Compounds and methods for treating bacterial infections

Abstract

Provided herein are antibacterial compounds represented by Formula I, (I); or a pharmaceutically acceptable salt thereof, wherein R 1 as defined herein. Also provided are pharmaceutical compositions comprising a compound of Formula I.

Description

Related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 539,171, filed September 19, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] According to the U.S. Centers for Disease Control and Prevention (CDC), an estimated 51,000 healthcare-associated Pseudomonas aeruginosa infections occur annually in the United States alone, with more than 6,000 (13%) of these infections stemming from multidrug-resistant strains. This results in an average of about 400 deaths per year. The European Centre for Disease Prevention and Control (ECDC) estimates even higher figures, estimating approximately 800,000 additional hospitalizations and 10,000 additional deaths in 2009 due to infections caused by drug-resistant Pseudomonas aeruginosa strains. Currently, the multidrug resistance rate of Pseudomonas aeruginosa is about 20% and is projected to rise to about 30% by 2040.

[0003] Current treatments for Pseudomonas aeruginosa include β-lactam antibiotics. While some β-lactam antibiotics have shown promise in vitro, most (if not all) are plagued by high levels of resistance in the clinical setting. Due to persistent resistance and the anticipated increase in infections, the development of new antimicrobials, particularly those unaffected or minimally affected by the resistance mechanisms currently observed in clinical settings, is a significant medical need. Summary of the Invention

[0004] This article provides antimicrobial compounds that, among other uses, can be used to treat bacterial infections. These compounds are represented by Formula I. (I); Or a pharmaceutically acceptable salt thereof, wherein R 1 As defined herein, pharmaceutical compositions comprising compound I are also provided. Detailed Implementation

[0005] 1. General description of compounds In some embodiments, this disclosure provides a compound of formula I: (I); Or its pharmaceutically acceptable salt, wherein R 1 It is -OC(O)R A ;and R A Selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted cycloalkyl, and optionally substituted (C1-C)20 )alkyl, wherein the optionally substituted (C1-C 20 The alkyl group may be discontinuous by one or more heteroatoms selected from O, N, and S, and wherein the (C1-C) 20 Two adjacent hydrogen atoms on the same carbon atom of one or more carbons on an alkyl group can form =O together.

[0006] 2. definition When used to describe chemical groups that may have multiple connection points, the hyphen (-) indicates the connection point between the group and the variable that defines it. For example, -NR d R e This means that the bonding point of the group is located on a nitrogen atom.

[0007] As used herein, the terms “halogen” and “halogen” refer to atoms selected from fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0008] The term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group. Unless otherwise stated, alkyl groups typically have 1 to 6 carbon atoms, i.e., (C1-C6)alkyl. As used herein, "(C1-C6)alkyl" means a group having 1 to 6 carbon atoms arranged linearly or branchedly.

[0009] "Alkoxy" refers to an alkyl group linked by an oxygen atom and is represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0010] Unless otherwise stated, the term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in the heteroaryl group may be quaternized. Heteroaryl groups can be monocyclic or bicyclic. Monocyclic heteroaryl groups include, for example, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, etc. Bicyclic heteroaryl groups include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, benzoxazolyl, benzoxadiazolyl, indazole, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalolinyl, pyrrolopyridyl, pyrrolopyridyl, pyrrolopyridyl, thienopyridyl, thienopyridyl, indolazinyl, purinyl, naphridyl, and pteridylyl. It should be understood that, when specified, optional substituents on the heteroaryl group may be present at any substituted position, including, for example, the position to which the heteroaryl group is attached.

[0011] Unless otherwise stated, the term "heterocyclic group" means a 4- to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that produces a stable structure. Heterocyclic groups can be monocyclic or bicyclic. Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyrrolylalkyl, pyrrolidone, piperidinyl, oxazolyl, piperazine, dioxylalkyl, dioxopentyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydrooxadiazolyl, and dihydroisooxazolyl. Bicyclic heterocyclic groups include, for example, unsaturated heterocyclic groups fused to another unsaturated heterocyclic group, cycloalkyl, aryl, or heteroaryl ring, such as, for example, benzo[a]dioxanepentyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, etc. It should be understood that, when specified, optional substituents on the heterocyclic group may be present at any substituted position, including, for example, the position to which the heterocyclic group is attached.

[0012] The term "spirocycle" refers to two rings that share a single ring atom (e.g., carbon).

[0013] The term "fusion" refers to two rings sharing two adjacent ring atoms.

[0014] The term "bridging" refers to two rings sharing three ring atoms.

[0015] The term "aryl" refers to an aromatic carbocyclic monocyclic or bicyclic system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl. In one respect, the aryl group is phenyl.

[0016] The term "cycloalkyl" refers to a saturated cyclic aliphatic monocyclic or bicyclic system having 3 to 10 carbon ring atoms as described herein. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It should be understood that, when specified, optional substituents on the cycloalkyl or cycloaliphatic group may be present at any substituted position, including, for example, the position to which the cycloalkyl group is attached.

[0017] The term "optionally substituted" means that one or more hydrogen atoms in the specified moiety can be replaced by suitable substituents. Unless otherwise stated, the "optionally substituted" group may have suitable substituents at each substituted position of the group, provided that the valence allows. Optional substituents include, but are not limited to, one or more groups selected from: cyano (-CN), halo, imino (=NH), nitro (-NO2), oxo (=O), -C(O)R i -C(O)OR i -C(O)NRii R iii 、-C(O)SR i 、-C(NR i )NR ii R iii 、-C(S)R i 、-C(S)OR i 、-C(S)NR ii R iii 、-OR i 、-OC(O)R i 、-OC(O)OR i 、-OC(O)NR ii R iii 、-OC(O)SR i 、-OC(NR i )NR ii R iii 、-OC(S)R i 、-OC(S)OR i 、-OC(S)NR ii R iii 、-OP(O)(OR ii )OR iii 、-OS(O)R i 、-OS(O)2R i 、-OS(O)NR ii R iii 、-OS(O)2NR ii R iii 、-NR ii R iii 、-NR i C(O)R iv 、-NR i C(O)OR iv 、-NR i C(O)NR ii R iii 、-NR a C(O)SR iv 、-NR i C(NR iv )NR ii R iii 、-NR i C(S)R iv 、-NR i C(S)OR iv 、-NR i C(S)NR ii R iii 、-NR i S(O)R iv 、-NR iS(O)2R iv -NR i S(O)NR ii R iii -NR i S(O)2NR ii R iv -SR i -S(O)R i -S(O)2R i -S(O)NR ii R iv -S(O)2NR ii R iv Alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is further optionally substituented by one or more, or in one embodiment, one, two, three, or four substituents. a Replace, where each R i R ii R iii and R iv Independently alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic, each optionally being substituented by one or more, or in one embodiment, one, two, three, or four substituents Q. a Replace, or R ii and R iii Together with the N atoms to which they are attached, they form Q groups that are optionally substituented by one or more, or in one embodiment, one, two, three, or four substituents. a Substituted heterocyclic groups, where each Q a Independently selected from cyano, halogen, imino, nitro, oxo, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, C 6-14 Aryl, heteroaryl, heterocyclic, -C(O)R v -C(O)OR v -C(O)NR vi R vii -C(O)SR v -C(NR) v )NR vi R vii -C(S)R v -C(S)OR v -C(S)NR vi R vii -OR v -OC(O)R v -OC(O)OR v -OC(O)NR vi Rvii 、 -OC(O)SR v 、 -OC(NR v )NR vi R vii 、 -OC(S)R v 、 -OC(S)OR v 、 -OC(S)NR vi R vii 、 -OP(O)(OR v )OR vi 、 -OS(O)R v 、 -OS(O)2R v 、 -OS(O)NR vi R vii 、 -OS(O)2NR v R vii 、 -NR vi R vii 、 -NR v C(O)R viii 、 -NR e C(O)OR vi 、 -NR v C(O)NR vi R vii 、 -NR v C(O)SR vi 、 -NR v C(NR viii )NR vi R vii 、 -NR v C(S)R viii 、 -NR v C(S)OR vi 、 -NR v C(S)NR vi R vii 、 -NR v S(O)R viii 、 -NR v S(O)2R viii 、 -NR v S(O)NR vi R vii 、 -NR v S(O)2NR vi R vii 、 -SR v 、 -S(O)R v 、 -S(O)2R v 、 -S(O)NR vi R vii and -S(O)2NR vi R vii ; where each Rv R vi R vii and R viii Independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclic; or (iii) R vi and R viii Together with the N atoms they are attached to, they form heterocyclic groups.

