8.20 (s, 1H), 8.58 (d, J = 9.6 Hz, 1H), 11.95 (s, 1H), 13.14 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.59, 8.49, 8.97, 10.90, 12.98, 17.88, 18.42, 20.76, 21.50, 22.56, 26.41, 29.70, 30.96, 33.40, 33.83, 36.93, 37.48, 38.56, 38.69, 39.18, 39.53, 40.51, 47.88, 50.39, 51.88, 51.98, 52.68, 54.32, 55.43, 55.57, 57.11, 57.66, 60.22, 69.85, 70.58, 71.45, 74.42, 102.60, 104.64, 106.23, 108.84, 110.90, 112.38, 112.58, 112.93, 115.25, 115.40, 117.96, 118.63, 120.53, 120.84, 123.23, 124.75, 124.89, 127.55, 128.45, 129.31, 130.36, 132.91, 134.49, 134.81, 135.21, 138.62, 139.87, 142.77, 148.00, 151.41, 153.34, 154.58, 161.98, 163.96, 165.67, 166.73, 169.25, 169.68, 169.90, 171.27, 172.01, 172.15, 172.73, 174.55, 195.53; HRMS (ESI) m / z: [M+H]+calcd for C94H115F3N12O231837.8228; found 1837.8271. h. SYNTHESIS OF COMPOUND 5204

[0365] Compound 5204 was synthesized from compound 4518 and 5-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)pentanoic acid following the method described for compound 5200 as a bright brick red solid (39.6 mg, 36.8 %);1H NMR (500 MHz, CDCl3) δ -0.30 (d, J = 6.9 Hz, 3H), 0.61 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.98 (d,J = 6.6 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 1.20 (d, J = 7.2 Hz, 3H), 1.26 (d, J = 6.9 Hz, 3H), 1.32 – 1.40 (m, 1H), 1.50 – 1.62 (m, 3H), 1.64 – 1.83 (m, 11H), 2.06 (s, 3H), 2.09 (s, 3H), 2.17 (s, 3H), 2.23 (s, 3H), 2.29 (s, 3H), 2.36 – 2.49 (m, 6H), 2.54 – 2.62 (m, 3H), 2.67 – 2.73 (m, 2H), 2.97 (d, J = 6.4 Hz, 2H), 2.99 – 3.11 (m, 5H), 3.13 – 3.23 (m, 3H), 3.45 –3.48 (m, 2H), 3.54 (t, J = 10.5 Hz, 1H), 3.63 (d, J = 4.1 Hz, 1H), 3.77 (t, J = 9.6 Hz, 2H), 4.41 (d, J = 7.9 Hz, 1H), 4.52 – 4.56 (m, 1H), 4.59 – 4.74 (m, 4H), 4.85 – 4.97 (m, 2H), 5.08 – 5.18 (m, 2H), 5.37 – 5.43 (m, 1H), 5.94 (dd, J = 15.5, 4.8 Hz, 1H), 6.09 (d, J = 7.3 Hz, 1H), 6.22 (d, J = 12.7 Hz, 1H), 6.40 (d, J = 11.1 Hz, 1H), 6.53 – 6.62 (m, 1H), 6.63 – 6.75 (m, 2H), 6.82 – 6.93 (m, 2H), 7.06 – 7.12 (m, 1H), 7.75 (s, 1H), 7.91 (t, J = 8.3 Hz, 1H), 8.27 (s, 1H), 8.66 (d, J = 9.6 Hz, 1H), 12.01 (s, 1H), 13.24 (s, 1H);13C NMR (126 MHz, CDCl3) δ 0.00, 6.56, 7.46, 7.94, 9.87, 12.12, 16.87, 17.34, 19.74, 20.47, 21.75, 25.61, 28.65, 29.93, 31.33, 32.37, 36.46, 37.56, 37.73, 38.33, 38.49, 39.80, 45.84, 46.86, 49.41, 50.93, 51.74, 53.34, 53.75, 54.00, 54.74, 56.08, 56.20, 56.91, 59.23, 68.20, 69.01, 69.58, 73.40, 101.43, 103.59, 105.14, 107.80, 109.97, 111.48, 111.86, 114.42, 116.92, 117.62, 119.51, 120.00, 122.17, 123.80, 128.27, 132.00, 133.25, 134.22, 137.60, 138.84, 141.73, 146.93, 150.52, 152.44, 153.62, 160.83, 162.80, 164.68, 166.27, 168.24, 168.69, 168.82, 170.70, 170.92, 171.13, 173.52, 194.46; HRMS (ESI) m / z: [M+H]+calcd for C87H111F3N12O221733.7966; found 1733.8025.

[0366] i. SYNTHESIS OF COMPOUND 5267

[0367] Compound 5267 was synthesized from compound 3349 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for compound 5192 as a bright brick red solid (99.8 mg, 65.2 %);1H NMR (500 MHz, CDCl3) δ -0.27 (d, J = 7.0 Hz, 3H), 0.62 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.41 (d, J = 6.6 Hz, 3H), 1.47 – 1.61 (m, 2H), 1.68 – 1.76 (m, 2H), 1.82 (s, 3H), 2.09 (s, 3H), 2.11 (s, 3H), 2.25 (s, 3H), 2.31 (s, 3H), 2.34 – 2.45 (m, 2H), 2.49 – 2.57 (m, 1H), 2.63 – 2.72 (m, 1H), 2.72 – 2.83 (m, 3H), 2.93 – 2.99 (m, 1H), 3.01 – 3.06 (m, 1H), 3.07 (s, 2H), 3.10 – 3.15 (m, 2H), 3.18 – 3.25 (m, 2H), 3.27 – 3.38 (m, 2H), 3.54 – 3.60 (m, 1H), 3.75 – 3.83 (m, 2H), 3.92 – 3.98 (m, 1H), 4.42 – 4.48 (m, 1H), 4.51 (d, J = 8.4 Hz, 1H), 4.64 (s, 1H), 4.68 – 4.75 (m, 2H), 4.97 (d, J = 10.7 Hz, 1H), 4.99 – 5.06 (m, 1H), 5.09 – 5.18 (m, 2H), 5.34 – 5.40 (m, 1H), 5.44 – 5.49 (m, 1H), 5.95 (dd, J = 15.6, 5.1 Hz, 1H), 6.15 – 6.25 (m, 2H), 6.41 (d, J = 11.0 Hz, 1H), 6.60 (dd, J = 15.8, 11.1 Hz, 1H), 6.67 – 6.73 (m, 1H), 6.73 – 6.79 (m, 2H), 6.81 – 6.94 (m, 3H), 7.81 (d, J = 2.9 Hz, 1H), 7.99 (t, J = 8.5 Hz, 1H), 8.31 (s, 1H), 8.61 (d, J = 9.8 Hz, 1H), 12.06 (s, 1H), 13.15 (s, 1H), 13.25 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 7.59, 8.49, 8.96, 10.91, 13.02, 17.87, 17.96, 18.42, 20.76, 21.23, 21.46, 25.02, 28.29, 29.70, 33.39, 36.69, 37.46, 38.53, 38.82, 39.48, 41.46, 47.79, 50.23, 50.90, 51.49, 51.93, 52.73, 54.36, 55.56, 57.14, 57.25, 58.39, 60.27, 69.68, 70.62, 72.13, 74.40, 102.55, 104.63, 106.32, 108.81, 110.72, 112.40,112.60, 113.03, 115.22, 117.99, 118.59, 120.50, 120.81, 123.23, 129.36, 132.79, 134.96, 135.21, 138.59, 139.88, 142.69, 142.82, 148.12, 151.38, 153.31, 154.62, 161.97, 162.07, 162.32, 163.95, 164.05, 165.93, 169.06, 169.20, 169.31, 169.70, 170.24, 170.91, 171.91, 171.94, 172.19, 174.57, 195.60; HRMS (ESI) m / z: [M+H]+calcd for C85H106F3N11O221690.7544; found 1690.7627. j. SYNTHESIS OFCOMPOUND5303

