Compositions and methods for treating non-tuberculosis mycobacteria infections

Abstract

Disclosed are antibacterial compositions containing an amine amphenicol prodrug such as f lorf enicol amine and methods of using such compositions either alone or in combination with other antibacterial agents in methods of treating a non- tuberculosis mycobacteria infection and improving the efficacy of an antibacterial agent.

Description

COMPOSITIONS AND METHODS FOR TREATING NON-TUBERCULOSIS MYCOBACTERIA INFECTIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit from U . S . Patent Application Serial Nos . 63 / 635, 720, filed April 18 , 2024 , the content of which is incorporated herein by reference in its entirety .STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under grant no . AI157312 awarded by the National Institutes of Health . The government has certain rights in this invention .BACKGROUND

[0003] The incidence of infections caused by fast-growing mycobacteria, such as Mycobacterium abscessus and Mycoba cterium avium are increasingly common, especially amongst immunocompromised individuals . Mycobacterium abscessus (Mab) is particularly challenging due to its intrinsic or acquired resistance to multiple antibiotics .

[0004] Although intrinsic drug resistance determinants vary across mycobacterial species, the whiB7 pathway has emerged as a conserved and key mechanism limiting the activity of different antibiotics against diverse mycobacterial pathogens . WhiB7 is a transcriptional activator that promotes the expression of a suite of intrinsic drug resistance determinants including the tap drug efflux pump; eis , an acetyltransferase that modifies and inactivates aminoglycosides ; erm, a ribosomal RNA methyltransferase whose activity prevents macrolide antibiotic engagement with the ribosome ; and hflX, a ribosome splitting factor that rescues drug-stalled ribosomes . WhiB7 is activated in response to,and protects against , a number of different antibiotics, particularly ribosome-targeting antibiotics like macrolides , lincosamides, oxazolidinones, and spectinomycin .

[0005] Despite prolonged poly-antimicrobial therapy, treatment of Mycobacterium abscessus infections often fails , leading to progressive morbidity and eventual mortality . Clofazimine and rifabutin are known anti-mycobacterial antibiotics , repurposed for use against Mycobacterium abscessus . In addition antimicrobials active against Mycobacterium abscessus include delamanid, pretomanid and PIPD1 , as well as beta-lactamase inhibitors avibactam, relebactam and vaborbactam . Previously unused antimicrobial combinations , e . g. , vancomycin-clarithromycin and dual betalactam therapy, have been shown to have a synergistic effect against Mycobacterium abscessus in experimental models . Further, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated Mycobacterium abscessus infection . While many of these therapeutics have shown activity against Mycobacteria abscessus, new therapeutic alternatives are needed .SUMMARY OF THE INVENTION

[0006] A method for treating a non-tuberculosis mycobacteria infection is provided, which includes administering to a subj ect in need of treatment an effective amount of florfenicol amine thereby treating the subject' s non - tuberculosis mycobacteria infection .

[0007] Also provides is a method for improving the efficacy of an antibacterial agent by administering to a subject in need thereof an antibacterial agent in combination with an amine amphenicol prodrug thereby improving the efficacy of the antibacterial agent .

[0008] A synergistic antibacterial composition is further provided, which is composed of an antibacterial agent and an amine amphenicol prodrug .BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG . 1 shows that florfenicol amine synergi zes with protein synthesis inhibitor antiobiotics .

[0010] FIG . 2 shows anti-resistance properties of spontaneously generated Mycobacteria abscessus mutants against florfenicol amine ( FLF-NH2) . LOF, loss-of-function mutation .DETAILED DESCRIPTION OF THE INVENTION

[0011] A selective WhiB7 -dependent inhibitor of Mycobacteria abscessus has now been found . The inhibitor is florfenicol amine, a metabolite of florfenicol , which exhibits a high degree of oral bioavailability . Florfenicol amine is bioactivated by Eis2 (Enhanced intracellular survival 2 ) and can be synergistically used in combination with standard-of- care antibiotics to block resistance development . Accordingly, provided herein are compositions containing florfenicol amine, and other amine amphenicol prodrugs, and methods of use of the same in the treatment of nontuberculosis mycobacteria infections and improving efficacy of standard-of-care antibiotics / antibacterial agents .

[0012] In one aspect, a method for treating a nontuberculosis mycobacteria infection is provided . According to this method, an effective amount of florfenicol amine is administered to a subject in need of such treatment thereby treating the subj ect' s non-tuberculosis mycobacteria infection . As used herein, the term "treating, " "treat" or "treatment" refers to curing as well as ameliorating at least one symptom of any condition or disease .

[0013] As used herein, florfenicol amine ( (1R, 2S) “2“amino-3- fluoro-1- ( 4- (methylsulf onyl) phenyl ) propan-l-ol ) is a compound having the following structure:As demonstrated herein, florfenicol amine is bioactivated by Eis2 to produce the antibacterial substance acetyl florfenicol .

[0014] A subject in need of treatment may be an animal species infected with or suspected of being infected with a non-tuberculosis mycobacteria species. In some aspects, the subject is a human. In some aspects, the subject is a livestock animal (e.g., raised for meat, milk, butter, eggs, fur, leather, feathers and / or wool) , beasts of burden, a research animal (e.g. , rat or mouse) , a companion animal, as well as an animal raised for / in a zoo, wild habitat and / or circus. Livestock animals include, e.g. , avian species (e.g. , chickens, turkeys, geese, duck, ostriches, etc.) , bovines (e.g., cattle, dairy cows, buffalo) , ovines (e.g., goats or sheep), porcines (e.g., hogs or pigs), equines (e.g. , horses) etc. A companion animal may be understood to include housecats (feline) , dogs (canine), rabbit species, horses (equine) , rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils, and hamsters) , primates (e.g., monkeys) and avians, such as pigeons, doves, parrots, parakeets, macaws, canaries, and the like .

[0015] Subjects benefiting from treatment with a composition described herein (e.g., florfenicol amine or other amine amphenicol prodrug, optionally in combination with an additional antibacterial agent) include, but are not limitedto, those with non-tuberculosis pulmonary infections resembling tuberculosis, in particular in subj ects with chronic lung diseases such as cystic fibrosis ; skin and soft tissue infections ; central nervous system infections ; bacteremia ; and ocular and other non-tuberculosis infections . In some aspects , a subj ect treated in accordance with a method exhibits one or more signs or symptoms of a non-tuberculosis mycobacteria infection . For example , skin infected with a non-tuberculosis mycobacterium is usually red, warm, tender to the touch, swollen, and / or painful . Infected areas can also develop boils or pus-filled vesicles . Other signs of infection are fever, chills , muscle aches , and a general feeling of illness . In some aspects, the subj ect has been diagnosed with a non-tuberculosis mycobacteria infection, e. g. , by culturing the organism from the infection site or, in severe cases , from a blood culture .

[0016] "Administering, " "administer, " or "administration" refers to the delivery of at least one antibacterial agent described herein (e . g. , florfenicol amine or other amine amphenicol prodrug, and optionally an additional antibacterial agent) or of a pharmaceutical composition containing at least one antibacterial agent described herein to an organism for the purpose of treating or preventing a non-tuberculosis mycobacteria infection . In the context of florfenicol amine or other amine amphenicol prodrug, an "effective amount" refers to that amount of florfenicol amine or amine amphenicol prodrug that will be bioactivated by Eis2 and in sufficient amounts to provide acetyl florfenicol or an acetyl amphenicol in a concentration at which it can relieve to some extent one or more of the symptoms of a non- tuberculosis mycobacteria infection in a subj ect . In some aspects , an effective amount refers to that amount of a florfenicol amine or amine amphenicol prodrug that , whenadministered to a subject, delivers the active compound to a subject in a sufficient concentration to: (1) reduce, and preferably eliminate, the population of bacterial cells in a subject's body; (2) inhibit (i.e., slow, or preferably stop) proliferation of the bacterial cells; (3) inhibit (i.e., slow, preferably stop) spread of the bacterial infection; and / or (4) relieve (preferably eliminate) one or more symptoms associated with the infection.

[0017] The terms "decrease," "reduce," or "inhibit," or variations thereof, are used herein generally to mean a decrease by a statistically significant amount. For example, "reduced," "reduction," "decrease," or "inhibit" may mean a decrease by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., as compared to a reference sample) , or any decrease between 10-100% as compared to a reference level, e.g. , as compared to a subject that has not been treated with florfenicol amine or an amine amphenicol prodrug.

[0018] Determination of an effective amount is well within the capability of those skilled in the art. Efficacy of the antibacterial agents and combinations of antibacterial agents described herein can be determined by standard pharmaceutical procedures in cell cultures and / or experimental animals. The dosage can be formulated for use in animal models so as to achieve a circulating concentration range that is at or greater than the minimum inhibitory concentration ("MIC") , e.g.fas determined according to the guidelines laid down by the Clinical and Laboratory Standards Institute (CLSI) . Such information can then be used to more accurately determine dosages useful in patients. Similarly, the toxicity of theantibacterial agents and combinations of antibacterial agents described herein can be depicted as LD50of the compound, which is a lethal dose for 50% of subjects in a group treated with a particular antibacterial agent or combination of antibacterial agents.

[0019] Non-tuberculosis mycobacteria infections that may be treated according to the methods described herein include those caused by or suspected to be caused by Mycobacterium species belonging to the Mycobacterium abscessus-chelonae clade, e.g. , Mycobacteria abscessus subsp. abscessus, Mycobacteria abscessus subsp. massiliense, Mycobacteria abscessus subsp. bolletii , or Mycobacteria chelonae. Other non-tuberculosis mycobacteria infections that may be treated include, e.g. , Mycobacterium kansasii, Mycobacterium mar inum, Mycobacterium scrofulaceum, Mycobacterium avium complex (e.g. , Mycobacterium avium, Mycobacterium intracellulare , Mycobacterium chimaera), Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium simiae, Mycobacterium malmoense, Mycobacterium szulgai, and Mycobacterium haemophilum, Mycobacterium fortuitum.

[0020] In some aspects, the florfenicol amine (and / or other antibacterial agents described herein) is administered in the form of a pharmaceutical composition. A "pharmaceutical composition" refers to a composition or formulation including an antibacterial agent described herein in admixture with a pharmaceutically acceptable excipient and / or carrier. In some aspects, the carrier is a solvent (e.g., water) . "Excipient" refers to an inert substance added to a pharmacological composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0021] The pharmaceutical composition may include about0.01% to about 99% (w / w) of at least one antibacterial agent described herein (e.g. , florfenicol amine or other amine amphenicol prodrug, and optionally an additional antibacterial agent) . For example, the pharmaceutical composition can include between about 0.01% to about 20% (w / w) of the antibacterial agent. In some embodiments, the antibacterial agent comprises greater than 1% (w / w) , greater than 5% (w / w) , greater than 10% (w / w) , greater than 15% (w / w) , greater than 20% (w / w) , greater than 25% (w / w) , greater than 30% (w / w) , greater than 35% (w / w) , greater than 40% (w / w) , greater than 45% (w / w) , greater than 50% (w / w) , greater than 55% (w / w) , greater than 60% (w / w) , greater than 65% (w / w) , greater than 70% (w / w) , greater than 75% (w / w) , greater than 80% (w / w) , greater than 85% (w / w) , greater than 90% (w / w) , or greater than 95% (w / w) of the total weight of the pharmaceutical composition.

[0022] The pharmaceutical composition may be formulated for administration by any appropriate route known in the art including, but not limited to, topical (including buccal and sublingual) and oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol) , pulmonary, nasal, and rectal administration. Exemplary modes of administration include, but are not limited to, topical, injection, infusion, instillation, inhalation, or ingestion. "Injection" includes, without limitation, intravenous, intramuscular, intra- arterial, intrathecal, intraventricular, intracapsular , intraorbital, intracardiac, intradermal, intraperitoneal, intralymphnodal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, intracerebral, spinal, and intracissternal injection and infusion. In some aspects, the pharmaceutical composition maybe in the form of a topical formulation, oral dosage, injectable, aerosol or inhalant. In some aspects, the pharmaceutical composition is given to those in need thereof in any art recognized form, i.e., solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, creams, ointments, salve, or aerosols, or the like, in unit or multidosage forms suitable for simple administration of precise dosages. Techniques for formulation and administration of drugs may be found in Remington's Pharmacological Sciences, Mack Publishing Co. , Easton, PA, latest edition.