[0018] When a compound is named or described by means of its structure, if no specific geometric isomer is specified, the name or structure should be understood to cover one geometric isomer and exclude other geometric isomers, mixtures of geometric isomers, or mixtures of all geometric isomers.

[0019] When naming or describing the stereochemistry of a compound by structural designation, the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to all other stereoisomers. The purity percentage by weight relative to all other stereoisomers is the ratio of the weight of one stereoisomer to the weight of the other stereoisomers.

[0020] Unless otherwise stated, all tautomer forms of the compounds described herein are within the scope of this invention.

[0021] The compounds described herein may exist in pharmaceutically acceptable salt forms. For use in pharmaceuticals, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts, such as, for example, ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and ammonium salts (such as tetrabutylammonium, trimethylammonium, tributylammonium, triisopropylammonium, and N,N-diisopropylethylammonium).

[0022] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or mediators that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0023] The terms "subject" and "patient" are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, a subject is a person in need of treatment.

[0024] The terms “inhibit,” “inhibition,” or “inhibiting” refer to a reduction in the baseline activity of a biological activity or process.

[0025] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing or alleviating a disease or condition or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., given a history of symptoms and / or given exposure to a particular organism or other susceptibility factors), i.e., preventative treatment. Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0026] The term "effective amount" or "therapeutic effective amount" includes the amount of the compound described herein that will elicit a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity associated with bacterial infection, improvement of symptoms of bacterial infection, or slowing or delaying the progression of bacterial infection. In one aspect, a therapeutic effective amount means a dose of about 0.01 to about 100 mg / kg body weight / day.

[0027] The terms “administer,” “administering,” or “administration” include any system or method of delivering a pharmaceutical composition or agent to a subject or to a specific area within or on the subject. In some embodiments of the invention, the agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, percutaneously, or via mucosae. In a preferred embodiment, the agent is administered intravenously. In another preferred embodiment, the agent is administered orally. Administration may be performed by a number of collaborating personnel. Administration includes, for example, prescribing the agent to be administered to the subject and / or providing instructions, directly or through another person, for taking a specific agent, whether by self-delivery (e.g., via oral delivery, subcutaneous delivery, intravenous delivery via a central catheter, etc.); or for delivery by trained professionals, such as intravenous delivery, intramuscular delivery, intratumoral delivery, etc.

[0028] 3. Description of exemplary compounds In a first embodiment, this disclosure provides a compound of formula I: (I); Or its pharmaceutically acceptable salt, wherein the variables are as described above.

[0029] In the second embodiment, R is in a compound of formula I or a pharmaceutically acceptable salt thereof. 1 It is -OC(O)aryl, -OC(O)(C1-C6)alkyl, , , , , or ; R 2 The group is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted cycloalkyl and optionally substituted (C1-C6)alkyl, wherein the optionally substituted (C1-C6)alkyl may be interrupted by one or more heteroatoms selected from O, N and S; R 3 R 3a R 4 and R 4a Each is independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, OH, -OC(O)(C1-C6)alkyl, O(C1-C6)alkylO(C1-C6)alkyl, -O(C1-C6)alkylC(O)(C1-C6)alkyl and -O(C1-C6)alkylC(O)(C1-C6)alkyl; R 5 Selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted cycloalkyl, optionally substituted (C1-C6)alkyl, -C(O)(C1-C 20 )alkyl, -C(O)aryl, -C(O)heterocyclic, -C(O)heteroaryl, wherein the (C1-C) group on the -C(O) group 20 Each of the alkyl, aryl, heterocyclic, and heteroaryl groups is optionally substituted, and the (C1-C2) group on the -C(O) group is substituted. 20 The alkyl group may be discontinuous by one or more heteroatoms selected from O, N, and S, and wherein the (C1-C) 20 Two adjacent hydrogen atoms on the same carbon atom of one or more carbon atoms in an alkyl group can form =O; R 6 and R 6a Each is independently hydrogen, aryl, or (C1-C6) alkyl; R 5a R 7 R7a and R 8 Each is independently a (C1-C6) alkyl group; R 6 and R 6a Each is independently hydrogen, aryl, or (C1-C6) alkyl; Each R 9 Independently hydrogen or (C1-C6) alkyl; and Both a and b are integers in the range of 1 to 20. Alternatively, as part of the second embodiment, it is -OC(O)phenyl, , , , , or .

[0030] In the third embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 It is hydrogen or (C1-C4)alkyl (e.g., hydrogen or CH3), wherein the remaining variables are as described above for Formula I or the second embodiment.

[0031] In the fourth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3a It is hydrogen or (C1-C4)alkyl (e.g., hydrogen or CH3), wherein the remaining variables are as described above for Formula I or the second or third embodiment.

[0032] In the fifth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 4 It is a (C1-C4) alkyl (e.g., CH3), wherein the remaining variables are as described above for any of the second to fourth embodiments of formula I.

[0033] In the sixth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 4a It is a (C1-C4) alkyl (e.g., CH3), wherein the remaining variables are as described above for any of the second to fifth embodiments.

[0034] In the seventh embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 5 It is (C1-C4)alkyl, (C1-C4)alkyl(phenyl) or -C(O)(C1-C 10 )alkyl, wherein (C1-C 10 The alkyl group is interrupted by one or more O atoms, and wherein the (C1-C) group is... 10The alkyl group contains two adjacent hydrogen atoms on the same carbon atom of one or more carbons that together form =O, wherein the remaining variables are as described above for any of the second to sixth embodiments. Alternatively, as part of the seventh embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 5 It is (C1-C4)alkyl, (C1-C4)alkyl(phenyl) or -C(O)(C1-C 10 )alkyl, wherein (C1-C 10 The alkyl group is CH3, CH2 (phenyl) or -C(O)(CH)CH3OC(O)CHCH3OC(O)CH3), wherein the remaining variables are as described above for any of the second to sixth embodiments.

[0035] In the eighth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 5a It is a (C1-C4) alkyl (e.g., CH3), wherein the remaining variables are as described above for any of the second to seventh embodiments.

[0036] In the ninth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 6 It is a (C1-C4) alkyl (e.g., CH2CH3), wherein the remaining variables are as described above for any of the second to eighth embodiments.

[0037] In the tenth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 6a It is a (C1-C4) alkyl (e.g., CH2CH3), wherein the remaining variables are as described above for any of the second to ninth embodiments.

[0038] In the eleventh embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 7 It is a (C1-C4) alkyl (e.g., CH3), wherein the remaining variables are as described above for any of the second to tenth embodiments of formula I.

[0039] In the twelfth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 7a It is a (C1-C4) alkyl (e.g., CH3), wherein the remaining variables are as described above for any of the second to eleventh embodiments.

[0040] In the thirteenth embodiment, a in the compound of formula I or a pharmaceutically acceptable salt thereof is 1, wherein the remaining variables are as described above for formula I or any of the second to twelfth embodiments.

[0041] In the fourteenth embodiment, b in the compound of formula I or a pharmaceutically acceptable salt thereof is an integer from 2 to 10 (e.g., 2, 4, 6, 8, or 10), wherein the remaining variables are as described above for any of the second to thirteenth embodiments of formula I. Alternatively, as part of the fourteenth embodiment, b in the compound of formula I or a pharmaceutically acceptable salt thereof is 2, wherein the remaining variables are as described above for any of the second to thirteenth embodiments of formula I.