[0368] Compound 5303 was synthesized from compound 4206 and 3-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)propanoic acid following the method described for compound 5192 as a brick red solid (36 mg, 21.2%);1H NMR (500 MHz, CDCl3) δ -0.03 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H), 1.14 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 6.6 Hz, 3H), 1.29 (d, J = 7.0 Hz, 2H), 1.47 (d, J = 6.7 Hz, 3H), 1.53 (s, 3H), 1.67 (d, J = 6.7 Hz, 3H), 1.72 (s, 3H), 1.77 – 1.85 (m, 1H), 1.95 – 2.04 (m, 2H), 2.07 (s, 3H), 2.10 – 2.21 (m, 2H), 2.33 (s, 3H), 2.35 (s, 3H), 2.50 (s, 3H), 2.54 (s, 3H), 2.56 (s, 3H), 2.79 (t, J = 7.4 Hz, 1H), 2.82 – 2.88 (m, 1H), 2.87 – 2.93 (m, 1H), 2.95 – 3.06 (m, 2H), 3.18 – 3.30 (m, 3H), 3.38 –3.49 (m, 2H), 3.73 – 3.86 (m, 2H), 4.03 (t, J = 10.9 Hz, 2H), 4.13 – 4.21 (m, 1H), 4.66 – 4.73 (m, 1H), 4.77 (d, J = 19.5 Hz, 1H), 4.82 (d, J = 8.4 Hz, 1H), 4.87 – 4.97 (m, 2H), 5.21 (d, J = 10.7 Hz, 1H), 5.24 – 5.31 (m, 1H), 5.33 – 5.42 (m, 2H), 5.58 – 5.64 (m, 1H), 5.68 (br.s, 1H), 6.20 (dd, J = 15.6, 5.0 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 6.48 (d, J = 12.7 Hz, 1H), 6.66 (d, J = 11.0 Hz, 1H), 6.82 – 6.90 (m, 2H), 6.91 – 6.97 (m, 1H), 6.97 – 7.05 (m, 2H), 7.15 (dd, J = 21.7, 9.1 Hz, 2H), 7.56 – 7.62 (m, 1H), 8.02 (d, J = 3.1 Hz, 1H), 8.23 (t, J = 8.5 Hz, 1H), 8.55 (s, 1H), 8.73 (d, J = 9.8 Hz, 1H), 12.30 (s, 1H), 13.44 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.59, 8.50, 8.98, 10.91, 13.02, 17.87, 18.13, 18.42, 20.76, 21.49, 28.34, 29.72, 32.46, 33.40, 36.91, 37.47, 38.55, 38.82, 39.22, 39.51, 40.89, 46.20, 47.73, 50.33, 51.78, 51.96, 52.79, 53.04, 54.40, 55.47, 55.64, 56.71, 57.12, 57.34, 60.04, 69.72, 70.58, 71.77, 74.41, 102.53, 104.63, 106.27, 108.83, 110.80, 112.61, 112.98, 115.39, 117.97, 118.62, 120.51, 120.74, 123.25, 124.87, 128.03, 129.32, 131.32, 131.96, 132.75, 134.77, 135.23, 138.62, 139.85, 142.74, 148.06, 151.37, 153.30, 154.60, 162.06, 163.94, 164.04, 165.85, 168.28, 169.25, 169.66, 170.30, 171.14, 171.45, 171.79, 172.10, 172.17, 174.56, 195.55; HRMS (ESI) m / z: [M+H]+calcd for C86H109F3N12O221719.7809; found 1719.7889.

[0369] k. SYNTHESIS OF COMPOUND 5312

[0370] Compound 5312 was synthesized from compound 4206 and 4-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)butanoic acid following the method described for compound 5192 as a brick red solid (34 mg, 15.8 %);1H NMR (500 MHz, CDCl3) δ -0.43 (d, J = 7.0 Hz, 3H), 0.47 (d, J = 7.0 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 1.06 (d, J = 6.7 Hz, 3H), 1.18 – 1.25 (m, 1H), 1.27 (d, J = 6.6 Hz, 3H), 1.36 – 1.44 (m, 1H), 1.55 – 1.60 (m, 1H), 1.66 (s, 3H), 1.70 – 1.83 (m, 4H), 1.93 (s, 3H), 1.94 (s, 3H), 2.04 (s, 3H), 2.10 (s, 3H), 2.15 (s, 3H), 2.16 – 2.22 (m, 2H), 2.23 – 2.27 (m, 2H), 2.31 – 2.42 (m, 3H), 2.51 – 2.68 (m, 5H), 2.79 – 2.87 (m, 3H), 2.91 (s, 3H), 2.96 – 3.12 (m, 4H), 3.16 – 3.23 (m, 1H), 3.35 (d, J = 7.0 Hz, 1H), 3.39 – 3.45 (m, 1H), 3.58 – 3.65 (m, 2H), 3.76 (dd, J = 13.1, 5.2 Hz, 1H), 4.26 – 4.33 (m, 1H), 4.36 (br.s, 1H), 4.41 (d, J = 8.4 Hz, 1H), 4.45 – 4.56 (m, 2H), 4.81 (d, J = 10.7 Hz, 1H), 4.84 – 4.90 (m, 1H), 4.92 – 5.00 (m, 2H), 5.19 – 5.27 (m, 2H), 5.80 (dd, J = 15.4, 5.2 Hz, 1H), 6.02 (d, J = 7.8 Hz, 1H), 6.07 (d, J = 12.7 Hz, 1H), 6.26 (d, J = 11.0 Hz, 1H), 6.45 (dd, J = 15.6, 11.0 Hz, 1H), 6.54 (t, J = 9.0 Hz, 1H), 6.57 – 6.63 (m, 2H), 6.65 (d, J = 10.1 Hz, 1H), 6.74 (dd, J = 21.7, 10.3 Hz, 2H), 7.64 (s, 1H), 7.83 (t, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.34 (d, J = 9.8 Hz, 1H), 11.92 (s, 1H), 12.97 (s, 1H), 13.09 (s, 1H), 13.32 (br.s, 1H); HRMS (ESI) m / z: [M+H]+calcd forC87H111F3N12O221733.7966; found 1733.8016.

[0371] l. SYNTHESIS OF COMPOUND 5313

[0372] Compound 5313 was synthesized following the method described for compound 5192 as a brick red solid;1H NMR (500 MHz, CDCl3) δ -0.27 (d, J = 7.0 Hz, 3H), 0.62 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H), 1.69 – 1.91 (m, 5H), 2.05 – 2.15 (m, 3H), 2.19 (s, 3H), 2.20 (s, 3H), 2.26 (s, 3H), 2.32 (s, 3H), 2.34 – 2.45 (m, 2H), 2.53 (t, J = 10.8 Hz, 1H), 2.71 – 2.83 (m, 3H), 2.83 – 2.98 (m, 2H), 3.06 (d, J = 12.7 Hz, 2H), 3.10 – 3.16 (m, 1H), 3.18 – 3.26 (m, 2H), 3.29 – 3.38 (m, 2H), 3.47 – 3.59 (m, 2H), 3.65 (d, J = 4.9 Hz, 1H), 3.75 – 3,80 (m, 2H), 3.82 – 3.98 (m, 3H), 4.37 – 4.44 (m, 1H), 4.50 (d, J = 8.4 Hz, 1H), 4.63 – 4.74 (m, 2H), 4.97 (d, J = 10.7 Hz, 1H), 5.00 – 5.05 (m, 1H), 5.09 – 5.19 (m, 2H), 5.35 (t, J = 7.0 Hz, 1H), 5.46 (br.s, 1H), 5.95 (dd, J = 15.6, 4.8 Hz, 1H), 6.10 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 12.5 Hz, 1H), 6.41 (dd, J = 10.5, 4.3 Hz, 1H), 6.60 (dd, J = 15.3, 11.5 Hz, 1H), 6.71 – 6.78 (m, 2H), 6.91 (dd, J = 24.3, 10.1 Hz, 2H), 7.57 (d, J = 3.1 Hz, 1H), 7.98 (t, J = 8.5 Hz, 1H), 8.31 (s, 1H), 8.58 (d, J = 9.9 Hz, 1H), 12.08 (s, 1H), 13.16 (s, 1H), 13.26 (br.s, 1H); HRMS (ESI)m / z: [M+H]+calcd for C85H106F3N11O231706.7493; found 1706.7579. m. SYNTHESIS OF COMPOUND 5334