[0023] The amount of a composition administered may be dependent upon the subject being treated, bacteria causing the infection, the severity of the infection, the manner of administration, i.e. , oral, intravenous, topical, etc., and the judgment of the prescribing physician or veterinarian.

[0024] In some aspects, florfenicol amine is administered in combination with one or more additional antibacterial agents (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 additional antibacterial agents) . Additional antibacterial agents (i.e. , antibacterial agents other than florfenicol amine or an amine amphenicol prodrug such as chloramphenicol amine, thiamphenicol amine, and / or azidamfenicol amine) include, but are not limited to, macrolides, oxazolidinones, aminoglycosides, lincosamides and / or non-f luorinated amphenicols (i.e. , amphenicols devoid of a fluorine group) . Examples of macrolides include, e.g., erythromycin, azithromycin, clarithromycin, dirithromycin, troleandomycin, spiramycin, telithromycin, carbomycin a, josamycin, kitasamycin, midecamycin acetate, oleandomycin, solithromycin, spiramycin, troleandomycin, cethromycin, solithromycin, spiramycin, ansamycin, oleandomycin, carbomycin and tylosin, or a mixture or combination thereof.Examples of oxazolidinones include, e.g. , linezolid, posizolid, tedizolid, radezolid, contezolid, or a mixture or combination thereof. Examples of aminoglycosides include, e.g. , streptomycin, neomycin, kanamycin, puromycin, gentamicin, tobramycin, amikacin, capreomycin, netilmicin, spectinomycin, sisomicin, dibekalin, isepamicin, dihydrostreptomycin, framycetin, ribostamycin, arbekacin, bekanamycin, dibekacin, hygromycin B, verdamicin and, astromicin, or a mixture or combination thereof. Examples of non-f luorinated amphenicols include chloramphenicol, thiamphenicol, azidamfenicol, or a mixture or combination thereof. Examples of lincosamides include, e.g. , lincomycin and clindamycin.

[0025] Other suitable antibacterial agents include, e.g. , beta-lactams including penicillin, cephalosporin and carbapenems such as carbapenem, imipenem and meropenem; monolactams such as penicillin G, penicillin V, methicillin, oxacillin, cioxacillin, dicloxacillin, nafcillin, ampicillin, azlocillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, f lucloxacillin, cepalothin, cephapirin, cephradine, cephaloridine, cefazolin, cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime, cefadroxil, cefalothin, cefalexin, cefuroxime, cefditoren, ceftazidime, ceftizoxime, ceftaroline fosamil, ceftaroline, ceftobiprole, aztreonam, ertapenem, doripenem and cilastatin; beta-lactamase inhibitors such as avibactam, relebactam and vaborbactam; penicillin combinations such as amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam and ticarcillin / clavulanate;quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin , levofloxacin, ciprofloxacin, temaf loxacin, lomef loxacin, fleroxacin, grepafloxacin, sparf loxacin, trovaf loxacin, clinaf loxacin, gatif loxacin, moxif loxacin, sitaf loxacin, ganefloxacin, gemi floxacin, pazuf loxacin, besif loxacin, ulifloxacin, prulifloxacin, cinoxacin, piromidic acid, pipemidic acid, rosoxacin, rufloxacin, balof loxacin, tosuf loxacin, delaf loxacin, nemonoxacin ; antibacterial sulfonamides and antibacterial sulphanilamides, including para-aminobenzoic acid, sulfadiazine , silver sulfadiazine, sulf isoxazole , sulfamethoxazole , sulfadimethoxine , sulfadoxine, sulfamethizole and sulfathalidine , mafenide , sulfacetamide , sulf isomidine , sulfanilimide, sulfasalazine and sulfonamidochrysoidine ; tetracyclines such as tetracycline, chlortetracycline , demeclocycline, oxytetracycline, methacycline , doxycycline, minocycline clomocycline, lymecycline , meclocycline , penimepicycline , and rolitetracycline ; nitroimidazoles such as delamanid, pretomanid, metronidazole , tinidazole, nimorazole, dimetridazole , ornidazole, megazol and azanidazole; polymyxins (such as polymyxin A, B, C, D) ; colistins; glycopeptides such as vancomycin, telavancin and teicoplanin; bacitracin ; isoniazid; rifamycins such as rifampicin ( also called rifampin) , rifapentine, rifabutin, bezoxazin, orifamycin and rifaximin; ethambutol ; ethionamide; aminosalicylic acid; cycloserine ; sulfones such as dapsone and sulfoxone sodium; clofazimine; thalidomide; streptogramins such as quinupristin and daf lopristin; or ansamycins , or any other antibacterial agent .

[0026] In addition to antibacterial agents , the methods and compositions herein may further include other active ingredients such as trace elements , vitamins , anti-inf lammatories {e.g. , both steroidal and non-steroidal antiinflammatory agents) , anti-fungals, anti-parasitics, antivirals, hormones and the like. The additional active ingredients may be administered in the same or different composition as the antibacterial agent (s) and be administered simultaneously or sequentially to the antibacterial agent (s) described herein.

[0027] As indicated herein, resistance to florfenicol amine leads to increased susceptibility to other antibacterial agents (FIG. 2) . Thus, in another aspect, a method of improving the efficacy of an antibacterial agent is provided. According to this method, one or more antibacterial agents, e.g., one or more of the additional antibacterial agents described herein (e.g., macrolides, oxazolidinones, aminoglycosides, lincosamides and / or non-fluorinated amphenicols) is administered in combination with one or more amine amphenicol prodrugs to a subject in need thereof thereby improving the efficacy of the antibacterial agent.

[0028] The terms "improve," "increase," or "enhance," or variations thereof, are used herein to generally mean an increase by a statistically significant amount. For example, an "increase," "enhancement" or "improvement" may mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5- fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.

[0029] "Prodrug" denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield the active drug, e.g., an amine of florfenicol is a prodrug that is activated by Eis2 to provide the antibacterial compound acetyl florfenicol in vivo.

[0030] An "amine amphenicol prodrug" refers to a compound of the amphenicol class of antibiotics / antibacterial agents that has been modified with at least one amine group thereby producing a prodrug that may be bioactivated by Eis2, or an ortholog thereof, expressed by pathogenic bacteria such as non-tuberculosis mycobacteria. More specifically, an amine amphenicol prodrug may have the structure of Formula I;Formula I wherein R is halo (i.e., Cl, F, Br or I) , -SO2CH3, -NO2, - SO2NH2, -SO2NHMe, -SO2NHEt, "CH3SO2, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or heterocyclo; and X is -OH, halo (i.e., Cl, F, Br or I), - OMe, -OCF3, -CF2, or -OCF3.

[0031] The term "aryl," as used herein, by itself or as part of another group, refers to an aromatic ring system having from 6 to 14 carbon atoms, i.e., C6-C14 aryl. Non-limiting exemplary aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In some aspects, the aryl group is phenyl. The term "substituted aryl," as used herein, by itself or as part of another group, refers to an aryl that is substituted with 1 to 5 substituents, e.g., one of more of “SO2CH3, - SO2(CH3)3, halo (i.e. , Cl, F, Br or I), -CH3, -SO2NH2, -SO2NHMe,-SO2NHEt, -N02, ”NH2, -CN, -OMe, -OCF3, -CF3, -NHSO2Me, - C(CH3)3, -C(=O)OH, -C(=O)CH3.

[0032] The term "heteroaryl," as used herein, by itself or as part of another group, refers to monocyclic and bicyclic aromatic ring systems having 5-14 ring members, i.e., 5-14 membered heteroaryls containing 1, 2, 3, or 4 heteroatoms (e.g. , N, 0, or S) . Non-limiting exemplary heteroaryl groups include thienyl, benzo [b] thienyl, naphtho [2, 3-b] thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl , naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH- carbazolyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. The term "substituted heteroaryl," as used herein, by itself or as part of another group, refers to a heteroaryl that is substituted with 1 to 4 substituents, e.g. , one of more of -SO2CH3, -SO2(CH3)3, halo (i.e. , Cl, F, Br or I) , -CH3, -SO2NH2, -SO2NHMe, -SO2NHEt, .

[0033] The term "heterocyclo, " as used herein, by itself or as part of another group, refers to saturated monocyclic, bicyclic, or tricyclic groups containing 3 to 14 ring members, i.e., 3-14 membered heterocyclos containing 1, 2, 3, or 4 heteroatoms. Each heteroatom may independently be oxygen, sulfur, or nitrogen. Each sulfur atom may independently be oxidized to a sulfoxide, i.e. , S(=0) , or a sulfone, i.e. , S(=0)2.

[0034] Additional amphenicols and synthesis of the same may be found in, e.g. , US 4,311,857; US 4,582, 918; US 4,973,750; US 4,876,350; US 5,227,494; US 4,743,700; US 5,567,844; US5,382,673; US 5,352,832 and US 5,663,361, each of which is incorporated herein by reference in its entirety.

[0035] Exemplary amine amphenicol prodrugs include, but are not limited to florfenicol amine, chloramphenicol amine, thiamphenicol amine, and azidamfenicol amine.

[0036] In some aspects, efficacy of an antibacterial agent is improved in a subject having or suspected of having a bacterial infection. In some aspects, efficacy of an antibacterial agent is improved in a subject having or suspected of having a non-tuberculosis mycobacteria infection. In some aspects, efficacy of an antibacterial agent is improved in a subject having or suspected of having a bacterial infection that is resistant to the antibacterial agent. In some aspects, efficacy of an antibacterial agent is improved in a subject having or suspected of having a nontuberculosis mycobacteria infection that is resistant to the antibacterial agent. In some aspects, efficacy of an antibacterial agent is improved in a subject having or suspected of having a bacterial infection (e.g., an actinomycete infection such as a non-tuberculosis mycobacteria) that is resistant to the antibacterial agent due to the activity of WhiB7, or orthologs thereof. WhiB7 proteins in mycobacteria and other actinomycetes are characterized by the presence of four invariant cysteine residues that bind a [4Fe-4S] cluster, a conserved p-turn G [I / V / L] W [G / A] G (SEQ ID NO:1) , a WhiB7-specif ic (EPW) motif adjacent to the p-turn and a C-terminal DNA binding AT-hook (RGRP) . In some aspects, efficacy of an antibacterial agent is improved in a subject having or suspected of having a bacterial infection (e.g. , an actinomycete infection such as a non-tuberculosis mycobacteria) that is resistant to the antibacterial agent due to the activity of Eis2, or orthologs thereof. Eis2 belongs to the GCN5-related N-acetyltransf erasefamily and shares structural similarity to Eis proteins or 'Eis-like proteins' from Mycobacterium tuberculosis (PDB:3uy5) , Mycobacterium smegmatis (PDB:4qb9) , Anabaena variabilis (PDB:2ozg) , Enteroccus faecalis (PDB:2hv2) , Bacillus anthracis (PDB:3n7z) , and Kribbella flavida (PDB:4my3) . In some aspects, efficacy of an antibacterial agent is improved in a subject having or suspected of having a bacterial infection (e.g.fan actinomycete infection such as a non-tuberculosis mycobacteria) that is resistant to the antibacterial agent due to the activity of an N- acetyltransf erase, in particular N-acetyltransferases responsible for aminoglycoside resistance.

[0037] In some aspects, the antibacterial agent is a macrolide, oxazolidinone, aminoglycoside, lincosamide or nonfluorinated amphenicol, as described elsewhere herein. In some aspects, the antibacterial agent is a macrolide and the amine amphenicol prodrug is florfenicol amine. In some aspects, the antibacterial agent is an oxazolidinone and the amine amphenicol prodrug is florfenicol amine. In some aspects, the antibacterial agent is an aminoglycoside and the amine amphenicol prodrug is florfenicol amine. In some aspects, the antibacterial agent is a lincosamide and the amine amphenicol prodrug is florfenicol amine. In some aspects, the antibacterial agent is a non-fluorinated amphenicol and the amine amphenicol prodrug is florfenicol amine .

[0038] In some aspects, an "improvement in efficacy" refers to a decrease or reduction, e.g. , 2-fold, 3-fold, 4-fold, 5- fold, 10-fold or up to 100-fold reduction, in toxicity of the antibacterial agent in the subject receiving the antibacterial agent.

[0039] In some aspects, an "improvement in efficacy" refers to the synergistic activity of the antibacterial agent andamine amphenicol prodrug to decrease the viability or kill a bacterial pathogen. "Synergy" is defined as the efficacy of a combination of therapeutic agents being greater than the sum of the effects of any agent administered alone. A synergistic effect may also be an effect that cannot be achieved by administration of any compound or other therapeutic agent as a single agent. A synergistic effect may include reducing bacterial pathogen viability (e.g. , nontuberculosis mycobacteria viability) , inducing bacterial cell death (e.g. , non-tuberculosis mycobacteria cell death) , and treating a bacterial infection (e.g. , a non-tuberculosis mycobacteria infection) . Synergy of antibacterial compounds is routinely determined in the art using conventional methods such as the checkerboard and the E test methods.