[0042] In the fifteenth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from -OC(O)C(CH3)3, , , , , , , , , , and The remaining variables are as described above for any of the second to fourteenth embodiments. Alternatively, as part of the thirteenth embodiment, R in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from , , , , , , , , , and The remaining variables are as described above for Formula I or any of the second through fourteenth embodiments. In another alternative, as part of the thirteenth embodiment, R in the compound of Formula I or a pharmaceutically acceptable salt thereof... 1 yes The remaining variables are as described above for Formula I or any of the second to fourteenth embodiments.

[0043] Specific examples of the compounds are provided in the embodiments. Pharmaceutically acceptable salts and neutral forms of these compounds are included herein.

[0044] 4. Uses, formulations and application The compounds described herein can be used to treat bacterial infections caused by one or more Gram-negative or atypical bacteria. Gram-negative bacteria include, but are not limited to, Haemophilus influenzae (Haemophilus influenzae). Haemophilus influenzae Acinetobacter baumannii ( Acinetobacter baumanniiBurkholderia spp. ( ) Burkholderia spp.), a certain type of Citrobacter spp. Citrobacter spp . ), Escherichia coli ( Escherichia coli ), a certain type of Enterobacter spp. Enterobacter spp.), Pseudomonas aeruginosa ( Pseudomonas aeruginosa ), a certain type of Klebsiella spp. Klebsiella spp.), Stenotrophomonas maltophilia ( Stenotrophomonas maltophila) Tula Francisella (Francisella tularensis) Yersinia spp. (Yersinia spp.), a certain type of Salmonella ( Salmonella spp.), a certain species of Shigella ( Shigella spp.), a certain species of Legionella ( Legionella spp.) and Neisseria gonorrhoeae ( Neisseria gonorrhoeae Atypical bacteria include, but are not limited to, Mycoplasma pneumoniae (…). Mycoplasma pneumoniae ), Chlamydia pneumoniae ( Chlamydophila pneumoniae ) and Legionella pneumophila ( Legionella pneumophila ).

[0045] In some respects, bacteria are resistant to one or more antimicrobial agents other than those described herein. The terms "drug resistance" and "antimicrobial resistance" refer to bacteria capable of surviving exposure to one or more antimicrobial agents. In one respect, the compounds described herein can be used to treat bacterial infections caused by Gram-negative bacteria or drug-resistant Gram-negative bacteria. In another respect, the compounds described herein can be used to treat bacterial infections caused by Enterobacteriaceae (…). Enterobacteriaceae ) such as E. coli ( E. coli ), Klebsiella pneumoniae ( K. pneumoniae ) and a certain type of Acinetobacter genus ( Acinetobacter Bacterial infections caused by *Pseudomonas aeruginosa*, *Acinetobacter baumannii*, or *Enterobacteriaceae*, as well as antimicrobial resistant forms, can be treated. Furthermore, the compounds described herein can be used to treat bacterial infections caused by *Pseudomonas aeruginosa*, as well as antimicrobial resistant forms. For example, resistance mechanisms in Gram-negative bacteria include, but are not limited to, extended-spectrum β-lactamase expression, metallo-β-lactamase expression, carbapenemase expression, DNA gyrase mutations, porin mutations, efflux system overexpression, lipopolysaccharide modification, and 16S rRNA methyltransferase expression.

[0046] In one aspect, the bacterial infection treated by the compound of the present invention is caused by Gram-negative bacteria. In another aspect, the bacterial infection treated by the compound of the present invention is caused by *Pseudomonas aeruginosa*, *Acinetobacter baumannii*, *Escherichia coli*, or *Klebsiella pneumoniae*, and other Enterobacteriaceae. In another aspect, the bacterial infection treated by the compound of the present invention is caused by *Pseudomonas aeruginosa*. In another aspect, the bacterial infection treated by the compound of the present invention is caused by antimicrobial-resistant Gram-negative bacteria. In yet another aspect, the bacterial infection treated by the compound of the present invention is caused by antimicrobial-resistant strains of *Pseudomonas aeruginosa*. In yet another aspect, the bacterial infection treated by the compound of the present invention is caused by Enterobacteriaceae. In yet another aspect, the bacterial infection treated by the compound of the present invention is caused by *Escherichia coli*, *Klebsiella pneumoniae*, or some genus *Acinetobacter*. In yet another aspect, the bacterial infection treated by the compound of the present invention is caused by a genus *Burkholderia*, *Bacillus anthracis*, etc. B. anthracis) Yersinia pestis (Y. pestis ) and Tula Francisella ( F. tularensis Caused by pathogens.

[0047] Bacterial infections treated by the compounds of this invention include, but are not limited to, respiratory infections (e.g., pneumonia), bloodstream infections (e.g., bacteremia), cardiac infections (e.g., endocarditis), CNS infections (e.g., meningitis, brain abscess), ear infections (e.g., otitis externa), eye infections (e.g., bacterial keratitis, endophthalmitis), gastrointestinal infections (diarrhea, enteritis, enterocolitis), urinary tract infections, skin infections, intra-abdominal infections, hospital-acquired infections, and wound / burn infections.

[0048] In one aspect, the compounds described herein inhibit penicillin-binding protein 3 (PBP3). Therefore, in one aspect, this disclosure provides a method for inhibiting bacterial PBP3, the method comprising administering to a subject in need one or more of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0049] In another aspect, the compounds described herein inhibit penicillin-binding protein 1 (e.g., PBP1a and / or PBP1b). Therefore, in one aspect, this disclosure provides a method for inhibiting bacterial PBP1, the method comprising administering to a subject in need one or more of the compounds described herein or pharmaceutically acceptable salts thereof. In another aspect, this disclosure provides a method for inhibiting bacterial PBP1 (e.g., PBP1a and / or PBP1b) and bacterial PBP3, the method comprising administering to a subject in need one or more of the compounds described herein or pharmaceutically acceptable salts thereof.

[0050] In another respect, the compounds described herein are not specific inhibitors of penicillin-binding protein 2 (PBP2).

[0051] According to another aspect, this disclosure provides pharmaceutically acceptable compositions comprising the compounds described herein, and pharmaceutically acceptable carriers. These compositions can be used to treat one or more of the aforementioned bacterial infections, as well as to inhibit PBP3.

[0052] The compositions described herein can be administered orally, parenterally, via inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implantable receptacles. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. This document includes liquid dosage forms, injectable formulations, solid dispersions, and dosage forms for topical or transdermal application of the compounds.

[0053] The amount of the provided compound that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on the patient to be treated and the specific mode of administration.

[0054] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of compounds provided in the composition will also depend on the specific compounds in the composition.

[0055] Example As depicted in the following examples, in some exemplary embodiments, compounds are prepared according to the following general procedure. It should be understood that although the general method describes the synthesis of some compounds herein, the following general method and other methods known to those skilled in the art can be applied to all compounds and subclasses and species of each of these compounds as described herein.

[0056] [(1R,7S)-7-[(Z)-N'-hydroxy-N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8,10-tetraazatricyclo[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutylammonium sulfate (A) can be prepared according to the procedure described in PCT / US2018 / 031593.