[0373] 5334 was synthesized from 5333 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for 5192 as a brick red solid;1H NMR (500 MHz, CDCl3) δ -0.27 (d, J = 7.0 Hz, 3H), 0.62 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.7 Hz, 3H), 1.33 – 1.43 (m, 1H), 1.51 (d, J = 6.7 Hz, 3H), 1.54 – 1.62 (m, 1H), 1.82 (s, 3H), 1.82 – 1.88 (m, 2H), 2.09 (s, 3H), 2.11 (s, 3H), 2.20 (s, 3H), 2.26 (s, 3H), 2.31 (s, 3H), 2.36 (s, 3H), 2.37 – 2.46 (m, 1H), 2.49 – 2.59 (m, 1H), 2.65 (d, J = 9.0 Hz, 1H), 2.76 – 2.80 (m, 3H), 2.90 – 2.99 (m, 1H), 3.00 – 3.11 (m, 4H), 3.10 – 3.17 (m, 2H), 3.18 – 3.26 (m, 2H), 3.31 (d, J = 8.4 Hz, 1H), 3.38 – 3.45 (m, 1H), 3.50 (d, J = 6.7 Hz, 1H), 3.55 – 3.61 (m, 1H), 3.66 (s, 1H), 3.73 – 3.82 (m, 2H), 3.89 – 3.98 (m, 2H), 4.33 – 4.40 (m, 1H), 4.44 (s, 1H), 4.59 (dd, J = 26.3, 11.2 Hz, 2H), 4.71 (d, J = 9.8 Hz, 1H), 4.89 (d, J = 11.3 Hz, 1H), 4.97 (d, J = 10.5 Hz, 1H), 5.05 – 5.16 (m, 3H), 5.34 – 5.39 (m, 1H), 5.48 (s, 1H), 5.95 (dd, J = 15.6, 5.0 Hz, 1H), 6.20 (dd, J = 26.8, 10.3 Hz, 2H), 6.43 (dd, J = 24.4, 10.5 Hz, 2H), 6.56 – 6.65 (m, 1H), 6.90 (dd, J = 20.0, 10.4 Hz, 2H), 6.99 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz,1H), 7.21 (t, J = 7.4 Hz, 1H), 7.78 (s, 1H), 8.01 (t, J = 8.4 Hz, 1H), 8.31 (s, 1H), 8.75 (d, J = 9.6 Hz, 1H), 12.07 (s, 1H), 13.15 (s, 1H), 13.25 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.59, 8.50, 8.96, 10.91, 12.94, 17.87, 18.09, 18.40, 20.77, 21.26, 21.46, 29.28, 29.68, 30.96, 33.40, 36.76, 37.46, 38.55, 38.78, 39.48, 39.72, 41.06, 47.93, 50.29, 51.53, 51.86, 52.59, 54.39, 55.42, 56.53, 57.14, 57.67, 58.44, 60.12, 66.72, 68.42, 69.96, 70.60, 71.88, 74.40, 104.63, 106.33, 108.81, 110.72, 113.10, 115.19, 118.00, 118.59, 120.50, 120.69, 123.24, 124.81, 126.34, 127.74, 128.67, 129.36, 129.95, 134.96, 135.21, 136.14, 138.45, 138.59, 142.70, 142.82, 148.12, 151.32, 153.24, 154.59, 165.71, 167.34, 169.18, 169.45, 169.70, 170.04, 171.09, 172.18, 172.76, 174.57, 195.60; HRMS (ESI) m / z: [M+H]+ calcd for C85H108FN11O231670.7682; found 1670.7772. n. SYNTHESIS OF COMPOUND 5335

[0374] 5335 was synthesized from 4206 and 6-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)hexanoic acid following the method described for 5192 as a brick red solid;1H NMR (500 MHz, CDCl3) δ -0.42 (d, J = 7.0 Hz, 3H), 0.48(d, J = 6.9 Hz, 3H), 0.75 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 1.17 – 1.27 (m, 3H), 1.29 (d, J = 6.6 Hz, 3H), 1.38 – 1.45 (m, 1H), 1.45 – 1.56 (m, 3H), 1.57 – 1.60 (m, 1H), 1.68 (s, 3H), 1.68 – 1.86 (m, 4H), 1.94 (s, 3H), 1.96 (s, 3H), 2.12 (s, 3H), 2.16 (s, 6H), 2.17 – 2.22 (m, 2H), 2.31 – 2.40 (m, 1H), 2.46 – 2.53 (m, 1H), 2.65 – 2.79 (m, 2H), 2.81 – 2.91 (m, 2H), 2.92 (s, 3H), 3.01 – 3.08 (m, 1H), 3.09 – 3.21 (m, 2H), 3.36 (d, J = 6.9 Hz, 1H), 3.40 – 3.48 (m, 1H), 3.58 – 3.68 (m, 3H), 3.76 (dd, J = 13.2, 5.1 Hz, 1H), 4.30 – 4.44 (m, 3H), 4.48 – 4.58 (m, 2H), 4.79 – 4.92 (m, 2H), 4.93 – 5.02 (m, 2H), 5.20 – 5.27 (m, 2H), 5.81 (dd, J = 15.4, 5.2 Hz, 1H), 6.02 – 6.11 (m, 2H), 6.27 (d, J = 11.1 Hz, 1H), 6.46 (dd, J = 15.5, 11.1 Hz, 1H), 6.55 (t, J = 9.0 Hz, 1H), 6.61 (d, J = 7.9 Hz, 2H), 6.76 (dd, J = 21.1, 10.3 Hz, 2H), 6.92 (d, J = 10.2 Hz, 1H), 7.67 (s, 1H), 7.84 (t, J = 8.5 Hz, 1H), 8.22 (s, 1H), 8.38 (d, J = 9.8 Hz, 1H), 11.97 (s, 1H), 12.88 (s, 1H), 13.08 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.61, 8.51, 8.98, 10.92, 13.00, 17.73, 18.08, 18.37, 20.77, 21.43, 24.40, 25.14, 26.58, 29.67, 30.96, 33.40, 33.84, 36.91, 37.46, 38.50, 38.76, 39.24, 39.46, 40.77, 46.08, 47.75, 49.11, 50.89, 52.02, 52.81, 54.27, 54.40, 55.36, 55.65, 56.54, 57.16, 57.23, 60.06, 69.80, 70.65, 71.57, 74.38, 102.50, 104.64, 106.53, 108.82, 110.36, 112.60, 113.24, 115.23, 118.03, 118.60, 120.45, 120.82, 123.24, 124.85, 129.44, 132.77, 135.20, 136.41, 138.58, 139.90, 142.66, 142.89, 148.36, 151.40, 153.32, 154.70, 162.04, 164.01, 166.07, 168.26, 169.17, 169.64, 170.28, 171.11, 171.84, 172.07, 172.21, 172.73, 174.60, 195.69; HRMS (ESI) m / z: [M+H]+ calcd for C89H115F3N12O221761.8279; found 1761.8368. o. SYNTHESIS OF COMPOUND 5336