[0040] In some aspects, an "improvement in efficacy" refers to a decrease or reduction in the development of resistance by a bacterial pathogen to the antibacterial agent. In some aspects, the development of resistance is reduced in a bacterial pathogen that expresses WhiB7 (or an ortholog thereof) and / or Eis2 (or an ortholog thereof) . In some aspects, resistance to an antibacterial agent is reduced in a non-tuberculosis mycobacterium.

[0041] In some aspects of the methods described herein, the antibacterial agent and amine amphenicol prodrug may be administered in a single composition or in separate compositions, and may be administered simultaneously, sequentially, or alternating with other therapeutic agents or treatment modalities.

[0042] In another aspect, a synergistic antibacterial composition including one or more antibacterial agents (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 antibacterial agents) and one or more amine amphenicol prodrugs (e.g., 1, 2, 3, or 4 amine amphenicol prodrugs) is provided. In some aspects, theantibacterial agent is a macrolide , aminoglycoside, lincosamide or non-fluorinated amphenicol , as described elsewhere herein . In some aspects , the amine amphenicol prodrug has the structure of Formula I . In some aspects , the amine amphenicol prodrug is florfenicol amine, chloramphenicol amine , thiamphenicol amine, or azidamfenicol amine .

[0043] The synergistic antibacterial composition may be presented in a pack, sachet, or dispenser device , such as a kit, which may contain one or more unit dosage forms containing the active ingredients . The pack may, for example, include metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration . The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals , which notice is reflective of approval by the agency of the form of the compositions or of human or veterinary administration . Such notice , for example, may be of the labeling approved by the U . S . Food and Drug Administration for prescription drugs or of an approved product insert . Compositions including one or more antibacterial agents and one or more amine amphenicol prodrugs formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition . In an optional aspect , the packaging comprises glass or plastic vials or other containers comprising multiple doses .

[0044] The following non-limiting examples are provided to further illustrate the present invention .EXAMPLESExample 1 : Materials and Methods

[0045] An timicrobial Susceptibility Testing. A series of amphenicol antibiotics and amine analogs thereof (Table 1 ) were screened for activity against Mycobacteria abscessus and select Mycobacteria abscessus mutants .TABLE 1-19-

[0046] Each compound was solubilized in DMSO and serially diluted 1 : 2 in a 384-well Echo PP source plate (Labcyte ) to generate a 12-point concentration range . Using a Beckman Echo 655 Acoustic Liquid Handler, 400 nL from each well of this source plate were then transferred to a 384-well black, clear bottom plate (ThermoFisher Scientific) . Additionally, 24 individual cell-death (AMK at 128 pg mL"1) and no drug (DMSO) controls were transferred and included for each plate . Midlog Mycobacteria abscessus ATCC 19977 (Mab} or isogenic deletion (AwhiB 7 and Aeis2) strains were diluted to an ODeoo of 0 . 0005 in Mueller Hinton Broth 2 (BBL™) and 40 pL was delivered to each well of the 384 -well assay plate containing compound using a Multidrop Combi (ThermoFisher Scientific ) . This resulted in a DMSO concentration of 1% . After media transfer, assay plates were then briefly centrifuged at 300 relative centrifugal force (RCF) and incubated for 4 days at 37 °C and 5% CO2. Plates were briefly removed from incubation and 4 pL of 0. 77 mM of resazurin ( final concentration 70 pM) was added to each well via a MultiDrop Combi and incubated for an additional 24 hours at 37 °C and 5% CO2 . After incubation, plates were sealed with a black light-absorbing film (AbsorbMax, RPI ) and the fluorescent intensity ( 540 / 590 ) was read using a PHERAstar FS Multilabel reader (BMG, Cary, NC ) . Raw fluorescent intensity values were normalized to no drug ( 100% viability) and cell death controls ( 0% viability) to estimate % viability . Susceptibility testing was performed in at least duplicate and IC50 values (mg / L) for each compound were calculated in GraphPad Prism version 10. 2 . 0 by using the equation [inhibitor] vs . normalized response - Variable slope .

[0047] Checkerboard Assays to Assess Synergy. Methods were repeated as above with the following exceptions . Compoundswere serially diluted 1 : 2 in a 384-well Echo PP plate to generate a 7-point concentration curve . Using a Beckman Echo 655 Acoustic Liquid Handler, 200 nL from each well of this source plate were then transferred to a 384-well black, clear bottom plate (ThermoFisher Scientific) . Linezolid and amikacin dose-response was transferred horizontally across the plate, whereas florfenicol and florfenicol amine were transferred vertically to the assay plate resulting in an 8x8 checkerboard with the highest concentration of both drugs in the top left and the lowest in the bottom right of each matrix . Plates were incubated and raw fluorescent intensity was read as described above . Values were normali zed to controls as described above and heat maps were generated in GraphPad Prism version 10 . 2 . 0 .

[0048] Selection of Florfenicol Amine Resistant Mutants . Florfenicol amine resistant Mab mutants were generated by plating 100 pL of drug-free, supersaturated culture (ODeoo > 0 . 8 ) of Mab ATCC 19977 onto CAMH (Cation-adj usted Mueller- Hinton) agar plates with 64 mg / L of florfenicol amine . Colonies were selected and grown in 5 mL of CAMH broth containing 64 mg / L of florfenicol amine for 3 days . Genomic DNA from cultures was then extracted using DNeasy® Blood and Tissue Kit (Qiagen ) and sequenced through SeqCenter ( Pittsburgh, PA) . Raw Illumina reads were aligned to Mab ATCC 19977 reference genome (Genome accession : NC_010397 ) and variants detected in CLC genomics workbench .Example 2 : Antimicrobial Activity of Amphenicol Antibiotics and Amine Analogs

[0049] Whole cell activity of related amphenicol antibiotics and amine analogs against Mycobacteria abscessus (Mab) and select mutants were tested (Table 2 ) .TABLE 2

[0050] The results of this analysis indicated that a metabolite of florfenicol , i . e . , florfenicol amine , had selective WhiB7-dependent activity against Mycobacterium abscessus . By comparison, close structural variants chloramphenicol amine and thiamphenicol amine were less active ( Table 2 ) .

[0051] Florfenicol amine is bioactivated into the antibiotic substance acetyl florfenicol by Eis2 (Mab4532c) , a Mycobacterium abscessus drug-modifying enzyme ( Scheme 1 ) .SCHEME 1

[0052] To determine whether florfenicol amine synergizes with standard-of-care antibiotics, Mycobacterium abscessus viability assays were conducted with florfenicol and florfenicol amine in combination with linezolid and amikacin .This analysis indicated that florfenicol amine was synergistic with linezolid and amikacin against Mycoba cteria abscessus infection ( FIG . 1 ) . Accordingly, florfenicol aminehas the potential to be highly synergistic with standard-of- care antibiotics for this highly resistant pathogen .

[0053] Spontaneous mutants generated against Mycobacteria abscessus possess inactivation mutations in either the transcription factor, WhiB7 (Mab3508c) , or the aminoglycoside acetylating enzyme, Eis2 (Mab4532c) . These mutations can be phenotypically identified based on colony-size ( FIG . 2 ) . Inactivating mutations in WhiB7 render several classes of ribosome targeting agents, e . g.zaminoglycosides and macrolides , more active . Mutations in Eis2 render aminoglycosides more active . Notably, resistance to florfenicol amine leads to increased susceptibility to antibiotics ( e . g.zclarithromycin, azithromycin, linezolid, capreomycin, hygromycin B, amikacin, kanamycin) ( FIG . 2 ) . Accordingly, the use of florfenicol amine or other amine amphenicols in combination with standard-of-care antibiotics may be effectively used to decrease the development of resistance to a number of different classes of antibiotics including macrolides , aminoglycosides and non-f luorinated amphenicols .Example 3 : Synthesis of AminomethylPhenicol Base

[0054] General Syn thetic Scheme for AminomethylPhenicol base

[0055] General Procedure for the synthesis of AminomethylPhenicol base . Phenicol compounds were added a IM HCI solution and refluxed overnight . After completion, the reaction mixture was extracted with ethyl acetate (EA) twice . The aqueous layer was then dried under reduced pressure to afford the AminomethylPhenicol base .

[0056] (1R,2R) -2-amino-l- (4-nitrophenyl ) propane-1 , 3-diol(5410) .1H NMR (500 MHz, DMSO) 5 8,17 (d, J=8.4 Hz, 2H) , 7.58 (d, J=8.4 Hz, 2H) , 4.66 (d, J=4.6 Hz, 1H) , 3.33 (dd, J=10.5, 5.6 Hz, 1H) , 3.16 (dd, J=10.5, 6.2 Hz, 1H) , 2.70 (q, J=5.6 Hz, 1H) .13C NMR (151 MHz, MeOD) 5 152.27, 148.71, 128.65 (2C), 124.35 (2C), 73.96, 63.95, 59.77. MS (ESI) : m / z 213 (M+H)+.

[0057] (1R,2R) -2-amino-l- (4- (methyl sulfonyl) phenyl) propane-1, 3-diol (5411) .3H NMR (400 MHz, MeOD) 5 8.00 (d, J=8.4 Hz, 2H) , 7.73 (d, J=8.4 Hz, 2H) , 4.93 (d, J=8.1 Hz, 1H) , 3.63 (dd, J=11.7, 3.7 Hz, 1H) , 3.45 (dd, J-11.7, 5.6 Hz, 1H) , 3.35 (ddd, J=8.7, 5.6, 3.7 Hz, 1H) , 3.14 (s, 3H) .13C NMR (151 MHz, MeOD) 5 148.44, 142.20, 129.01 (2C) , 128.85 (2C) , 71.25, 59.91, 59.67, 44.28. MS (ESI) : m / z 246 (M+H)+.

[0058] (1R,2S) -2-amino-3-fluoro-l- (4- (methylsulfonyl) phenyl) propan-l-ol (5412) .1H NMR (500 MHz, D2O) 5 8.04 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H) , 5.10 (d, J=8.3 Hz, 1H), 4.65 (ddd, J=46.4, 12.1, 2.8 Hz, 1H) , 4.43 (ddd, J=46.2, 11.3, 4.9 Hz, 1H), 3.84 (ddt, J=24.2, 8.0, 3.5 Hz, 1H) , 3.29 (s, 3H) .13C NMR (126 MHz, D2O) 5 145.31, 139.26, 127.96 (2C) , 127.82 (2C), 80.53 (d, J=169.0 Hz), 69.40 (d, J=6.0 Hz), 56.35 (d, J=18.0 Hz), 43.15. MS (ESI) : m / z 248 (M+H)+.Example 4 : Synthesis of AminomethylPhenicol Biaryl Compounds

[0059] General Synthetic Scheme for AminomethylPhenicol Bia ryl Compounds .

[0060] General Procedure for the synthesis ofAminomethylPhenicol Biaryl Compounds, Method 1. To (45,51?)“4- (fluoromethyl) -5- (4-iodophenyl) -2-phenyl-4 , 5- dihydrooxazole (0.200 g, 0.525 mmol) in toluene (3.3 mL) , ethanol (1.2 mL) , and water (1.2 mL) in a microwave vial was added boronic acid (0.114 g, 0.525 mmol) and K2CO3 (0.218 g, 1.57 mmol) and the mixture was degassed with N2 for 20 min. Pd(PPh3)4 (0.030 g, 0.026 mmol) was added and the mixture was degassed with N2 for an additional 20 min. The vial was sealed and heated to 60 °C for 22.5 h. Cooled to room temperature,CH2CI2 and water added, washed with water, extracted with CH2CI2 (2x) , dried (Na2SCh) , and concentrated under reduced pressure to give the crude residue which was purified by chromatography on Si02 (0-30-50% EtOAc / hexanes) to give the biaryl intermediate.