[0057] Intermediate 1: [(1R,7S)-7-[(Z)-N'-(2,2-dimethylpropionyloxy)-N-methyl-formamidinyl]-5-methyl 9-oxo-4,5,8,10-tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutyl sulfate ammonium salts 2,2-Dimethylpropionyl chloride (0.04 mL, 0.34 mmol) was added to a solution of [(1R,7S)-7-[(Z)-N'-hydroxy-N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8,10-tetraazatricyclo[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutylammonium sulfate (200 mg, 0.34 mmol) and triethylamine (0.05 mL, 0.34 mmol) in DCM (3.4 mL) at 0 °C. The reaction mixture was warmed to room temperature, stirred for 15 min, concentrated, and purified by silica gel chromatography (0%-100% acetone / DCM) to give the title compound as a white solid, 195 mg (85%). 15 H 22 N6O7S: LCMS: m / z 431 [M+H]+, 429 [MH]- Example 1: [(1R,7S)-7-[(Z)-N'-(2,2-dimethylpropionyloxy)-N-methyl-formamidinyl]-5-methyl Sodium sulfate of 9-oxo-4,5,8,10-tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl] Dowex® 50WX8 100-200 (25 g) was prepared by stirring in 2N NaOH (50 mL) for 1 hour. The resin was then loaded onto a column and washed with water until the eluent was at a neutral pH. The column was then washed with a 1:1 mixture of water, acetone, and water. [(1R,7S)-7-[(Z)-N'-(2,2-dimethylpropionyloxy)-N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8,10-tetraazatricyclo[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutylammonium sulfate (193.2 mg, 0.29 mmol) was dissolved in water containing a small amount of acetone and loaded onto the column. The title compound was eluted with water, frozen, and lyophilized to give a white solid, 113.9 mg (88%). 15 H 22 N6O7S: LCMS: m / z 431 [M+H]+, 429 [MH]-. 1HNMR: (300 mHz, DMSO): 1.20 (s, 9H), 3.03 (d, J = 5.1 Hz, 3H), 3.33 (m, 2H), 3.69 (s, 3H), 4.70 (s, 1H), 5.64 (s, 1H), 6.40 (m, 1H), 7.32 (s, 1H).

[0058] Intermediate 2: [(1R,7S)-7-[(Z)-N'-benzoyloxy-N-methyl-formamidinyl]-5-methyl-9-oxo- 4,5,8,10-Tetraazatricyclo[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutylammonium sulfate The title compound was prepared using benzoyl chloride according to the procedure for intermediate 1. A white solid, 188.9 mg (80%), was obtained. 17 H 18 N6O7S: LCMS: m / z 451 [M+H]+, 449 [MH]- Example 2: [(1R,7S)-7-[(Z)-N'-benzoyloxy-N-methyl-formamidinyl]-5-methyl-9-oxo- Sodium 4,5,8,10-tetraazatricyclo[6.2.1.02,6]undec-2(6),3-dien-10-yl]sulfate The title compound was prepared from intermediate 2 according to the procedure of Example 1, yielding a white solid, 119.1 mg (92%). 17 H 18 N6O7S: LCMS: m / z 451 [M+H]+, 449 [MH]-. 1H NMR: (300 mHz, DMSO): 3.05 (d, J =4.8 Hz, 3H), 3.41 (m, 2H), 3.75 (s, 3H), 4.73 (m, 1H), 5.71 (s, 1H), 6.98 (m,1H), 7.35 (s, 1H), 7.53 (m, 2H), 7.65 (m, 1H), 8.19 (m, 2H).

[0059] Intermediate 3: [(1R,7S)-7-[(Z)-N'-(4-ethoxy-4-oxo-butyryl)oxy-N-methyl-formamidinium] [6.2.1.02,6]undec-2(6),3-dien-10-yl]thio Tetrabutylammonium salt The title compound was prepared using ethyl 4-chloro-4-oxo-butyrate according to the procedure of intermediate 1. A white solid, 212.2 mg (87%), was obtained. 16 H 22 N6O9S: LCMS: m / z 475 [M+H]+, 473 [MH]- Example 3: [(1R,7S)-7-[(Z)-N'-(4-ethoxy-4-oxo-butyryl)oxy-N-methyl-formamidinium] [6.2.1.02,6]undec-2(6),3-dien-10-yl]thio sodium salt The title compound was prepared from intermediate 3 according to the procedure in Example 1, yielding a white solid, 126.1 mg (86%). 16 H 22N6O9S: LCMS: m / z 475 [M+H]+, 473 [MH]-. 1H NMR: (300 mHz, DMSO): 1.18 (t, J =7.2 Hz, 3H), 2.62 (m, 4H), 3.01 (d, J = 4.8 Hz, 3H), 3.33 (m, 2H), 3.66 (s,3H), 4.06 q, J = 7.2 Hz, 2H), 4.70 (m, 1H), 5.64 (s, 1H), 6.85 (m, 1H), 7.32 (s, 1H).

[0060] Intermediate 4: [(1R,7S)-7-[(Z)-N'-(2-acetoxypropionyloxy)-N-methyl-methamidinyl]-5-methyl 9-oxo-4,5,8,10-tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutyl sulfate ammonium salts The title compound was prepared using (2-chloro-1-methyl-2-oxo-ethyl)acetate according to the procedure of intermediate 1. A white solid, 177.1 mg (75%), was obtained. 15 H 20 N6O9S: LCMS: m / z 461 [M+H]+, 459 [MH]- Example 4: [(1R,7S)-7-[(Z)-N'-(2-acetoxypropionyloxy)-N-methyl-methamidinyl]-5-methyl Sodium sulfate of 9-oxo-4,5,8,10-tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl] The title compound was prepared from intermediate 4 according to the procedure in Example 1, yielding a white solid, 114.4 mg (85%). 15 H 20 N6O9S: LCMS: m / z 461 [M+H]+, 459 [MH]-. 1H NMR: (300 mHz, DMSO): 1.42 (d, J =6.9 Hz, 3H), 2.07 (s, 3H), 3.03 (d, J = 4.8 Hz, 3H), 3.34 (m, 2H), 3.67 (s,3H), 4.70 (m, 1H), 5.15 (q, J = 6.9 Hz, 1H), 5.67 (m, 1H), 6.90 (m, 1H), 7.35(s, 1H).

[0061] Intermediate 5: [(1R,7S)-7-[(Z)-N'-diethoxyphosphoryloxy-N-methyl-formamidinyl]-5-methyl- 9-Oxo-4,5,8,10-Tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutylammonium sulfate The title compound was prepared using 1-[chloro(ethoxy)phosphoryl]oxyethane according to the procedure of intermediate 1. The compound was obtained as a white solid, 178 mg (72%). C 14 H 23 N6O9PS: LCMS: m / z 483 [M+H]+, 481 [MH]-.

[0062] Example 5: [(1R,7S)-7-[(Z)-N'-diethoxyphosphoryloxy-N-methyl-formamidinyl]-5-methyl- Sodium 9-oxo-4,5,8,10-tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl]sulfate The title compound was prepared from intermediate 5 according to the procedure in Example 1, yielding a white solid, 33.1 mg (27%). 14 H 23 N6O9PS: LCMS: m / z 483 [M+H]+, 481 [MH]-. 1H NMR: (300 mHz, DMSO): 1.23 (t, J= 7.2 Hz, 3H), 3.01 (d, J = 5.1 Hz, 3H), 3.36 (m, 2H), 3.64 (s, 3H), 3.93 (m,4H), 4.71 (m, 1H), 5.66 (s, 1H), 6.89 (m, 1H), 7.33 (s, 1H).

[0063] Intermediate 6: 2-[2-(2-methoxyethoxy)ethoxy]acetyl chloride Oxaloyl chloride (0.77 mL, 8.98 mmol) was added dropwise to a solution of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (1000 mg, 5.61 mmol) in toluene (0.56 mL). The reaction mixture was heated at 65 °C for 4 hours, and then concentrated to remove the solvent and excess reagent. The resulting yellow oil was dried overnight under vacuum at 40 °C, yielding 1103 mg (100%).

[0064] Intermediate 7: [(1R,7S)-7-[(Z)-N'-[2-[2-(2-methoxyethoxy)ethoxy]acetyl]oxy- [N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8,10-tetraazatricyclo[6.2.1.02,6]undec-2(6),3-di [Alken-10-yl]tetrabutylammonium sulfate The title compound was prepared using 2-[2-(2-methoxyethoxy)ethoxy]acetyl chloride (intermediate 6) according to the procedure for intermediate 1. The compound was given as a white solid, 194.4 mg (76%). C 17 H 26 N6O 10 S: LCMS: m / z 507 [M+H]+, 505 [MH]-.