[0375] Compound 5336 was synthesized from compound 4206 (102 mg, 0.119 mmol) and 3-(2-(4-(((benzyloxy)carbonyl)amino)piperazin-1-yl)ethoxy)propanoic acid following the method described for compound 5192 as a brick red solid (68.3 mg, 32.5 % over three steps);1H NMR (500 MHz, CDCl3) δ -0.27 (d, J = 7.0 Hz, 3H), 0.62 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.44 (d, J = 6.6 Hz, 3H), 1.53 – 1.60 (m, 1H), 1.82 (s, 3H), 1.85 – 1.90 (m, 1H), 1.91 – 1.93 (m, 1H), 1.95 – 2.01 (m, 1H), 2.09 (s, 3H), 2.10 (s, 3H), 2.20 (s, 3H), 2.26 (s, 3H), 2.31 (s, 3H), 2.53 (t, J = 10.9 Hz, 1H), 2.61 (t, J = 6.2 Hz, 1H), 2.82 – 2.90 (m, 2H), 2.92 – 3.06 (m, 5H), 3.07 (s, 3H), 3.16 – 3.35 (m, 4H), 3.51 (d, J = 7.9 Hz, 1H), 3.55 – 3.61 (m, 1H), 3.72 (d, J = 12.1 Hz, 3H), 3.79 (dd, J = 19.7, 6.4 Hz, 3H), 3.91 (dd, J = 13.3, 5.2 Hz, 2H), 4.46 – 4.52 (m, 1H), 4.52 – 4.59 (m, 1H), 4.63 – 4.73 (m, 2H), 4.97 (d, J = 10.7 Hz, 1H), 4.99 – 5.06 (m, 1H), 5.13 (dd, J = 13.8, 6.6 Hz, 2H), 5.36 – 5.46 (m, 2H), 5.96 (dd, J = 15.5, 5.1 Hz, 1H), 6.21 (dd, J = 18.6, 10.2 Hz, 2H), 6.40 – 6.43 (m, 1H), 6.56 – 6.65 (m, 1H), 6.69 (t, J = 9.0 Hz, 1H), 6.76 (d, J = 6.0 Hz, 2H), 6.90 (dd, J = 21.0, 10.1 Hz, 2H), 7.18 (d, J = 9.9 Hz, 1H), 7.82 (s, 1H), 7.99 (t, J = 8.5 Hz, 1H), 8.37 (s, 1H), 8.54 (d, J = 9.6 Hz, 1H), 12.11 (s, 1H), 13.03 (s, 1H), 13.23 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.61, 8.52, 8.98, 10.89, 13.00, 17.74, 18.04, 18.40, 20.75, 21.43, 25.62, 29.67, 30.96, 33.39, 34.79, 36.85, 37.46, 38.48, 38.77, 39.30, 39.46, 40.72, 46.01, 47.76, 49.13, 51.60, 52.04, 52.79, 54.19, 54.41, 55.38, 55.68,56.46, 56.69, 57.18, 60.08, 66.25, 67.98, 69.79, 70.68, 71.82, 74.38, 102.50, 104.64, 106.51, 108.81, 110.40, 112.60, 113.23, 115.38, 118.03, 118.57, 120.46, 120.83, 123.25, 124.85, 129.42, 132.78, 135.23, 138.58, 142.66, 142.91, 148.35, 151.40, 153.33, 154.72, 162.03, 163.95, 166.19, 168.18, 169.17, 169.64, 170.29, 170.71, 171.04, 171.89, 172.06, 172.22, 174.60, 195.69; HRMS (ESI) m / z: [M+H]+calcd for C88H113F3N12O231763.8072; found 1763.8101. p. SYNTHESIS OF COMPOUND 5368

[0376] 5368 was synthesized from 5366 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for 5200 as a brick red solid;1H NMR (500 MHz, CDCl3) δ -0.28 (d, J = 6.9 Hz, 3H), 0.62 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.6 Hz, 3H), 1.33 – 1.42 (m, 1H), 1.51 – 1.60 (m, 1H), 1.74 (d, J = 7.2 Hz, 1H), 1.76 – 1.89 (m, 3H), 1.97 – 2.06 (m, 2H), 2.07–2.15 (m, 6H), 2.20 (s, 3H), 2.25 (s, 3H), 2.31 (s, 3H), 2.77 (s, 3H), 2.89 – 2.96 (m, 1H), 2.98–3.01 (m, 2H), 3.06 (s, 3H), 3.08 – 3.16 (m, 3H), 3.18 – 3.28 (m, 3H), 3.37 (d, J = 13.1 Hz, 1H), 3.47 – 3.59 (m, 3H), 3.65 – 3.76 (m, 2H), 3.78 – 3.89 (m, 3H), 4.43 – 4.53 (m, 2H), 4.59 – 4.76 (m, 3H), 4.91 – 5.00 (m, 2H), 5.03 – 5.18 (m, 3H), 5.24 (d, J = 6.6 Hz, 1H), 5.96 (dd, J = 15.5, 5.1 Hz, 1H), 6.07 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 12.7 Hz, 1H), 6.42 (d, J = 11.3 Hz, 1H), 6.62 (dd, J = 15.6, 11.1 Hz, 1H), 6.72 (dd, J = 15.9, 8.5 Hz, 2H), 6.86 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 9.9 Hz, 1H), 7.63 (s, 1H), 7.97 (t, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.63 (d, J = 9.8 Hz, 1H), 12.05 (s, 1H), 13.21 (s, 1H), 13.25 (s, 1H), 13.48 (br.s, 1H); ESI-MS: [m / z+H+] = 1693.49.q. SYNTHESIS OF COMPOUND 5369

[0377] 5369 was synthesized from 5367 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for 5200 as a brick red solid;1H NMR (500 MHz, CDCl3) δ -0.40 (d, J = 6.9 Hz, 3H), 0.50 (d, J = 7.0 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H), 1.37 – 1.46 (m, 2H), 1.54 – 1.60 (m, 2H), 1.67 – 1.78 (m, 5H), 1.94 (s, 3H), 1.98 (s, 3H), 1.98 (s, 3H), 2.04 (dd, J = 13.0, 6.9 Hz, 1H), 2.15 (s, 3H), 2.22 (s, 3H), 2.52 – 2.62 (m, 3H), 2.64 – 2.70 (m, 2H), 2.76 – 2.83 (m, 2H), 2.93 (d, J = 12.8 Hz, 2H), 2.96 (s, 3H), 3.08 – 3.18 (m, 3H), 3.37 – 3.50 (m, 3H), 3.66 (d, J = 9.6 Hz, 1H), 3.75 (d, J = 4.6 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 4.05 (q, J = 7.2 Hz, 3H), 4.39 (d, J = 8.3 Hz, 1H), 4.54 – 4.65 (m, 3H), 4.81 (dd, J = 27.9, 9.8 Hz, 2H), 4.94 (dt, J = 10.1, 5.2 Hz, 1H), 4.99 – 5.08 (m, 2H), 5.81 (dd, J = 15.3, 5.1 Hz, 1H), 5.94 (d, J = 7.2 Hz, 1H), 6.17 (d, J = 12.5 Hz, 1H), 6.26 (d, J = 11.0 Hz, 1H), 6.31 – 6.41 (m, 1H), 6.44 – 6.57 (m, 3H), 6.75 – 6.85 (m, 2H), 7.43 (s, 1H), 7.79 (t, J = 8.4 Hz, 1H), 7.92 (s, 1H), 8.12 (s, 1H), 8.48 (d, J = 9.8 Hz, 1H), 11.91 (s, 1H), 12.97 (s, 1H), 13.18 (s, 1H), 13.55 (s, 1H); ESI-MS: [m / z+H+] = 1707.28. r. SYNTHESIS OF COMPOUND 5385

[0378] To a mixture of 4206 (200 mg, 0.233 mmol) and 2-(4-oxocyclohexyl)acetic acid (40.1 mg, 0.257 mmol) in THF were added N-ethyl-N-isopropylpropan-2-amine (90 µl, 0.513 mmol) and N,N-dimethylpyridin-4-amine (7.13 mg, 0.058 mmol). Then 2,4,6- trichlorobenzoyl chloride (52.2 µl, 0.257 mmol) was added to the above solution. The mixture was stirred at room temperature for two hours. The solvent was removed and the residue was purified by flash silica gel chromatography with ethyl acetate:MeOH 95:5 as eluent. Combined product fractions were concentrated to give B as a white solid (123.7 mg,1.00 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.39 – 1.56 (m, 4H), 1.61 – 1.70 (m, 2H), 1.81 – 1.97 (m, 3H), 2.07 – 2.15 (m, 3H), 2.31 (s,3H), 2.34 – 2.45 (m, 8H), 2.48 – 2.55 (m, 1H), 2.79 (d, J = 10.7 Hz, 1H), 2.94 – 3.06 (m, 2H), 3.21 (dd, J = 12.1, 8.4 Hz, 1H), 3.58 (dd, J = 12.1, 9.2 Hz, 1H), 3.73 – 3.84 (m, 2H), 3.92 (dd, J = 13.2, 5.0 Hz, 1H), 4.43 – 4.55 (m, 2H), 4.57 (d, J = 8.2 Hz, 1H), 4.62 – 4.73 (m, 2H), 5.03 (d, J = 9.8 Hz, 1H), 5.07 – 5.13 (m, 1H), 5.34 – 5.45 (m, 2H), 6.16 (d, J = 7.8 Hz, 1H), 6.67 – 6.83 (m, 3H), 6.85 – 6.95 (m, 2H), 7.79 (s, 1H), 8.00 (t, J = 8.5 Hz, 1H), 8.50 (d, J = 10.1 Hz, 1H); ESI-MS: [m / z+H+] = 996.92.