[0061] To the biaryl intermediate (0.046 g, 0.108 mmol) in a microwave vial was added 3N HC1 (1.5 mL) and the vial was sealed and heated to 105°C for 1 day. 6N HC1 (1 mL) was added, and the reaction mixture was heated to 105 °C for an additional day. Cooled to 0°C, and 3M NaOH was added until the solution was basic (pH 8-9) and the mixture was extracted with EtOAc (2x) , dried (Na2S04) , and concentrated under reduced pressure to give the free base which was dissolved in CH2CI2 (1 mL) and 4N HCl / dioxane (0.3 mL) was added and the solution was concentrated under reduced pressure to give the product as the hydrochloride salt. This hydrolysis step is also applicable for the synthesis of example 5746, ensuring efficient conversion under the described conditions.

[0062] General Procedure for the synthesis of Aminomethyl Phenicol Biaryl Compounds, Method 2. To a microwave vial containing (4S,5R)-4-(fluoromethyl)-5-(4- iodophenyl ) -2-phenyl-4 , 5-dihydrooxazole (0.360 g, 0.944 mmol) was added 3N HC1 (2.0 mL) . The vial was sealed and heated at 105°C for 24 hours. The solvent was then removed under reduced pressure, and the residue was treated with N,N- diisopropylethylamine (0.366 g, 2.83 mmol) and di-tert-butyl dicarbonate (0.309 g, 1.416 mmol) for 2 hours. The reaction mixture was purified by column chromatography (0-30-50% EtOAc / hexanes) to afford tert-butyl ( ( 1R, 2S ) -3-f luoro-1- hydroxy-1- (4-iodophenyl) propan-2-yl) carbamate (0.320 g, 0.810 mmol) .

[0063] To a microwave vial containing tert-butyl ( (lR,2S)-3- fluoro-l-hydroxy-1- (4-iodophenyl) propan-2-yl) carbamate(0.300 g, 0.638 mmol) in THF (3.3 mL) and water (1.1 mL) was added the corresponding phenylboronate ester (0.638 mmol) and K2CO3(0.176 g, 1.27 mmol) . Pd(dppf)Cl2(0.023 g, 0.032 mmol) was then added. The vial was sealed and heated at 70 °C for 24 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (EA) and washed with water. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (0-30-50% EtOAc / hexanes ) to afford the biaryl intermediate (0.375 mmol) .

[0064] The biaryl intermediate was then dissolved in 4M HC1 in dioxane (2 mL) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to afford the final product as the hydrochloride salt.

[0065] (lRf2S) -2-amino-3-fluoro-l- (4 ' - (methylsulfonyl) -[ 1 , 1 ' -biphenyl] -4-yl) propan-l-ol hydrochloride (5539) .1H NMR (400 MHz, D20) 5 8.06 (d, <7=8.5 Hz, 2H) , 7.96 (d, <7=8.6 Hz, 2H) , 7.84 (d, <7=8.3 Hz, 2H) , 7.62 (d, <7=8.2 Hz, 2H) , 5.04 (d, <7=8.8 Hz, 1H) , 4.67 (ddd, <7=46.5, 11.2, 2.8 Hz, 1H) , 4.47 (ddd, <7=46.3, 11.2, 5.0 Hz, 1H) , 3.95-3.81 (m, 1H) , 3.32 (s, 3H) .13C NMR (126 MHz, D2O) 5 145.9, 139.5, 139.0, 137.6, 128.1 (2 C) , 128.0 (2 C) , 127.7 (2 C) , 127.5 (2 C) , 81.3, 80.0, 69.9, 69.9, 56.6, 56.4, 43.3. MS (ESI) : m / z 324 (M+H)+.

[0066] (1R,2S) -2-amino-3-fluoro-l- (2 ' -fluoro-4 ' -(methylsulfonyl) -[1,1 ' -biphenyl ] -4-yl) propan- 1 -ol hydrochloride (5580) .NMR (400 MHz, D2O) 5 7.92-7.81 (m, 3H) , 7.79-7.74 (m, 2H) , 7.63 (d, 7-8.1 Hz, 2H) , 5.04 (d, 7=8.8 Hz, 1H) , 4.76-4.59 (m, 1H) , 4.49 (ddd, 7=46.3, 11.2, 5.0 Hz, 1H), 3.95-3.82 (m, 1H), 3.35 (s, 3H) .13C NMR (126 MHz, D2O) 5 158.1, 139.4, 139.4, 139.2, 134.6, 134.2, 132.2, 132.2, 129.8, 129.7, 127.1 (2 C) , 123.4, 123.3, 115.4, 115.2, 81.3, 80.0, 69.9, 69.9, 56.6, 56.5, 43.2. MS (ESI) : m / z 342 (M+H)+.

[0067] (1R,2S) -2-amino-3-fluoro-l- (4 ' - (isopropylsulfonyl) -[1,1 ’ -biphenyl] ~4~yl)propan-l-ol hydrochloride (5581).1H NMR (400 MHz, D2O) 5 7.96 (m, 4H) , 7.82 (d, 7=7.8 Hz, 2H) , 7.62 (d, J=1.9 Hz, 2H) , 5.03 (d, <7=8.8 Hz, 1H) , 4.66 (ddd, 7=46.6, 11.1, 2.8 Hz, 1H) , 4.47 (ddd, 7=46.3, 11.2, 5.0 Hz, 1H) , 3.95- 3.82 (m, 1H), 3.54 (sept, 7=6.8 Hz, 1H) , 1.30 (d, 7=6.8 Hz, 6H) .13C NMR (126 MHz, D2O) 5146.0, 139.4, 139.0, 133.6, 129.3 (2 C) , 128.0 (2 C) , 127.9 (2 C) , 127.5 (2 C) , 81.3, 80.0, 69.9, 69.9, 56.6, 56.4, 55.7 14.54 (2 C) . MS (ESI) : m / z 250 (M+H)+.

[0068] (1R,2S) -2-amino-3-fluoro-l- (4- ( 1-methyl-lH-pyrazol-4-yl) phenyl) propan-l-ol dichydrochloride (5582) .XH NMR (400 MHz, D2O) 5 8.04 (s, 1H) , 7.96 (d, 7=1.0 Hz, 1H) , 7.69 (d, 7=8.1 Hz, 2H) , 7.49 (d, 7=8.1 Hz, 2H) , 4.95 (d, 7=8.9 Hz,1H) , 4.64 (ddd, J=46.5, 11.2, 2.9 Hz, 1H) , 4.45 (ddd, J=46.3, 11.2, 5.0 Hz, 1H) , 3.95 (s, 3H) , 3.91-3.73 (m, 1H) .13C NMR (126 MHz, D2O) 6 136.64, 136.39, 132.75, 129.11, 127.44, 125.79, 121.84, 81.34, 80.00, 70.03, 69.98, 56.56, 56.42, 38.18. MS (ESI) : m / z 250 (M+H)+.

[0069] (1R,2S) -2-amino-3-fluoro-l- (3 ' -fluoro-4 ' -(me thyl sulfonyl) -[1,1 ' -biphenyl ] -4~yl)propan-l-ol hydrochloride (5610).:LH NMR (400 MHz, D2O) 6 7.91 (t, J=8.0 Hz, 1H), 7.74 (d, <7=8.2 Hz, 2H) , 7.68-7.61 (m, 2H) , 7.53 (d, <7=8.1 Hz, 2H) , 4.94 (d, <7=8.8 Hz, 1H) , 4.65-4.49 (m, 1H) , 4.38 (ddd, <7=46.3, 11.2, 4.9 Hz, 1H) , 3.84-3.73 (m, 1H) , 3.35 (s, 3H) .13C NMR (126 MHz, D2O) 5 160.5, 158.5, 149.1, 149.1, 139.5, 138.4, 129.7, 128.0 (2 C) , 127.5 (2 C) , 125.0, 124.9,123.4, 123.4, 115.7, 115.5, 81.3, 80.0, 69.9, 69.8, 56.6,56.4, 43.2, 43.2. MS (ESI) : m / z 342 (M+H)+.

[0070] (1R,2S) -2-amino-3~fluoro-l~ (4- (pyrimidin-5- yl) phenyl) propan-l-ol hydrochloride (5611) .rH NMR (400 MHz, D2O) 5 9.07 (s, 1H) , 9.03 (s, 2H) , 7.74 (d, <7=8.0 Hz, 2H) , 7.57 (d, <7=8.1 Hz, 2H) , 4.95 (d, J- 8.7 Hz, 1H) , 4.57 (ddd, <7=46.5, 11.2, 2.8 Hz, 1H) , 4.38 (ddd, <7=46.2, 11.2, 4.9 Hz, 1H) , 3.84-3.73 (m, 1H) .13C NMR (126 MHz, D2O) 6 155.7 (2 C) , 155.0 (2 C), 139.6, 134.1, 134.0, 127.7 (2 C) , 81.3, 80.0, 69.9, 69.8, 56.6, 56.4. MS (ESI) : m / z 284 (M+H)+.

[0071] (1R,2S) -2-amino-3-fluoro~l- (3 ' -methyl -4 '-(methyl sulfonyl ) - [1 , 1 ' -biphenyl ] -4-yl) propan-l-ol hydrochloride (5612).XH NMR (400 MHz, DzO) 5 8.04 (d, 7=8.2 Hz, 1H), 7.81 (d, 7=8.2 Hz, 2H) , 7.78-7.71 (m, 2H) , 7.61 (d, 7=8.1 Hz, 2H), 5.03 (d, 7=8.8 Hz, 1H) , 4.66 (ddd, 7=46.6,11.3, 2.8 Hz, 1H), 4.47 (ddd, 7=46.2, 11.2, 5.0 Hz, 1H) , 3.88 (ddt, 7=24.0, 8.4, 4.2 Hz, 1H) , 3.34 (s, 3H) , 2.73 (s , 3H) .13C NMR (126 MHz, D2O) 5 145.7, 139.4, 138.9, 138.4, 135.8,131.3, 129.3, 127.9 (2 C) , 127.4 (2 C) , 125.1, 81.3, 80.0, 70.0, 69.9, 56.6, 56.4, 42.8, 19.5. MS (ESI) : m / z 374 (M+H)+.

[0072] (1R,2S) -2-amino-3-fluoro-l- (4- (pyridin-3- yl) phenyl) propan-l-ol hydrochloride (5640) .XH NMR (400 MHz, D2O) 6 9.10 (s, 1H) , 8.89 (dd, 7=8.3, 1.8 Hz, 1H) , 8.80 (d, 7=5.8 Hz, 1H), 8.21-8.14 (m, 1H) , 7.88 (d, 7=7.9 Hz, 2H) , 7.70 (d, 7=7.9 Hz, 2H) , 5.07 (d, 7=8.8 Hz, 1H) , 4.76-4.57 (m, 1H), 4.48 (ddd, 7=46.3, 11.2, 4.9 Hz, 1H) , 3.89 (ddd, 7=24.1, 8.6, 4.1 Hz, 1H) .13C NMR (126 MHz, D2O) 5 144.7, 140.4, 139.8, 139.7, 139.4, 134.4, 128.1, 127.9, 127.4, 81.3, 80.0, 69.8, 69.8, 56.6, 56.4. MS (ESI) : m / z 283 (M+H)+.

[0073] (1R,2S) -2-ami.no-3-fl.UQ.ro-l.- (4- ( 6-(methylsulfonyl) pyri din -3 ~yl ) ph enyl) propan- l-ol hydrochloride (5641) . ’H NMR (400 MHz, DzO) 6 9.01 (s, 1H) , 8.41 (d, J=7.9 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H) , 7.85 (d, J=7.9Hz, 2H) , 7.66 (d, J=7.9 Hz, 2H) , 5.05 (d, J=8.7 Hz, 1H) , 4.76-4.59 (m, 1H) , 4.48 (ddd, J=46.3, 11.2, 4.9 Hz, 1H) , 3.99-3.79(m, 1H) , 3.37 (d, <J=1.3 Hz, 3H) . MS (ESI) : m / z 361 (M+H)+.

[0074] (1R,2S) -2 -amino-3- fluoro- 1- (4 ’ -nitro- [ 1fl ' - biphenyl] -4-yl) propan-l-ol (5651) .3H NMR (500 MHz, MeOD) 5 8.33-8.30 (m, 2H) , 7.89-7.87 (m, 2H) , 7.76-7.73 (m, 2H) , 7.55- 7.52 (m, 2H) , 4.70 (d, J=6.6 Hz, 1H) , 4.47-4.32 (m, 1H) , 4.31- 4.15 (m, 1H) , 3.21-3.09 (m, 1H) .13C NMR (126 MHz, MeOD) 5 148.49 (d, J=5.8 Hz), 144.43, 139.47, 128.88 (2C) , 128.51 (5C), 125.09 (2C), 85.18 (d, J=168.3 Hz), 74.07 (d, J=5.8 Hz), 58.50 (d, J=18.3 Hz) . MS (ESI) : m / z 291 (M+H)+.