[0065] Example 6: [(1R,7S)-7-[(Z)-N'-[2-[2-(2-methoxyethoxy)ethoxy]acetyl]oxy- [N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8,10-tetraazatricyclo[6.2.1.02,6]undec-2(6),3-di [Alken-10-yl]sodium sulfate The title compound was prepared from intermediate 7 by additional purification using an ISCO (C18Aq column, 0%–50% acetonitrile / water) according to the procedure of Example 1, yielding a white solid, 72.8 mg (51%). 17 H 26 N6O 10 S: LCMS: m / z 507 [M+H]+, 505 [MH]-. 1H NMR: (300 mHz, DMSO): 3.01 (d, J = 4.8 Hz, 3H), 3.24 (s, 3H), 3.36 (m,2H), 3.43 (m, 2H), 3.51 (m, 4H), 3.59 (m, 2H), 3.67 (s, 3H), 4.19 (s, 2H), 4.71 (m, 1H), 6.91 (m, 1H), 7.34 (s, 1H).

[0066] Intermediate 8: [(1R,7S)-7-[(Z)-N'-(2-benzyloxypropionyloxy)-N-methyl-formamidinyl]-5-methyl 9-oxo-4,5,8,10-tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutyl sulfate ammonium salts The title compound was prepared using 2-benzyloxypropionyl chloride according to the procedure for intermediate 1. A white solid, 205.3 mg (80%), was obtained. 20 H 24 N6O8S: LCMS: m / z 509 [M+H]+, 507 [MH]-.

[0067] Example 7: [(1R,7S)-7-[(Z)-N'-(2-benzyloxypropionyloxy)-N-methyl-formamidinyl]-5-methyl Sodium sulfate of 9-oxo-4,5,8,10-tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl] The title compound was prepared from intermediate 8 according to the procedure of Example 1, yielding a white solid, 116.3 mg (80%). 20 H 24N6O8S: LCMS: m / z 509 [M+H]+, 507 [MH]-. 1H NMR: (300 mHz, DMSO): 1.38 (d, J =6.9 Hz, 3H), 3.02 (d, J = 4.8 Hz, 3H), 3.37 (m, 2H), 3.67 (s, 3H), 4.21 (q, J= 6.9 Hz, 1H), 4.49 (q, J = 12 Hz, 2H), 4.72 (m, 1H), 5.67 (s, 1H), 6.81 (m,1H), 7.29 (m, 6H).

[0068] Intermediate 9: 2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]acetyl chloride The title compound was prepared using 2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]acetic acid (500 mg, 1.88 mmol) and dried under vacuum for 2 hours according to the procedure for intermediate 6. 534 mg (100%) of the compound was obtained as a yellow oil.

[0069] Intermediate 10: [(1R,7S)-7-[(Z)-N'-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy] [[ ...][[[[[[[[[[[][[[[[[[[][[[[[[[[[][[[[[[[][[[[[[][[[[[[][[[[[[][[[[[[][[[[[[[][[[[[[][[[[[[[][[[[[[[][[[[[[[][[[[[[[][[[[[[][[[[[[[[][[[[[[[][[[[[[[][[[[[[[][[[[[[[][[[[[[[[][[[[[[[][[[[[[[] [6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutylammonium sulfate The title compound was prepared using 2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]acetyl chloride (121.1 mg, 0.43 mmol) (intermediate 9) according to the procedure for intermediate 1. A white solid, 264 mg (74%), was obtained. 21 H 34 N6O 12 S: LCMS: m / z 595 [M+H]+, 593 [MH]-.

[0070] Example 8: (4R,8S)-8-((Z)-N'-((2,5,8,11,14-pentahexadecane-16-acyl)oxy)-N- (methylformamidinyl)-1-methyl-6-oxo-4,8-dihydro-1H-4,7-bridged methylenepyrazolo[3,4-e][1,3]diazepine 5(6H)-Sodium bisulfate The title compound was prepared from intermediate 10 by additional purification using an ISCO (C18Aq column, 0%-50% acetonitrile / water) according to the procedure of Example 1, yielding a white solid, 116.4 mg (60%). 21 H 34 N6O 12S: LCMS: m / z 595 [M+H]+, 593 [MH]-. 1H NMR: (300 mHz, DMSO) 3.01 (d, J = 4.8 Hz, 3H), 3.24 (s, 3H), 3.36 (m,2H), 3.43 (m, 2H), 3.51 (m, 13H), 3.59 (m, 2H), 3.67 (s, 3H), 4.19 (s, 2H), 4.71 (m, 1H), 5.64 (s, 1H), 6.91 (m, 1H), 7.34 (s, 1H).

[0071] Intermediate 11: 2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy [By]ethoxy]acetyl chloride The title compound was prepared using 2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (500 mg, 1.41 mmol) and dried under vacuum for 2 hours according to the procedure for intermediate 6. 526 mg (100%) of the compound was obtained as a yellow oil.

[0072] Intermediate 12: [(1R,7S)-7-[(Z)-N'-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]] [Ethoxy] [Ethoxy] [Ethoxy] [Ethoxy] [Acetyl] [Oxy-N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8, 10-Tetraazatricyclo[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutylammonium sulfate The title compound was prepared using 2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetyl chloride (158.58 mg, 0.43 mmol) (intermediate 11) according to the procedure for intermediate 1. A white solid, 277 mg (71%), was obtained. C 25 H 42 N6O 14 S: LCMS: m / z 683 [M+H]+, 681 [MH]-.

[0073] Example 9: [(1R,7S)-7-[(Z)-N'-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]] [Ethoxy] [Ethoxy] [Ethoxy] [Ethoxy] [Acetyl] [Oxy-N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8, Sodium 10-tetraazatricyclo[6.2.1.02,6]undec-2(6),3-dien-10-yl]sulfate The title compound was prepared from intermediate 12 by additional purification using an ISCO column (C18Aq column, 0%-50% acetonitrile / water) according to the procedure of Example 1, yielding a white solid, 137.8 mg (65%). 25 H 42 N6O 14S: LCMS: m / z 683 [M+H]+, 681 [MH]-. 1H NMR: (300 mHz, DMSO) 3.01 (d, J = 4.8 Hz, 3H), 3.24 (s, 3H), 3.36 (m,2H), 3.43 (m, 2H), 3.51 (m, 21H), 3.59 (m, 2H), 3.67 (s, 3H), 4.19 (s, 2H), 4.71 (m, 1H), 5.64 (s, 1H), 6.90 (m, 1H), 7.34 (s, 1H).

[0074] Intermediate 13: 2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy] Ethoxy]Ethoxy]Ethoxy]Ethoxy]acetyl chloride The title compound was prepared using 2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (500 mg, 1.13 mmol) and dried under vacuum for 2 hours according to the procedure for intermediate 6. 521 mg (100%) of the compound was obtained as a yellow oil.

[0075] Intermediate 14: [(1R,7S)-7-[(Z)-N'-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)] [Ethoxy] [Ethoxy] [Ethoxy] [Ethoxy] [Ethoxy] [Ethoxy] [Ethoxy] [Acetyl] [Oxy-N-methyl-formamidinyl]- 5-Methyl-9-oxo-4,5,8,10-tetraazatricyclic[6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrasulfate Butylammonium salt The title compound was prepared using 2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl chloride (196.05 mg, 0.43 mmol) (intermediate 13) according to the procedure of intermediate 1. A white solid, 251.5 mg (57%), was obtained. C 29 H 50 N6O 16 S: LCMS: m / z771 [M+H]+, 769 [MH]-.