[0379] To the solution of B (22 mg, 0.022 mmol) and 3-amino-4-iminorifamycin-S (12.07, 0.017 mmol) in THF were added ammonium acetate (10.49 mg, 0.14 mmol) and zinc powder (1.1 mg, 0.017 mmol). The resulted mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the brick red residue was purified through Waters PrepLC System with water (0.1% formic acid) and methanol (0.1% formic acid) as eluent to give compound 5385 as bright purplish red solid. HRMS (ESI) m / z: [M+H]+calcd for C86H106F3N11O211686.7595; found 1686.7640. s. SYNTHESIS OFCOMPOUND5386

[0380] 5386 was synthesized from 5367 (35 mg, 0.035 mmol) following the method described for 5385 as a dark purplish red solid (30.6 mg, 56.7%); HRMS (ESI) m / z: [M+H]+calcd for C86H106F3N11O211686.7595; found 1686.7622.t. SYNTHESIS OF COMPOUND 5396

[0381] 5396 was synthesized from 5395 with 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for 5192 as brick red solid;1H NMR (500 MHz, CDCl3) δ -0.44 (d, J = 6.9 Hz, 3H), 0.47 (d, J = 6.9 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H), 1.18 – 1.29 (m, 2H), 1.31 – 1.34 (m, 1H), 1.36 – 1.42 (m, 1H), 1.53 – 1.59 (m, 2H), 1.67 (s, 3H), 1.86 – 1.91 (m, 1H), 1.94 (s, 3H), 1.96 (s, 3H),2.11 (s, 3H), 2.15 (s, 3H), 2.51 – 2.64 (m, 3H), 2.70 (t, J = 13.2 Hz, 1H), 2.75 – 2.82 (m, 1H), 2.91 (s, 3H), 3.02 – 3.09 (m, 2H), 3.29 – 3.42 (m, 2H), 3.62 – 3.76 (m, 3H), 3.91 – 3.98 (m, 1H), 4.28 – 4.39 (m, 2H), 4.45 – 4.59 (m, 4H), 4.79 – 4.90 (m, 2H), 4.92 – 5.03 (m, 2H), 5.18 – 5.25 (m, 1H), 5.81 (dd, J = 15.5, 5.1 Hz, 1H), 6.00 (s, 1H), 6.08 (d, J = 12.5 Hz, 1H), 6.28 (d, J = 11.1 Hz, 1H), 6.41 – 6.49 (m, 1H), 6.51 – 6.64 (m, 3H), 6.68 – 6.79 (m, 2H), 7.18 (d, J = 9.3 Hz, 1H), 7.47 – 7.54 (m, 1H), 7.79 (t, J = 8.5 Hz, 1H), 8.16 (s, 1H), 8.43 (d, J = 9.8 Hz, 1H), 11.96 (s, 1H), 12.94 (s, 1H), 13.07 (s, 1H), 13.32 (br.s, 1H);13C NMR (126 MHz, CDCl3) δ 7.61, 8.49, 8.96, 10.85, 13.91, 17.90, 18.39, 20.72, 20.78, 21.11, 21.48, 25.58, 28.08, 29.73, 33.37, 36.18, 37.47, 38.47, 38.55, 39.34, 39.52, 41.19, 47.21, 50.29, 51.21, 52.36, 52.60, 54.08, 55.61, 56.38, 57.11, 57.94, 60.40, 61.08, 62.57, 70.04, 70.63, 74.34, 102.51, 104.66, 106.51,108.89, 110.34, 112.66, 113.15, 115.22, 117.98, 118.73, 120.39, 120.97, 123.17, 124.51, 124.60, 124.87, 129.26, 133.04, 135.33, 138.58, 139.82, 142.74, 142.92, 148.25, 151.43, 153.36, 154.54, 162.00, 163.88, 166.08, 168.31, 169.13, 169.54, 169.60, 169.75, 169.89, 170.32, 171.44, 171.91, 172.17, 174.56, 195.68; HRMS (ESI) m / z: [M+H]+calcd for C85H107F3N12O221705.7653; found. u. SYNTHESIS OFCOMPOUND5401

[0382] 5401 was synthesized from 4518 with 2-(4-oxopiperidin-1-yl)acetic acid following the method described for 5200 and 5385 as a dark purple solid;1H NMR (500 MHz, CDCl3) δ -0.01 (d, J = 7.0 Hz, 3H), 0.67 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H), 1.11 (d, J = 7.0 Hz, 3H), 1.29 (d, J = 6.6 Hz, 3H), 1.31 – 1.39 (m, 6H), 1.54 (t, J = 8.1 Hz, 1H), 1.84 (s, 3H), 2.09 (s, 3H), 2.12 (s, 3H), 2.15 – 2.21 (m, 1H), 2.24 (s, 3H), 2.29 – 2.34 (m, 1H), 2.36 (s, 3H), 2.40 (s, 3H), 2.42 – 2.49 (m, 2H), 2.59 (t, J = 9.8 Hz, 1H), 2.67 – 2.74 (m, 1H), 2.83 (t, J = 11.5 Hz, 1H), 3.03 – 3.11 (m, 3H), 3.16 (s, 3H), 3.23 – 3.30 (m, 2H), 3.61 – 3.68 (m, 1H), 3.76 (d, J = 9.3 Hz, 1H), 3.81 – 3.95 (m, 2H), 4.12 (d, J = 14.0 Hz, 1H), 4.48 (d, J = 8.4 Hz, 1H), 4.59 – 4.71 (m, 2H), 4.74 – 4.85 (m, 4H), 4.87 (d, J = 10.4 Hz, 1H), 4.95 – 5.02 (m, 2H), 5.18 (dd, J = 12.5, 6.9 Hz, 1H), 5.28 (q, J = 7.0, 6.6 Hz, 1H), 5.52 (t, J = 7.4 Hz, 1H), 6.10 (dd, J = 15.7, 7.2 Hz, 1H), 6.21 (t, J = 10.1 Hz, 2H), 6.33 (d, J = 10.4 Hz, 1H), 6.44 (dd, J = 15.9, 10.4 Hz, 1H), 6.72 – 6.83 (m, 3H), 6.95(dd, J = 19.5, 10.2 Hz, 2H), 7.80 (d, J = 8.1 Hz, 1H), 7.89 (s, 1H), 7.97 (t, J = 8.5 Hz, 1H), 8.20 (s, 2H), 8.36 (s, 1H), 8.83 (d, J = 9.8 Hz, 1H), 8.97 (s, 1H), 14.72 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.64, 8.78, 10.56, 11.18, 13.18, 17.47, 17.80, 18.40, 20.32, 20.74, 21.00, 21.77, 29.71, 33.03, 34.38, 35.26, 37.56, 37.73, 38.09, 38.78, 39.25, 39.40, 40.61, 41.06, 46.98, 48.02, 51.29, 51.53, 52.84, 54.43, 54.70, 54.82, 56.05, 57.02, 57.12, 60.40, 69.12, 70.18, 72.84, 73.20, 80.16, 92.88, 102.40, 104.93, 107.32, 108.82, 111.78, 112.76, 114.61, 115.31, 115.46, 115.74, 121.22, 124.14, 124.63, 124.83, 125.05, 130.92, 133.06, 133.31, 139.93, 141.02, 142.04, 143.78, 151.64, 153.57, 154.80, 155.87, 161.80, 163.78, 164.30, 166.02, 167.55, 168.28, 168.57, 169.86, 171.64, 171.90, 172.07, 172.33, 181.65, 192.97; HRMS (ESI) m / z: [M+H]+calcd for C84H105F3N12O211675.7547; found 1675.7565. v. SYNTHESIS OF COMPOUND 5402