[0075] (1R,2S) -1- ([1,1 ’-biphenyl ] -4-yl) -2-amino-3- fluoropropan-l-ol (5675) .:,H NMR (500 MHz, D2O) 5 7.81-7.70 (m, 4H) , 7.55 (t, J=9.0 Hz, 4H) , 7.46 (t, J=7.5 Hz, 1H) , 5.06 (dd, J=72.1, 7.6 Hz, 1H) , 4.63 (dd, J=46.9, 11.5 Hz, 1H) , 4.44 (ddd, J=46.1, 11.2, 4.8 Hz, 1H) , 3.99-3.79 (m, 1H) .13C NMR (126 MHz, D2O) 6 141.37, 139.86, 137.66, 129.17 (2C) , 127.99, 127.56 (d, J-5.2 Hz) (2C) , 127.37, 126.97 (d, J=4.3 Hz) (3C), 80.48 (dd, J=168.5, 50.9 Hz), 69.87 (dd, J=32.1,6.1 Hz), 56.01 (dd, <7=133.2, 17.6 Hz) . MS (ESI) : m / z 246 (M+H)+.

[0076] 4* - ( (1R,2S) -2-amino-3- fluoro- 1 -hydroxypropyl) -[1,1 ' - biphenyl] -4-sulfonamide (5676) .(500 MHz, D2O) 6 7.99 (dt, 7=8.3, 1.3 Hz, 2H) , 7.91-7.85 (m, 2H) , 7.84-7.77 (m, 2H) , 7.59 (dd, <7=8.2, 1.9 Hz, 2H) , 5.01 (dd, <7=8.8, 1.9 Hz, 1H) , 4.72-4.55 (m, 1H) , 4.44 (ddt, J=46.2, 11.2, 3.3 Hz, 1H) , 3.85 (ddd, <7=24.0, 8.9, 4.7 Hz, 1H) .i3C NMR (126 MHz, D2O) 5 144.57, 140.07, 139.68, 138.76, 127.87 (d, 7=10.2 Hz) (4C) , 127.44 (2C), 126.46 (2C) , 80.66 (d, 7=168.8 Hz), 69.92 (d, 7=5.9 Hz), 56.52 (d, 7=17.9 Hz) . MS (ESI) : m / z 325 (M+H)+.

[0077] 4 ' - ( (1R,2S) -2-amino-3-fluoro-l-hydroxypropyl) -[1,1 ’ - biphenyl ] -4-carbonitrile (5677) . Ml NMR (500 MHz, D2O) 5 8.09 (d, 7=8.0 Hz, 2H) , 7.80 (dd, 7=7.9, 3.4 Hz, 4H) , 7.57 (d, 7=7.9 Hz, 2H) , 5.03-4.97 (m, 1H) , 4.63 (dd, 7=46.5, 11.1 Hz, 1H), 4.53-4.36 (m, 1H) , 3.85 (d, 7=25.3 Hz, 1H) .13C NMR (126 MHz, D2O) 5 144.75, 140.19, 138.52, 130.28 (2C) , 128.97, 127.81 (2C), 127.40 (2C) , 127.07 (2C) , 80.67 (d, 7=168.7 Hz), 69.94 (d, 7=5.9 Hz), 56.53 (d, 7=17.7 Hz) . MS (ESI) : m / z 271 (M+H) +.

[0078] (1R,2S) -2-amino-3-fluoro-l- (4 ' - (tri fluoromethyl) -[1,1 ’ -biphenyl ] -4-yl) propan-l-ol hydro chloride (5684) . Ml NMR(400 MHz, MeOD) 6 7.84 (d, <7=8.1 Hz, 2H) , 7.79-7.73 (m, 4H) , .59 (d, J-7.8 Hz, 2H) , 4.90 (d, J=8.6 Hz, 1H) , 4.71-4.51 (m, H) , 4.40 (ddd, <7=46.7, 11.0, 4.9 Hz, 1H) , 3.77-3.57 (m, 1H) . 3C NMR (101 MHz, MeOD) 6 145.76, 142.43, 141.62, 141.59, 41.29, 130.97, 130.65, 129.00, 128.96, 128.88, 128.82, 28.78, 128.11, 127.36, 127.12, 127.08, 127.06, 127.04, 27.02, 127.00, 124.67, 82.95, 81.25, 71.38, 71.33, 58.84, 8.66. MS (ESI) : m / z 314 (M+H)+.

[0079] (1R,2S) -2-amino-3~fluoro-l- (4 ' - (tri fluoromethoxy) -[1 , 1 ' -biphenyl] -4-yl) propan-l-ol hydrochloride (5685) . *H NMR (400 MHz, MeOD) 5 7.78-7.64 (m, 4H) , 7.60-7.47 (m, 2H) , 7.43- .29 (m, 2H) , 4.85 (s, 1H) , 4.57 (ddd, J=47.1, 10.8, 2.9 Hz, 1H), 4.38 (ddd, <7=46.8, 10.8, 4.9 Hz, 1H) , 3.58 (ddt, J=26.9, 8.2, 3.5 Hz, 1H) .13C NMR (101 MHz, MeOD) 5 149.95, 149.93, 141.24, 140.88, 140.73, 129.46, 128.36, 128.31, 122.30,82.91, 81.22, 71.34, 71.29, 58.45, 58.27. MS (ESI) : m / z 330(M+H) +.

[0080] (4 ’ - ( (1R,2S) -2-amino-3-fluoro-l -hydroxypropyl) -[1 , 1 ' -biphenyl] ~4~yl) (imino) (methyl) -16-sulfanone hydrochloride (5686). ’H NMR (400 MHz, D2O) 6 8.01 (d, <7=8.1 Hz, 2H) , 7.86 (d, <7=8.2 Hz, 2H) , 7.77 (d, <7=7.9 Hz, 2H) , 7.59 (d, <7=7.9 Hz, 2H) , 5.02 (d, <7=8.9 Hz, 1H) , 4.65 (ddd, <7=46.4, 11.3, 2.8 Hz, 1H), 4.45 (ddd, <7=46.2, 11.2, 4.9 Hz, 1H) , 3.98 - 3.74 (m, 1H) , 3.32 (s, 3H) .13C NMR (101 MHz, D2O) 5 145.48, 139.31, 139.02, 138.44, 128.08, 128.00, 127.97, 127.50,81.50, 79.82, 69.94, 69.88, 56.62, 56.44, 44.53. MS (ESI) : m / z 323 (M+H)+.

[0081] (1R,2S) -2-amino-3-fluoro-l- (4- (6- (2-methyl-2H- tetrazol-5 -yl ) pyri din -3 -yl ) phenyl) propan -l-ol hydro ch lor ide(400 MHz, D2O) 5 8.81 (s, 1H) , 8.29 (d, <7=8.3 Hz, 1H), 8.13 (d, <7=8.3 Hz, 1H) , 7.77-7.67 (m, 2H) , 7.57 (d, <7=7.8 Hz, 2H) , 5.02 (d, <7=8.8 Hz, 1H) , 4.75-4.57 (m, 1H) , 4.56-4.37 (m, 4H) , 3.86 (dt, J=24.3, 4.4 Hz, 1H) .13C NMR (101 MHz, D2O) 5 161.45, 145.10, 141.41, 139.69, 138.68, 137.71, 135.30, 127.62, 127.43, 123.48, 81.50, 79.82, 69.83, 69.77,56.60, 56.42, 39.92. MS (ESI) : m / z 329(M+H)+.

[0082] N- (4 ’ - ( (1R,2S) -2-amino-3-fluoro-l -hydroxypropyl ) - [1,1 ' -biphenyl J -4-yl) methanesulf onamide hydrochloride(5716).XH NMR (400 MHz, D2O) 6 7.77-7.60 (m, 4H) , 7.64-7.48 (m, 2H) , 7.45-7.28 (in, 2H) , 4.99 (d, J=8.9 Hz, 1H), 4.73-4.29(m, 2H) , 3.98-3.70 (m, 1H) , 3.12 (s, 3H) .13C NMR (101 MHz, D2O) 5 215.40, 140.35, 140.22, 137.72, 137.20, 137.15, 136.18, 128.09, 127.38, 127.35, 127.32, 127.26, 126.96, 122.28,122.26, 81.54, 79.86, 70.05, 69.99, 56.63, 56.46, 38.33. MS (ESI) : m / z 339 (M+H)+.

[0083] (1R,2S) -2-amino-l - (4 ' - (tert-butyl) -[1,1 ’ -biphenyl ] -4-yl) -3-fluoropropan-l-ol hydrochloride (5717) .XH NMR (400 MHz, D2O) 5 7.44-7.17 (m, 8H) , 4.84 (d, J=9.6 Hz, 1H) , 4.32 (dd, J=46.7, 10.7 Hz, 1H) , 4.07 (dd, J=46.9, 10.3 Hz, 1H) , 3.72-3.52 (m, 1H) , 1.12 (s, 9H) .13C NMR (101 MHz, D2O) 5 150.22, 140.54, 137.71, 137.05, 127.39, 127.02, 126.56,125.64, 81.14, 79.45, 70.04, 69.98, 56.65, 56.48, 33.89, 30.81. MS (ESI) : m / z 302 (M+H}+.

[0084] 4 ' - ( (1R,2S) -2 -amino-3- fluoro- 1 -hydroxypropyl) - [1,1 ' - biphenyl] -4-carboxylic acid hydrochloride (5718) .XH NMR (400 MHz, D2O) 6 8.14-7.99 (m, 2H) , 7.75 (dd, J=7.5, 1.3 Hz, 4H) , 7.65-7.45 (m, 2H) , 4.92 (d, J=9.2 Hz, 1H) , 4.57 (ddd, <7=46.8, 11.1, 2.8 Hz, 1H) , 4.36 (ddd, J=46.4, 11.2, 4.8 Hz, 1H) , 3.73 (dddd, <7=24.4, 9.2, 4.8, 2.8 Hz, 1H) .13C NMR (101 MHz, D2O) 6 170.93, 146.21, 141.56, 140.38, 131.51, 130.39, 128.93, 128.75, 128.20, 82.57, 80.88, 71.33, 71.27, 58.22, 58.05. MS (ESI) : m / z 290 (M+H)+.

[0085] 1- (4 ' - ( (1R,2S) -2-amino-3-fluoro-l-hydroxypropyl) -[1 , 1 ’ -biphenyl] -4-yl) ethan-l-one hydrochloride (5720) .1H NMR (400 MHz, MeOD) 5 8.14-8.01 (m, 2H) , 7.79 (ddd, <7=8.5, 4.4, 2.0 Hz, 4H), 7.65-7.53 (m, 2H) , 4.90 (d, <7=8.6 Hz, 1H) , 4.71- 4.52 (m, 1H), 4.41 (ddd, <7=46.7, 11.0, 4.9 Hz, 1H) , 3.65 (dddd, <7=24.0, 8.6, 4.9, 2.9 Hz, 1H) , 2.64 (s, 3H) .13C NMR (101 MHz, MeOD) 6 198.68, 145.02, 140.22, 139.99, 135.94, 128.80, 127.37, 127.23, 126.81, 81.35, 79.66, 69.79, 69.73, 57.22, 57.05, 25.35. MS (ESI) : m / z 288 (M+H)+.

[0086] (1R,2S) -2-amino-3-fluoro-l - (4- (pyridin-4- yl)phenyl)propan-l-ol dihydrochloride (5721) . Ml NMR (400 MHz, MeOD) 6 8.93-8.89 (m, 2H) , 8.48-8.44 (m, 2H) , 8.14-8.07 (m, 2H), 7.75 (dd, <7=8.4, 2.8 Hz, 2H) , 4.98 (d, <7=8.4 Hz, 1H) , 4.64 (ddd, <7=46.9, 11.0, 2.9 Hz, 1H) , 4.42 (ddd, <7=46.7,11.0, 4.9 Hz, 1H), 3.76-3.57 (m, 1H) .13C NMR (101 MHz, D2O) 5 142.98, 137.66, 134.67, 128.57, 127.47, 126.13, 126.01, 123.98, 81.49, 79.82, 69.96, 69.90, 56.58, 56.41. MS (ESI) : m / z 247 (M+H)+.