[0076] Example 10: (4R,8S)-8-((Z)-N'-((2,5,8,11,14,17,20,23,26-nonaoxaoctadecane- 28-Acyl)oxy)-N-methylformamidinyl)-1-methyl-6-oxo-4,8-dihydro-1H-4,7-bridged methylenepyrazolo[3,4- [e][1,3]diazaphen-5(6H)-yl sodium bisulfate The title compound was prepared from intermediate 14 by additional purification using an ISCO column (C18Aq column, 0%–50% acetonitrile / water) according to the procedure of Example 1, yielding a white solid, 63.9 mg (32%). 29 H 50N6O 16 S: LCMS: m / z 771 [M+H]+, 769 [MH]-. 1H NMR: (300 mHz, DMSO) 3.01 (d, J = 4.8 Hz, 3H), 3.24 (s, 3H), 3.36 (m,2H), 3.43 (m, 2H), 3.51 (m, 29H), 3.59 (m, 2H), 3.67 (s, 3H), 4.19 (s, 2H), 4.71 (m, 1H), 5.64 (s, 1H), 6.91 (m, 1H), 7.34 (s, 1H).

[0077] Intermediate 15: 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy] Ethoxy]Ethoxy]Ethoxy]Ethoxy]Ethoxy]Ethoxy]Ethoxy]Ethyl chloride] The title compound was prepared using 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (500 mg, 0.94 mmol) and dried under vacuum for 2 hours according to the procedure for intermediate 6. 517 mg (100%) of the compound was obtained as a yellow oil.

[0078] Intermediate 16: [(1R,7S)-7-[(Z)-N'-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethyl)]] [Oxygen]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]oxy] [N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8,10-tetraazatricyclo[6.2.1.02,6]undec-2(6),3- [dien-10-yl]tetrabutylammonium sulfate The title compound was prepared using 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl chloride (233.53 mg, 0.43 mmol) (intermediate 15) according to the procedure of intermediate 1. The compound was obtained as a colorless oil, 322.6 mg (69%). C 33 H 58 N6O 18 S: LCMS: m / z 859 [M+H]+, 857 [MH]-.

[0079] Example 11: (4R,8S)-8-((Z)-N'-((2,5,8,11,14,17,20,23,26,29,32-undecanoxatri Tetradecane-3,4-acyl)oxy)-N-methylformamidinyl)-1-methyl-6-oxo-4,8-dihydro-1H-4,7-bridged methylenepyrazole [3,4-e][1,3]diazaphen-5(6H)-yl sodium bisulfate The title compound was prepared from intermediate 16 by additional purification using an ISCO column (C18Aq column, 0%-50% acetonitrile / water) according to the procedure of Example 1, yielding a white solid, 164.7 mg (64%). 33 H 58 N6O 18 S: LCMS: m / z 859 [M+H]+, 857 [MH]-. 1H NMR: (300 mHz, DMSO) 3.01 (d, J = 4.8 Hz, 3H), 3.24 (s, 3H), 3.36 (m,2H), 3.43 (m, 2H), 3.51 (m, 37H), 3.59 (m, 2H), 3.67 (s, 3H), 4.19 (s, 2H), 4.71 (m, 1H), 5.64 (s, 1H), 6.91 (m, 1H), 7.34 (s, 1H).

[0080] Intermediate 17: [(1S)-2-benzyloxy-1-methyl-2-oxo-ethyl](2S)-2-hydroxypropionate Camphorsulfonic acid (80.59 mg, 0.35 mmol) was added to a solution of (3S,6S)-3,6-dimethyl-1,4-dioxane-2,5-dione (500 mg, 3.47 mmol) and benzyl alcohol (0.32 mL, 3.12 mmol) in toluene at room temperature. The reaction mixture was heated to 80 °C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a 1:1 brine:water solution. The organic matter was dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (0%–5% methanol / DCM) yielded the desired product as a colorless liquid, 685 mg (78%). 13 H 16 O5:LCMS:m / z 253 [M+H]+.

[0081] Intermediate 18: [(1S)-2-[(1S)-2-benzyloxy-1-methyl-2-oxo-ethoxy]-1-methyl-2-oxo- [Ethyl](2S)-2-acetoxypropionate [(1S)-2-chloro-1-methyl-2-oxo-ethyl](2S)-2-hydroxypropionate (400 mg, 1.59 mmol) (intermediate 17) and triethylamine (0.22 mL, 1.59 mmol) in DCM (6 mL) was added at 0 °C. The reaction mixture was warmed to room temperature, stirred for 1 hour, and concentrated. C18Aq ISCO (100% water to 100% acetonitrile / water) gave a product as a colorless oil, 276.8 mg (48%). 18 H 22 O8:LCMS:m / z 367 [M+H]+.

[0082] Intermediate 19: (2S)-2-[(2S)-2-[(2S)-2-acetoxypropionyl]oxypropionyl]oxypropionic acid A solution of (2S)-2-[(2S)-2-[(2S)-2-acetoxypropionyl]oxypropionyl]oxypropionic acid (191.1 mg, 0.69 mmol) (intermediate 18) in methanol (4 mL) was degassed with nitrogen, and Pd / C (80.4 mg, 0.08 mmol) was added. The mixture was degassed again and placed under a hydrogen balloon for 1 hour. The reaction mixture was washed with nitrogen, filtered through a 0.45 u filter, and concentrated to give a colorless oil, 191.1 mg (92%). 11 H 16 O8: LCMS: m / z 277 [M+H]+ Intermediate 20: [(1S)-2-[(1S)-2-chloro-1-methyl-2-oxo-ethoxy]-1-methyl-2-oxo-ethyl] (2S)-2-acetoxypropionate The title compound was prepared using (2S)-2-[(2S)-2-[(2S)-2-acetoxypropionyl]oxypropionyl]oxypropionic acid (191.1 mg, 0.69 mmol) (intermediate 19) and dried under vacuum for 2 h according to the procedure for intermediate 6. The compound was obtained as a yellow oil, 174.8 mg (86%).

[0083] Intermediate 21: [(1R,7S)-7-[(Z)-N'-[(2S)-2-[(2S)-2-[(2S)-2-acetoxypropionyl]oxy] [[Oxypropionyl]oxypropionyl]oxy-N-methyl-formamidinyl]-5-methyl-9-oxo-4,5,8,10-tetraazatricyclic] [6.2.1.02,6]undec-2(6),3-dien-10-yl]tetrabutylammonium sulfate The title compound was prepared using [(1S)-2-[(1S)-2-chloro-1-methyl-2-oxo-ethoxy]-1-methyl-2-oxo-ethyl](2S)-2-acetoxypropionate (125.34 mg, 0.43 mmol) (intermediate 20) according to the procedure for intermediate 1. The compound was obtained as a white solid, 329.9 mg (92%). 21 H 28 N6O 13 S: LCMS: m / z 605 [M+H]+, 603[MH]-.

[0084] Example 12: (7S,10S,Z)-7-methyl-3-((4R,8S)-1-methyl-6-oxo-5-(sulfonoxy)-4,5,6, 8-Tetrahydro-1H-4,7-bridged methylenepyrazolo[3,4-e][1,3]diazaphen-8-yl)-6,9-dioxo-5,8-dioxo- Sodium 2,4-diazaundec-3-en-10-yl(2S)-2-acetoxypropionate The title compound was prepared from intermediate 21 by additional purification using an ISCO (C18Aq column, 0%-50% acetonitrile / water) according to the procedure of Example 1, yielding a white solid, 159.3 mg (65%). 21 H 28 N6O 13 S: LCMS: m / z 605 [M+H]+, 603 [MH]-. 1H NMR: (300 mHz, DMSO) 1.38 (m, 9H), 1.99 (m, 3H), 2.96 (d, J=4.8 Hz,3H), 3.22 (m, 2H), 3.59 (s, 3H), 4.63 (m, 1H), 5.09 (m, 3H), 5.60 (s, 1H), 6.82 (m, 1H), 7.25 (m, 1H).

[0085] Microbiological testing. According to Clinical and Laboratory Standards Institute (CLSI) guideline M07-A10 ( Methods for Dilution Antimicrobial Susceptibilty Tests for Bacteria that Grow Aerobically The 11th edition (Institute for Clinical and Laboratory Standardization, 2018) determined the minimum inhibitory concentrations (MICs) of Comparative A and Example 6 against Klebsiella pneumoniae isolate ARC2356. The results are summarized in Table 1.