[0383] 5402 was synthesized from 5395 with 2-(4-oxopiperidin-1-yl)acetic acid following the method described for 5200 and 5385 as a dark purple solid;1H NMR (500 MHz, CDCl3) δ 0.90 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H), 1.44 – 1.58 (m, 3H), 1.75 (d, J = 12.7 Hz, 1H), 1.79 (s, 3H), 1.81 –1.92 (m, 3H), 2.08 (s, 3H), 2.10 (s, 3H), 2.19 (dd, J = 13.1, 6.4 Hz, 1H), 2.35 (s, 3H), 2.39 (s, 3H), 2.42 – 2.55 (m, 3H), 2.76 (d, J = 9.6 Hz, 1H), 2.89 (t, J = 13.0 Hz, 1H), 2.93 – 3.00 (m, 1H), 3.04 – 3.13 (m, 2H), 3.14 (s, 2H), 3.24 – 3.31 (m, 1H), 3.38 (dd, J = 18.3, 8.1 Hz, 1H), 3.47 – 3.54 (m, 1H), 3.61 (t, J = 10.8 Hz, 1H), 3.73 (d, J = 9.9 Hz, 1H), 3.89 (dd, J = 11.2, 5.4 Hz, 1H), 3.95 (dd, J = 12.3, 5.9 Hz, 1H), 4.15 – 4.22 (m, 1H), 4.47 – 4.52 (m, 1H), 4.54 (d, J = 8.5 Hz, 1H), 4.69 – 4.83 (m, 4H), 5.04 – 5.11 (m, 1H), 5.18 (dd, J = 12.6, 7.2 Hz, 1H), 5.30 (q, J = 7.9, 7.5 Hz, 1H), 5.45 (d, J = 7.5 Hz, 1H), 6.07 (dd, J = 15.4, 6.7 Hz, 1H), 6.20 (dd, J = 20.1, 10.0 Hz, 2H), 6.33 (d, J = 10.4 Hz, 1H), 6.44 (dd, J = 15.4, 10.2 Hz, 1H), 6.77 (dd, J = 30.2, 7.3 Hz, 3H), 6.92 (d, J = 12.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.71 (s, 1H), 8.02 (t, J = 8.5 Hz, 1H), 8.29 (s, 1H), 8.61 (d, J = 9.8 Hz, 1H), 9.04 (s, 1H), 14.59 (s, 1H);13C NMR (126 MHz, CDCl3) δ 7.64, 8.77, 10.92, 11.22, 12.97, 17.40, 18.45, 20.26, 20.74, 21.02, 21.15, 21.87, 24.97, 28.02, 29.78, 33.00, 35.03, 35.81, 36.45, 37.61, 38.21, 38.57, 39.60, 41.24, 47.03, 51.29, 51.50, 52.37, 52.57, 54.08, 55.61, 56.46, 56.91, 57.28, 60.48, 60.71, 62.64, 70.00, 72.62, 73.11, 80.73, 92.77, 102.61, 105.08, 107.39, 108.95, 111.60, 112.43, 112.63, 114.74, 115.24, 115.39, 115.58, 120.91, 123.97, 124.60, 124.89, 130.82, 132.92, 133.50, 139.66, 141.25, 141.75, 144.29, 151.41, 153.33, 154.49, 155.83, 161.99, 164.06, 165.88, 168.16, 168.65, 169.72, 170.09, 170.44, 171.30, 171.56, 171.89, 172.38, 181.51, 192.72. w. SYNTHESIS OF COMPOUND 5424

[0384] 5424 was synthesized from 4555 with 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for 5192 as brick red solid;1H NMR (500 MHz, CDCl3) δ -0.37 (d, J = 6.9 Hz, 3H), 0.53 (d, J = 6.9 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.91 – 0.95 (m, 6H), 1.12 (d, J = 6.6 Hz, 3H), 1.25 – 1.33 (m, 1H), 1.43 – 1.49 (m, 1H), 1.54 (dt, J = 14.3, 7.3 Hz, 1H), 1.61 – 1.67 (m, 1H), 1.73 (s, 3H), 1.74 – 1.80 (m, 1H), 1.81 – 1.92 (m, 2H), 2.00 (s, 3H), 2.01 (s, 3H), 2.11 (s, 3H), 2.16 (s, 3H), 2.22 (s, 3H), 2.24 – 2.30 (m, 2H), 2.31 – 2.36 (m, 1H), 2.41 – 2.47 (m, 1H), 2.69 – 2.77 (m, 3H), 2.83 – 2.89 (m, 1H), 2.91 – 2.96 (m, 1H), 2.98 (s, 2H), 3.02 – 3.08 (m, 2H), 3.09 – 3.16 (m, 2H), 3.19 – 3.29 (m, 2H), 3.41 (d, J = 6.9 Hz, 1H), 3.49 (dd, J = 12.1, 9.1 Hz, 1H), 3.63 – 3.73 (m, 3H), 3.81 – 3.87 (m, 1H), 4.36 – 4.44 (m, 2H), 4.50 (d, J = 8.2 Hz, 1H), 4.56 (d, J = 11.0 Hz, 1H), 4.62 (d, J = 9.9 Hz, 1H), 4.65 – 4.71 (m, 1H), 4.88 (d, J = 10.7 Hz, 1H), 4.97 – 5.07 (m, 2H), 5.31 – 5.39 (m, 2H), 5.86 (dd, J = 15.5, 5.1 Hz, 1H), 6.10 – 6.19 (m, 2H), 6.30 (s, 1H), 6.45 – 6.55 (m, 1H), 6.56 – 6.63 (m, 1H), 6.63 – 6.73 (m, 2H), 6.78 (d, J = 11.9 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.04 – 7.13 (m, 1H), 7.73 – 7.79 (m, 1H), 7.89 (t, J = 8.5 Hz, 1H), 8.22 (s, 1H), 8.38 (d, J = 9.8 Hz, 1H), 11.97 (s, 1H), 13.05 (s, 1H), 13.17 (d, J = 16.1 Hz, 1H), 13.34 (br.s, 1H);13C NMR (126 MHz, CDCl3) δ 7.59, 8.50, 8.95, 10.59, 10.90, 12.98, 17.87, 18.52, 20.77, 21.46, 25.81, 29.68, 33.37, 36.79, 37.47, 38.50, 38.75, 39.37, 39.49, 40.67, 46.39, 50.13, 51.46, 52.01, 52.73, 53.17, 54.23,54.30, 55.34, 55.81, 56.82, 57.14, 57.32, 58.26, 59.99, 69.98, 70.68, 71.98, 74.40, 102.44, 104.01, 105.95, 108.82, 110.68, 112.66, 113.40, 115.37, 118.00, 118.61, 120.49, 121.37, 122.80, 124.82, 128.91, 132.76, 135.15, 138.59, 140.02, 142.69, 148.58, 150.73, 153.82, 154.77, 161.23, 163.67, 166.48, 168.56, 169.22, 169.74, 171.09, 171.70, 171.91, 172.57, 174.57, 195.61; HRMS (ESI) m / z: [M+H]+calcd for C86H109F3N12O221719.7809; found 1719.7847. x. SYNTHESIS OF COMPOUND 5425