[0087] (1R,2S) -2-amino-3-fluoro-l- (4- (thiophen-2- yl) phenyl) propan-l-ol hydrochloride (5741) . 'H NMR (400 MHz, D2O) 6 7.81-7.71 (m, 2H) , 7.48 (dtd, J=8.4, 2.4, 1.1 Hz, 4H) , 7.23-7.15 (m, 1H) , 4.95 (d, J=8.9 Hz, 1H) , 4.72-4.27 (m, 2H) , 3.99-3.73 (m, 1H) .13C NMR (101 MHz, D2O) 5 142.98, 137.66, 134.67, 128.57, 127.47, 126.13, 126.01, 123.98, 81.49, 79.82, 69.96, 69.90, 56.58, 56.41. MS (ESI) : m / z 252 (M+H)+.

[0088] (1R,2S) -2-ainino-3-fluoro-l- (4- (thiophen-3- yl)phenyl) propan-l-ol hydrochloride (5742) .XH NMR (400 MHz, D2O) 6 7.83-7.71 (m, 3H) , 7.64-7.43 (m, 4H) , 4.96 (d, J=8.9 Hz, 1H), 4.75-4.32 (m, 2H) , 4.04-3.76 (m, 1H) .13C NMR (101 MHz, D2O) 6 140.89, 140.87, 137.33, 136.08, 127.42, 127.39, 126.77, 126.03, 121.44, 81.52, 79.85, 70.03, 69.97, 56.61, 56.44. MS (ESI) : m / z 252 (M+H)+.

[0089] (1R,2S) -2-amino-3-fluoro-l- (3 ' - (methylsulfonyl) -[ 1 , 1 ’ -biphenyl] -4-yl) propan-l-ol hyrochloride (5743) .1H NMR(400 MHz, D2O) 6 8.14 (t, 7=1.9 Hz, 1H) , 7.96 (dddd, <7=21.1, 7.9, 1.9, 1.1 Hz, 2H), 7.82-7.68 (m, 3H) , 7.64-7.50 (m, 2H) , 5.01 (d, <7=8.9 Hz, 1H) , 4.64 (ddd, <7=46.5, 11.2, 2.8 Hz, 1H) , 4.45 (ddd, <7=46.3, 11.2, 4.9 Hz, 1H) , 3.95-3.79 (m, 1H) , 3.29 (s, 3H) .13C NMR (101 MHz, D2O) 5 141.34, 139.38, 139.37, 138.61, 132.84, 130.31, 127.73, 127.47, 126.03, 125.12,81.54, 79.87, 69.98, 69.93, 56.62, 56.44, 43.27. MS (ESI) : m / z 324 (M+H)+.

[0090] (1R,2S) -2-amino-3-fluoro-l- (4- (isoxazol-4- yl) phenyl) propan- l-ol (5744) .NMR (500 MHz, D2O) 5 9.05 (d, <7=1.1 Hz, 1H) , 8.88 (d, <7=1.0 Hz, 1H) , 7.72 (d, 7=8.1 Hz, 2H) , 7.53 (d, <7=8.0 Hz, 2H) , 4.97 (d, <7=8.7 Hz, 1H) , 4.63 (ddd, 7=46.6, 11.2, 2.8 Hz, 1H), 4.44 (ddd, <7=46.2, 11.2, 4.9 Hz, 1H) , 3.89-3.77 (m, 1H) .13C NMR (126 MHz, D2O) 5 155.00, 148.53, 138.19, 129.11, 127.51 (2C) , 126.98 (2C) , 120.56, 80.66 (d, <7=168.6 Hz), 69.91 (d, <7=5.9 Hz), 56.48 (d, <7=17.7 Hz) . MS (ESI) : m / z 237 (M+H)+.

[0091] (1R,2S) -2-amino-3-fluoro-l- (4- (isoquinolin-6- yl) phenyl) propan-l-ol (5745) .1H NMR (500 MHz, D2O) 6 9.62 (s, 1H), 8.57-8.43 (m, 4H) , 8.34 (d, <7=8.7 Hz, 1H) , 8.00 (d, <7=7.8 Hz, 2H) , 7.68 (d, 7=8.1 Hz, 2H) , 5.06 (d, 7=8.7 Hz, 1H), 4.48 (ddd, <7=46.2, 11.2, 4.8 Hz, 1H) , 3.89 (d, <7=25.2Hz, 1H) , 3.34 (s, 1H) .13C NMR (126 MHz, DMSO) 5 155.31,152.08, 143.30, 142.19 (d, 7=119.7 Hz), 137.79, 135.63,128.30, 127.30, 127.13 (2C) , 126.73 (2C) , 126.58, 123.48,120.60, 82.56 (d, <7=168.5 Hz), 70.27 (d, <7=6.0 Hz), 55.83 (d, <7=19.4 Hz) . MS (ESI) : m / z 297 (M+H)+.

[0092] (1R,2S) -2-amino-l - (4 ' -amino- [1,1' -biphenyl] -4-yl) -3- fluoropropan-l-ol dihydrochloride (5756) . ‘H NMR (400 MHz, D2O) 5 7.83 (dd, <7=8.2, 1.2 Hz, 2H) , 7.78 (d, <7=8.1 Hz, 2H) , 7.59 (d, <7=8.0 Hz, 2H) , 7.53-7.49 (m, 2H) , 5.01 (d, <7=8.9 Hz, 1H), 4.64 (ddd, <7=46.5, 11.2, 2.8 Hz, 1H) , 4.45 (ddd, <7=46.3, 11.2, 4.9 Hz, 1H) , 3.96-3.80 (m, 1H) .13C NMR (101 MHz, D2O) 5 140.61, 140.00, 138.24, 129.75, 128.53, 127.67, 127.45, 123.35, 81.50, 79.83, 69.99, 69.94, 56.63, 56.45. MS (ESI) : m / z 261 (M+H)+.

[0093] (1R,2S) -2-amino-l- (4 ’ -chloro- [1 , 1 ' -biphenyl] -4-yl) -3-fluoropropan-l-ol (5759) .XH NMR (500 MHz, DMSO) 5 8.11 (d, <7=7.7 Hz, 1H) , 7.70 (d, <7=8.0 Hz, 1H) , 7.66 (dd, <7=7.5, 5.2 Hz, 2H) , 7.59-7.50 (m, 3H) , 7.47 (d, <7=8.2 Hz, 1H) , 6.07 (d, <7=9.4 Hz, 1H) , 4.65 (ddd, <7=46.9, 11.3, 2.6 Hz, 1H) , 4.31 (ddd, <7=46.1, 11.1, 3.5 Hz, 1H) , 4.23-4.09 (m, 1H) .13C NMR (126 MHz, DMSO) 5 139.69, 138.16, 135.18, 133.87, 132.75, 129.88, 128.98 (2C) , 128.61 (d, <7=13.4 Hz) (2C) , 128.00, 127.24, 80.97 (d, <7=169.7 Hz), 73.33 (d, <7=5.1 Hz), 53.39 (d, <7=18.0 Hz) . MS (ESI) : m / z 280 (M+H)+.

[0094] ( 1R, 2S) -2-amino-3-f luoro-1- (4- (6-morpholinopyridin-3-yl ) phenyl) propan-l-ol dihydrochloride (5765) .1H NMR (400 MHz, D2O) 6 8.36 (dd, J = 9.6, 2.4 Hz, 1H) , 8.21 (d, J = 2.4Hz, 1H) , 7.81 - 7.72 (m, 2H) , 7.61 (d, d = 8.4 Hz, 2H) , 7.43(d, d = 9.8 Hz, 1H), 5.01 (d, J - 8.8 Hz, 1H) , 4.64 (ddd, d= 46.5, 11.2, 2.8 Hz, 1H) , 4.45 (ddd, d = 46.3, 11.2, 4.9 Hz, 1H) , 3.96 (t, d = 4.9 Hz, 4H) , 3.92 - 3.78 (m, 1H) , 3.76 (s, 4H) .13C NMR (101 MHz, D2O) 6 215.40, 151.54, 143.02, 138.85, 134.96, 133.07, 127.68, 126.91, 125.90, 113.09, 81.48, 79.81, 69.91, 69.85, 65.44, 56.59, 56.42, 45.60. MS (ESI) : m / z 332 (M+H) +.

[0095] (1R, 2S) -2-amino-3-fluoro-l- (4 ' -fluoro- [1, 1 ' - biphenyl] -4-yl) propan-l-ol, HC1 (5769) .XH NMR (500 MHz, D2O) 5 7.77 - 7.68 (m, 4H) , 7.57 - 7.52 (m, 2H) , 7.26 (t, J = 8.8Hz, 2H) , 4.98 (d, J = 8.9 Hz, 1H) , 4.63 (ddd, J = 46.4, 11.2,2.8 Hz, 1H), 4.44 (ddd, J = 46.2, 11.2, 5.0 Hz, 1H) , 3.90 - 3.80 (m, 1H) .13C NMR (126 MHz, D20) 5 162.51 (d, J - 244.7Hz), 140.52 (d, J = 11.9 Hz), 137.53, 136.03 (d, J = 3.1 Hz),128.76, 128.69, 127.45 (2C) , 127.35 (2C) , 115.83, 115.66, 80.67 (d, J = 168.6 Hz), 69.98 (d, J = 6.0 Hz), 56.53 (d, J = 17.6 Hz) . MS (ESI) : m / z 264 (M+H)+.

[0096] ( 1R, 2S) -2-amino-3-f luoro-1- (4 ' - (hydroxymethyl) -[1,1 '-biphenyl] -4-yl) propan-l-ol, HC1 (5770)NMR (500 MHz, D2O) 5 7.76 (dd, J = 24.5, 7.7 Hz, 4H) , 7.54 (dd, J = 22.1, 7.9 Hz, 4H) , 4.99 (d, J = 8.8 Hz, 1H) , 4.70 (s, 2H) , 4.68 - 4.35 (m, 2H), 3.83 (t, J = 4.9 Hz, 1H) .13C NMR (126 MHz, D2O) 5 141.01, 139.86, 139.23, 137.70, 128.13 (2C) , 127.50 (2C) , 127.37 (2C), 127.15 (2C) , 80.68 (d, J = 168.9 Hz), 71.12 (d, J = 104.6 Hz), 63.50, 56.54 (d, J = 17.5 Hz) . MS (ESI) : m / z 276 (M+H)+.Example 5 : Synthesis of AminomethylPhenicol Compounds with Saturated Heterocycles

[0097] General Synthetic Scheme for AminomethylPhenicolCompounds with Saturated Heterocycles.

[0098] General Procedure for the Synthesis of AiriinoinethylPhenicol Compounds with Saturated Heterocycles . To a reaction flask, add Pd(OAc)2(1.3 mg, 0.011 mmol) , dicyclohexyl (2 ' , 61-di isopropoxy- [1,1’ -biphenyl] -2- yl)phosphane (8.3 mg, 0.018 mmol) , CS2CO3 (239 mg, 0.735 mmol) , amine (0.525 mmol), and (4S, 5R) -4- (fluoromethyl) -5- ( 4-iodophenyl) -2-phenyl-4 , 5-dihydrooxazole (200 mg, 0.525 mmol) in anhydrous 1,4-dioxane (5.0 ml) . Charge the mixture with nitrogen gas three times. Stir the reaction mixture at 100°C until completion.

[0099] After cooling to room temperature, pour the reaction mixture into water and extract with ethyl acetate (EA) . Combine the organic layers, dry with Na2SO4, and filter through a pad of Celite. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel flash chromatography to obtain the AminomethylPhenicol Saturated Phenyl-Heterocycle intermediate (0.388 mmol) .

[0100] To the intermediate (0.388 mmol) , add 3N HC1 (1.5 mL) in a microwave vial, seal, and heat at 105°C for 24 hours. Afterward, add 3M NaOH until the solution becomes basic (pH 8-9) , then extract the mixture with EtOAc (2*) , dry over Na2SO4, and concentrate under reduced pressure to obtain the free base. Dissolve the free base in CH2C12(1 mL) and add 4N HCl / dioxane (0.3 mL) . Concentrate under reduced pressure to afford the product as the hydrochloride salt.6 7.29-7.22 (m, 2H) , 7.03-6.94 (m, 2H) , 4.64-4.52 (m, 1H) ,4.50-4.46 (m, 1H) , 4.29 (ddd, 7=47.3, 9.4, 3.8 Hz, 1H) , 4.21- 4.04 (m, 1H) , 3.85-3.80 (m, 4H) , 3.16-3.07 (m, 4H) .13C NMR(126 MHz, MeOD) 6 152.79 (d, 7=9.6 Hz), 134.55 (d, 7=54.5 Hz), 128.80 (d, <7=41.6 Hz) (2C) , 117.11 (d, <7=5.1 Hz) (2C) , 85.68 (dd, 7=167.2, 35.0 Hz), 74.89 (dd, 7=29.8, 6.7 Hz), 68.14 (2C) , 59.23-57.15 (m) , 50.86 (d, <7=3.8 Hz) (2C) . MS (ESI) : jn / z 255 (M+H) + .