[0086] Table 1. Summary of MICs of Comparative A and Example 6 against Klebsiella pneumoniae ARC2356

[0087] Animal Welfare Statement: All in vivo procedures were performed in accordance with the Animal Welfare Act (9 CFR 3) under an IACUC protocol reviewed by Entasis and under the supervision of the attending veterinarian on site.

[0088] A mouse model of neutropenia. An in vivo infection model of neutropenia in mice was established as previously described (2,3). All procedures were performed in accordance with the IACUC policy and guidelines approved by Entasis and OLAW standards. Briefly, female CD1 mice (20–22 gm, Charles River Laboratories) were acclimatized for 5 days prior to the start of the study. Animals were housed in cages of 3 with free access to food and water. On day-4 and day-1, mice were induced to have neutropenia by intraperitoneal administration of two doses of cyclophosphamide at a dose volume of 10 mL / kg and 100 mg / kg, respectively.

[0089] Klebsiella pneumoniae isolate ARC2356 was prepared from overnight plate cultures for infection. A portion of the plate was resuspended in sterile saline and adjusted to an OD of 0.1 at 625 nm. The adjusted bacterial suspension was further diluted to approximately 5.0 x 10⁻⁶. 5 CFU / mouse inoculum. Mice were anesthetized with isoflurane and infected by intratracheal injection of 50 μL of the prepared inoculum. Infected animals were returned to their cages to recover from anesthesia. The actual inoculum volume was 8.0 x 10⁻⁶. 5 CFU / mouse lung. Plate counts were performed on the inoculum to confirm inoculum concentration, and treatment was initiated 2 hours after bacterial challenge.

[0090] Comparative compound A, Example 6, and the positive control levofloxacin were formulated in water for injection (WFI) and administered subcutaneously. A mediator (no treatment) control was included as a dose group. Levofloxacin was administered at 160 mg / kg q24h. All dose concentrations were adjusted to deliver the target mg / kg dose within a dose volume of 10 mL / kg. Comparative compound A was administered at doses of 10 and 50 mg / kg q3h, and Example 6 was administered at equivalent doses of Comparative compound A at 10 and 50 mg / kg q3h. Formulation efficacy was validated by LC / MS / MS. Comparative compound A and Example 6 were administered at q3h dose intervals to achieve targeted non-binding exposure. Animals were euthanized 24 hours after treatment initiation, and lung tissue was aseptically collected and homogenized. Bacterial colony counting of the tissue homogenate was performed by serial dilution on TSA plates incubated overnight at 35°C before colony (CFU) counting. The results were recorded at log 24 hours after treatment. 10 Efficacy was measured by changes in CFU / g lung. The results are summarized in Table 2.

[0091] Table 2. Targeting Klebsiella pneumoniae Summary of the ARC2356 mouse lung infection model

[0092] Nearly equivalent reductions in CFU load were observed in the dosage groups of Comparative Compound A and Example 6, administered subcutaneously at 10 and 50 mg / kg q3h. These data suggest that once Example 6 is administered, the compound is effectively hydrolyzed to Comparative Compound A, thereby producing the same efficacy as when Comparative Compound A is administered on its own.

[0093] Mouse pharmacokinetics Following subcutaneous administration, pharmacokinetic analyses of Analytical Compound A and Example 6 were performed using a satellite group of infected animals. Absolute dose levels of 10, 50, and 250 mg / kg were evaluated. Three animals were used at each blood collection time point, with three time points per animal – two submandibular blood collections and one terminal blood collection via cardiac puncture. Blood samples (50 µL) were collected in K2EDTA micro-blood collection tubes and processed into plasma. The resulting plasma was diluted 1:1 with a solution of SigmaFast protease inhibitor (10 mg / mL in water) and then stored at -70°C. Time points were 0.25, 0.5, 1, 2, 4, and 6 hours post-administration.

[0094] Bioanalytical assays Calibration standards and quality control samples were prepared by serial dilution in a 1:1 (by volume) blank mouse plasma:SigmaFast protease inhibitor solution. SigmaFast was prepared by dissolving one tablet in 10 mL of deionized water (10 mg / mL). Aliquots (50 µl) of each standard were transferred together with plasma samples (diluted separately) to 96-well plates and treated with 200 µl of crash solution to precipitate proteins. The crash solution consisted of 100% acetonitrile containing 0.1% formic acid and 250 ng / mL amisulbutamide (Millipore-Sigma) as an internal standard. The plates were then vortexed and centrifuged, and the supernatant was transferred for LC / MS / MS analysis. Instrument conditions used for LC / MS / MS analysis are summarized in Table 3.

[0095] Table 3. LC-MS / MS conditions for determining Comparative A and Example 6 in treated mouse plasma

[0096] MRM conversion:

[0097] protein binding Plasma protein binding of Comparative A was determined by rapid equilibration dialysis. Plasma was freshly prepared from mouse blood samples drawn into tubes containing K2EDTA (an anticoagulant). Plasma was prepared using a benchtop centrifuge and centrifuged according to the tube manufacturer's instructions and specifications (Beckton Dickinson), then placed on ice before use. The combined plasma samples were centrifuged at 2,000 rpm (approximately 1,400 g) for 15 minutes at 4°C to remove debris. Approximately 90% of the clear supernatant fraction was transferred to individual tubes. The sample (500 μL) was then doped with 100× DMSO stock solution (100 μM, 0.5 mM, and 10 mM compounds in DMSO) to achieve final concentrations of 1, 5, and 100 μM, respectively, transferred to the top of the filter chamber, and equilibrated for 15 minutes before centrifugation. The filtrate tube was centrifuged at 14,000 g for 15 minutes at 4°C. Next, 50 μL of the filtrate was precipitated with 300 μL of acetonitrile containing 250 ng / mL amisulbutamide as an internal standard, and the sample was analyzed by LC / MS / MS as previously described.

[0098] Pharmacokinetics and exposure analysis PK model fitting was performed using Phoenix WinNonLin 8.1 (Certara LP, Princeton, NJ) to fit concentration-time curve data for Comparative A obtained from single doses of 10, 50, and 250 mg / kg. A two-compartment model using extravascular first-order absorption rate input provided the best fit for subcutaneous PK obtained across the entire dose range. Parameter estimates were used to interpolate unbound exposures above the concentrations (MICs) summarized in Table 4, while taking into account protein binding at the 22% value determined for Comparative A.

[0099] Table 4. Estimated percentage of time above MIC in plasma of comparator A after subcutaneous administration to CD-1 mice q3h.

[0100] Given that the MICs of Comparative Compound A and Example 6 are 0.25 and 4 µg / mL, respectively, the estimated time > MIC values ​​at the 10 mg / kg q3h dose level are 45% and 14.5%, respectively, and at the 50 mg / kg q3h dose level, the estimated time > MIC values ​​are 78% and 30%, respectively. Based on the observation that bactericidal activity of this compound class requires a time > MIC greater than 50%, and the observation of the same degree of bacterial load reduction in both dose groups of Comparative Compound A and Example 6, the data indicate that Example 6 is completely converted to Comparative Compound A once it is systemically absorbed from the subcutaneous compartment.

[0101] Example 6: Transformation in mouse and human plasma The conversion of Example 6 to Comparative A was evaluated in vitro in mouse and human plasma prepared in K2EDTA tubes at 37°C and compared with incubation runs in phosphate-buffered saline (PBS) at the same concentration. Aliquots (25 µL) were taken at 0, 0.25, 0.5, 1, 2, 4, 6, and 24 hours after compound addition and analyzed by LC-MS / MS as previously described. The concentration of Example 6 during incubation was 31.5 µM. The concentrations of Example 6 and Comparative A in the samples were determined to determine mass balance (Example 6 + Comparative A relative to the initial Example 6 concentration) and to determine the primary degradation / conversion of Example 6 to Comparative A. The results are summarized in Table 5.