[0385] 5425 was synthesized from 4752 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for 5192 as a brick red solid;1H NMR (500 MHz, CDCl3) δ -0.33 (d, J = 6.9 Hz, 3H), 0.56 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H), 1.17 (d, J = 6.7 Hz, 3H), 1.35 (d, J = 6.9 Hz, 3H), 1.39 (d, J = 6.6 Hz, 3H), 1.47 – 1.55 (m, 1H), 1.63 – 1.71 (m, 1H), 1.76 (s, 3H), 1.78 – 1.85 (m, 1H), 2.03 (s, 3H), 2.05 (s, 3H), 2.14 (s, 6H), 2.20 (s, 3H), 2.25 (s, 3H), 2.33 – 2.39 (m, 1H), 2.39 – 2.52 (m, 2H), 2.73 – 2.78 (m, 3H), 2.91 – 2.99 (m, 2H), 3.01 (s, 3H), 3.05 – 3.10 (m, 2H), 3.13 – 3.19 (m, 2H), 3.21 – 3.32 (m, 2H), 3.45 (d, J = 7.2 Hz, 1H), 3.51 – 3.59 (m, 2H), 3.72 – 3.83 (m, 4H), 4.11 (s, 1H), 4.44 – 4.51 (m, 1H), 4.51 – 4.57 (m, 2H), 4.60 (d, J = 10.1 Hz, 1H), 4.89 – 4.98 (m, 2H), 5.00 –5.10 (m, 3H), 5.22 (t, J = 7.4 Hz, 1H), 5.40 (s, 1H), 5.89 (dd, J = 15.5, 5.1 Hz, 1H), 6.12 – 6.19 (m, 2H), 6.35 (d, J = 11.3 Hz, 1H), 6.54 (dd, J = 16.9, 11.2 Hz, 1H), 6.64 (t, J = 9.0 Hz, 1H), 6.67 – 6.73 (m, 2H), 6.83 (d, J = 12.1 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.95 – 7.99 (m, 1H), 8.26 (s, 1H), 8.63 (d, J = 9.8 Hz, 1H), 12.01 (s, 1H), 13.07 (s, 1H), 13.19 (s, 1H), 13.35 (br.s, 1H);13C NMR (126 MHz, CDCl3) δ 7.59, 8.50, 8.95, 10.90, 12.09, 17.01, 17.85, 18.05, 18.38, 20.77, 21.45, 29.71, 31.45, 33.37, 37.46, 38.49, 38.70, 39.05, 39.48, 40.12, 48.73, 50.12, 51.44, 52.27, 52.80, 54.36, 55.22, 55.60, 57.14, 58.04, 58.60, 59.97, 61.48, 69.03, 69.67, 70.67, 72.11, 74.39, 102.50, 104.62, 106.35, 108.81, 110.65, 112.37, 113.06, 115.24, 115.39, 118.00, 118.58, 120.48, 120.84, 123.23, 124.72, 124.88, 129.41, 132.87, 135.15, 138.58, 139.99, 142.68, 143.55, 148.16, 151.39, 153.31, 154.74, 162.03, 164.51, 166.29, 168.13, 169.13, 169.70, 169.99, 171.55, 171.98, 172.20, 175.24, 195.62; HRMS (ESI) m / z: [M+H]+calcd for C85H106F3N11O231706.7493; found 1706.7535. y. SYNTHESIS OFCOMPOUND5435

[0386] 5435 was synthesized from 5434 and 2-(4- (((benzyloxy)carbonyl)amino)piperazin-1-yl)acetic acid following the method described for 5192 as a brick red solid;1H NMR (500 MHz, CDCl3) δ -0.44 (d, J = 7.0 Hz, 3H), 0.47 (d, J= 6.9 Hz, 3H), 0.74 (d, J = 7.2 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H), 1.18 – 1.24 (m, 1H), 1.27 (d, J = 6.7 Hz, 3H), 1.37 – 1.43 (m, 1H), 1.57 (dd, J = 9.0, 7.0 Hz, 1H), 1.67 (s, 3H), 1.79 – 1.90 (m, 3H), 1.94 (s, 3H), 1.96 (s, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 2.17 (s, 3H), 2.25 – 2.33 (m, 2H), 2.50 – 2.57 (m, 1H), 2.56 – 2.61 (m, 1H), 2.67 (d, J = 10.7 Hz, 1H), 2.79 – 2.86 (m, 2H), 2.92 (s, 3H), 2.96 (s, 3H), 2.99 – 3.09 (m, 3H), 3.27 – 3.43 (m, 3H), 3.63 (t, J = 10.1 Hz, 2H), 3.94 (dd, J = 12.0, 7.4 Hz, 1H), 4.30 – 4.41 (m, 3H), 4.46 – 4.57 (m, 3H), 4.79 – 4.91 (m, 2H), 4.93 – 5.01 (m, 2H), 5.23 (dd, J = 8.5, 3.5 Hz, 1H), 5.78 – 5.84 (m, 1H), 6.03 – 6.10 (m, 2H), 6.28 (d, J = 11.0 Hz, 1H), 6.41 – 6.50 (m, 1H), 6.54 (t, J = 9.0 Hz, 1H), 6.61 (d, J = 5.6 Hz, 2H), 6.74 (dd, J = 20.2, 10.3 Hz, 2H), 7.00 (d, J = 9.9 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.80 (t, J = 8.5 Hz, 1H), 8.17 (s, 1H), 8.34 (d, J = 9.6 Hz, 1H), 11.96 (s, 1H), 12.93 (s, 1H), 13.08 (s, 1H), 13.30 (br.s, 1H);13C NMR (126 MHz, CDCl3) δ 7.61, 8.51, 8.97, 10.86, 12.93, 17.89, 18.06, 18.39, 20.71, 20.78, 21.48, 29.62, 33.39, 36.45, 37.47, 38.48, 38.76, 39.11, 39.52, 40.57, 45.65, 47.11, 48.38, 50.32, 51.22, 52.37, 52.63, 54.17, 54.39, 55.19, 56.26, 56.32, 57.12, 60.02, 61.10, 69.76, 70.62, 74.35, 102.44, 104.66, 106.53, 108.88, 110.36, 112.43, 112.62, 113.16, 115.24, 115.39, 118.00, 118.69, 120.40, 120.91, 123.19, 124.66, 124.83, 129.28, 132.83, 135.31, 135.38, 138.58, 140.06, 142.74, 142.91, 148.26, 151.44, 153.36, 154.76, 162.01, 163.88, 166.17, 168.41, 169.15, 169.58, 169.61, 170.24, ...

Claims

CLAIMS What is claimed is:

1. A compound having a structure represented by a formula:, wherein X is selected from ‒O‒, ‒N(R10)‒, and ‒CH(R10)‒; wherein R10is selected from hydrogen, C1-C4 alkyl, ‒C(O)R20, and ‒C(O)‒L‒ R21; wherein L is a linker; wherein R20is selected from C1-C4 alkyl and Ar1; wherein Ar1is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R21is a residue of a rifamycin analog; wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; wherein each of R2aand R2bis independently selected from hydrogen, halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1- C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl;wherein R3is selected from hydrogen, ‒OH, ‒OC(O)‒L‒R21, ‒NH2, ‒NH‒L‒R21, ‒L‒ C(O)‒R21, and NHC(O)‒L‒R21; wherein R4is selected from hydrogen, C1-C4 alkyl, ‒OH, and ‒CH2OH; and wherein R5 is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, provided that either R3is ‒OC(O)‒L‒R21, ‒NH‒L‒R21, ‒L‒C(O)‒R21, or NHC(O)‒ L‒R21, or X is ‒N(R10)‒ or ‒CH(R10)‒ and R10is ‒C(O)‒L‒R21.

2. The compound of claim 1, wherein X is ‒N(R10)‒.

3. The compound of claim 1 or claim 2, wherein R10is C1-C4 alkyl.

4. The compound of claim 1 or claim 2, wherein R10is methyl.

5. The compound of of claim 1 or claim 2, wherein R10is ‒C(O)‒L‒R21.

6. The compound of claim 1, wherein X is ‒CH(R10).

7. The compound of claim 6, wherein R10is hydrogen.

8. The compound of claim 6, wherein R10is ‒C(O)‒L‒R21.

9. The compound of claim 1, wherein X is ‒O‒.

10. The compound of any one of claims 1 to 9, wherein each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

11. The compound of any one of claims 1 to 9, wherein each of R1a, R1b, and R1cis independently selected from hydrogen, halogen, and C1-C4 alkyl.

12. The compound of any one of claims 1 to 9, wherein each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, ‒Cl, and C1-C4 alkyl.

13. The compound of any one of claims 1 to 9, wherein each of R1a, R1b, and R1cis independently selected from hydrogen, ‒F, and methyl.

14. The compound of any one of claims 1 to 9, wherein R1bis hydrogen and each of R1aand R1cis independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

15. The compound of any one of claims 1 to 9, wherein R1bis hydrogen and each of R1aand R1cis independently selected from hydrogen, ‒F, ‒Cl and C1-C4 alkyl.

16. The compound of any one of claims 1 to 9, wherein R1bis hydrogen and each of R1aand R1cis independently selected from hydrogen, ‒F, and methyl.

17. The compound of any one of claims 1 to 16, wherein each of R2aand R2bis independently selected from halogen, ‒NH2, ‒OH, ‒NO2, ‒CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

18. The compound of any one of claims 1 to 16, wherein each of R2aand R2bis independently selected from hydrogen, halogen, and C1-C6 alkyl.