[0102] 4- (4- ((1R,2S) -2-amino-3-fluoro-l- hydroxypropyl) phenyl) thiomorpholine 1,1-dioxide (5652) .1H NMR (500 MHz, D2O) 5 7.38 (d, <7=8.5 Hz, 2H) , 7.16 (d, 7=8.6 Hz, 2H) , 4.83 (d, 7=9.2 Hz, 1H) , 4.63-4.46 (m, 1H) , 4.42-4.26 (m, 1H), 3.97-3.91 (m, 4H) , 3.80-3.68 (m, 1H) , 3.32-3.26 (m, 4H) .13C NMR (126 MHz, D2O) 6 146.59, 131.26, 128.28 (2C) , 116.95 (2C), 80.61 (d, 7=168.7 Hz), 69.70 (d, 7=6.0 Hz), 56.53, 49.04 (2C) , 47.25 (2C) . MS (ESI) : m / z 303 (M+H)+.hydroxypropyl) phenyl) thiomorpholine 1 , 1-dioxide (5747) .lH NMR (500 MHz, D2O) 5 7.40 (d, 7=8.5 Hz, 2H) , 7.17 (d, 7=8.7 Hz, 2H), 4.99 (d, 7=6.7 Hz, 1H) , 4.76-4.66 (m, 1H) , 3.99-3.93 (m, 4H) , 3.85 (dtd, 7=21.3, 6.0, 3.3 Hz, 1H) , 3.30 (dd, 7=6.8, 3.7 Hz, 4H) .13C NMR (126 MHz, D2O) 6 147.05, 129.86, 127.93 (2C), 116.77 (2C), 80.35 (d, 7=168.3 Hz), 69.43 (d, 7=6.3Hz), 55.47 (d, <7=17.3 Hz), 49.09 (2C) , 46.76 (2C) . MS (ESI) : m / z 303 (M+H)+.

[0104] (1R,2S) -2-amino-3-fluoro-l- (4- (piperazin-1- yl)phenyl)propan-l-ol (5757) .XH NMR (500 MHz, D2O) 5 7.43 (d, <7=8.8 Hz, 2H) , 7.18 (d, <7=8.7 Hz, 2H) , 4.87 (d, <7=9.2 Hz, 1H), 4.57 (ddd, <7=46.6, 11.3, 2.8 Hz, 1H) , 4.37 (ddd, <7=46.2, 11.2, 4.9 Hz, 1H) , 3.78 (dddd, <7=24.3, 9.1, 4.9, 2.8 Hz, 1H) , 3.50 (dd, <7=6.8, 3.4 Hz, 4H) , 3.44 (dd, <7=5.0, 2.9 Hz, 4H) .13C NMR (126 MHz, D2O) 5 149.81, 131.98, 128.01 (2C) , 117.82 (2C), 80.61 (d, <7=168.6 Hz), 69.77 (d, <7=6.0 Hz), 56.49 (d, <7=17.6 Hz), 46.60 (2C) , 42.92 (2C) . MS (ESI) : m / z 254 (M+H)+.

[0105] (1S,2S) -2-amino-3-fluoro-l- (4- (piperazin-1- yl ) phenyl ) propan-l-ol (5758) .1H NMR (500 MHz, D2O) 6 7.43 (d, <7=8.7 Hz, 2H) , 7.21 (d, <7=8.8 Hz, 2H) , 5.02 (d, <7=6.5 Hz, 1H), 4.75-4.60 (m, 1H) , 3.86 (dtd, J=21.0, 5.9, 2.9 Hz, 1H) , 3.52 (dd, <7=7.0, 3.4 Hz, 4H) , 3.45 (dd, <7=6.5, 3.7 Hz, 4H) .13C NMR (126 MHz, D2O) 5 149.24, 131.85, 127.70, 118.07, 80.26 (d, <7=168.2 Hz), 69.46 (d, <7=6.3 Hz), 55.45 (d, <7=17.5 Hz), 46.85, 42.83. MS (ESI) : m / z 254 (M+H)+.Example 6 : Synthesis of Acylated AminomethylPhenicolCompounds

[0106] General Procedure for the synthesis of acylated aminomethylphenicol compounds. To a suspension of amine(0.050 g, 0.176 mmol) in dry CH2CI2 (0.6 mL) was added EtaN (0.05 mL, 0.4 mmol) and the reaction mixture was stirred for 5 min and the homogeneous mixture was cooled to 0°C. Acetyl chloride (0.018 g, 0.229 mmol) in dry CH2CI2 (0.5 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 20 min. Diluted with water, washed with IN HC1, saturated NaHCOa, extracted with EtOAc (3x) , dried (Na2SO4) , and concentrated under reduced pressure to give the product.

[0107] N-((1R,2S) -3-fluoro-l-hydroxy-l - (4~ (methylsulfonyl) phenyl) propan-2-yl) acetamide (5510) . !H NMR (500 MHz, MeOD) 6 7.92 (d, J=8.2 Hz, 2H) , 7.67 (d, <7=8.1 Hz, 2H), 5.03 (d, 7=3.3 Hz, 1H) , 4.67-4.51 (m, 1H) , 4.43-4.27 (m, 2H) , 3.11 (s, 3H) , 1.86 (s, 3H) .13C NMR (126 MHz, MeOD) 5 173.49, 150.09, 141.03, 128.43 (2C) , 128.19 (2C) , 82.97 (d, 7=171.4 Hz) , 71.40 (d, 7=4.7 Hz), 55.98 (d, 7=20.9 Hz) , 44.38, 22.29. MS (ESI) : m / z 290 (M+H)+.

[0108] N-((1R,2R) -1, 3 -dihydroxy-1- (4-(methylsulf onyl) phenyl) propan-2-yl) acetamide (5561) .:lH NMR (500 MHz, MeOD) 6 7.90 (d, 7=8.1 Hz, 2H) , 7.66 (d, 7=8.2 Hz, 2H) , 5.08 (d, 7=3.2 Hz, 1H) , 4.13 (td, 7=6.5, 3.2 Hz, 1H) , 3.74 (dd, J=10.9, 6.9 Hz, 1H) , 3.61-3.50 (m, 1H) , 3.11 (s, 3H) , 1.85 (s, 3H) .13C NMR (126 MHz, MeOD) 6 173.20, 150.76, 140.59, 128.18 (2C) , 127.92 (2C) , 71.67, 62.30, 57.75, 44.23, 22.25. MS (ESI) ; m / z 288 (M+H)+.

[0109] N- ( (1R,2S) -3-fluoro-l-hydroxy-l-(4’~(methylsulfonyl) - [1 , 1 ' -biphenyl ] -4-yl) propan-2-yl ) acetamide (5678) .(500 MHz, MeOD) 5 8.02 (d, J- 8.5 Hz, 2H) , 7.89 (d, <7=8.5 Hz, 2H) , 7.70 (d, J=8.3 Hz, 2H) , 7.54 (d, J=8.3 Hz, 2H) , 4.97 (d, <7=4.2 Hz, 1H) , 4.51 (dd, <7=9.0, 5.6 Hz, 1H) , 4.40-4.31 (m, 2H) , 4.27 (dd, <7=9.1, 5.8 Hz, 1H) , 3.16 (s, 3H) , 1.92 (s, 3H) .13C NMR (126 MHz, MeOD) 5 173.79, 147.73, 144.16, 140.77, 139.78, 129.20 (20) , 129.03 (2C) , 128.42 (d, <7=7.6 Hz) (4C) , 83.35 (d, J=170.7 Hz), 72.10 (d, <7=4.7 Hz) , 56.59 (d, <7=20.3 Hz) , 44.63, 22.63. MS (ESI) : m / z 366 (M+H)+.Example 7: Synthesis of 4- ( (1R, 2S) -2-amino-3-fluoro-l- hydroxypropyl) benzenesulfonamide hydrochloride (5609)

[0110] Formation of Benzylthio Derivative . To a microwave vial containing (4S, 5R) -4- (fluoromethyl) -5- (4 -iodophenyl) -2- phenyl-4 , 5-dihydrooxazole (100 mg, 0.262 mmol) in toluene (2 mL) and dioxane (2 mL) was added DIPEA (67.8 mg, 0.525 mmol) . The mixture was heated to 90°C, followed by the addition ofbenzyl mercaptan (34.2 mg, 0.275 mmol) , xantphos (22.77 mg, 0.039 mmol) , and Pd2(dba)3 (24.02 mg, 0.026 mmol) . The reaction mixture was heated at 90 °C for 6 hours, then cooled to 0°C. The resultant solid was filtered, washed with water, and dried in vacuo to give (4S,5R)-5-(4-(benzylthio)phenyl)- 4- ( fluoromethyl) -2-phenyl-4 , 5-dihydrooxazole (99 mg, 0.262 mmol) . The product was purified by column chromatography using 25-30% EtOAc in hexane.

[0111] Oxidation to Sulfonyl Chloride. To an ice-cold solution of (4S, 5R) -5- (4- (benzylthio) phenyl) -4- ( fluoromethyl) -2-phenyl-4 , 5-dihydrooxazole (100 mg, 0.265 mmol) in CHDCN-HOAc-HQO (10 mL - 0.375 mL - 0.25 mL) was added 2, 4-dichloro-5, 5-dimethylhydantoin (104 mg, 0.530 mmol) . The reaction mixture was stirred at 0°C for 2 hours, then concentrated under reduced pressure. The crude product was diluted with CHDC1D (10 mL) , and the solution was cooled to 0°C. A 5% aqueous NaHCOO solution (15 mL) was added slowly at 0°C. The mixture was stirred at 0°C for 15 minutes, and the organic layer was washed once more with a brine solution at 0°C. The organic phase was dried over MgSOQ, filtered, and concentrated to dryness (93 mg) .

[0112] Formation of Sulfonamide. To a solution of 4-( (4S,5R)- 4- (fluoromethyl) -2-phenyl-4, 5-dihydrooxazol-5- yl) benzenesulfonyl chloride (100 mg, 0.283 mmol) in dry DCM (10 mL) at 0°C, aqueous ammonia (10 mL) was added dropwise. The reaction progress was monitored by TLC. Upon completion, the reaction was quenched with water and extracted with EtOAc (3 x 20 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4- ( (4S, 5R) -4- (fluoromethyl) -2-phenyl-4, 5- dihydrooxazol-5-yl) benzenesulfonamide (93 mg, 0.278 mmol) .

[0113] Hydrolysis and Hydrochloride Salt Formation. To a microwave vial containing 4- ( (4S, 5R) -4- (fluoromethyl) -2--41-phenyl-4 , 5-dihydrooxazol-5-yl ) benzenesulf onamide (73 mg, 0.218 mmol) , AcOH (0.8 mL) and 3N HC1 (0.8 mL) were added. The vial was sealed and heated to 100°C for 24 hours. After cooling to room temperature, 3M NaOH was added until the solution became basic. The reaction mixture was extracted with EtOAc, dried over MgSOD, and concentrated under reduced pressure to afford the crude residue as a clear oil. The residue was treated with 4M HC1 in dioxane, forming the hydrochloride salt (28 mg, 0.113 mmol) .

[0114] 1H NMR (500 MHz, D20) 5 7.98 (d, J = 8.1 Hz, 1H) , 7.69 (d, J = 8.1 Hz, 2H), 7.47 (hept, J = 4.6 Hz, 4H) , 5.07 (d, J = 8.3 Hz, 1H) , 4.73 - 4.57 (m, 1H) , 4.43 (ddt, J = 41.3, 11.1, 5.5 Hz, 1H) , 3.83 (ddt, <7 - 24.2, 8.3, 3.6 Hz, 1H) .13C NMR (126 MHz, D2O) 5 143.81, 141.71, 129.18 (2C) , 128.77 (2C) , 80.56 (d, J - 169.0 Hz) , 69.44 (d, J = 6.0 Hz), 56.37 (d, J = 17.8 Hz) . MS (ESI) : m / z 249 (M+H)+.Example 8: Synthesis of (1S,2R) -1 , 3-dif luoro-1- (4-(me thy 1 sulfonyl) phenyl) propan-2 -amine hydrochloride (5683)5683

[0115] To a solution of ( 1R, 2S ) -2-amino-3-f luoro-1- ( 4-(methylsulfonyl) phenyl) propan-l-ol (500 mg, 2.02 mmol) in methanol (MeOH) was added N, N-diisopropylethylamine (DIPEA)(784 mg, 6.07 mmol) and di-tert-butyl dicarbonate (662 mg, 3.03 mmol) . The reaction mixture was stirred at room temperature for 2 hours and then dried under reduced pressure. The residue was purified by column chromatography to afford the intermediate tert-butyl ( (1R, 2S) -3-fluoro-l-hydroxy-l- ( 4- (methylsulfonyl ) phenyl ) propan-2-yl ) carbamate (610 mg) .