[0102] Rapid and quantitative conversion of Example 6 to Comparative A was observed in mouse and human plasma. The conversion of Example 6 to Comparative A in mouse plasma was consistent with the efficacy observed in a neutropenic lung infection model following subcutaneous administration of Example 6.

[0103] Table 5. Conversion of Example 6 to Comparative A in mouse and human plasma at 31.5 µM concentration in 24 hours at 37°C.

[0104] ND = Not measured Stability of Comparative Compound A and Example 6 in water for injection (WFI) at 10 and 100 mg / mL at room temperature and 2°C-4°C.

[0105] The solution stability of Comparative Compound A and Example 6 was evaluated in parallel at ambient temperature (room temperature) over a 21-hour process in water for injection (WFI) at concentrations of 10 and 100 mg / mL. Series samples (25 µL) were obtained at approximately 0, 0.5, 1, 2, 4, 6, 8, and 20 hours after solubilization and analyzed by LC-MS / MS as previously described. The first-order degradation rate constants of Comparative Compound A and Example 6 were determined by regression analysis of the concentration-time data. The results regarding the stability of Comparative Compound A and Example 6 at ambient temperature (room temperature) and 2°C–4°C are summarized in Table 6.

[0106] Table 6. Stability of Comparative A and Example 6 in water for injection (WFI) at room temperature and 2°C–4°C.

[0107] The contents of all references cited throughout this application (including bibliographies, published patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly known to a person skilled in the art.

Claims

1. A compound of formula I: (I) Or its pharmaceutically acceptable salt, wherein R 1 It is -OC(O)R A ;and R A Selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted cycloalkyl, and optionally substituted (C1-C) 20 )alkyl, wherein the optionally substituted (C1-C 20 The alkyl group may be discontinuous by one or more heteroatoms selected from O, N, and S, and wherein the (C1-C) 20 Two adjacent hydrogen atoms on the same carbon atom of one or more carbons on an alkyl group can form =O together.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is -OC(O)aryl, -OC(O)(C1-C6)alkyl, , , , , or ; R 2 The group is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted cycloalkyl and optionally substituted (C1-C6)alkyl, wherein the optionally substituted (C1-C6)alkyl may be interrupted by one or more heteroatoms selected from O, N and S; R 3 R 3a R 4 and R 4a Each is independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, OH, -OC(O)(C1-C6)alkyl, O(C1-C6)alkylO(C1-C6)alkyl, -O(C1-C6)alkylC(O)(C1-C6)alkyl and -O(C1-C6)alkylC(O)(C1-C6)alkyl; R 5 Selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted cycloalkyl, optionally substituted (C1-C6)alkyl, -C(O)(C1-C 20 )alkyl, -C(O)aryl, -C(O)heterocyclic, -C(O)heteroaryl, wherein the (C1-C) group on the -C(O) group 20 Each of the alkyl, aryl, heterocyclic, and heteroaryl groups is optionally substituted, and the (C1-C2) group on the -C(O) group is substituted. 20 The alkyl group may be discontinuous by one or more heteroatoms selected from O, N, and S, and wherein the (C1-C) 20 Two adjacent hydrogen atoms on the same carbon atom of one or more carbons in an alkyl group can form =O; R 5a R 7 R 7a and R 8 Each is independently a (C1-C6) alkyl group; R 6 and R 6a Each is independently hydrogen, aryl, or (C1-C6) alkyl; Each R 9 Independently hydrogen or (C1-C6) alkyl; and Both a and b are integers in the range of 1 to 20.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -OC(O)phenyl, , , , , or .

4. The compound of claim 2 or 3 or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen or (C1-C4) alkyl.

5. The compound of any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen or CH3.

6. The compound of any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen or (C1-C4) alkyl.

7. The compound of any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen or CH3.

8. The compound of any one of claims 2 to 7, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a (C1-C4) alkyl group.

9. The compound of any one of claims 2 to 8, or a pharmaceutically acceptable salt thereof, wherein R 4 It is CH3.

10. The compound of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, wherein R 4a It is a (C1-C4) alkyl group.

11. The compound of any one of claims 2 to 10, or a pharmaceutically acceptable salt thereof, wherein R 4a It is CH3.

12. The compound of any one of claims 2 to 11, or a pharmaceutically acceptable salt thereof, wherein R 5 It is (C1-C4)alkyl, (C1-C4)alkyl(phenyl) or -C(O)(C1-C 10 )alkyl, wherein (C1-C 10 The alkyl group is interrupted by one or more O atoms, and wherein the (C1-C) group is... 10 =O is formed by two adjacent hydrogen atoms on the same carbon atom of one or more carbon atoms on an alkyl group.

13. The compound of any one of claims 2 to 12, or a pharmaceutically acceptable salt thereof, wherein R 5 It is CH3, CH2 (phenyl) or -C(O)(CH)CH3OC(O)CHCH3OC(O)CH3).

14. The compound of any one of claims 2 to 13, or a pharmaceutically acceptable salt thereof, wherein R 5a It is a (C1-C4) alkyl group.

15. The compound of any one of claims 2 to 14, or a pharmaceutically acceptable salt thereof, wherein R 5a It is CH3.

16. The compound of any one of claims 2 to 15, or a pharmaceutically acceptable salt thereof, wherein R 6 It is a (C1-C4) alkyl group.

17. The compound of any one of claims 2 to 16, or a pharmaceutically acceptable salt thereof, wherein R 6 It is CH2CH3.

18. The compound of any one of claims 2 to 17, or a pharmaceutically acceptable salt thereof, wherein R 6a It is a (C1-C4) alkyl group.

19. The compound of any one of claims 2 to 18, or a pharmaceutically acceptable salt thereof, wherein R 6a It is CH2CH3.

20. The compound of any one of claims 2 to 19, or a pharmaceutically acceptable salt thereof, wherein R 7 It is a (C1-C4) alkyl group.

21. The compound of any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof, wherein R 7 It is CH3.

22. The compound of any one of claims 2 to 21, or a pharmaceutically acceptable salt thereof, wherein R 7a It is a (C1-C4) alkyl group.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 7a It is CH3.

24. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein a is 1.

25. The compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein b is an integer from 2 to 10.

26. The compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein b is 2, 4, 6, 8 or 10.

27. The compound of any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, wherein b is 2.

28. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -OC(O)C(CH3)3, , , , , , , , , , and .

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from , , , , , , , , , and .

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 1 yes .

31. The compound of claim 1, wherein the compound is selected from... 、 、 、 、 、 、 , , , , and ; or a pharmaceutically acceptable salt of any of the foregoing.

32. The compound of claim 1, wherein the compound is ； Or its pharmaceutically acceptable salt.

33. The pharmaceutically acceptable salt according to any one of claims 1 to 32, wherein the pharmaceutically acceptable salt is a sodium salt.

34. The compound of claim 1, wherein the compound is a pharmaceutically acceptable salt having the following structural formula: 。 35. A pharmaceutical composition comprising the compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

36. A method of treating a bacterial infection in a subject in need, the method comprising administering to the subject an effective amount of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, or a composition of claim 35.

37. The method of claim 36, wherein the bacterial infection is caused by Gram-negative bacteria.

38. The method of claim 36 or 37, wherein the bacterial infection is caused by Pseudomonas aeruginosa.

39. The method of claim 36 or 37, wherein the bacterial infection is caused by Enterobacteriaceae.

40. The method of claim 36 or 37, wherein the bacterial infection is caused by one of Escherichia coli, Klebsiella pneumoniae, or Acinetobacter.

41. The method of claim 40, wherein the bacterial infection is caused by a pathogen selected from a species of Burkholderia, Bacillus anthracis, Yersinia pestis, and Tulafrancsis.

42. A method for inhibiting bacterial penicillin-binding protein 3 (PBP3) and optionally bacterial PBP1a / b in a subject of need, the method comprising administering to the subject an effective amount of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, or the composition of claim 35.

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