19. The compound of any one of claims 1 to 16, wherein each of R2aand R2bis independently selected from hydrogen, ‒F, ‒Cl and C1-C6 alkyl.

20. The compound of any one of claims 1 to 16, wherein each of R2aand R2bis independently selected from halogen and C1-C6 alkyl.

21. The compound of any one of claims 1 to 16, wherein each of R2aand R2bis independently selected from ‒F and methyl.

22. The compound of any one of claims 1 to 21, wherein R3is ‒OH.

23. The compound of any one of claims 1 to 21, wherein R3is ‒OC(O)‒L‒R21.

24. The compound of any one of claims 1 to 23, wherein R4is hydrogen.

25. The compound of any one of claims 1 to 23, wherein R4is ‒OH.

26. The compound of any one of claims 1 to 25, wherein the linker is selected from C1- C8 alkyl, C4-C7 cycloalkyl, and ‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl).

27. The compound of any one of claims 1 to 26, wherein the residue of the rifamycin analog has a structure represented by a formula selected from: ,wherein R22is selected from C1-C4 alkyl and C1-C4 alkoxy.

28. The compound of claim 1, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1, wherein the compound has a structure represented by a formula:, wherein L is a linker selected from C1-C8 alkyl and ‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl), or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

35. The compound of claim 33, wherein the residue of the rifamycin analog has a structure represented by a formula selected from:,,wherein R22is selected from C1-C4 alkyl and C1-C4 alkoxy.

36. The compound of claim 33, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, wherein the compound has a structure represented by a formula:, wherein L is a linker selected from C1-C8 alkyl and ‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl), or a pharmaceutically acceptable salt thereof.

38. The compound of claim 37, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

39. The compound of claim 37, wherein the residue of the rifamycin analog has a structure represented by a formula selected from:,,wherein R22is selected from C1-C4 alkyl and C1-C4 alkoxy.

40. The compound of claim 37, wherein the compound has a structure represented by a formula:,41. The compound of claim 1, wherein the compound has a structure represented by a formula:, wherein L is a linker selected from C1-C8 alkyl and ‒(C1-C4 alkyl)‒O‒(C1-C4 alkyl), or a pharmaceutically acceptable salt thereof.

42. The compound of claim 37, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

43. The compound of claim 37, wherein the residue of the rifamycin analog has a structure represented by a formula selected from:,,wherein R22is selected from C1-C4 alkyl and C1-C4 alkoxy.

44. The compound of claim 37, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound is selected from:,. or a pharmaceutically acceptable salt thereof.

46. The compound of claim 1, wherein the compound is selected from:,,,,,,,,,,,,,,,or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

48. A method for treating an infectious disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, thereby treating the infectious disease in the subject.

49. The method of claim 48, wherein the subject is a mammal.

50. The method of claim 48, wherein the subject is a human.

51. The method of any one of claims 48 to 50, wherein the effective amount is a therapeutically effective amount.

52. The method of any one of claims 48 to 50, wherein the effective amount is a prophylactically effective amount.

53. The method of any one of claims 48 to 52, wherein the infectious disease is a biofilm- mediated disease.

54. The method of claim 53, wherein the biofilm-mediated disease is selected from bacterial endocarditis, bacteremia, prostatitis, rhinosinusitis, otitis media, an urinary tract infection (UTI), periodontitis, a wound infection, a diabetic foot ulcer, a catheter-associated bloodstream infection, an implant-associated infection, ventilator-associated pneumonia, and osteomyelitis.

55. The method of any one of claims 48 to 52, wherein the infectious disease is due to a prosthetic joint infection.

56. The method of any one of claims 48 to 52, wherein the infectious disease is due to or complicated by the presence of intracellular bacteria.

57. The method of any one of claims 48 to 52, wherein the infectious disease is due to a Gram-positive bacterial infection.

58. The method of claim 57, wherein the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, an enterococcal infection, a vancomycin-resistant enterococci (VRE) infection, anthrax, and toxic shock.

59. The method of claim 57, wherein the Gram-positive bacterial infection is methicillin- resistant Staphylococcus aureus (MRSA).

60. The method of claim 57, wherein the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp..

61. The method of claim 60, wherein Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE).

62. The method of claim 57, wherein the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae.

63. The method of claim 57, wherein the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes.

64. The method of claim 57, wherein the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).

65. The method of any one of claims 48 to 52, wherein the subject has been diagnosed with a need for treatment of the infectious disease prior to the administering step.

66. The method of any one of claims 48 to 52, further comprising the step of identifying a subject in need of treatment of the infectious disease.

67. The method of any one of claims 48 to 52, further comprising administering to the subject an effective amount of an antibacterial agent.

68. The method of claim 67, wherein the compound and the antibacterial agent are administered simultaneously.

69. The method of claim 68, wherein the compound and the antibacterial agent are co- formulated.

70. The method of claim 67, wherein the compound and the antibacterial agent are administered sequentially.

71. The method of claim 67, wherein the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin.

72. A method for activating ClpP protease in a cell, the method comprising contacting the cell with an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, thereby activating ClpP protease in the cell.

73. The method of claim 72, wherein the cell is a bacterial cell.

74. The method of claim 73, wherein the bacterial cell is a Gram-positive bacterial cell.

75. The method of claim 72, wherein the cell is a fungus.

76. The method of claim 72, wherein contacting is via administration to a subject.

77. The method of claim 76, wherein the subject has been diagnosed with a need for treatment of an infectious disease prior to the administering step.

78. The method of claim 77, wherein the infectious disease a biofilm-mediated disease, is due to a prosthetic joint infection, and / or is due to a Gram-positive bacterial infection.

79. The method of claim 76, wherein the subject has been diagnosed with a need for activating ClpP protease prior to the administering step.

80. A method for activating ClpP protease in a subject, the method comprising administering to the subject an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, thereby activating ClpP protease in the subject.

81. The method of claim 80, wherein the subject is a mammal.

82. The method of claim 80, wherein the subject is a human.

83. The method of claim 80, wherein the subject has been diagnosed with a need for activating ClpP protease prior to the administering step.

84. The method of claim 80, further comprising identifying a subject in need of activation of ClpP protease prior to the administering step.

85. A kit comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an antimicrobial agent; (b) instructions for treating an infectious disease; and (c) instructions for administering the compound in connection with treating an infectious disease.

86. The kit of claim 85, wherein the antimicrobial agent is selected from an antibacterial agent, an antiviral agent, an antifungal agent, and an antiparasitic agent.

87. The kit of claim 86, wherein the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, enoxacin, enviomycin, ertepenem, ethambutol, flucloxacillin, fosfomycin,furazolidone, gatifloxacin, gentamicin, imipenem, isoniazid, kanamycin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oritavancin, oxytetracycline, penicillin, piperacillin, platensimycin, polymixin B, quinupristin, retapamulin, rifabutin, rifampin, rifapentine, roxithromycin, sparfloxacin, spectinomycin, sulbactam, sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, telithromycin, telavancin, temafloxacin, tetracycline, tedolizid, thioacetazone, thioridazine, ticarcillin, tinidazole, tobramycin, torezolid, tosufloxacin, trimethoprim, troleandomycin, trovafloxacin, and vancomycin.

88. The kit of claim 86, wherein the antiviral agent is selected from acyclovir, oseltamivir, cidofovir, lamivudine, nitazoxanide, ribavirin, famciclovir, foscarnet, vidarabine, and fomibirsen.

89. The kit of claim 86, wherein the antifungal agent is selected from clotrimazole, econazole, micronazole, terbinafine, fluconazole, ketoconazole, nystatin, and amphotericin.

90. The kit of claim 86, wherein the antiparasitic agent is selected from metronidazole, furazolidone, tinidazole, albendazole, pyrantel pamoate, ivermectin, chloroquine, quinine, mefloquine, primaquine, sulfadozine-pyrimethamine, doxycycline, atovaquone-proguanil, and artemetherlumefantrine.

91. The kit of claim 85, wherein the compound and the antimicrobial agent are co- packaged.

92. The kit of claim 85, wherein the compound and the antimicrobial agent are co- formulated.

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