[0116] A solution of tert-butyl ( (1R, 2S) -3-fluoro-l-hydroxy- 1- (4- (methylsulfonyl) phenyl) propan-2-yl) carbamate (400 mg) in anhydrous dichloromethane (CH2CI2, 20 mL) and DIPEA (521 mg, 3.5 mmol) was added dropwise to a cooled (-78°C) solution of diethylaminosulfur trifluoride (DAST) (371 mg, 2.303 mmol) in anhydrous CH2C12(15 mL) under a nitrogen atmosphere over 1 hour. The reaction mixture was then gradually warmed to room temperature and stirred for 18 hours. After completion, water was added, and the mixture was extracted with CH2CI2. The aqueous phase was further extracted with CH2CI2, and the combined organic extracts were washed with saturated brine, dried over Na2S04, and concentrated under reduced pressure to yield a dark reddish-brown oil. The crude product was purified by silica gel column chromatography (10% ethyl acetate / n- hexane) to afford tert-butyl ( ( IS , 2R) -1 , 3-dif luoro-1- ( 4- (methylsulf onyl ) phenyl) propan-2-yl) carbamate (100 mg) .

[0117] The obtained compound was then treated with 4M HC1 in dioxane for 2 hours, followed by drying under reduced pressure to yield 5683 as the hydrochloride salt.

[0118] iR NMR (400 MHz, D2O) 6 8.11 (d, J — 8.1 Hz, 2H) , 7.77 (d, J = 8.1 Hz, 2H) , 6.21 (dd, J = 45.7, 4.0 Hz, 1H) , 4.76 - 4.56 (m, 2H), 4.34 - 4.16 (m, 1H) , 3.32 (d, J = 1.5 Hz, 3H) .13C NMR (101 MHz, D2O) 5 139.94, 127.92, 126.65, 126.57, 90.83, 89.04, 79.78, 78.09, 54.07, 43.14. MS (ESI) : m / z 250 (M+H)+.Example 9: Synthesis of (1R, 2R) -2-amino-3-methoxy-l- (41- (methyl sulfonyl) - [1,1 ’ -biphenyl] -4-yl) propan-l-ol hydrochloride (5688)

[0119] ( (4R, 5R) -5“ (4-iodophenyl) -2-phenyl-4, 5- dihydrooxazol-4-yl) methanol (300 mg, 0.791 mmol) was dissolved in anhydrous DMF under an ice bath. Sodium hydride (97%, 22.78 mg, 0.949 mmol) was added, and the mixture was stirred for 30 minutes. lodomethane (168 mg, 1.187 mmol) was then added, and the reaction was allowed to proceed to completion .

[0120] Upon completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford ( 4R, 5R) -5- ( 4-iodophenyl ) -4- (methoxymethyl) -2-phenyl~4 , 5-dihydrooxazole (250 mg) .

[0121] The obtained intermediate was then subjected to General Procedure for the Synthesis of AminomethylPhenicol Biaryl Compounds, Method 1, to yield 5688.

[0122] ’-H NMR (400 MHz, D2O) 5 7.96 (d, J = 8.1 Hz, 2H) , 7.82 (d, J = 8.2 Hz, 2H) , 7.72 (d, 7.9 Hz, 2H) , 7.56 (d, <J =8.0 Hz, 2H) , 4.93 (d, J = 8.7 Hz, 1H) , 3.79 - 3.65 (m, 1H) , 3.53 - 3.36 (m, 2H) , 3.34 (s, 3H) , 3.27 (s, 3H) .13C NMR (101 MHz, D2O) 5 145.71, 139.49, 139.11, 137.49, 127.90, 127.86, 127.60, 127.43, 70.71, 70.50, 68.73, 58.69, 56.32, 43.31. MS (ESI) : m / z 336 (M+H)+.Example 10: Synthesis of (1R, 2S) -2-amino“3 , 3-dif luoro-1- (4 ' - (methylsulfonyl) - [1,11-biphenyl] -4 -yl) propan- l-ol hydrochloride (5689)

[0123] ( (4R, 5R) -5- (4 -iodophenyl) -2-phenyl-4, 5- dihydrooxazol-4-yl) methanol (200 mg, 0.527 mmol) was dissolved in anhydrous dichloromethane (DCM) under an ice bath. Dess-Martin periodinane (336 mg, 0.791 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After completion, the reaction mixture was washed with water and brine. The organic layer was dried over Na2SO4and concentrated under reduced pressure to afford the crude aldehyde (80 mg, 0.212 mmol) .

[0124] The aldehyde (80 mg, 0.212 mmol) was dissolved in anhydrous DCM (10 mL) and cooled to -78 °C. Diethylaminosulfur trifluoride (DAST, 103 mg, 0.636 mmol) was added dropwise. After the addition, the mixture was gradually warmed to room temperature and stirred overnight. The reaction was quenched with water (10 mL) , washed sequentially with water and saturated sodium bicarbonate, and then concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 15% EtOAc in hexane) to afford (4S, 5R) -4- (difluoromethyl) -5- (4 -iodophenyl) -2-phenyl-4, 5- dihydrooxazole as a solid (40 mg, 0.1 mmol) .

[0125] The obtained intermediate was then subjected to General Procedure for the Synthesis of AminomethylPhenicol Biaryl Compounds, Method 1, to yield 5689.(400 MHz, D2O) 5 8.08 - 7.96 (m, 2H) , 7.90 (d, J = 7.8 Hz, 2H) , 7.80 (d, J - 7.8 Hz, 2H) , 7.63 (d, J = 8.0 Hz, 2H) , 5.97 (t, J = 52.7 Hz, 1H) , 5.09 (d, J = 8.2 Hz, 1H) , 4.24 - 4.00 (m, 1H) , 3.30 (d, J = 1.3 Hz, 3H) .13C NMR (101 MHz, D2O) 6 145.72, 139.61, 138.03, 137.59, 128.11, 128.02, 127.64, 127.46, 112.76 (t, J = 243.6 Hz) ., 69.04, 68.98, 57.73, 57.53, 57.33, 43.31. MS (ESI) : m / z 342 (M+H)+.Example 11: Synthesis of (S)-l-fluoro-3-(4-(methylsulfonyl) phenyl) propan-2 -amine hydrochloride (5719)

[0127] A solution of florfenicol (1.0 g, 2.79 mmol) in acetonitrile (15.0 mL) was treated with carbon tetrabromide (1.11 g, 3.35 mmol) and triphenylphosphine (0.879 g, 3.35 mmol) and stirred at room temperature overnight. The reaction mixture was evaporated to yield a yellow residue, which was purified by flash chromatography to afford the bromo compound (0.5 g, 1.187 mmol) as a white powder.

[0128] A solution of the bromo compound (0.1 g, 0.24 mmol) in methanol (5.0 mL) was treated with 10% palladium on charcoal (10 mg) and stirred at room temperature overnight under a balloon of hydrogen. The reaction mixture was filtered, evaporated, and purified by chromatography to yield the debrominated compound (70 mg, 0.21 mmol) as a white film,

[0129] A solution of the debrominated compound (70 mg, 0.21 mmol) in acetic acid (3.0 mmol) was treated with 10% sulfuric acid (15 mL) and heated to 110°C for 12 h. The reaction mixture was cooled to room temperature, and the pH was adjusted to 14 using 10M aqueous sodium hydroxide. The mixture was then extracted with dichloromethane (3 x 30 mL) , dried over Na2S04, and evaporated to afford the crude amine as ayellow oil. The final compound was purified using a C18 column, yielding 40 mg of 5719.

[0130] XH NMR (400 MHz, MeOD) 6 8.05 - 7.95 (m, 2H) , 7.64 -NMR (101 MHz, MeOD) 6 142.63, 141.27, 131.38, 128.98, 83.43, 81.72, 53.41, 53.23, 44.10, 35.12, 35.07. MS (ESI) : m / z 232 (M+H)+.Example 12: Synthesis of (lR,2S)-2-amino-3-fluoro-l-(4- iodophenyl) propan- l-ol (5746)

[0131] Following the General Procedure for the synthesis of AminomethylPhenicol Biaryl Compounds (Method 1) , the hydrolysis step was performed to obtain 5746 from (4S,5R)-4- ( fluoromethyl) -5- (4 -iodophenyl) -2-phenyl-4, 5- dihydrooxazole .

[0132] XH2H) , 7.24 (d, J = 8.1 Hz, 2H) , 4.90 (d, J = 8.6 Hz, 1H) , 4.68 - 4.54 (m, 1H) , 4.41 (ddd, J = 46.3, 11.2, 5.0 Hz, 1H) , 3.83 - 3.72 (m, 1H) .13C NMR (126 MHz, D2O) 6 138.20, 138.13 (2C) , 128.58(2C) , 94.29, 80.61 (d, J = 168.8 Hz) , 69.72 (d, J = 5.9 Hz), 56.36 (d, J = 17.7 Hz) . MS (ESI) : m / z 296 (M+H)+.Example 13: Eis2 -dependent anti -Mycobacterium abscessus activity of AminomethylPhenicol analogs

[0133] Activity of AminomethylPhenicol analogs is presented in Table 3.TABLE 3

Claims

What is claimed is :1 . A method for treating a non-tuberculosis mycobacteria infection comprising administering to a subj ect in need of treatment an effective amount of florfenicol amine t'hereby treating the subj ect ' s non-tuberculosis mycobacteria infection .2 . The method of claim 1 , wherein the non-tuberculosis mycobacteria is Mycobacteria abscessus subsp . abscessus, Mycobacteria abscessus subsp. massiliense, Mycobacteria abscessus subsp. bolletii , or Mycobacteria chelonae .

3. The method of claim 1, further comprising administering an additional antibacterial agent .4 . The method of claim 3 , wherein the additional antibacterial agent is a macrolide, oxazolidinone , aminoglycoside , lincosamide , tetracycline , clofazimine , spectinomycin, and / or non-f luorinated amphenicol .

5. A method for improving the efficacy of an antibacterial agent comprising administering to a subj ect in need thereof an antibacterial agent in combination with an amine amphenicol prodrug thereby improving the efficacy of the antibacterial agent .

6. The method of claim 5, wherein the amine amphenicol prodrug reduces toxicity, synergizes with the antibacterial agent , and / or reduces the development of resistance to the antibacterial agent .

7. The method of claim 5, wherein the antibacterial agent is a macrolide, oxazolidinone, aminoglycoside, lincosamide, tetracycline, clofazimine, spectinomycin, and / or nonfluorinated amphenicol.

8. The method of claim 5, wherein the amine amphenicol prodrug is florfenicol amine, chloramphenicol amine, thiamphenicol amine, or azidamfenicol amine.

9. The method of claim 5, wherein the amine amphenicol prodrug has the structure of Formula I:Formula I whereinR is halo, -SO2CH3, -NO2, “SO2NH2, -SO2NHMe, -SO2NHEt, - CH3SO2, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or heterocyclo; andX is -OH, halo, -OMe, -OCF3, -CF2, or -OCF3.

10. A synergistic antibacterial composition comprising an antibacterial agent and an amine amphenicol prodrug.

11. The synergistic antibacterial composition of claim 10, wherein the antibacterial agent is a macrolide, oxazolidinone, aminoglycoside, lincosamide and / or nonfluorinated amphenicol.

12. The synergistic antibacterial composition of claim 10, wherein the amine amphenicol prodrug is florfenicolamine, chloramphenicol amine , thiamphenlcol amine, or azidamf enicol amine .

13. The synergistic antibacterial composition of claim 10 , wherein the amine amphenicol prodrug has the structure of Formula I :Formula I whereinR is halo, -SO2CH3, -NO2, -SO2NH2, -SO2NHMe, -SO2NHEt, - CH3SO2 , substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, or heterocyclo; andX is -OH, halo, -OMe, -OCF3 , -CF2, or -OCF3.

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